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Introduction and objectives: The goals of transurethral resection of a bladder tumor (TUR) are to completely resect the lesions and to make a correct diagnosis in order to adequately stage the patient. It is well known that the presence of detrusor muscle in the specimen is a prerequisite to minimize the risk of under staging. Persistent disease after resection of bladder tumors is not uncommon and is the reason why the European Guidelines recommended a re-TUR for all T1 tumors. It was recently published that when there is muscle in the specimen, re-TUR does not influence progression or cancer specific survival. We present here the patient and tumor factors that may influence the presence of residual disease at re-TUR. Material and methods: In our retrospective cohort of 2451 primary T1G3 patients initially treated with BCG, pathology results for 934 patients (38.1%) who underwent re-TUR are available. 74% had multifocal tumors, 20% of tumors were more than 3 cm in diameter and 26% had concomitant CIS. In this subgroup of patients who underwent re-TUR, there was no residual disease in 267 patients (29%) and residual disease in 667 patients (71%): Ta in 378 (40%) and T1 in 289 (31%) patients. Age, gender, tumor status (primary/recurrent), previous intravesical therapy, tumor size, tumor multi-focality, presence of concomitant CIS, and muscle in the specimen were analyzed in order to evaluate risk factors of residual disease at re-TUR, both in univariate analyses and multivariate logistic regressions. Results: The following were not risk factors for residual disease: age, gender, tumor status and previous intravesical chemotherapy. The following were univariate risk factors for presence of residual disease: no muscle in TUR, multiple tumors, tumors >= 3 cm, and presence of concomitant CIS. Due to the correlation between tumor multi-focality and tumor size, the multivariate model retained either the number of tumors or the tumor diameter (but not both), p < 0.001. The presence of muscle in the specimen was no longer significant, while the presence of CIS only remained significant in the model with tumor size, p < 0.001. Conclusions: The most significant factors for a higher risk of residual disease at re-TUR in T1G3 patients are multifocal tumors and tumors more than 3 cm. Patients with concomitant CIS and those without muscle in the specimen also have a higher risk of residual disease. (C) 2021 AEU. Published by Elsevier Espana, S.L.U. All rights reserved.

Purpose: Improved risk stratification and predictive biomarkers of treatment response are needed for non-muscle-invasive bladder cancer (NMIBC). Here we assessed the clinical utility of targeted RNA and DNA molecular profiling in NMIBC. Experimental Design: Gene expression in NMIBC samples was profiled by NanoString nCounter, an RNA quantification platform, from two independent cohorts (n = 28, n = 50); targeted panel sequencing was performed in a subgroup (n = 50). Gene signatures were externally validated using two RNA sequencing datasets of NMIBC tumors (n = 438, n = 73). Established molecular subtype classifiers and novel gene expression signatures were assessed for associations with clinicopathologic characteristics, somatic tumor mutations, and treatment outcomes. Results: Molecular subtypes distinguished between low-grade Ta tumors with FGFR3 mutations and overexpression (UROMOL-class 1) and tumors with more aggressive clinicopathologic characteristics (UROMOL-classes 2 and 3), which were significantly enriched with TERT promoter mutations. However, UROMOL subclasses were not associated with recurrence after bacillus Calmette-Guérin (BCG) immunotherapy in two independent cohorts. In contrast, a novel expression signature of an inflamed tumor microenvironment (TME) was associated with improved recurrence-free survival after BCG. Expression of immune checkpoint genes (PD-L1/PD-1/CTLA-4) was associated with an inflamed TME, but not with higher recurrence rates after BCG. FGFR3 mutations and overexpression were both associated with low immune signatures. Conclusions: Assessment of the immune TME, rather than molecular subtypes, is a promising predictive biomarker of BCG response. Modulating the TME in an immunologically “cold” tumor warrants further investigation. Integrated transcriptomic and exome sequencing should improve treatment selection in NMIBC.

