Longitudinal associations of adherence to lifestyle recommendations and health-related quality of life in patients with non-muscle invasive bladder cancer.

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.

One-carbon metabolism biomarkers and risk of urothelial cell carcinoma in the European prospective investigation into cancer and nutrition.

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.

Epidemiology, prevention, screening, diagnosis, and evaluation: update of the ICUD-SIU joint consultation on bladder cancer.

PURPOSE: To update current recommendations on prevention, screening, diagnosis, and evaluation of bladder cancer (BC) based on a thorough assessment of the most recent literature on these topics. METHODS: A non-systematic review was performed, including articles until June 2017. A variety of original articles, reviews, and editorials were selected according to their epidemiologic, demographic, and clinical relevance. Assessment of the level of evidence and grade of recommendations was performed according to the International Consultation on Urological Diseases grading system. RESULTS: BC is the ninth most common cancer worldwide with 430,000 new cases in 2012. Currently, approximately 165,000 people die from the disease annually. Absolute incidence and prevalence of BC are expected to rise significantly during the next decades because of population ageing. Tobacco smoking is still the main risk factor, accounting for about 50% of cases. Smoking cessation is, therefore, the most relevant recommendation in terms of prevention, as the risk of developing BC drops almost 40% within 5 years of cessation. BC screening is not recommended for the general population. BC diagnosis remains mainly based on cystoscopy, but development of new endoscopic and imaging technologies may rapidly change the diagnosis algorithm. The same applies for local, regional, and distant staging modalities. CONCLUSIONS: A thorough understanding of epidemiology, risk factors, early detection strategies, diagnosis, and evaluation is essential for correct, evidence-based management of BC patients. Recent developments in endoscopic techniques and imaging raise the hope for providing better risk-adopted approaches and thereby improving clinical outcomes.

Dietary patterns and risk of recurrence and progression in non-muscle-invasive bladder cancer.

The association of dietary factors with urinary bladder cancer prognosis has scarcely been investigated, and results of studies conducted to date are inconsistent. We investigated whether empirically derived dietary patterns are associated with risks of recurrence and progression in non-muscle-invasive bladder cancer (NMIBC) patients. Data from 595 newly diagnosed NMIBC patients from an ongoing prospective cohort study were used to derive dietary patterns using exploratory factor analysis. Factor scores were calculated and then categorized in sex-specific tertiles. Multivariable-adjusted proportional hazards regression models were used to estimate hazard ratios and 95% confidence intervals for the associations between tertiles of adherence to the dietary patterns and risks of recurrence and progression. We identified four dietary patterns: "fruits and vegetables," "Western," "low-fat," and "Tex-Mex." Patients in the highest tertile of adherence to the Western pattern experienced a 1.48 times higher risk of recurrence (95% CI 1.06-2.06) compared to patients in the lowest tertile. No statistically significant associations of a Western diet with risk of progression or of the other dietary patterns with risk of recurrence and progression were found. Overall, we found that adherence to a Western diet was associated with a higher risk of recurrence but further studies are needed to confirm our findings.

Relationship between menopausal hormone therapy and mortality after breast cancer The MARIEplus study, a prospective case cohort.

Cohort studies of breast cancer (BC) patients, but not of disease-free women at inclusion, have found menopausal hormone therapy (MHT) to be associated with decreased BC specific mortality (BCM). Here, the German population-based MARIEplus BC cohort was analyzed to further elucidate associations of prediagnostic MHT with BCM (and modification by tumor characteristics), recurrence, and secondarily with other cause and overall mortality. Enrolled 2002-2005, incident invasive BC cases (N = 3,321) were followed up for a median of 6.1 years. Cox proportional hazards models adjusted for tumor characteristics, mammography and lifestyle were applied. Compared with never users of MHT, current users at date of diagnosis had significantly lower BCM (Hazard ratio (HR) 0.72, 95% CI 0.53-0.97) and risk of recurrence (HR 0.61, 95% CI 0.46-0.82). The MHT related reduced BCM was confined to patients with low grade tumors (HR 0.44, 95% CI 0.28-0.70; phet = 0.01) and not modified by estrogen receptor or nodal status. BCM decreased with MHT duration in current and increased in past users (phet = 0.015). Mortality due to causes other than BC and overall mortality were also reduced in current MHT users (HR 0.51, 95% CI 0.32-0.81, HR 0.66, 95% CI 0.52-0.86, respectively). Favorable tumor characteristics and mammographic surveillance could not fully explain associations of current MHT use with BCM and recurrence risk. Thus, the study contributes to the evidence that prediagnostic MHT does not have a negative impact on prognosis after BC. The restriction of a reduced BCM to low grade tumors should be confirmed in independent studies.

