Cumulative incidence of and risk factors for BCG infection after adjuvant BCG instillations.

OBJECTIVES: To investigate the cumulative incidence proportion of disseminated or local Bacillus Calmette-Guérin (BCG) infections after adjuvant BCG instillations in patients with non-muscle-invasive bladder cancer (NMIBC). PATIENTS AND METHODS: We 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. RESULTS: The 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. CONCLUSIONS: These 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.

Bladder cancer grading using the four-tier combination of the World Health Organization (WHO) 1973 and WHO 2004 classifications.

OBJECTIVE: To investigate the impact of grading in urothelial bladder cancer (UBC) stages Ta and T1, comparing the World Health Organization (WHO) grading classifications of 1973 (WHO73) and 2004 (WHO04) and a combination of these (WHO73/04). PATIENTS AND METHODS: All patients with primary Ta and T1 UBC in the Östergötland region, Sweden, between 1992 and 2007 were included. From 1992, we introduced a new programme for management and follow-up of UBC, including prospectively performed registration of all patients, a systematic description of the location and size of all tumours, primary resection and intravesical treatment in the case of recurrence. All tumour specimens were retrospectively reviewed in 2008 and graded according to the WHO73 and WHO04. A combination of WHO73/04, Grade 1 (G1), Grade 2 low grade (G2LG), Grade 2 high grade (G2HG) and Grade 3 (G3) was analysed in relation to clinical variables and outcomes. RESULTS: There were 769 patients with a median age of 72 years and a median follow-up duration of 74 months. Recurrence was noted in 484 patients (63%) and progression in 80 patients (10%). Recurrence was more common in multiple tumours, larger tumours and in tumours of higher grade (G2LG, G2HG and G3). Progression was more common in tumours classified as larger, T1 and G2HG and G3. Notably, in tumours classified as G2HG, recurrence and progression were more common than in the G2LG group. Harrell's concordance index for the WHO73/04 was higher for recurrence and progression than in the WHO73 or WHO04. CONCLUSION: In the four-tier combined WHO73/04 for urothelial cancer, we observed two G2 sub-groups, G2HG and G2LG. There was a better outcome in the latter group, and the importance of G1 and G3 tumours could be fully evaluated. The WHO73/04 had greater accuracy for recurrence and progression than either the WHO73 or WHO04.

Telomerase reverse transcriptase mutation and the p53 pathway in T1 urinary bladder cancer.

OBJECTIVE: To study the telomerase reverse transcriptase (TERT) mutation and the p53 pathway in T1 urinary bladder cancer (UBC). MATERIALS AND METHODS: This prospectively performed population-based study included all patients in the Southeast Healthcare Region in Sweden with T1 UBC registered in the period 1992-2001, inclusive. Given that p53 and TERT are important factors for tumour proliferation, although their interrelationships are unknown, we assessed both the TERT and the p53 mutations. Furthermore, we conducted a p53 immunohistochemistry (IHC) analysis using two thresholds for p53 positivity: 10% of tumour cells and 50% of tumour cells (p53 IHC50%). Cox proportional hazards analysis and Kaplan-Meier curves were used to study time to tumour progression. RESULTS: Out of 158 patients, we observed the TERT mutation in 74 (47%), the p53 mutation in 48 (30%), and p53 IHC50% positivity in 72 patients (46%). The TERT mutation was more common in p53 mutation-positive patients (P = 0.009), and the latter group also had more patients with p53 IHC50%-positive tumour cells (P = 0.02). In the TERT mutation-negative tumours a p53-positive mutation was associated with a shorter time to progression (P = 0.03) compared to patients with p53-negative mutation. In contrast, in tumours with both TERT mutation positivity and p53 mutation positivity, a longer time to progression was observed in the group with p53 IHC50% positivity compared to the group with p53 IHC50%-negative tumours. CONCLUSIONS: In stage T1 UBC, the combination of the TERT mutation and the p53 mutation was associated with tumour progression. A protective effect of the TERT promotor mutation against tumour progression induced by the p53 mutation and subsequent p53 accumulation in tumour cells might be possible, but further investigations are necessary.

