MicroRNA as a Biomarker for Diagnostic, Prognostic, and Therapeutic Purpose in Urinary Tract Cancer

The incidence of urologic cancers, including kidney, upper tract urothelial, and bladder malignancies, is increasing globally, with a high percentage of cases showing metastasis upon diagnosis and low five-year survival rates. MicroRNA (miRNA), a small non-coding RNA, was found to regulate the expression of oncogenes and tumor suppressor genes in several tumors, including cancers of the urinary system. In the current review, we comprehensively discuss the recently reported up-or down-regulated miRNAs as well as their possible targets and regulated pathways involved in the development, progression, and metastasis of urinary tract cancers. These miRNAs represent potential therapeutic targets and diagnostic/prognostic biomarkers that may help in efficient and early diagnosis in addition to better treatment outcomes.

Recurrent activating mutations in AHR act as drivers of urinary tract cancer

Bladder cancer is a common cancer with a high recurrence rate and with limited progress in treatment and survival of patients with advanced stages of the disease. The tumorigenesis of bladder cancer is still poorly understood, but identification of genetic contributors to its development may provide leads for targeted therapeutic approaches. By an in-depth analysis of whole-genome sequencing data of metastasized urinary tract cancer samples, we identified a novel recurrent in-frame deletion of exons 8 and 9 in the aryl hydrocarbon receptor (AHR) gene, encoding a ligand-activated transcription factor with context-specific physiological functions. The deletion (AHRΔe8-9) is highly specific to urinary tract cancer and occurs in 10.7% of metastatic lesions. Additionally, a recurrent AHR hotspot point mutation and AHR gene amplifications were identified indicating that alterations in the AHR gene are a key cancer driver event for urinary tract cancer adding up to a prevalence of ~19% (40 out of 206). The hotspot point mutation results in an amino acid change (AHRQ383H) in the ligand-binding domain of the protein and causes altered ligand affinities such as AHRQ383H activation upon incubation with the AhR antagonist CH-2233191. The in-frame deletion of exons 8 and 9 disrupt the ligand-binding domain and result in a constitutive nuclear localization of the protein and ligand-independent transcriptional activation. The constitutive activation of the AhR pathway by the hAHRΔe8-9 mutant in mouse bladder organoids induces dedifferentiation and enables anchorage independent growth. In conclusion, our results indicate that AhR is a key proto-oncogene and cancer driver gene in urinary tract cancer and emphasize the potential of the AhR pathway as a target for therapeutic interventions.

Acute urinary retention and risk of cancer: population based Danish cohort study

Objective To examine the risk of urogenital, colorectal, and neurological cancers after a first diagnosis of acute urinary retention. Design Nationwide population based cohort study. Setting All hospitals in Denmark. Participants 75 983 patients aged 50 years or older with a first hospital admission for acute urinary retention during 1995-2017. Main outcome measures Absolute risk of urogenital, colorectal, and neurological cancer and excess risk of these cancers among patients with acute urinary retention compared with the general population. Results The absolute risk of prostate cancer after a first diagnosis of acute urinary retention was 5.1% (n=3198) at three months, 6.7% (n=4233) at one year, and 8.5% (n=5217) at five years. Within three months of follow-up, 218 excess cases of prostate cancer per 1000 person years were detected. An additional 21 excess cases per 1000 person years were detected during three to less than 12 months of follow-up, but beyond 12 months the excess risk was negligible. Within three months of follow-up the excess risk for urinary tract cancer was 56 per 1000 person years, for genital cancer in women was 24 per 1000 person years, for colorectal cancer was 12 per 1000 person years, and for neurological cancer was 2 per 1000 person years. For most of the studied cancers, the excess risk was confined to within three months of follow-up, but the risk of prostate and urinary tract cancer remained increased during three to less than 12 months of follow-up. In women, an excess risk of invasive bladder cancer persisted for several years. Conclusions Acute urinary retention might be a clinical marker for occult urogenital, colorectal, and neurological cancers. Occult cancer should possibly be considered in patients aged 50 years or older presenting with acute urinary retention and no obvious underlying cause.