Genome-wide association study yields variants at 20p12.2 that associate with urinary bladder cancer.

Genome-wide association studies (GWAS) of urinary bladder cancer (UBC) have yielded common variants at 12 loci that associate with risk of the disease. We report here the results of a GWAS of UBC including 1670 UBC cases and 90 180 controls, followed by replication analysis in additional 5266 UBC cases and 10 456 controls. We tested a dataset containing 34.2 million variants, generated by imputation based on whole-genome sequencing of 2230 Icelanders. Several correlated variants at 20p12, represented by rs62185668, show genome-wide significant association with UBC after combining discovery and replication results (OR = 1.19, P = 1.5 × 10(-11) for rs62185668-A, minor allele frequency = 23.6%). The variants are located in a non-coding region approximately 300 kb upstream from the JAG1 gene, an important component of the Notch signaling pathways that may be oncogenic or tumor suppressive in several forms of cancer. Our results add to the growing number of UBC risk variants discovered through GWAS.

Evidence of gene-environment interactions between common breast cancer susceptibility loci and established environmental risk factors.

Various common genetic susceptibility loci have been identified for breast cancer; however, it is unclear how they combine with lifestyle/environmental risk factors to influence risk. We undertook an international collaborative study to assess gene-environment interaction for risk of breast cancer. Data from 24 studies of the Breast Cancer Association Consortium were pooled. Using up to 34,793 invasive breast cancers and 41,099 controls, we examined whether the relative risks associated with 23 single nucleotide polymorphisms were modified by 10 established environmental risk factors (age at menarche, parity, breastfeeding, body mass index, height, oral contraceptive use, menopausal hormone therapy use, alcohol consumption, cigarette smoking, physical activity) in women of European ancestry. We used logistic regression models stratified by study and adjusted for age and performed likelihood ratio tests to assess gene-environment interactions. All statistical tests were two-sided. We replicated previously reported potential interactions between LSP1-rs3817198 and parity (Pinteraction = 2.4 × 10(-6)) and between CASP8-rs17468277 and alcohol consumption (Pinteraction = 3.1 × 10(-4)). Overall, the per-allele odds ratio (95% confidence interval) for LSP1-rs3817198 was 1.08 (1.01-1.16) in nulliparous women and ranged from 1.03 (0.96-1.10) in parous women with one birth to 1.26 (1.16-1.37) in women with at least four births. For CASP8-rs17468277, the per-allele OR was 0.91 (0.85-0.98) in those with an alcohol intake of <20 g/day and 1.45 (1.14-1.85) in those who drank ≥ 20 g/day. Additionally, interaction was found between 1p11.2-rs11249433 and ever being parous (Pinteraction = 5.3 × 10(-5)), with a per-allele OR of 1.14 (1.11-1.17) in parous women and 0.98 (0.92-1.05) in nulliparous women. These data provide first strong evidence that the risk of breast cancer associated with some common genetic variants may vary with environmental risk factors.

Determinants of long-term fatigue in breast cancer survivors: results of a prospective patient cohort study.

OBJECTIVE: Fatigue is among the most distressing symptoms across the breast cancer continuum. However, little is known about the factors contributing to long-term persisting fatigue. Therefore, we explored determinants of long-term physical, affective, and cognitive fatigue in a prospective cohort of breast cancer patients. METHODS: Breast cancer patients recruited in a population-based case-control study (MARIE study) provided comprehensive data on sociodemographics, lifestyle, and preexisting medical conditions. At follow-up (median 6.3 years post-diagnosis, MARIEplus), disease-free cancer survivors (N = 1928) reported current fatigue using a validated multidimensional questionnaire. Additionally, survivors retrospectively rated their fatigue levels before diagnosis, during the treatment phase, and 1 year post-surgery. Linear regression analyses were performed. RESULTS: As major determinants of long-term physical, affective, and cognitive fatigue, multiple regression analyses revealed preexisting psychological or depressive disorders, migraine, analgesic use, peripheral arterial obstructive disease (PAOD), and arthritis. A physically inactive lifestyle and obesity were associated with persisting physical fatigue. Aromatase inhibitors were also associated with long-term fatigue, especially cognitive fatigue. Chemotherapy and, to a lower extent, radiotherapy were major contributors to the development of fatigue during the treatment phase, yet were not associated with long-term fatigue. CONCLUSIONS: Although the development of fatigue in breast cancer patients seems largely impacted by cancer therapy, for the long-term persistence of fatigue, preexisting medical or psychological conditions related to depression or pain and lifestyle factors appear to be more relevant. Physicians, psycho-oncologists, and researchers may need to distinguish between acute fatigue during therapy and long-term persisting fatigue with regard to its pathophysiology and treatment.