Intra-operative hypotension is a known predictor of adverse events and poor outcomes following major surgery. Hypotension often occurs on induction of anaesthesia, typically attributed to hypovolaemia and the haemodynamic effects of anaesthetic agents. We assessed the efficacy of fluid optimisation for reducing the incidence of hypotension upon anaesthesia induction. This prospective protocol enrolled 283 patients undergoing radical cystectomy and randomised them to goal-directed fluid therapy (n = 142) or standard fluid therapy (n = 141). Goal-directed fluid therapy patients received fluid optimisation based on stroke volume response to passive leg raise before induction; those with positive passive leg raise received intravenous crystalloid fluid boluses until stroke volume was optimised. Baseline mean arterial pressure was measured on the morning of surgery and upon operating room arrival. This post-hoc analysis defined haemodynamic instability as either a > 30% relative drop in mean arterial pressure compared to baseline or absolute mean arterial pressure < 55 mmHg, within 15 minutes of induction. Forty-two (30%) goal-directed fluid therapy patients underwent fluid optimisation after finding an intravascular fluid deficit via passive leg raise testing; 106 (75%) goal-directed fluid therapy and 112 (79%) standard fluid therapy patients met criteria for haemodynamic instability. There was no significant difference in haemodynamic instability incidence between the goal-directed fluid therapy and standard fluid therapy groups using absolute mean arterial pressure drop below 55 mmHg (p=0.58) or using pre-surgical testing or pre-surgical mean arterial pressure values as baseline (p = 0.21, p = 0.89); however, the difference in haemodynamic instability incidence was significant using the operating room baseline mean arterial pressure (p = 0.004). We conclude that fluid optimisation before induction of general anaesthesia did not significantly impact haemodynamic instability.

Purpose: The goals of transurethral resection of a bladder tumor (TUR) are to completely resect the lesions and to make a correct diagnosis to adequately stage and treat the patient. Persistent disease after TUR is not uncommon and is why re-TUR is recommended in T1G3 patients. When there is T1 tumor in the re-TUR specimen, very high risks of progression (82%) have been reported. We analyze the risks of recurrence, progression to muscle-invasive disease and cancer-specific mortality (CSM) according to tumor stage at re-TUR in T1G3 patients treated with BCG. Methods: In our retrospective cohort of 2451 T1G3 patients, 934 patients (38.1%) underwent re-TUR. 667 patients had residual disease (71.4%): Ta in 378 (40.5%), T1 in 289 (30.9%) patients. Times to recurrence, progression and CSM in the three groups were estimated using cumulative incidence functions and compared using the Cox regression model. Results: During a median follow-up of 5.2 years, 512 patients recurred. The recurrence rate was significantly higher in patients with a T1 at re-TUR (P < 0.001). Progression rates differed according to the pathology at re-TUR, 25.3% in T1, 14.6% in Ta and 14.2% in case of no residual tumor (P < 0.001). Similar trends were seen in both patients with and without muscle in the original TUR specimen. Conclusions: Patients with T1G3 tumors and no residual disease or Ta at re-TUR have better recurrence, progression and CSM rates than previously reported, with a CSM rate of 13.1 and a 25.3% progression rate in re-TUR T1 disease. © 2018, Springer-Verlag GmbH Germany, part of Springer Nature.

Purpose: To evaluate the oncological impact of postponing radical cystectomy (RC) to allow further conservative therapies prior to progression in a large multicentre retrospective cohort of T1-HG/G3 patients initially treated with BCG. Methods: According to the time of RC, the population was divided into 3 groups: patients who did not progress to muscle-invasive disease, patients who progressed before radical cystectomy and patients who experienced progression at the time of radical cystectomy. Clinical and pathological outcomes were compared across the three groups. Results: Of 2451 patients, 509 (20.8%) underwent RC. Patients with tumors > 3 cm or with CIS had earlier cystectomies (HR = 1.79, p = 0.001 and HR = 1.53, p = 0.02, respectively). Patients with tumors > 3 cm, multiple tumors or CIS had earlier T3/T4 or N + cystectomies. In patients who progressed, the timing of cystectomy did not affect the risk of T3/T4 or N + disease at RC. Patients with T3/T4 or N + disease at RC had a shorter disease-specific survival (HR = 4.38, p < 0.001), as did patients with CIS at cystectomy (HR = 2.39, p < 0.001). Patients who progressed prior to cystectomy had a shorter disease-specific survival than patients for whom progression was only detected at cystectomy (HR = 0.58, p = 0.024) Conclusions: Patients treated with RC before experiencing progression to muscle-invasive disease harbor better oncological and survival outcomes compared to those who progressed before RC and to those upstaged at surgery. Tumor size and concomitant CIS at diagnosis are the main predictors of surgical treatment while tumor size, CIS and tumor multiplicity are associated with extravesical disease at surgery. © 2018, Springer-Verlag GmbH Germany, part of Springer Nature.