1284 Comparison of British Association of Urological Surgeons (BAUS) 2008 and NICE 2015 Guidelines for Patients with Suspected Urinary Tract Cancer: An Audit of Haematuria Referrals

Introduction BAUS guidelines for the investigation of haematuria were replaced by NICE guidelines in 2015. However, both criteria are currently used to refer patients to our Haematuria Clinic. We audit the haematuria referrals made to our unit and compare cancer yield. Method A retrospective review of all two-week wait haematuria referrals to a single UK teaching hospital between October 2019 and April 2020 was performed. Referrals were stratified into two groups: BAUS 2008 and NICE 2015 referral criteria. The outcomes of haematuria investigations were analyzed and the incidence of urinary tract cancer (UTC) compared between groups. Results 316 referrals were analyzed. Of these, 123 (39%) and 193 (61%) referrals were made using BAUS and NICE criteria respectively. 233 (74%) patients were investigated for visible haematuria of which 68 (29%) were referred using BAUS criteria and 165 (71%) using NICE. UTC was identified in 20% of patients referred using NICE criteria and 4.4% using BAUS criteria. 83 (26%) patients were referred with non-visible haematuria. Of these, 55 (66%) were referred using BAUS criteria and 28 (34%) using NICE. UTC was identified in 2.5% of patients referred using BAUS criteria. No UTC was identified in referrals using NICE criteria. Conclusions Despite BAUS haematuria guidelines being superseded by NICE guidelines in 2015, these older guidelines still account for 40% of our two-week wait referrals. Furthermore, NICE guidelines have a higher cancer yield for visible haematuria compared to BAUS guidelines and should therefore take precedence to avoid subjecting patients to unnecessary and costly investigations.

Pyuria as a Predictive Marker of Bacillus Calmette–Guérin Unresponsiveness in Non-Muscle Invasive Bladder Cancer

This study aims to investigate the clinical role of preoperative pyuria for predicting bacillus Calmette–Guérin (BCG) unresponsiveness in non-muscle invasive bladder cancer (NMIBC). We performed a logistic regression analysis on 453 patients with NMIBC who were treated with BCG immunotherapy after a transurethral resection of bladder tumours, to evaluate predictive factors of BCG unresponsiveness. We also analysed univariate and multivariable survival data to estimate the prognostic impact of pyuria. Of the total study population, 37.6% (170/453) of patients had BCG unresponsiveness. A multivariable logistic regression analysis revealed that a history of upper urinary tract cancer (odds ratio (OR): 1.86, 95% confidence interval (CI): 1.04–3.32, p-value = 0.035) and the presence of pyuria (OR: 1.51, 95% CI: 1.01–2.27, p = 0.047) and tumour multiplicity (OR: 1.80, 95% CI: 1.18–2.75, p-value < 0.001) were significant predictors of BCG unresponsiveness. A Cox proportional hazards analysis model showed that pyuria was a significant prognostic factor for progression-free survival (hazard ratio: 4.51, 95% CI: 1.22–16.66, p = 0.024). A history of upper urinary tract cancer and the presence of pyuria and tumour multiplicity are predictive markers of BCG unresponsiveness. For patients with NMIBC who have preoperative pyuria, treatment using BCG should be considered cautiously.