Computed tomography urography with corticomedullary phase can exclude urinary bladder cancer with high accuracy.

BACKGROUND: To evaluate the diagnostic accuracy of computed tomography-urography (CTU) to rule out urinary bladder cancer (UBC) and whether patients thereby could omit cystoscopy. METHODS: All patients evaluated for macroscopic hematuria with CTU with cortico-medullary phase (CMP) and cystoscopy at our institute between 1st November 2016 and 31st December 2019 were included. From this study cohort a study group consisting of all UBC patients and a control group of 113 patients randomly selected from all patients in the study cohort without UBC. Two radiologists blinded to all clinical data reviewed the CTUs independently. CTUs were categorized as positive, negative or indeterminate. Diagnostic accuracy and proportion of potential omittable cystoscopies were calculated for the study cohort by generalizing the results from the study group. RESULTS: The study cohort consisted of 2195 patients, 297 of which were in the study group (UBC group, n = 207 and control group, n = 90). Inter-rater reliability was high (κ 0.84). Evaluation of CTUs showed that 174 patients were assesessed as positive (showing UBC), 46 patients as indeterminate (not showing UBC but with limited quality of CTU), and 77 patients as negative (not showing UBC with good quality of CTU). False negative rate was 0.07 (95%, CI 0.04-0.12), false positive rate was 0.01 (95% CI 0.0-0.07) and negative predictive value was 0.99 (95% CI 0.92-1.0). The area under the curve was 0.93 (95% CI 0.90-0.96). Only 2.9% (3/102) with high-risk tumors and 11% (12/105) with low- or intermediate-risk tumors had a false negative CTU. Cystoscopy could potentially have been omitted in 57% (1260/2195) of all evaluations. CONCLUSIONS: CTU with CMP can exclude UBC with high accuracy. In case of negative CTU, it might be reasonable to omit cystoscopy, but future confirmative studies with possibly refined technique are needed.

Modulation of the inflammatory response after sclerotherapy for hydrocoele/spermatocoele.

OBJECTIVE: To investigate the modulation of the inflammatory response after sclerotherapy for hydrocoele/spermatocoele. PATIENTS AND METHODS: All patients with hydrocoele or spermatocoele presenting at the Department of Urology, University Hospital, Linköping, Sweden, from 2006 to 2012, were included in this prospective observational study of sclerotherapy for hydrocoele/spermatocoele using polidocanol as a sclerosing agent and adjuvant antibiotic and anti-inflammatory medication (AAAM) for modulation of the inflammatory response. Patients were clinically evaluated within 24-48 h after a complication or adverse event possibly related to sclerotherapy. Evaluation of cure was scheduled after 3 months and re-treatment, if necessary was carried out in the same manner as the first treatment. Groups of patients were compared using the chi-squared test and logistic regression analysis. RESULTS: From a total of 191 patients, AAAM was given to 126, of whom 5% had subclinical epididymitis/swelling (SES) compared to 26% of the patients without AAAM (P < 0.001). No other complication was observed. The rate of cure for the whole group of patients was 93% after one or two treatments and significantly higher in the group with AAAM than in the group without AAAM (96% vs 88%, P = 0.03). CONCLUSIONS: Modulation of the inflammatory response after sclerotherapy resulted in a lower incidence of SES and an increased cure rate.

Period-specific mean annual hospital volume of radical cystectomy is associated with outcome and perioperative quality of care: a nationwide population-based study.

