An Updated Meta-Analysis of Treatment in Patients with Heart Failure Complicated Ventricular Functional Mitral Regurgitation.

Background: Ventricular functional mitral regurgitation (FMR) is a common morbidity in patients with heart failure (HF). In addition to guideline-directed medical therapy, mitral valve (MV) repair or replacement has become an option for such patients. However, the impact of different treatments on cardiac remodeling, function, and clinical outcomes remains unclear. Methods: We systematically searched PubMed, EMBASE, Medline, Clinical Trials.gov, and the Cochrane Central Register of Controlled Trials with search terms related to mitral regurgitation, mitral valve repair, surgical mitral valve replacement, mitral annuloplasty device, and MitraClip. The outcomes were left ventricular ejection fraction (LVEF), left ventricular (LV) remodeling, all-cause mortality, cardiovascular death, and HF hospitalization. Sensitivity analysis was performed by removing high-bias risk studies. The analysis was done by Review Manager 5.4 Analyzer and MedCalc Statistical Software version 19.2.6. Results: This meta-analysis included 10 studies with a total of 2533 patients (567 with transcatheter MitraClip, 823 with surgical MV repair, 651 with surgical MV replacement, and 492 with medical therapy). Our meta-analysis revealed that surgical MV repair had significant improvement in LVEF compared to the surgical MV replacement (mean differences (MD) 2.32, [95% CI 0.39, 4.25]), while transcatheter MitraClip treatment was associated with LVEF reduction (MD -4.82, [95% CI -7.29, -2.34]). In terms of LV remodeling, transcatheter MitraClip treatment was associated with improvement in left ventricular end-diastolic volume (MD -10.36, [95% CI -18.74, -1.99]). Furthermore, compared to surgical MV replacement, surgical MV repair was not associated with a reduction of all-cause mortality (risk ratio (RR) 0.83, [95% CI 0.61, 1.13]) and cardiovascular death (RR 0.95, [95% CI 0.56, 1.62]), while transcatheter MitraClip was associated with reduced risk of all-cause mortality (RR 0.87, [95% CI 0.78, 0.98]). Conclusions: Surgical MV repair was associated with significant improvement in LVEF but had no significant effect on all-cause mortality compared to surgical MV replacement. Transcatheter MitraClip was associated with better long-term survival than the non-MitraClip group, thus, transcatheter MitraClip could be considered an alternative treatment in patients with HF-complicated ventricular FMR.

Associations between live birth and cardiometabolic disease in Southwest Chinese women.

BACKGROUND: China has undergone a significant socioeconomic transformation over the past few decades due to the implementation of family planning policies. These societal changes have resulted in an increased susceptibility among females to developing cardiometabolic diseases (CMD). Unfortunately, studies investigating the correlation between family planning policies in China and the incidence of CMD remain scarce. METHODS: Data from 1,226 females, aged 30 years or older with ≥ 1 live birth, undergoing routine physical examinations between January 2018 and December 2021 were collected, and they were grouped by number of live births 1, 2, and ≥ 3. A binary logistic regression model was employed to examine the association between the number of live births with CMD. Furthermore, the subgroup analysis was performed to elucidate the impact of the implementation of family planning policies with CMD. RESULTS: Women with live births ≥ 3 tended to be older, had higher gravidities, a greater proportion of central obesity, general obesity, hypertension, and dyslipidemia (all P < 0.05). Across the three groups (live birth = 1, =2 and ≥ 3), the odds ratio (OR) with 95% CI for obesity were: 1.00, 3.32 (2.36-4.69), and 5.73 (3.79-8.68); for dyslipidemia were: 1.00, 1.75 (1.29-2.39), and 2.02 (1.38-2.94); and for CMD were: 1.00, 1.91 (1.44-2.54), and 2.15 (1.46-3.15), respectively (all P < 0.05). In addition, based on the different periods of the childbearing policy in China, a subgroup analysis (where age was divided into ≤ 45, 45-65, and ≥ 65 years old) found that each additional live birth increased the prevalence risk of obesity and CMD in the younger generations, while hypertension and dyslipidemia in the elder generation. CONCLUSIONS: Higher live births are positively associated with the prevalence of CMD among women in Southwest China. Moreover, giving birth after the implementation of the one-child policy tends to have a higher risk of developing CMD.