Background Potential differences in efficacy of different bacillus Calmette-Guérin (BCG) strains are of importance for daily practice, especially in the era of BCG shortage. Objective To retrospectively compare the outcome with BCG Connaught and BCG TICE in a large study cohort of pT1 high-grade non–muscle-invasive bladder cancer patients. Design, setting, and participants Individual patient data were collected for 2,451 patients with primary T1G3 tumors from 23 centers who were treated with BCG for the first time between 1990 and 2011. Outcome measurements and statistical analysis Using Cox multivariable regression and adjusting for the most important prognostic factors in this nonrandomized comparison, BCG Connaught and TICE were compared for time to recurrence, progression, and the duration of cancer specific survival and overall survival. Results and limitations Information on the BCG strain was available for 2,099 patients: 957 on Connaught and 1,142 on TICE. Overall, 765 (36%) patients received some form of maintenance BCG, 560 (59%) on Connaught and 205 (18%) on TICE. Without maintenance, Connaught was more effective than TICE only for the time to first recurrence (hazard ratio [HR] = 1.48; 95% CI: 1.20–1.82; P

Objectives: To determine if a re-transurethral resection (TUR), in the presence or absence of muscle at the first TUR in patients with T1-high grade (HG)/Grade 3 (G3) bladder cancer, makes a difference in recurrence, progression, cancer specific (CSS) and overall survival (OS). Patients and methods: In a large retrospective multicentre cohort of 2451 patients with T1-HG/G3 initially treated with bacille Calmette–Guérin, 935 (38%) had a re-TUR. According to the presence or absence of muscle in the specimen of the primary TUR, patients were divided in four groups: group 1 (no muscle, no re-TUR), group 2 (no muscle, re-TUR), group 3 (muscle, no re-TUR) and group 4 (muscle, re-TUR). Clinical outcomes were compared across the four groups. Results: Re-TUR had a positive impact on recurrence, progression, CSS and OS only if muscle was not present in the primary TUR specimen. Adjusting for the most important prognostic factors, re-TUR in the absence of muscle had a borderline significant effect on time to recurrence [hazard ratio (HR) 0.67, P = 0.08], progression (HR 0.46, P = 0.06), CSS (HR 0.31, P = 0.07) and OS (HR 0.48, P = 0.05). Re-TUR in the presence of muscle in the primary TUR specimen did not improve the outcome for any of the endpoints. Conclusions: Our retrospective analysis suggests that re-TUR may not be necessary in patients with T1-HG/G3, if muscle is present in the specimen of the primary TUR. © 2015 The Authors BJU International © 2015 BJU International Published by John Wiley & Sons Ltd

Background: Potential differences in efficacy of different bacillus Calmette-Guerin (BCG) strains are of importance for daily practice, especially in the era of BCG shortage. Objective: To retrospectively compare the outcome with BCG Connaught and BCG TICE in a large study cohort of pT1 high-grade non muscle-invasive bladder cancer patients. Design, setting, and participants: Individual patient data were collected for 2,451 patients with primary T1G3 tumors from 23 centers who were treated with BCG for the first time between 1990 and 2011. Outcome measurements and statistical analysis: Using Cox multivariable regression and adjusting for the most important prognostic factors in this nonrandomized comparison, BCG Connaught and TICE were compared for time to recurrence, progression, and the duration of cancer specific survival and overall survival. Results and limitations: Information on the BCG strain was available for 2,099 patients: 957 on Connaught and 1,142 on TICE. Overall, 765 (36%) patients received some form of maintenance BCG, 560 (59%) on Connaught and 205 (18%) on TICE. Without maintenance, Connaught was more effective than TICE only for the time to first recurrence (hazard ratio [HR] = 1.48; 95% CI: 1.20-1.82; P < 0.001). With maintenance, TICE was more effective than Connaught for the time to first recurrence (HR = 0.66; 95% CI: 0.47-0.93; P = 0.019) with a trend for cancer specific survival (HR = 0.36; 95% CI: 0.14-0.92; P = 0.033). For time to progression and overall survival, Connaught and TICE had a similar efficacy. Compared to no maintenance therapy, maintenance BCG significantly reduced the risk of recurrence, progression and death, both overall, and disease specific, for TICE, but not for Connaught. Conclusions: We found that BCG Connaught results in a lower recurrence rate as compared with BCG TICE when no maintenance is used. However, the opposite is true when maintenance is given. Patient summary: As there is currently a BCG shortage, information on the efficacy of different BCG strains is important. In this nonrandomized retrospective comparison in over 2,000 patients, we found that BCG Connaught reduces the recurrence rate compared to BCG TICE when no maintenance is used, but the opposite is true when maintenance is given. (C) 2016 Elsevier Inc. All rights reserved.