OBJECTIVE: To investigate the association between hospital volume and overall survival (OS), cancer-specific survival (CSS), and quality of care of patients with bladder cancer who undergo radical cystectomy (RC), defined as the use of extended lymphadenectomy (eLND), continent reconstruction, neoadjuvant chemotherapy (NAC), and treatment delay of <3 months. PATIENTS AND METHODS: We used the Bladder Cancer Data Base Sweden (BladderBaSe) to study survival and indicators of perioperative quality of care in all 3172 patients who underwent RC for primary invasive bladder cancer stage T1-T3 in Sweden between 1997 and 2014. The period-specific mean annual hospital volume (PSMAV) during the 3 years preceding surgery was applied as an exposure and analysed using univariate and multivariate mixed models, adjusting for tumour and nodal stage, age, gender, comorbidity, educational level, and NAC. PSMAV was either categorised in tertiles, dichotomised (at ≥25 RCs annually), or used as a continuous variable for every increase of 10 RCs annually. RESULTS: PSMAV in the highest tertile (≥25 RCs annually) was associated with improved OS (hazard ratio [HR] 0.87, 95% confidence interval [CI] 0.75-1.0), whereas the corresponding HR for CSS was 0.87 (95% CI 0.73-1.04). With PSMAV as a continuous variable, OS was improved for every increase of 10 RCs annually (HR 0.95, 95% CI 0.90-0.99). Moreover, higher PSMAV was associated with increased use of eLND, continent reconstruction and NAC, but also more frequently with a treatment delay of >3 months after diagnosis. CONCLUSIONS: The current study supports centralisation of RC for bladder cancer, but also underpins the need for monitoring treatment delays associated with referral.

Risk of bladder cancer by disease severity in relation to metabolic factors and smoking: A prospective pooled cohort study of 800,000 men and women.

Previous studies on metabolic factors and bladder cancer (BC) risk have shown inconsistent results and have commonly not investigated associations separately by sex, smoking, and tumor invasiveness. Among 811,633 participants in six European cohorts, we investigated sex-specific associations between body mass index (BMI), mid-blood pressure (BP, [systolic + diastolic]/2), plasma glucose, triglycerides, total cholesterol and risk of BC overall, non-muscle invasive BC (NMIBC) and muscle invasive BC (MIBC). Among men, we additionally assessed additive interactions between metabolic factors and smoking on BC risk. During follow-up, 2,983 men and 754 women were diagnosed with BC. Among men, triglycerides and BP were positively associated with BC risk overall (hazard ratio [HR] per standard deviation [SD]: 1.17 [95% confidence interval (CI) 1.06-1.27] and 1.09 [1.02-1.17], respectively), and among women, BMI was inversely associated with risk (HR: 0.90 [0.82-0.99]). The associations for BMI and BP differed between men and women (pinteraction ≤ 0.005). Among men, BMI, cholesterol and triglycerides were positively associated with risk for NMIBC (HRs: 1.09 [95% CI 1.01-1.18], 1.14 [1.02-1.25], and 1.30 [1.12-1.48] respectively), and BP was positively associated with MIBC (HR: 1.23 [1.02-1.49]). Among women, glucose was positively associated with MIBC (HR: 1.99 [1.04-3.81]). Apart from cholesterol, HRs for metabolic factors did not significantly differ between MIBC and NMIBC, and there were no interactions between smoking and metabolic factors on BC. Our study supports an involvement of metabolic aberrations in BC risk. Whilst some associations were significant only in certain sub-groups, there were generally no significant differences in associations by smoking or tumor invasiveness.

Radio-guided sentinel lymph node detection and lymph node mapping in invasive urinary bladder cancer: a prospective clinical study.