Elevated levels of MMP12 sourced from macrophages are associated with poor prognosis in urothelial bladder cancer.

BACKGROUND: Urothelial bladder cancer is most frequently diagnosed at the non-muscle-invasive stage (NMIBC). However, recurrences and interventions for intermediate and high-risk NMIBC patients impact the quality of life. Biomarkers for patient stratification could help to avoid unnecessary interventions whilst indicating aggressive measures when required. METHODS: In this study, immuno-oncology focused, multiplexed proximity extension assays were utilised to analyse plasma (n = 90) and urine (n = 40) samples from 90 newly-diagnosed and treatment-naïve bladder cancer patients. Public single-cell RNA-sequencing and microarray data from patient tumour tissues and murine OH-BBN-induced urothelial carcinomas were also explored to further corroborate the proteomic findings. RESULTS: Plasma from muscle-invasive, urothelial bladder cancer patients displayed higher levels of MMP7 (p = 0.028) and CCL23 (p = 0.03) compared to NMIBC patients, whereas urine displayed higher levels of CD27 (p = 0.044) and CD40 (p = 0.04) in the NMIBC group by two-sided Wilcoxon rank-sum tests. Random forest survival and multivariable regression analyses identified increased MMP12 plasma levels as an independent marker (p < 0.001) associated with shorter overall survival (HR = 1.8, p < 0.001, 95% CI:1.3-2.5); this finding was validated in an independent patient OLINK cohort, but could not be established using a transcriptomic microarray dataset. Single-cell transcriptomics analyses indicated tumour-infiltrating macrophages as a putative source of MMP12. CONCLUSIONS: The measurable levels of tumour-localised, immune-cell-derived MMP12 in blood suggest MMP12 as an important biomarker that could complement histopathology-based risk stratification. As MMP12 stems from infiltrating immune cells rather than the tumor cells themselves, analyses performed on tissue biopsy material risk a biased selection of biomarkers produced by the tumour, while ignoring the surrounding microenvironment.

Significant reduction in diabetes distress and improvements in psychosocial outcomes: A pilot test of an intervention to reduce diabetes distress in adults with type 1 diabetes and moderate-to-severe diabetes distress (REDUCE).

AIM: To pilot-test an intervention, co-designed with people with type 1 diabetes (T1DM) and diabetes specialist nurses, to reduce diabetes distress (DD) in adults with T1DM and moderate-to-severe DD. METHODS: A group-based programme to reduce DD in people with T1DM and moderate-to-severe DD (REDUCE) was pilot-tested in four groups with five bi-weekly two and a half-hour meetings facilitated by two trained diabetes specialist nurses. Data collection included baseline and post-intervention questionnaires measuring DD and psychosocial outcomes and semi-structured interviews with participants post-intervention (n = 18). Data were analysed using descriptive statistics and systematic text condensation. RESULTS: Twenty-five adults with T1DM participated in the study. The median age and diabetes duration of participants were 50 (IQR: 32;57.5) years and 26 (IQR: 18;45) years, respectively. Seventeen (68%) were women. The pilot study showed a significant reduction in DD (measured by Type 1 Diabetes Distress Scale) between baseline and post-intervention from 2.6 ± 0.7 to 1.9 ± 0.6 (mean ± SD) (p < 0.001). The largest reductions were seen on the subscales: powerlessness 1.2 ± 1.1, eating distress 0.9 ± 1.2 and fear of hypoglycaemia 0.8 ± 1.0 (mean ± SD). Significant improvements were also seen for quality of life, diabetes empowerment and emotion regulation. Qualitative data showed that REDUCE supported participants in verbalizing emotions and seeing worries in a more constructive perspective. Acknowledgement of negative diabetes experiences eased negative self-judgments. Sharing experiences among peers increased relatedness and reduced loneliness. CONCLUSION: Participation in REDUCE was associated with significant reduction in DD and significant increase in quality of life. Larger scale studies are planned to determine sustained effectiveness of REDUCE.