Introduction and Objectives: The impact of prognostic factors in T1G3 patients (pts) is critical for proper treatment decision making, however most available data are from small series of pts. The aim of the current study is to assess prognostic factors in a large group of pts who received BCG as initial treatment of T1G3 tumours and identify a subgroup of high risk pts who should be considered for early cystectomy. Patients and Methods: Individual pt data were collected for 1743 ptsfrom 20 centers who received induction or maintenance BCG between 1990 and 2008. Using Cox regression analysis, the prognostic importance of the following variables were assessed for time to recurrence, progression to muscle invasive disease and overall survival:age (70yrs), gender, primary T1G3 vs. recurrent T1G3 after previous non T1G3 tumour, tumour size (3 cm), multiplicity (single vs. multiple), concomitant CIS (no/yes), and maintenance BCG (no/yes). Results: Median age was 68yrs, 84% were male, 89% were primary T1G3, 50% had multifocal disease, 67% had tumours less than 3 cm, 24% had concomitant CIS, 30% had a restaging TUR, 52% received some sort of maintenance BCG. With a follow up out to 15 years, 801 pts (46%) recurred, 326 (19%) progressed, 291 underwent cystectomy (17%) and 409 (23%) died, 151 (9%) due to bladder cancer. In multivariate analyses, the most important prognostic factors (p70, size >3 cm and presence of CIS. Progression free rates at 10 yrs were 84%, 75%, 66% and 28% for patients with 0, 1, 2 and 3 bad factors while the corresponding overall survival rates were 78%, 56%, 45% and 6%, respectively. Conclusion: T1G3 patients treated with BCG have a heterogeneous prognosis, with overall survival at 10 yrs ranging from 78% to 6%. Although maintenance BCG improves outcome as compared to induction alone, fit pts over 70 yrs of age with tumours greater than 3 cm and concomitant CIS should be considered for an early cystectomy.

Background The impact of prognostic factors in T1G3 non-muscle-invasive bladder cancer (BCa) patients is critical for proper treatment decision making. Objective To assess prognostic factors in patients who received bacillus Calmette-Guérin (BCG) as initial intravesical treatment of T1G3 tumors and to identify a subgroup of high-risk patients who should be considered for more aggressive treatment. Design, setting, and participants Individual patient data were collected for 2451 T1G3 patients from 23 centers who received BCG between 1990 and 2011. Outcome measurements and statistical analysis Using Cox multivariable regression, the prognostic importance of several clinical variables was assessed for time to recurrence, progression, BCa-specific survival, and overall survival (OS). Results and limitations With a median follow-up of 5.2 yr, 465 patients (19%) progressed, 509 (21%) underwent cystectomy, and 221 (9%) died because of BCa. In multivariable analyses, the most important prognostic factors for progression were age, tumor size, and concomitant carcinoma in situ (CIS); the most important prognostic factors for BCa-specific survival and OS were age and tumor size. Patients were divided into four risk groups for progression according to the number of adverse factors among age ≥70 yr, size ≥3 cm, and presence of CIS. Progression rates at 10 yr ranged from 17% to 52%. BCa-specific death rates at 10 yr were 32% in patients ≥70 yr with tumor size ≥3 cm and 13% otherwise. Conclusions T1G3 patients ≥70 yr with tumors ≥3 cm and concomitant CIS should be treated more aggressively because of the high risk of progression. Patient summary Although the majority of T1G3 patients can be safely treated with intravesical bacillus Calmette-Guérin, there is a subgroup of T1G3 patients with age ≥70 yr, tumor size ≥3 cm, and concomitant CIS who have a high risk of progression and thus require aggressive treatment. © 2014 European Association of Urology.

Context: Intravesical bacillus Calmette-Guerin (BCG) is a standard conservative treatment for patients with high-risk non-muscle-invasive bladder cancer (NMIBC). Many patients will experience recurrence or progression following BCG and are termed BCG failures. Objective: To summarise the current treatment options available for patients with high-risk NMIBC who experience BCG failure. Evidence acquisition: We searched the Medline, Embase, and Cochrane Trials databases for studies of BCG failure using predetermined relevant Medical Subject Heading terms and free text terms. Evidence synthesis: Radical cystectomy (RC) should be strongly recommended when a patient has been deemed to fail BCG, if the patient is fit and fully informed of the risks, benefits, and quality-of-life issues. RC achieves long-term survival in excess of 90% with ongoing improvements in morbidity. While other salvage intravesical therapies have to be considered oncologically inferior to RC, several options are now available if bladder preservation is the objective. The options can be categorised as immunotherapy, chemotherapy, device-assisted therapy, and sequential combinations of these newer modalities with conventional therapy. Some agents have shown specific promise in BCG-failure patients (eg, gemcitabine, thermochemotherapy, taxane chemotherapy), and some modalities have been shown to be effective only in non-BCG-failure cohorts (eg, electromotive mitomycin). Conclusions: The definition, prediction, and treatment of BCG failure remain unclear secondary to inconsistent studies and the heterogeneous entity of patients with NMIBC. RC should be the default position upon failing BCG, but if bladder preservation is sought, then several promising intravesical salvage options are available. It will be necessary to individually tailor the management of such patients based on tumour risk and medical profiles. Currently data are still inadequate to formulate definitive recommendations, and larger studies of salvage intravesical agents are urgently required. (C) 2012 European Association of Urology. Published by Elsevier B. V. All rights reserved.