OBJECTIVES: To investigate the possibility of detecting sentinel lymph nodes (SNs) in patients with urinary bladder cancer (BCa) intra-operatively and whether the histopathological status of the identified SNs reflected that of the lymphatic field. PATIENTS AND METHODS: We studied 103 patients with BCa pathological stage T1-T4 who were treated with cystectomy and pelvic lymph node (LN) dissection during 2005-2011 at the Department of Urology, Linköping University Hospital. Radioactive tracer Nanocoll 70 MBq and blue dye were injected into the bladder wall around the primary tumour before surgery. SNs were detected ex vivo during the operation with a handheld Geiger probe (Gamma Detection System; Neoprobe Corp., Dublin, OH, USA). All LNs were formalin-fixed, sectioned three times, mounted on slides and stained with haematoxylin and eosin. An experienced uropathologist evaluated the slides. RESULTS: The mean age of the patients was 69 years, and 80 (77%) were male. Pathological staging was T1-12 (12%), T2-20 (19%), T3-48 (47%) and T4-23 (22%). A mean (range) number of 31 (7-68) nodes per patient were examined, totalling 3 253 nodes. LN metastases were found in 41 patients (40%). SNs were detected in 83 of the 103 patients (80%). Sensitivity and specificity for detecting metastatic disease by SN biopsy (SNB) varied between LN stations, with average values of 67% and 90%, respectively. LN metastatic density (LNMD) had a significant prognostic impact; a value of ≥8% was significantly related to shorter survival. Lymphovascular invasion (LVI) occurred in 65% of patients (n = 67) and was significantly associated with shorter cancer-specific survival (P < 0.001). CONCLUSION: We conclude that SNB is not a reliable technique for peri-operative localization of LN metastases during cystectomy for BCa; however, LNMD has a significant prognostic value in BCa and may be useful in the clinical context and in BCa oncological and surgical research. LVI was also found to be a prognostic factor.

Fast-track access to urologic care for patients with macroscopic haematuria is efficient and cost-effective: results from a prospective intervention study.

BACKGROUND: The delay between onset of macroscopic haematuria and diagnosis of bladder cancer is often long. METHODS: We evaluated timely diagnosis and health-care costs for patients with macroscopic haematuria given fast-track access to diagnostics. During a 15-month period, a telephone hotline for fast-track diagnostics was provided in nine Swedish municipalities for patients aged ⩾50 years with macroscopic haematuria. The control group comprised 101 patients diagnosed with bladder cancer in the same catchment area with macroscopic haematuria who underwent regular diagnostic process. RESULTS: In all 275 patients who called 'the Red Phone' hotline were investigated, and 47 of them (17%) were diagnosed with cancer and 36 of those had bladder cancer. Median time from patient-reported haematuria to diagnosis was 29 (interquartile range (IQR) 14-104) days and 50 (IQR 27-165) days in the intervention and the control group, respectively (P=0.03). The median health-care costs were lower in the intervention group (655 (IQR 655-655) EUR) than in the control group (767 (IQR 490-1096) EUR) (P=0.002). CONCLUSIONS: Direct access to urologic expertise and fast-track diagnostics is motivated for patients with macroscopic haematuria to reduce diagnostic intervals and lower health-care expenditures.

Emmprin Expression Predicts Response and Survival following Cisplatin Containing Chemotherapy for Bladder Cancer: A Validation Study.

PURPOSE: Neoadjuvant chemotherapy before cystectomy is recommended. To our knowledge the subset of patients likely to benefit has not been identified. We validate emmprin and survivin as markers of chemotherapy response. MATERIALS AND METHODS: Tumor specimens were obtained before therapy from a total of 250 patients with T1-T4 bladder cancer enrolled in 2 randomized trials comparing neoadjuvant chemotherapy before cystectomy with a surgery only arm. Protein expression was determined by immunohistochemistry. RESULTS: Expression was categorized according to predefined cutoffs reported in the literature. Data were analyzed with the Kaplan-Meier method and Cox models. Patients in the chemotherapy cohort with negative emmprin expression had significantly higher down staging overall survival than those with positive expression (71% vs 38%, p<0.001). The values for cancer specific survival were 76% and 56%, respectively (p<0.027). In the cystectomy only cohort emmprin expression was not associated with overall survival (46% vs 35%, p=0.23) or cancer specific survival (55% vs 51%, p=0.64). Emmprin negative patients had an absolute risk reduction of 25% in overall survival (95% CI 11-40) and a number needed to treat of 4 (95% CI 2.5-9.3). Survivin expression was not useful as a biomarker in this study. Limitations were the retrospective design and heterogeneity coupled with the time difference between the trials. CONCLUSIONS: Patients with emmprin negative tumors have a better response to neoadjuvant chemotherapy before cystectomy than those with positive expression.