BMaps: A Web Application for Fragment-Based Drug Design and Compound Binding Evaluation.

Fragment-based drug design uses data about where, and how strongly, small chemical fragments bind to proteins, to assemble new drug molecules. Over the past decade, we have been successfully using fragment data, derived from thermodynamically rigorous Monte Carlo fragment-protein binding simulations, in dozens of preclinical drug programs. However, this approach has not been available to the broader research community because of the cost and complexity of doing simulations and using design tools. We have developed a web application, called BMaps, to make fragment-based drug design widely available with greatly simplified user interfaces. BMaps provides access to a large repository (>550) of proteins with 100s of precomputed fragment maps, druggable hot spots, and high-quality water maps. Users can also employ their own structures or those from the Protein Data Bank and AlphaFold DB. Multigigabyte data sets are searched to find fragments in bondable orientations, ranked by a binding-free energy metric. The designers use this to select modifications that improve affinity and other properties. BMaps is unique in combining conventional tools such as docking and energy minimization with fragment-based design, in a very easy to use and automated web application. The service is available at https://www.boltzmannmaps.com.

Honokiol improves endothelial function in type 2 diabetic rats via alleviating oxidative stress and insulin resistance.

We aimed to examine the effect of Honokiol (HKL) on endothelial dysfunction in type 2 diabetic rats and its possible mechanism. A high-fat diet and streptozotocin (STZ) were used to establish the type 2 diabetic model in rats. Part of these rats were intraperitoneally injected with HKL 10 mg/kg daily. Then the expression of Ser1177 phosphorylation of endothelial nitric oxide synthase (p-eNOS), eNOS, and CD31, vasodilation function, insulin signaling, indicators of oxidative stress and relative signaling pathway were measured. Human umbilical vein endothelial cells (HUVECs) were used to explore the underlying mechanism of the effect of HKL on high glucose-related endothelial injury in vitro. The data showed that HKL could reverse the decline of the expression of p-eNOS and CD31, endothelium-related vasodilation dysfunction, insulin resistance and activation of oxidative stress induced by type 2 diabetes in vivo. The similar results were obtained in vitro. In summary, our study demonstrates that HKL improves endothelial function and diminishes insulin resistance and oxidative stress, suggesting that HKL could be used as a treatment option for diabetes in the future.

Sex differences on outcomes following left atrial appendage occlusion in atrial fibrillation: A systematic review and meta-analysis.

There is a lack of sufficient data on sex-related differences in outcomes of nonvalvular atrial fibrillation (AF) patients following left atrial appendage occlusion (LAAO). We conducted a meta-analysis to investigate the procedural complications and long-term outcomes after LAAO in women versus men. We screened Medline, EMBASE, Cochrane Center Register of Controlled Trials, and Clinical Trials.gov. The inclusion criteria were studies targeting the sex-related differences in outcomes in nonvalvular AF patients treated by LAAO. Procedural endpoints of interest included success rate, pericardial complications, major bleeding, and vascular complications during hospitalization. Long-term outcomes included all-cause mortality and ischemic stroke during follow-up. Studies that merely considered sex in the subgroup analysis were not included. Six observational studies with a total of 64,035 patients were identified. The procedural success rates did not differ between sexes (odds ratio [OR]: 0.98, 95% confidence interval [CI]: 0.89-1.09, p = 0.77), while women experienced more pericardial complications (OR: 1.78, 95% CI: 1.58-2.01, p < 0.00001), major bleedings (OR: 2.04, 95% CI: 1.75-2.39, p < 0.00001), and vascular complications (OR: 1.75, 95% CI: 1.41-2.17, p < 0.00001) than men. The sensitivity analysis performed by removing the largest study showed good stability. The long-term mortality and stroke rates did not differ between women and men in either the 1-year subgroup or the 2-year subgroup. In conclusion, despite comparable procedural success rates, women have a significantly higher incidence of pericardial complications, major bleeding, and vascular complications following LAAO. The long-term mortality and stroke rates do not differ between the sexes.