Circulating 25-hydroxyvitamin D and postmenopausal breast cancer survival: Influence of tumor characteristics and lifestyle factors?

We previously reported that lower post-diagnostic circulating 25-hydroxyvitamin D [25(OH)D] concentrations were associated with higher risk of overall mortality and distant disease in stage I-IV postmenopausal breast cancer survivors. This association was now re-examined in an extended dataset to investigate potential effect modification by tumor characteristics and lifestyle factors. A prospective cohort study was conducted in Germany including 2,177 incident stage I-IV postmenopausal breast cancer patients aged 50-74 years. Patients were diagnosed between 2001 and 2005 and median follow-up time was 5.3 years. Cox proportional hazards models were stratified by age at diagnosis, study center and season of blood collection and adjusted for other prognostic factors. A meta-analysis of studies on circulating 25(OH)D and mortality in breast cancer patients was performed to summarize evidence. Lower concentrations of 25(OH)D were significantly associated with higher risk of overall mortality [hazard ratio (HR) lowest vs. highest tertile = 1.86; 95% confidence interval (CI): 1.22, 2.82; p-trend = 0.002] and distant disease (HR = 1.76; 95% CI: 1.24, 2.49; p-trend = 0.003) in stage I-IIIa but not in stage IIIb-IV breast cancer patients. No significant interaction by lifestyle factors was observed (all p-interaction > 0.05). The meta-analysis yielded significant associations with overall and breast cancer-specific mortality (lowest vs. highest quantile: HR = 1.52; 95% CI: 1.22, 1.88 and HR = 1.74; 95% CI: 1.23, 2.40, respectively). In conclusion, post-diagnostic circulating 25(OH)D concentrations were associated with overall mortality and distant disease in stage I-IIIa postmenopausal breast cancer patients. This association was not strongly modified by lifestyle factors.

Enterolactone concentrations and prognosis after postmenopausal breast cancer: assessment of effect modification and meta-analysis.

We previously reported that high concentrations of enterolactone, a lignan metabolite, are associated with lower mortality in 1,140 breast cancer patients from Germany. Using an extended set of 2,182 patients aged 50-74 years at diagnosis (2001-2005) and prospectively followed up until 2009, we investigated whether the association with mortality differs by lifestyle factors and tumor characteristics. Hazard ratios (HR) and 95% confidence intervals (CI) were estimated using multivariable Cox regression. Potential differential effects by tumor characteristics and lifestyle factors were assessed and a meta-analysis of five studies addressing lignan exposure and breast cancer prognosis was performed to summarize evidence. Median enterolactone concentrations were 17.4 (± 30.5 standard deviation) and 22.9 nmol L(-1) (± 44.8), respectively, for 269 deceased and 1,913 patients still alive. High enterolactone concentrations were significantly associated with lower all-cause mortality (per 10 nmol L(-1) : HR 0.94, 95% CI 0.90-0.98), breast cancer-specific mortality (HR 0.94, 0.89-0.99), and distant disease-free survival (HR 0.94, 0.90-0.98). Associations were found for stage 0-IIIA but not for stage IIIB-IV disease (p(het) = 0.01) and were stronger in patients with BMI <25 kg m(-2) than those with BMI ≥ 25 (p(het) = 0.04). In patients with healthy lifestyle (BMI <25, nonsmoker, physically active), the inverse association with all-cause mortality was still apparent (HR 0.92, 0.85-0.99). The meta-analysis yielded significant associations both for all-cause (HR 0.57, 0.42-0.78) and breast cancer-specific mortality (HR 0.54, 0.39-0.75). Our findings show that high lignan exposure is associated with reduced mortality in breast cancer patients. The inverse association observed in this study cannot be entirely explained by a healthy lifestyle.

Plasma and dietary carotenoids and vitamins A, C and E and risk of colon and rectal cancer in the European Prospective Investigation into Cancer and Nutrition.

