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The European Association of Urology (EAU) 2021 prognostic model for non–muscle-invasive bladder cancer (NMIBC) is based on the World Health Organization (WHO) 1973 and/or WHO 2004/2022 grading systems for patients who did not receive bacillus Calmette-Guérin (BCG) instillations and is widely used to assess the risk of progression. The estimated risk of progression affects the type of adjuvant intravesical instillation (chemotherapy or BCG), with primary radical cystectomy recommended for patients with the highest risk of progression. We applied the EAU 2021 prognostic model in a population-based setting for 3392 patients with primary NMIBC diagnosed in 2013–2014 according to the BladderBaSe 2.0 database. We assessed the model calibration by comparing the 5-yr progression probability observed in our cohort with the predicted progression probability assigned for the risk groups in the original EAU study, and evaluated the discrimination according to Harrell’s C index. At 5-yr follow-up, 394 patients had experienced disease progression. The progression probability observed was 4.9% (95% confidence interval [CI] 3.5–6.3%), 8.6% (95% CI 6.9–10%), 25% (95% CI 22–28%), and 23% (95% CI 14–30%) for the low-, intermediate-, high-, and very high-risk groups, respectively. The discrimination at 5 yr was 0.72 (95% CI 0.69–0.78) for the overall cohort and 0.74 (95% CI 0.70–0.80) in the group excluding the 811 patients who received BCG instillations. Showing moderate predictive ability, the EAU 2021 prognostic model has clinical utility in population-based settings despite underestimation of the observed progression risk in the low- and high-risk groups in the current study.

Patient summary

We looked at how well a model predicted the risk of progression of non–muscle-invasive bladder cancer using results for a group of Swedish patients. Approximately one in four patients in the high-risk category progress to more advanced disease within 5 yr. Doctors and patients need to consider the probability of progression in the high-risk category when making shared decisions on which treatment is best for an individual patient.

Understanding the molecular landscape of nonmuscle-invasive bladder cancer (NMIBC) is essential to improve risk assessment and treatment regimens. We performed a comprehensive genomic analysis of patients with NMIBC using whole-exome sequencing (n = 438), shallow whole-genome sequencing (n = 362) and total RNA sequencing (n = 414). A large genomic variation within NMIBC was observed and correlated with different molecular subtypes. Frequent loss of heterozygosity in FGFR3 and 17p (affecting TP53) was found in tumors with mutations in FGFR3 and TP53, respectively. Whole-genome doubling (WGD) was observed in 15% of the tumors and was associated with worse outcomes. Tumors with WGD were genomically unstable, with alterations in cell-cycle-related genes and an altered immune composition. Finally, integrative clustering of multi-omics data highlighted the important role of genomic instability and immune cell exhaustion in disease aggressiveness. These findings advance our understanding of genomic differences associated with disease aggressiveness in NMIBC and may ultimately improve patient stratification.

Background and objective: It has been suggested that urinary tract infections (UTIs) are associated with delayed diagnosis of bladder cancer (BC). Our aim was to investigate prediagnostic treatments related to UTI and the relation to BC diagnostic delay, reflected by advanced disease at diagnosis. Methods: We used data from the BladderBaSe 2.0 with data of treatments related to UTI up to 3 yr before BC diagnosis (2008-2019) for BC patients in comparison to a matched reference population. We investigated the association between UTI treatments and more advanced disease at diagnosis in the BC cohort. We used generalized ordered logistic regression to calculate odds ratios (ORs) for more advanced disease as an ordered outcome: non-muscle-invasive BC (NMIBC), muscle-invasive BC (MIBC), and metastatic BC (MBC). Key findings and limitations: The study population included 29 921 BC patients and 149 467 matched reference subjects. The proportions of individuals receiving UTI treatment were higher in the patient groups than in the corresponding reference groups, with the greatest differences observed for the MIBC and MBC subgroups. The OR for the risk of more advanced disease (MIBC or MBC) with at least one UTI treatment versus none was 1.28 (95% confidence interval [CI] 1.19-1.37) for men and 1.42 (95 % CI 1.27- 1.58) for women. The association to risk of more advanced disease increased with the number of UTI treatments for both sexes. Conclusions and clinical implications: Further studies on the effects of treatments related to UTI in combination with other factors are needed to identify reasons for possible delays in the BC diagnostic pathway. Patient summary: We found that for patients with bladder cancer, previous antibiotic treatment for a urinary tract infection was linked to more advanced disease at diagnosis. Further studies are needed to identify reasons for possible delays in the diagnosis of bladder cancer. (c) 2024 The Author(s). Published by Elsevier B.V. on behalf of European Association of Urology. This is an open access article under the CC BY license (http://creativecommons.