Immunotherapy for non-muscle-invasive bladder cancer: from the origins of BCG to novel therapies.

Supplies of intravesical Bacillus Calmette-Guérin (BCG), the first-line treatment for most intermediate- and high-risk non-muscle-invasive bladder cancers (NMIBC), have proven unreliable over the past decade. This review considers the evolution of BCG immunotherapy for NMIBC: from the discovery of the antitumour side effects of tuberculosis and subsequently the BCG vaccine, to recent advances in novel immunotherapeutic agents. We summarize the evidence for alternative options to standard intravesical BCG therapy regimens and describe the potential for immune response manipulating drugs in the treatment of NMIBC. These new agents, including immune checkpoint inhibitors, toll-like receptor agonists and recombinant viral vectors, may provide better options in the management of NMIBC in the future.

Lay abstract Many patients with non-invasive bladder cancers may need treatments into the bladder, including one called Bacillus Calmette-Guérin (BCG). Unfortunately, the supplies of BCG have been interrupted and somewhat unreliable since 2012. Because of this, we have been forced to look at other means of treating our patients using drugs similar to BCG. This has made us think about how BCG treatment was first developed more than 40 years ago and how it has evolved as a treatment for bladder cancer. In this article, we review the current uses of BCG and other treatments for bladder cancer and explore what the future may hold for bladder cancer treatment.

Ankyrin-2 genetic variants: A case of Ankyrin-B syndrome.

Inherited cardiac arrhythmias (ICA) have become one of the leading causes of sudden cardiac death in people under 40 years old. Variants in the ankyrin-B or ankyrin-2 genes will result in several cardiac arrhythmias ranging from sinus node dysfunction to life-threatening arrhythmias. In this case study, we report a typical ankyrin-2 variant, in which ventricular tachyarrhythmias might be reproduced through exercise or stress tests.

Blood Urea Nitrogen for Short-Term Prognosis in Patients with Cardiogenic Shock Complicating Acute Myocardial Infarction.

Purpose: Cardiogenic shock (CS) is the leading cause of death in patients with acute myocardial infarction (AMI). Our study aimed to evaluate the short-term prognostic value of admission blood urea nitrogen (BUN) in patients with CS complicating AMI. Materials and Methods: 218 consecutive patients with CS after AMI were enrolled. The primary endpoint was 30-day mortality. The association of admission BUN and 30-day mortality and major adverse cardiovascular event (MACE) was investigated by Cox regression. The integrated discrimination improvement (IDI) and net reclassification improvement (NRI) further examined the predictive value of BUN. Results: During a period of 30-day follow-up, 105 deaths occurred. Compared to survivors, nonsurvivors had significantly higher admission BUN (p < 0.001), creatinine (p < 0.001), BUN/creatinine (p = 0.03), and a lower glomerular filtration rate (p < 0.001). The area under the curve (AUC) of the 4 indices for predicting 30-day mortality was 0.781, 0.734, 0.588, and 0.773, respectively. When compared to traditional markers associated with CS, the AUC for predicting 30-day mortality of BUN, lactate, and left ventricular ejection fraction were 0.781, 0.776, and 0.701, respectively. The optimal cut-off value of BUN for predicting 30-day mortality was 8.95 mmol/L with Youden-Index analysis. Multivariate Cox analysis indicated BUN >8.95 mmol/L was an important independent predictor for 30-day mortality (HR 2.08, 95%CI 1.28-3.36, p = 0.003) and 30-day MACE (HR 1.85, 95%CI 1.29-2.66, p = 0.001). IDI (0.053, p = 0.005) and NRI (0.135, p = 0.010) showed an improvement in the accuracy for mortality prediction of the new model when BUN was included compared with the standard model of predictors in previous scores. Conclusion: An admission BUN >8.95 mmol/L was robustly associated with increased short-term mortality and MACE in patients with CS after AMI. The prognostic value of BUN was superior to other renal markers and comparable to traditional markers. This easily accessible index might be promising for early risk stratification in CS patients following AMI.

Adjuvant chemotherapy in upper tract urothelial carcinoma (the POUT trial): a phase 3, open-label, randomised controlled trial.