FAP imaging in rare cancer entities—first clinical experience in a broad spectrum of malignancies

Purpose 68 Ga-FAPI (fibroblast activation protein inhibitor) is a rapidly evolving and highly promising radiotracer for PET/CT imaging, presenting excellent results in a variety of tumor entities, particularly in epithelial carcinomas. This retrospective analysis sought to evaluate the potential and impact of FAPI-PET/CT in rare cancer diseases with respect to improvement in staging and therapy, based on tracer uptake in normal organs and tumors. Material and methods Fifty-five patients with rare tumor entities, defined by a prevalence of 1 person out of 2000 or less, received a 68 Ga-FAPI-PET/CT scan. Fourteen women and 41 men (median age 60) were included within the following subgroups: cancer of unknown primary (n = 10), head and neck cancer (n = 13), gastrointestinal and biliary-pancreatic cancer (n = 17), urinary tract cancer (n = 4), neuroendocrine cancer (n = 4), and others (n = 7). Tracer uptake was quantified by standardized uptake values SUVmax and SUVmean and the tumor-to-background ratio (TBR) was determined (SUVmax tumor/SUVmean organ). Results In 20 out of 55 patients, the primary tumor was identified and 31 patients presented metastases (n = 88), characterized by a high mean SUVmax in primary (10.1) and metastatic lesions (7.6). The highest uptake was observed in liver metastases (n = 6) with a mean SUVmax of 9.8 and a high TBR of 8.7, closely followed by peritoneal carcinomatosis (n = 16) presenting a mean SUVmax of 9.8 and an excellent TBR of 29.6. In terms of the included subgroups, the highest uptake regarding mean SUVmax was determined in gastrointestinal and biliary-pancreatic cancer with 9.8 followed closely by urinary tract cancer with 9.5 and head and neck cancer (9.1). Conclusion Due to excellent tumor visualization and, thereby, sharp contrasts in terms of high TBRs in primary and metastatic lesions in different rare malignancies, 68 Ga-FAPI-PET/CT crystallizes as a powerful and valuable imaging tool, particularly with respect to epithelial carcinomas, and therefore an enhancement to standard diagnostics imaging methodologies. The realization of further and prospective studies is of large importance to confirm the potential of FAP imaging in oncology.

FAP-Imaging in Rare Cancer Entities - First Clinical Experience in a Broad Spectrum of Malignancies

Purpose: 68Ga-FAPI (fibroblast activation protein inhibitor) is a rapidly evolving and highly promising radiotracer for PET/CT imaging, presenting excellent results in a variety of tumor entities, particularly in epithelial carcinomas. This retrospective analysis sought to evaluate the potential and impact of FAPI-PET/CT in rare cancer diseases with respect to improvement in staging and therapy, based on tracer uptake in normal organs and tumors.Material and Methods: 55 patients with rare tumor entities, defined by a prevalence of 1 person out of 2000 or less, received a 68Ga-FAPI-PET/CT scan. 14 women and 41 men (median age 60) were included within the following subgroups: cancer of unknown primary (n=10), head-and-neck-cancer (n=13), gastro-intestinal and biliary-pancreatic cancer (n=17), urinary tract cancer (n=4), neuroendocrine cancer (n=4) and others (n=7). Tracer uptake was quantified by standardized uptake values SUVmax and SUVmean and the tumor-to-background ratio (TBR) was determined (SUVmax tumor/ SUVmean organ). Results: In 20 out of 55 patients the primary tumor was identified and 31 patients presented metastases (n=88), characterized by a high mean SUVmax in primary (10.1) and metastatic lesions (7.6). Highest uptake was observed by liver metastases (n=6) with a mean SUVmax of 9.8 and a high TBR of 8.7, closely followed by peritoneal carcinomatosis (n=16) presenting a mean SUVmax of 9.8 and an excellent TBR of 29.6. In terms of the included subgroups the highest uptake regarding mean SUVmax was determined in gastro-intestinal and biliary-pancreatic cancer with 9.8 followed closely by urinary tract cancer with 9.5 and head-and-neck cancer (9.1). Conclusion Due to excellent tumor visualization and, thereby, sharp contrasts in terms of high TBRs in primary and metastatic lesions in different rare malignancies, 68Ga-FAPI-PET/CT crystallizes as a powerful and valuable imaging tool, particularly with respect to epithelial carcinomas, and therefore an enhancement to standard diagnostics imaging methodologies. The realization of further and prospective studies is of large importance to confirm the potential of FAP-imaging in oncology.