Carotenoids and vitamins A, C and E are possibly associated with a reduced colorectal cancer (CRC) risk through antioxidative properties. The association of prediagnostic plasma concentrations and dietary consumption of carotenoids and vitamins A, C and E with the risk of colon and rectal cancer was examined in this case-control study, nested within the European Prospective Investigation into Cancer and Nutrition study. Plasma concentrations of carotenoids (α- and ß-carotene, canthaxanthin, ß-cryptoxanthin, lutein, lycopene, zeaxanthin) and vitamins A (retinol), C and E (α-, ß- and γ- and δ-tocopherol) and dietary consumption of ß-carotene and vitamins A, C and E were determined in 898 colon cancer cases, 501 rectal cancer cases and 1,399 matched controls. Multivariable conditional logistic regression models were performed to estimate incidence rate ratios (IRR) and corresponding 95% confidence intervals (CIs). An association was observed between higher prediagnostic plasma retinol concentration and a lower risk of colon cancer (IRR for highest quartile = 0.63, 95% CI: 0.46, 0.87, p for trend = 0.01), most notably proximal colon cancer (IRR for highest quartile = 0.46, 95% CI: 0.27, 0.77, p for trend = 0.01). Additionally, inverse associations for dietary ß-carotene and dietary vitamins C and E with (distal) colon cancer were observed. Although other associations were suggested, there seems little evidence for a role of these selected compounds in preventing CRC through their antioxidative properties.

Association of pre-diagnosis physical activity with recurrence and mortality among women with breast cancer.

Evidence is emerging that physical activity (PA) may improve overall survival after breast cancer diagnosis. However, the effect of PA on breast cancer recurrence and on cause-specific mortality is less investigated. We assessed the association of pre-diagnosis PA with recurrence, overall and cause-specific survival in a prospective cohort study in Germany including 3,393 non-metastatic breast cancer patients aged 50-74 years. Cox proportional hazards models were calculated adjusted for relevant prognostic factors. During a median follow-up of 5.6 years, 367 patients deceased. Overall mortality was significantly inversely associated with pre-diagnosis recreational PA. However, this effect was mainly attributed to deaths due to causes other than breast cancer. Multiple fractional polynomial analyses yielded a nonlinear association with markedly increased non-breast cancer mortality for women who did not engage in any sports or cycling in the years before the breast cancer diagnosis with a hazard ratio (HR, none vs. any) of 1.71, 95% confidence interval (1.16, 2.52). There were no further risk reductions with increasing activity levels. The association with breast cancer-specific mortality showed a similar dose-response but was far less pronounced with HR (none vs. any) = 1.22 (0.91, 1.64). In contrast, regarding cancer recurrence the dose-response was linear. However, this association was restricted to estrogen/progesterone receptor-negative (ER-/PR-) cases (p interaction = 0.033) with HR (highest vs. no recreational PA) = 0.53 (0.24, 1.16), p trend = 0.0045. Thus, breast cancer patients with a physically inactive lifestyle pre-diagnosis may decease prematurely irrespective of their cancer prognosis. Higher levels of exercise may reduce the risk of recurrence of ER-/PR- breast tumors.

Walking, bicycling, and sports in postmenopausal breast cancer survivors--results from a German patient cohort study.

OBJECTIVES: Physical activity (PA) is increasingly discussed as a means to achieve both physical and psychological benefits for breast cancer patients and survivors. However, little is known about activity-specific PA behavior following diagnosis. Our objectives were to describe sports and active transportation in the course of breast cancer and to identify factors associated with these activities. METHODS: We used data from a German cohort study including 1067 postmenopausal breast cancer survivors aged 50-75 years. Data were collected about walking and bicycling for transportation purposes and sports before diagnosis, during therapy, and 1 year after surgery. Associations between these activities and clinical, behavioral, and social characteristics were analyzed with logistic regression. RESULTS: The proportions of physically active women decreased significantly during therapy compared with before diagnosis (walking: 75.1% vs. 89.7%; bicycling: 19.3% vs. 56.5%; sports: 14.8% vs. 64.5%; all p < 0.001). Calisthenics, swimming, and walking for exercise were the most frequent types of sport. Chemotherapy/radiotherapy was negatively associated with sports (odds ratio [OR]: 0.35 [0.17-0.73]) but positively associated with walking during therapy (OR: 2.08 [1.04-4.15]). Although sociodemographic factors showed weak associations with PA, participation in rehabilitation increased the likelihood for bicycling (OR: 1.48 [1.06-2.09]) and sports (OR: 1.88 [1.38-2.58]) 1 year after surgery. CONCLUSIONS: The majority of women stopped exercising and bicycling during breast cancer therapy. Interventions promoting in particular moderate activities after breast cancer diagnosis are required for this population. Increasing participation in rehabilitation might help to increase the proportion of women who bicycle and engage in sports after breast cancer diagnosis.