BACKGROUND: Urothelial carcinomas of the upper urinary tract (UTUCs) are rare, with poorer stage-for-stage prognosis than urothelial carcinomas of the urinary bladder. No international consensus exists on the benefit of adjuvant chemotherapy for patients with UTUCs after nephroureterectomy with curative intent. The POUT (Peri-Operative chemotherapy versus sUrveillance in upper Tract urothelial cancer) trial aimed to assess the efficacy of systemic platinum-based chemotherapy in patients with UTUCs. METHODS: We did a phase 3, open-label, randomised controlled trial at 71 hospitals in the UK. We recruited patients with UTUC after nephroureterectomy staged as either pT2-T4 pN0-N3 M0 or pTany N1-3 M0. We randomly allocated participants centrally (1:1) to either surveillance or four 21-day cycles of chemotherapy, using a minimisation algorithm with a random element. Chemotherapy was either cisplatin (70 mg/m2) or carboplatin (area under the curve [AUC]4·5/AUC5, for glomerular filtration rate <50 mL/min only) administered intravenously on day 1 and gemcitabine (1000 mg/m2) administered intravenously on days 1 and 8; chemotherapy was initiated within 90 days of surgery. Follow-up included standard cystoscopic, radiological, and clinical assessments. The primary endpoint was disease-free survival analysed by intention to treat with a Peto-Haybittle stopping rule for (in)efficacy. The trial is registered with ClinicalTrials.gov, NCT01993979. A preplanned interim analysis met the efficacy criterion for early closure after recruitment of 261 participants. FINDINGS: Between June 19, 2012, and Nov 8, 2017, we enrolled 261 participants from 57 of 71 open study sites. 132 patients were assigned chemotherapy and 129 surveillance. One participant allocated chemotherapy withdrew consent for data use after randomisation and was excluded from analyses. Adjuvant chemotherapy significantly improved disease-free survival (hazard ratio 0·45, 95% CI 0·30-0·68; p=0·0001) at a median follow-up of 30·3 months (IQR 18·0-47·5). 3-year event-free estimates were 71% (95% CI 61-78) and 46% (36-56) for chemotherapy and surveillance, respectively. 55 (44%) of 126 participants who started chemotherapy had acute grade 3 or worse treatment-emergent adverse events, which accorded with frequently reported events for the chemotherapy regimen. Five (4%) of 129 patients managed by surveillance had acute grade 3 or worse emergent adverse events. No treatment-related deaths were reported. INTERPRETATION: Gemcitabine-platinum combination chemotherapy initiated within 90 days after nephroureterectomy significantly improved disease-free survival in patients with locally advanced UTUC. Adjuvant platinum-based chemotherapy should be considered a new standard of care after nephroureterectomy for this patient population. FUNDING: Cancer Research UK.

Prognostic value of neutrophil-lymphocyte ratio in cardiogenic shock complicating acute myocardial infarction: A cohort study.

BACKGROUNDS: Cardiogenic shock (CS) is the most severe complication after acute myocardial infarction (AMI) with mortality above 50%. Inflammatory response is involved in the pathology of CS and AMI. In this study, we aimed to evaluate the prognostic value of admission neutrophil-lymphocyte ratio (NLR) in patients with CS complicating AMI. METHODS: Two hundred and seventeen consecutive patients with CS after AMI were divided into two groups according to the admission NLR cut-off value ≤7.3 and >7.3. The primary outcome was 30-day all-cause mortality and the secondary end-point was the composite events of major adverse cardiovascular events (MACE), including all-cause mortality, ventricular tachycardia/ventricular fibrillation, atrioventricular block, gastrointestinal haemorrhage and non-fatal stroke. Cox proportional hazard models were performed to analyse the association of NLR with the outcome. NLR cut-off value was determined by Youden index. RESULTS: Patients with NLR > 7.3 were older and presented with lower lymphocyte count, higher admission heart rate, B-type natriuretic peptide, leucocyte, neutrophil and creatinine (all P < .05). During a period of 30-day follow-up after admission, mortality in patients with NLR > 7.3 was significantly higher than in patients with NLR ≤ 7.3 (73.7% vs. 26.3%, P < .001). The incidence of MACE was also remarkably higher in patients with NLR > 7.3 (87.9% vs. 53.4%, P < .001). After multivariable adjustment, NLR > 7.3 remained an independent predictor for higher risk of 30-day mortality (HR 2.806; 95%CI 1.784, 4.415, P < .001) and MACE (HR 2.545; 95%CI 1.791, 3.617, P < .001). CONCLUSIONS: Admission NLR could be used as an important tool for short-term prognostic evaluation in patients with CS complicating AMI and higher NLR is an independent predictor for increased 30-day all-cause mortality and MACE.