PET/CT versus conventional CT for detection of lymph node metastases in patients with locally advanced bladder cancer.

BACKGROUND: We studied patients treated with radical cystectomy for locally advanced bladder cancer to compare the results of both preoperative positron emission tomography/computed tomography (PET/CT) and conventional CT with the findings of postoperative histopathological evaluation of lymph nodes. METHODS: Patients who had bladder cancer and were candidates for cystectomy underwent preoperative PET/CT using 18-fluorodeoxyglucose (FDG) and conventional CT. The results regarding lymph node involvement were independently evaluated by two experienced radiologists and were subsequently compared with histopathology results, the latter of which were reassessed by an experienced uropathologist (HO). RESULTS: There were 54 evaluable patients (mean age 68 years, 47 [85%] males and 7 [15%] females) with pT and pN status as follows: < pT2-14 (26%), pT2-10 (18%), and > pT2-30 (56%); pN0 37 (69%) and pN+ 17 (31%). PET/CT showed positive lymph nodes in 12 patients (22%), and 7 of those cases were confirmed by histopathology; the corresponding results for conventional CT were 11 (20%) and 7 patients (13%), respectively. PET/CT had 41% sensitivity, 86% specificity, 58% PPV, and 76% NPV, whereas the corresponding figures for conventional CT were 41%, 89%, 64%, and 77%. Additional analyses of the right and left side of the body or in specified anatomical regions gave similar results. CONCLUSIONS: In this study, PET/CT and conventional CT had similar low sensitivity in detecting and localizing regional lymph node metastasis in bladder cancer.

5-Year outcome of a randomized prospective study comparing bacillus Calmette-Guérin with epirubicin and interferon-α2b in patients with T1 bladder cancer.

PURPOSE: In a multicenter, prospectively randomized study we evaluated the 5-year outcomes of bacillus Calmette-Guérin alone compared to a combination of epirubicin and interferon-α2b in the treatment of patients with T1 bladder cancer. MATERIALS AND METHODS: Transurethral resection was followed by a second resection and bladder mapping. Stratification was for grade and carcinoma in situ. Followup entailed regular cystoscopy and cytology during the first 5 years. The end points assessed in this analysis were recurrence-free survival, time to treatment failure and progression, cancer specific survival and prognostic factors. RESULTS: The study recruited 250 eligible patients. The 5-year recurrence-free survival rate was 38% in the combination arm and 59% in the bacillus Calmette-Guérin arm (p = 0.001). The corresponding rates for the other end points were not significantly different, as free of progression 78% and 77%, treatment failure 75% and 75%, and cancer specific survival 90% and 92%, respectively. The type of treatment, tumor size and tumor status at second resection were independent variables associated with recurrence. Concomitant carcinoma in situ was not predictive of failure of bacillus Calmette-Guérin therapy. An independent factor for treatment failure was remaining T1 stage at second resection. CONCLUSIONS: Bacillus Calmette-Guérin was more effective than the tested combination therapy. The currently recommended management with second resection and 3-week maintenance bacillus Calmette-Guérin entails a low risk of cancer specific death. More aggressive treatment in patients with infiltrative tumors at second resection might improve these results. In particular, concomitant carcinoma in situ was not a predictive factor for poor outcome after bacillus Calmette-Guérin therapy.

Shortened time to diagnosis for patients suspected of urinary bladder cancer managed in a standardized care pathway was associated with an improvement in tumour characteristics.