Cohort profile - the Renal cell cancer: Lifestyle, prognosis and quality of life (ReLife) study in the Netherlands.

PURPOSE: The Renal cell cancer: Lifestyle, prognosis and quality of life (ReLife) study is set up to obtain insight into the association of patient and tumour characteristics, lifestyle habits and circulating biomarkers with body composition features in patients with localised renal cell cancer (RCC). Further, it aims to assess the association of body composition features, lifestyle habits and circulating biomarkers with clinical outcomes, including health-related quality of life. PARTICIPANTS: The ReLife study is a multicentre prospective cohort study involving 368 patients with newly diagnosed stages I-III RCC recruited from January 2018 to June 2021 from 18 hospitals in the Netherlands. At 3 months, 1 year and 2 years after treatment, participants fill out a general questionnaire and questionnaires about their lifestyle habits (eg, diet, physical activity, smoking and alcohol consumption), medical history and health-related quality of life. At all three time points, patients wear an accelerometer and have blood samples taken. CT scans for body composition analysis are being collected. Permission is asked for collection of tumour samples. Information about disease characteristics, treatment of the primary tumour and clinical outcomes is being collected from medical records by the Netherlands Cancer Registry. FINDINGS TO DATE: A total of 836 invited patients were eligible and 368 patients were willing to participate and were included (response rate 44%). The mean age of patients was 62.5±9.0 years and 70% was male. The majority had stage I (65%) disease and were treated with radical nephrectomy (57%). Data collection at 3 months and 1 years after treatment have been finalised. FUTURE PLANS: Data collection at 2 years after treatment is expected to be finalised in June 2023 and longitudinal clinical data will continue to be collected. Results of studies based on this cohort are important to develop personalised evidence-based lifestyle advice for patients with localised RCC to enable them to get more control over their disease course.

Adherence to lifestyle recommendations after non-muscle invasive bladder cancer diagnosis and risk of recurrence.

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.

Global trends in the epidemiology of bladder cancer: challenges for public health and clinical practice.

Bladder cancer is among the ten most common cancers globally, causes considerable morbidity and mortality and is, therefore, a substantial burden for health-care systems. The incidence of bladder cancer is affected by demographic trends, most notably population growth and ageing, as well as exposure to risk factors, especially tobacco smoking. Consequently, the incidence has not been stable throughout the world over time, nor will it be in the near future. Further primary prevention efforts are of the utmost importance to reduce the medical and financial burden of bladder cancer on populations and health-care systems. Simultaneously, less-invasive and lower-cost approaches for the diagnosis of both primary and recurrent bladder cancers are required to address challenges posed by the increasing shortage of health-care professionals and limited financial resources worldwide. In this regard, urinary biomarkers have demonstrated promising diagnostic accuracy and efficiency. Awareness of the risk factors and symptoms of bladder cancer should also be increased in society, particularly among health-care professionals and high-risk groups. Studies investigating the associations between lifestyle factors and bladder cancer outcomes are scarce and should be a research priority. In this Review, we outline global trends in bladder cancer incidence and mortality, and discuss the main risk factors influencing bladder cancer occurrence and outcomes. We then discuss the implications, challenges and opportunities of these epidemiological trends for public health and clinical practice.

Body mass index and waist circumference in relation to risk of recurrence and progression after non-muscle invasive bladder cancer.