The Sirenic Links between Diabetes, Obesity, and Bladder Cancer.

There is considerable evidence of a positive association between the incidence of type 2 diabetes mellitus (T2DM) and obesity with bladder cancer (BCa), with the link between T2DM and obesity having already been established. There also appear to be potential associations between Pleckstrin homology domain containing S1 (PLEKHS1) and the Insulin-like Growth Factor (IGF) axis. Seven literature searches were carried out to investigate the backgrounds of these potential links. PLEKHS1 is a candidate biomarker in BCa, with mutations that are easily detectable in urine and increased expression seemingly associated with worse disease states. PLEKHS1 has also been implicated as a potential mediator for the onset of T2DM in people with obesity. The substantial evidence of the involvement of IGF in BCa, the role of the IGF axis in obesity and T2DM, and the global prevalence of T2DM and obesity suggest there is scope for investigating the links between these components. Preliminary findings on the relationship between PLEKHS1 and the IGF axis signal possible associations with BCa progression. This indicates that PLEKHS1 plays a role in the pathogenesis of BCa that may be mediated by members of the IGF axis. Further detailed research is needed to establish the relationship between PLEKHS1 and the IGF axis in BCa and determine how these phenomena overlap with T2DM and obesity.

Fruit consumption and the risk of bladder cancer: A pooled analysis by the Bladder Cancer Epidemiology and Nutritional Determinants Study.

While the association between fruit consumption and bladder cancer risk has been extensively reported, studies have had inadequate statistical power to investigate associations between types of fruit and bladder cancer risk satisfactorily. Fruit consumption in relation to bladder cancer risk was investigated by pooling individual data from 13 cohort studies. Cox regression models with attained age as time scale were used to estimate hazard ratios (HRs) for intakes of total fruit and citrus fruits, soft fruits, stone fruits, tropical fruits, pome fruits and fruit products. Analyses were stratified by sex, smoking status and bladder cancer subtype. During on average 11.2 years of follow-up, 2836 individuals developed incident bladder cancer. Increasing fruit consumption (by 100 g/day) was inversely associated with the risk of bladder cancer in women (HR = 0.92; 95% CI 0.85-0.99). Although in women the association with fruit consumption was most evident for higher-risk nonmuscle invasive bladder cancer (NMIBC; HR = 0.72; 95% CI 0.56-0.92), the test for heterogeneity by bladder cancer subtype was nonsignificant (P-heterogeneity = .14). Increasing fruit consumption (by 100 g/day) was not associated with bladder cancer risk in men (HR = 0.99; 95% CI 0.94-1.03), never smokers (HR = 0.96; 95% CI 0.88-1.05), former smokers (HR = 0.98; 95% CI 0.92-1.05) or current smokers (HR = 0.95; 95% CI 0.89-1.01). The consumption of any type of fruit was not found to be associated with bladder cancer risk (P values > .05). Our study supports no evidence that the consumption of specific types of fruit reduces the risk of bladder cancer. However, increasing total fruit consumption may reduce bladder cancer risk in women.

Modeling the Complex Exposure History of Smoking in Predicting Bladder Cancer: A Pooled Analysis of 15 Case-Control Studies.