Objectives: To evaluate whether the implementation of standardized care pathway (SCP) for patients with suspected urinary bladder cancer (UBC) was associated with changes in tumour characteristics. Additionally, the study aims to explore whether there was a shift in the selection of patients prioritized for immediate evaluation regarding suspicion of UBC. Materials and Methods: The study included all patients diagnosed with UBC in the NU Hospital Group between 2010 and 2019. To evaluate changes associated with SCP, patients were divided into two diagnostic time periods, either before (2010-2015) or during (2016-2019) the implementation of the SCP. To evaluate which patients were prioritized for prompt evaluation within 13 days, logistic regression analysis was performed on all patients before and during SCP. Results: Median time to transurethral resection of the tumour in urinary bladder (TURBT) decreased from 29 days (interquartile range [IQR] 16-48) before SCP to 12 days (IQR 8-19) during SCP (p < 0.001) with a clear break from 2016. The proportion of cT2 + tumours decreased during SCP from 26% to 20% (p = 0.035). In addition, tumours detected during SCP were smaller (p = 0.023), but with more multiple lesions (p = 0.055) and G3 tumours (p = 0.007). During SCP, there was no statistically significant difference between the groups of patients with TURBT within or after 13 days. In contrast, before SCP, a majority of the patients treated within 13 days had advanced tumours and were admitted from the emergency ward. Conclusions: The implementation of an SCP for suspected UBC was associated with improved tumour characteristics. Interestingly, during SCP, there were no substantial differences in patients' or tumours' characteristics among those who underwent TURBT within or after 13 days. This indicates that the 13-day timeframe for TURBT might be prolonged, especially in less urgent cases in order to facilitate a prioritization of more severe cases with treatable disease.

A novel model of artificial intelligence based automated image analysis of CT urography to identify bladder cancer in patients investigated for macroscopic hematuria.

OBJECTIVE: To evaluate whether artificial intelligence (AI) based automatic image analysis utilising convolutional neural networks (CNNs) can be used to evaluate computed tomography urography (CTU) for the presence of urinary bladder cancer (UBC) in patients with macroscopic hematuria. METHODS: Our study included patients who had undergone evaluation for macroscopic hematuria. A CNN-based AI model was trained and validated on the CTUs included in the study on a dedicated research platform (Recomia.org). Sensitivity and specificity were calculated to assess the performance of the AI model. Cystoscopy findings were used as the reference method. RESULTS: The training cohort comprised a total of 530 patients. Following the optimisation process, we developed the last version of our AI model. Subsequently, we utilised the model in the validation cohort which included an additional 400 patients (including 239 patients with UBC). The AI model had a sensitivity of 0.83 (95% confidence intervals [CI], 0.76-0.89), specificity of 0.76 (95% CI 0.67-0.84), and a negative predictive value (NPV) of 0.97 (95% CI 0.95-0.98). The majority of tumours in the false negative group (n = 24) were solitary (67%) and smaller than 1 cm (50%), with the majority of patients having cTaG1-2 (71%). CONCLUSIONS: We developed and tested an AI model for automatic image analysis of CTUs to detect UBC in patients with macroscopic hematuria. This model showed promising results with a high detection rate and excessive NPV. Further developments could lead to a decreased need for invasive investigations and prioritising patients with serious tumours.

Diagnostic pathways and treatment strategies in upper tract urothelial carcinoma in Sweden between 2015 and 2021: a population-based survey.

OBJECTIVE: To report national data on diagnostics and treatment of upper tract urothelial carcinoma (UTUC) from the Swedish National Registry of Urinary Bladder Cancer (SNRUBC). PATIENTS AND METHODS: Data from 2015 to 2021 were retrieved, and descriptive analyses were performed regarding incidence, diagnostic modalities, preoperative tumor staging, quality indicators for treatment including the use of standardized care pathways (SCP) and multidisciplinary tumor boards (MDTB). Time trends were explored for the study period. RESULTS: Registrations included 1,213 patients with renal pelvic cancer and 911 patients with ureteric cancer with a median age of 74 (interquartile range [IQR] 70-77) and 75 (IQR 71-78) years, respectively. Incidence rates of UTUC were stable, as were proportions of curative treatment intent. Median number of days from referral to treatment was 76 (IQR 57-99) and 90 (IQR 72-118) days, respectively, for tumors of the renal pelvis and ureter, which remained unchanged after introduction of SCP in 2016. Noticeable trends included stable use of kidney-sparing surgery and increased use of MDTB. For radical nephroureterectomy (RNU), robot-assisted technique usage increased even for non-organ-confined tumors (cT3-4) and in one out of three patients undergoing RNU a bladder cuff excision was not registered. CONCLUSIONS: The population-based SNRUBC with high coverage contributes to the knowledge about UTUC with granular and generalizable data. The present study reveals a high proportion of patients not subjected to curatively intended treatment and suggests unmet needs to shorten lead times to treatment and use of bladder cuff excision when performing radical surgery for UTUC in Sweden.