BACKGROUND: Obesity may be associated with increased risk of recurrence and progression in patients with non-muscle invasive bladder cancer (NMIBC), but evidence is limited and inconsistent. We examined the associations of body mass index (BMI), waist circumference, and waist-to-hip ratio (WHR) with risk of recurrence and progression among patients with NMIBC. METHODS: This prospective study included 1029 patients diagnosed with primary NMIBC between 2014 and 2017. Patients reported weight 2 years before diagnosis at baseline, and weight, waist and hip circumference at 3 months postdiagnosis. Associations were quantified using Cox proportional hazard analyses, adjusted for clinical and lifestyle characteristics. RESULTS: More than half of patients were overweight (49%) or obese (19%) after diagnosis. During a median follow-up time of 3.6 years, 371 patients developed ≥1 recurrence and 53 experienced progression. No associations with recurrence were observed for BMI (HRper 5 kg/m2 0.94; 95% CI 0.82, 1.07), waist circumference (HRper 10 cm 0.95; 95% CI 0.86, 1.05), or WHR (HRper 0.1 unit 0.90; 95% CI 0.76, 1.06). In contrast, higher BMI was associated with a 40% increased risk of progression, with only the 2-year prediagnosis association reaching statistical significance (HRper 5 kg/m2 1.42; 95% CI 1.09, 1.84). No associations for pre-to-postdiagnosis weight change were found. CONCLUSION: General and abdominal obesity were not associated with recurrence risk among patients with NMIBC, but might be associated with increased risk of progression. Studies with sufficient sample size to stratify by tumor stage and treatment are needed to better understand whether and how obesity could influence prognosis.

Health-related Quality of Life During the First 4 Years After Non-Muscle-invasive Bladder Cancer Diagnosis: Results of a Large Multicentre Prospective Cohort.

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.

Trends in Diet and Cancer Research: A Bibliometric and Visualization Analysis.

Diet plays a critical role for patients across the cancer continuum. The World Cancer Research Fund International and the American Cancer Society have published evidence supporting the role of nutrition in cancer prevention. We conducted an analysis of the literature on dietary nutrients and cancer to uncover opportunities for future research. The objective of the bibliometric analysis was to describe trends in peer-reviewed publications on dietary components and cancer and to highlight research gaps. PubMed was queried for manuscripts with diet- and cancer-related keywords and Medical Subject Headings (MeSH) terms. Metadata covering 99,784 publications from 6469 journals were analyzed to identify trends since 1970 on diet topics across 19 tumor types. Publications focused largely on breast, colorectal, and liver cancer, with fewer papers linking diet with other cancers such as brain, gallbladder, or ovarian. With respect to "unhealthy" diets, many publications focused on high-fat diets and alcohol consumption. The largest numbers of publications related to "healthy" diets examined the Mediterranean diet and the consumption of fruits and vegetables. These findings highlight the need for additional research focused on under-investigated cancers and dietary components, as well as dietary studies during cancer therapy and post-therapy, which may help to prolong survivorship.

Intravesical BCG in patients with non-muscle invasive bladder cancer induces trained immunity and decreases respiratory infections.

BACKGROUND: BCG is recommended as intravesical immunotherapy to reduce the risk of tumor recurrence in patients with non-muscle invasive bladder cancer (NMIBC). Currently, it is unknown whether intravesical BCG application induces trained immunity. METHODS: The aim of this research was to determine whether BCG immunotherapy induces trained immunity in NMIBC patients. We conducted a prospective observational cohort study in 17 NMIBC patients scheduled for BCG therapy and measured trained immunity parameters at 9 time points before and during a 1-year BCG maintenance regimen. Ex vivo cytokine production by peripheral blood mononuclear cells, epigenetic modifications, and changes in the monocyte transcriptome were measured. The frequency of respiratory infections was investigated in two larger cohorts of BCG-treated and non-BCG treated NMIBC patients as a surrogate measurement of trained immunity. Gene-based association analysis of genetic variants in candidate trained immunity genes and their association with recurrence-free survival and progression-free survival after BCG therapy was performed to investigate the hypothesized link between trained immunity and clinical response. RESULTS: We found that intravesical BCG does induce trained immunity based on an increased production of TNF and IL-1ß after heterologous ex vivo stimulation of circulating monocytes 6-12 weeks after intravesical BCG treatment; and a 37% decreased risk (OR 0.63 (95% CI 0.40 to 1.01)) for respiratory infections in BCG-treated versus non-BCG-treated NMIBC patients. An epigenomics approach combining chromatin immuno precipitation-sequencing and RNA-sequencing with in vitro trained immunity experiments identified enhanced inflammasome activity in BCG-treated individuals. Finally, germline variation in genes that affect trained immunity was associated with recurrence and progression after BCG therapy in NMIBC. CONCLUSION: We conclude that BCG immunotherapy induces trained immunity in NMIBC patients and this may account for the protective effects against respiratory infections. The data of our gene-based association analysis suggest that a link between trained immunity and oncological outcome may exist. Future studies should further investigate how trained immunity affects the antitumor immune responses in BCG-treated NMIBC patients.