BACKGROUND: Few studies have modeled smoking histories by combining smoking intensity and duration to show what profile of smoking behavior is associated with highest risk of bladder cancer. This study aims to provide insight into the association between smoking exposure history and bladder cancer risk by modeling both smoking intensity and duration in a pooled analysis. METHODS: We used data from 15 case-control studies included in the bladder cancer epidemiology and nutritional determinants study, including a total of 6,874 cases and 17,727 controls. To jointly interpret the effects of intensity and duration of smoking, we modeled excess odds ratios per pack-year by intensity continuously to estimate the risk difference between smokers with long duration/low intensity and short duration/high intensity. RESULTS: The pattern observed from the pooled excess odds ratios model indicated that for a fixed number of pack-years, smoking for a longer duration at lower intensity was more deleterious for bladder cancer risk than smoking more cigarettes/day for a shorter duration. We observed similar patterns within individual study samples. CONCLUSIONS: This pooled analysis shows that long duration/low intensity smoking is associated with a greater increase in bladder cancer risk than short duration/high intensity smoking within equal pack-year categories, thus confirming studies in other smoking-related cancers and demonstrating that reducing exposure history to a single metric such as pack-years was too restrictive.

Health-related quality of life around the time of diagnosis in patients with bladder cancer.

OBJECTIVES: To quantify the health-related quality of life (HRQoL) of patients with bladder cancer around the time of diagnosis and to test the hypotheses of a two-factor model for the HRQoL questionnaire QLQ-C30. METHODS: From participants in the Bladder Cancer Prognoses Programme, a multicentre cohort study, sociodemographic data were collected using semi-structured face-to-face interviews. Answers to the QLQ-C30 were transformed into a scale from 0 to 100. HRQoL data were analysed in multivariate analyses. The hypothesized two-factor (Physical and Mental Health) domain structure of the QLQ-C30 was also tested with confirmatory factor analyses (CFA). RESULTS: A total of 1160 participants (78%) completed the questionnaire after initial visual diagnosis and before pathological confirmation. Despite non-muscle-invasive bladder cancer (NMIBC) being associated with a higher HRQoL than carcinoma invading bladder muscle, only the domain Role Functioning was clinically significantly better in patients with NMIBC. Age, gender, bladder cancer stage and comorbidity all had a significant influence on QLQ-C30 scores. The CFA showed an overall good fit of the hypothesized two-factor model. CONCLUSION: This study identified a baseline reference value for HRQoL for patients with bladder cancer, which allows better evaluation of any changes in HRQoL as disease progresses or after treatment. In addition, a two-factor (Physical and Mental Health) model was developed for the QLQ-C30.

Targeted deep sequencing of urothelial bladder cancers and associated urinary DNA: a 23-gene panel with utility for non-invasive diagnosis and risk stratification.

OBJECTIVES: To develop a focused panel of somatic mutations (SMs) present in the majority of urothelial bladder cancers (UBCs), to investigate the diagnostic and prognostic utility of this panel, and to compare the identification of SMs in urinary cell-pellet (cp)DNA and cell-free (cf)DNA as part of the development of a non-invasive clinical assay. PATIENTS AND METHODS: A panel of SMs was validated by targeted deep-sequencing of tumour DNA from 956 patients with UBC. In addition, amplicon and capture-based targeted sequencing measured mutant allele frequencies (MAFs) of SMs in 314 urine cpDNAs and 153 urine cfDNAs. The association of SMs with grade, stage, and clinical outcomes was investigated by univariate and multivariate Cox models. Concordance between SMs detected in tumour tissue and cpDNA and cfDNA was assessed. RESULTS: The panel comprised SMs in 23 genes: TERT (promoter), FGFR3, PIK3CA, TP53, ERCC2, RHOB, ERBB2, HRAS, RXRA, ELF3, CDKN1A, KRAS, KDM6A, AKT1, FBXW7, ERBB3, SF3B1, CTNNB1, BRAF, C3orf70, CREBBP, CDKN2A, and NRAS; 93.5-98.3% of UBCs of all grades and stages harboured ≥1 SM (mean: 2.5 SMs/tumour). RAS mutations were associated with better overall survival (P = 0.04). Mutations in RXRA, RHOB and TERT (promoter) were associated with shorter time to recurrence (P < 0.05). MAFs in urinary cfDNA and cpDNA were highly correlated; using a capture-based approach, >94% of tumour SMs were detected in both cpDNA and cfDNA. CONCLUSIONS: SMs are reliably detected in urinary cpDNA and cfDNA. The technical capability to identify very low MAFs is essential to reliably detect UBC, regardless of the use of cpDNA or cfDNA. This 23-gene panel shows promise for the non-invasive diagnosis and risk stratification of UBC.