ObjectivesTo investigate the cumulative incidence proportion of disseminated or local Bacillus Calmette-Guerin (BCG) infections after adjuvant BCG instillations in patients with non-muscle-invasive bladder cancer (NMIBC).Patients and MethodsWe analysed the timing and occurrence of BCG infections and absolute and relative risk in relation to patient characteristics available in the Swedish nationwide database 'BladderBaSe 2.0'. The cumulative incidence proportion of a BCG infection was indicated by a reported diagnosis of tuberculosis (TB) in the patient registry or filing a prescription for tuberculostatic drugs.ResultsThe cumulative incidence proportion was 1.1% at the 5-year follow-up in 5033 patients exposed to adjuvant BCG instillations. The incidence rate was highest during the first 2 years after start of BCG instillations. Women had a lower risk than men (hazard ratio 0.23, 95% confidence interval 0.07-0.74). Age and calendar time at diagnosis, comorbidity, tumour risk group, previous medication with corticosteroids, immunosuppressive drugs, or time between transurethral resection of the bladder tumour and commencing the adjuvant BCG instillation were not associated with risk.ConclusionsThese data further supports that the overall risk of a BCG infection after BCG-instillation treatment for NMIBC is low. The great majority of infections occur in the first 2 years, calling for an awareness of the diverse symptoms of BCG infection during this period. We provide evidence for male sex as a risk factor; however, the statistical precision is low and with a risk of selection bias, making it difficult to rule out the other suggested risk factors without further studies with different approaches.

Objectives: To test the hypothesis that the Swedish national policy of abandoning testing for asymptomatic microscopic haematuria (AMH) introduced in 1999 did not adversely affect the prognosis of patients with urinary bladder cancer. Specific aims were to investigate possible effects on (1) Diagnostic delay as represented by stage distribution at diagnosis, (2) Survival and mortality trends, also in comparison to other countries and (3) National health care costs.

Material and methods: The design was an observational study using open sources on patients included in the Swedish National Bladder Cancer Registry 1997-2016. Outcome measures were: Changes in initial tumour presentation during 5 years after the change and long-term relative survival and mortality in comparison to the other Nordic countries. Costs related to investigations were estimated based on the national price lists.

Results: The proportion of patients diagnosed with muscle-invasive bladder cancer decreased following the policy change. The long-term relative 5-year survival increased during the study period. Mortality has remained constant during the period. In comparison to the other Nordic countries, Sweden remains among those with the best outcome despite a more restrictive approach. Cost savings because of the policy change were estimated to be substantial.

Conclusions: Based on open-source registry data, the new restrictive policy was not found to adversely affect the survival of patients with urinary bladder cancer in Sweden. These observations argue against a major negative impact of abandoning further work-up for patients with AMH and may be of use for other countries when revising guidelines. The reduced number of patients undergoing investigation may allow for increased focus and be a relief both for caregivers and the health budget.

Background: Cancer immunity is based on the interaction of a multitude of cells in the spatial context of the tumour tissue. Clinically relevant immune signatures are therefore anticipated to fundamentally improve the accuracy in predicting disease progression.

Methods: Through a multiplex in situ analysis we evaluated 15 immune cell classes in 1481 tumour samples. Single-cell and bulk RNAseq data sets were used for functional analysis and validation of prognostic and predictive associations.

Findings: By combining the prognostic information of anti-tumoural CD8+ lymphocytes and tumour supportive CD68+CD163+ macrophages in colorectal cancer we generated a signature of immune activation (SIA). The prognostic impact of SIA was independent of conventional parameters and comparable with the state-of-art immune score. The SIA was also associated with patient survival in oesophageal adenocarcinoma, bladder cancer, lung adenocarcinoma and melanoma, but not in endometrial, ovarian and squamous cell lung carcinoma. We identified CD68+CD163+ macrophages as the major producers of complement C1q, which could serve as a surrogate marker of this macrophage subset. Consequently, the RNA-based version of SIA (ratio of CD8A to C1QA) was predictive for survival in independent RNAseq data sets from these six cancer types. Finally, the CD8A/C1QA mRNA ratio was also predictive for the response to checkpoint inhibitor therapy.

Interpretation: Our findings extend current concepts to procure prognostic information from the tumour immune microenvironment and provide an immune activation signature with high clinical potential in common human cancer types.

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-naive 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.