Diagnostic value of repeated comprehensive investigation with CT urography and cystoscopy for recurrent macroscopic haematuria.

Objectives: To perform a descriptive analysis of a series of patients with recurrent macroscopic haematuria after a primary standard evaluation including computed tomography urography (CTU) and cystoscopy negative for urinary bladder cancer (UBC) and upper tract urothelial cancer (UTUC) and to identify potential factors associated with occurrence of recurrent macroscopic haematuria. Methods: All patients older than 50 years who underwent urological investigation for macroscopic haematuria with both cystoscopy and CTU 2015-2017 were retrospectively reviewed. A descriptive analysis of the primary and later investigations for recurrent macroscopic haematuria was performed. To investigate the association between explanatory variables and the occurrence of recurrent macroscopic haematuria, a Poisson regression analysis was performed. Results: A total of 1395 eligible individuals with primary standard investigation negative for UBC and UTUC were included. During a median follow-up of 6.2 (IQR 5.3-7) years, 248 (18%) patients had recurrent macroscopic haematuria, of whom six patients were diagnosed with UBC, two with prostate cancer, one with renal cell carcinoma and one had a suspected UTUC at the repeated investigation. Within 3 years, 148 patients (11%) experienced recurrent macroscopic haematuria, of whom two patients were diagnosed with low-grade UBC (TaG1-2), one with T2G3 UBC and one with low-risk prostate cancer. The presence of an indwelling catheter, use of antithrombotic medication, pathological findings at CTU or cystoscopy or history of pelvic radiotherapy were all statistically significant independent predictors for increased risk for recurrent macroscopic haematuria. Conclusion: In the case of recurrent macroscopic haematuria within 3 years of primary standard evaluation for urinary tract cancer, there was a low risk of later urological malignancies in patients initially negative for UBC and UTUC. Therefore, waiting 3 years before conducting another complete investigation in cases of recurrent macroscopic haematuria might be appropriate.

Treatment Related to Urinary Tract Infections Is Associated with Delayed Diagnosis of Urinary Bladder Cancer: A Nationwide Population-based Study.

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.

MDM2 SNP309 promoter polymorphism and p53 mutations in urinary bladder carcinoma stage T1.

BACKGROUND: Urinary bladder carcinoma stage T1 is an unpredictable disease that in some cases has a good prognosis with only local or no recurrence, but in others can appear as a more aggressive tumor with progression to more advanced stages. The aim here was to investigate stage T1 tumors regarding MDM2 promoter SNP309 polymorphism, mutations in the p53 gene, and expression of p53 and p16 measured by immunohistochemistry, and subsequently relate these changes to tumor recurrence and progression. We examined a cohort of patients with primary stage T1 urothelial carcinoma of the bladder and their tumors. METHODS: After re-evaluation of the original slides and exclusions, the study population comprised 141 patients, all with primary stage T1 urothelial carcinoma of the bladder. The hospital records were screened for clinical parameters and information concerning presence of histologically proven recurrence and progression. The paraffin-embedded tumor material was evaluated by immunohistochemistry. Any mutations found in the p53 gene were studied by single-strand conformation analysis and Sanger sequencing. The MDM2 SNP309 polymorphism was investigated by pyrosequencing. Multivariate analyses concerning association with prognosis were performed, and Kaplan-Meier analysis was conducted for a combination of changes and time to progression. RESULTS: Of the 141 patients, 82 had at least one MDM2 SNP309 G allele, and 53 had a mutation in the p53 gene, but neither of those anomalies was associated with a worse prognosis. A mutation in the p53 gene was associated with immunohistochemically visualized p53 protein expression at a cut-off value of 50%. In the group with p53 mutation Kaplan-Meier analysis showed higher rate of progression and shorter time to progression in patients with immunohistochemically abnormal p16 expression compared to them with normal p16 expression (p = 0.038). CONCLUSIONS: MDM2 SNP309 promoter polymorphism and mutations in p53 were not associated with worse prognosis in this cohort of patients with primary stage T1 urinary bladder carcinoma. However, patients with abnormal p16 expression and a mutated p53 gene had a higher rate of and a shorter time to progression, and p53 gene mutation was associated with an abnormal immunohistochemistry for p53 at a cut-off of 50%.