Patients choose certainty over burden in bladder cancer surveillance.

BACKGROUND: Due to the high risk of recurrence of non-muscle invasive bladder cancer, all patients undergo regular cystoscopic surveillance for early detection. As cystoscopy is invasive, costly and increases the burden of the disease considerably, there is significant ongoing research and development into non-invasive urinary biomarker substitutes. This study aims to assess the level of sensitivity required before patients accept a new urinary biomarker. METHODS: We studied the preferences for a hypothetical diagnostic urinary biomarker and compared this to usual care (cystoscopy) at different levels of sensitivity among 437 patients with bladder cancer (354 men and 83 women) from the UK Bladder Cancer Prognosis Programme. A standard gamble approach was used to estimate the minimally acceptable sensitivity (MAS) of the new biomarker. Additionally, non-parametric statistical analyses were performed to investigate the association between surveillance preference and various patient characteristics. RESULTS: Almost half of patients (183, 43%) would not replace cystoscopy with a urinary biomarker unless it was 100% sensitive. The median MAS was 99.9999%, and nearly 85% of patients demanded a sensitivity of at least 99% before preferring a urinary biomarker test over cystoscopy. These results were consistent across all patient characteristics and demographic categories. CONCLUSIONS: Our results indicate that patients demand urinary biomarkers as sensitive as cystoscopy before they would be willing to forego cystoscopy for bladder cancer surveillance.

Tropomyosins: Potential Biomarkers for Urothelial Bladder Cancer.

Despite the incidence and prevalence of urothelial bladder cancer (UBC), few advances in treatment and diagnosis have been made in recent years. In this review, we discuss potential biomarker candidates: the tropomyosin family of genes, encoded by four loci in the human genome. The expression of these genes is tissue-specific. Tropomyosins are responsible for diverse cellular roles, most notably based upon their interplay with actin to maintain cellular processes, integrity and structure. Tropomyosins exhibit a large variety of splice forms, and altered isoform expression levels have been associated with cancer, including UBC. Notably, tropomyosin isoforms are detectable in urine, offering the potential for non-invasive diagnosis and risk-stratification. This review collates the basic knowledge on tropomyosin and its isoforms, and discusses their relationships with cancer-related phenomena, most specifically in UBC.

The association between smoking cessation before and after diagnosis and non-muscle-invasive bladder cancer recurrence: a prospective cohort study.

BACKGROUND: Smoking is a major risk factor for bladder cancer, but the relationship between smoking cessation after initial treatment and bladder cancer recurrence has been investigated less frequently and not prospectively yet. METHODS: 722 non-muscle-invasive bladder cancer (NMIBC) patients (pTa, pT1, and CIS) from the prospective Bladder Cancer Prognosis Programme (BCPP) cohort, selected in the UK between 2005 and 2011, provided complete data on smoking behavior before and up to 5 years after diagnosis. The impact of smoking behavior on NMIBC recurrence was explored by multivariable Cox regression models investigating time-to-first NMIBC recurrence. RESULTS: Over a median follow-up period of 4.21 years, 403 pathologically confirmed NMIBC recurrences occurred in 210 patients. Only 25 current smokers at diagnosis quit smoking (14%) during follow-up and smoking cessation after diagnosis did not decrease risk of recurrence compared to continuing smokers (p = 0.352). CONCLUSIONS: Although quitting smoking after diagnosis might reduce the risk of recurrence based on retrospective evidence, this is not confirmed in this prospective study because the number of NMIBC patients quitting smoking before their first recurrence was too low. Nevertheless, this indicates an important role for urologists and other health care professionals in promoting smoking cessation in NMIBC.