The emerging role of cell cycle protein p53 expression by tumor cells and M2-macrophage infiltration in urinary bladder cancer.

PURPOSE: To investigate the association between p53 expression in tumor cells and intratumoral macrophage infiltration in muscle-invasive urinary bladder cancer (MIBC) in relation to clinical and pathological variables and outcomes after radical cystectomy. METHODS: Tumor specimens of the primary tumor from patients treated with radical cystectomy for MIBC were immunostained with the M2-macrophage-specific marker CD163 and the cell cycle protein p53. The expression of these markers was analyzed in relation to patients´ and tumor characteristics and outcome. RESULTS: Out of 100 patients with urinary bladder cancer (UBC) pathological stage T1-4 N0-3 M0, 77% were men. The patients had a median age of 69 years and 80% had nonorgan-confined tumors (pT3-4). Lymph node metastasis was found in 42 (42%) of all patients. P53-positive expressions were found in 63 (63%) patients. Strong macrophage infiltration in the tumor microenvironment was shown in 74 (74%) patients. Combinations of CD163/p53 status were as follows: CD163+/p53+, 50%; CD163+/p53-, 24%; CD163-/p53+, 13%; and CD163-/p53-, 13%. Patients with CD163+/P53+ had higher proportions of organ-confined tumors. CONCLUSIONS: In the present series of patients with MIBC treated with cystectomy, we found that high CD163+ macrophage infiltration in the tumor micro-environment often was combined with p53+ cancer cells. This simultaneous expression of p53 by tumor cells and increased infiltration of M2-macrophages in the tumor microenvironment was associated with improved CSS, which might indicate a possible protective effect of M2 macrophages in p53+ tumors. Further investigations are needed to explore the biological relation between mutational burden and immune profile in MIBC.

A Validation Study of cT-Categories in the Swedish National Urinary Bladder Cancer Register-Norrland University Hospital.

BACKGROUND: In Sweden, all patients with urinary bladder cancer (UBC) are recorded in the Swedish National Register for Urinary Bladder Cancer (SNRUBC). The purpose of this study was to validate the registered clinical tumour categories (cT-categories) in the SNRUBC for Norrland University Hospital, Sweden, from 2009 to 2020, inclusive. METHODS: The medical records of all 295 patients who underwent radical cystectomy for the treatment of UBC were reviewed retrospectively. Possible factors impacting the cT-categories were identified. To optimise cT-classification, computed tomography urography of all patients with suspected tumour-associated hydronephrosis (TAH) or suspected tumour in bladder diverticulum (TIBD) were retrospectively reviewed by a radiologist. Discrepancy was tested with a logistic regression model. RESULTS: cT-categories differed in 87 cases (29.5%). Adjusted logistic regression analysis found TIBD and TAH as significant predictors for incorrect registration; OR = 7.71 (p < 0.001), and OR = 17.7, (p < 0.001), respectively. In total, 48 patients (68.6%) with TAH and 12 patients (52.2%) with TIBD showed discrepancy regarding the cT-category. Incorrect registration was mostly observed during the years 2009-2012. CONCLUSION: The study revealed substantial incorrect registration of cT-categories in SNRUBC. A major part of the misclassifications was related to TAH and TIBD. Registration of these variables in the SNRUBC might be considered to improve correct cT-classification.