Multiparametric Magnetic Resonance Imaging in the follow-up of non-muscle-invasive bladder tumors after intravesical instillations: a promising tool.

PURPOSE: The standard follow-up for non-muscle-invasive bladder cancer is based on cystoscopy. Unfortunately, post-instillation inflammatory changes can make the interpretation of this exam difficult, with lower specificity. This study aimed to evaluate the interest of bladder MRI in the follow-up of patients following intravesical instillation. METHODS: Data from patients who underwent cystoscopy and bladder MRI in a post-intravesical instillation setting between February 2020 and March 2023 were retrospectively collected. Primary endpoint was to evaluate and compare the diagnostic performance of cystoscopy and bladder MRI in the overall cohort (n = 67) using the pathologic results of TURB as a reference. The secondary endpoint was to analyze the diagnostic accuracy of cystoscopy and bladder MRI according to the appearance of the lesion on cystoscopy [flat (n = 40) or papillary (n = 27)]. RESULTS: The diagnostic performance of bladder MRI was better than that of cystoscopy, with a specificity of 47% (vs. 6%, p < 0.001), a negative predictive value of 88% (vs. 40%, p = 0.03), and a positive predictive value of 66% (vs. 51%, p < 0.001), whereas the sensitivity did not significantly differ between the two exams. In patients with doubtful cystoscopy and negative MRI findings, inflammatory changes were found on TURB in most cases (17/19). The superiority in MRI bladder performance prevailed for "flat lesions", while no significant difference was found for "papillary lesions". CONCLUSIONS: In cases of doubtful cystoscopy after intravesical instillations, MRI appears to be relevant with good performance in differentiating post-therapeutic inflammatory changes from recurrent tumor lesions and could potentially allow avoiding unnecessary TURB.

Machine-learning approach for prediction of pT3a upstaging and outcomes of localized renal cell carcinoma (UroCCR-15).

OBJECTIVES: To assess the impact of pathological upstaging from clinically localized to locally advanced pT3a on survival in patients with renal cell carcinoma (RCC), as well as the oncological safety of various surgical approaches in this setting, and to develop a machine-learning-based, contemporary, clinically relevant model for individual preoperative prediction of pT3a upstaging. MATERIALS AND METHODS: Clinical data from patients treated with either partial nephrectomy (PN) or radical nephrectomy (RN) for cT1/cT2a RCC from 2000 to 2019, included in the French multi-institutional kidney cancer database UroCCR, were retrospectively analysed. Seven machine-learning algorithms were applied to the cohort after a training/testing split to develop a predictive model for upstaging to pT3a. Survival curves for disease-free survival (DFS) and overall survival (OS) rates were compared between PN and RN after G-computation for pT3a tumours. RESULTS: A total of 4395 patients were included, among whom 667 patients (15%, 337 PN and 330 RN) had a pT3a-upstaged RCC. The UroCCR-15 predictive model presented an area under the receiver-operating characteristic curve of 0.77. Survival analysis after adjustment for confounders showed no difference in DFS or OS for PN vs RN in pT3a tumours (DFS: hazard ratio [HR] 1.08, P = 0.7; OS: HR 1.03, P > 0.9). CONCLUSIONS: Our study shows that machine-learning technology can play a useful role in the evaluation and prognosis of upstaged RCC. In the context of incidental upstaging, PN does not compromise oncological outcomes, even for large tumour sizes.

External validation of the computerized analysis of TRUS of the prostate with the ANNA/C-TRUS system: a potential role of artificial intelligence for improving prostate cancer detection.

PURPOSE: Prostate cancer (PCa) imaging has been revolutionized by the introduction of multi-parametric Magnetic Resonance Imaging (mpMRI). Transrectal ultrasound (TRUS) has always been considered a low-performance modality. To overcome this, a computerized artificial neural network analysis (ANNA/C-TRUS) of the TRUS based on an artificial intelligence (AI) analysis has been proposed. Our aim was to evaluate the diagnostic performance of the ANNA/C-TRUS system and its ability to improve conventional TRUS in PCa diagnosis. METHODS: We retrospectively analyzed data from 64 patients with PCa and scheduled for radical prostatectomy who underwent TRUS followed by ANNA/C-TRUS analysis before the procedure. The results of ANNA/C-TRUS analysis with whole mount sections from final pathology. RESULTS: On a per-sectors analysis, sensitivity, specificity, negative predictive value (NPV), positive predictive value (PPV) and accuracy were 62%, 81%, 80%, 64% and 78% respectively. The values for the detection of clinically significant prostate cancer were 69%, 77%, 88%, 50% and 75%. The diagnostic values for high grade tumours were 70%, 74%, 91%, 41% and 74%, respectively. Cancer volume (≤ 0.5 or greater) did not influence the diagnostic performance of the ANNA/C-TRUS system. CONCLUSIONS: ANNA/C-TRUS represents a promising diagnostic tool and application of AI for PCa diagnosis. It improves the ability of conventional TRUS to diagnose prostate cancer, preserving its simplicity and availability. Since it is an AI system, it does not hold the inter-observer variability nor a learning curve. Multicenter biopsy-based studies with the inclusion of an adequate number of patients are needed to confirm these results.

Efficacy of hyperthermic intravesical chemotherapy (HIVEC) in patients with non-muscle invasive bladder cancer after BCG failure.

PURPOSE: To evaluate hyperthermic intravesical chemotherapy (HIVEC) efficacy regarding 1-year disease-free survival (RFS) rate and bladder preservation rate in patients with non-muscle invasive bladder cancer (NMIBC) who fail bacillus Calmette-Guérin (BCG) therapy. METHODS: This is a multicenter retrospective series from a national database (7 expert centers). Between January 2016 and October 2021, patients treated with HIVEC for NMIBC who failed BCG have been included in our study. These patients had a theoretical indication for cystectomy but were ineligible for surgery or refused it. RESULTS: A total of 116 patients treated with HIVEC and with a follow-up > 6 months were included in this study and retrospectively analyzed. The median follow-up was 20.6 months. The 12 month-RFS (recurrence-free survival) rate was 62.9%. The bladder preservation rate was 87.1%. Fifteen patients (12.9%) progressed to muscle infiltration, three of them having a metastatic disease at the time of progression. Predictive factors of progression were T1 stage, high grade and very high-risk tumors according to the EORTC classification. CONCLUSION: Chemohyperthermia using HIVEC achieved an RFS rate of 62.9% at 1 year and enabled a bladder preservation rate of 87.1%. However, the risk of progression to muscle-invasive disease is not negligible, particularly for patients with very high-risk tumors. In these patients who fail BCG, cystectomy should remain the standard of care and HIVEC may be discussed cautiously for patients who are not eligible for surgery and well informed of the risk of progression.

Artificial intelligence to improve cytology performance in urothelial carcinoma diagnosis: results from validation phase of the French, multicenter, prospective VISIOCYT1 trial.

PURPOSE: Cytology and cystoscopy, the current gold standard for diagnosing urothelial carcinomas, have limits: cytology has high interobserver variability with moderate or not optimal sensitivity (particularly for low-grade tumors); while cystoscopy is expensive, invasive, and operator dependent. The VISIOCYT1 study assessed the benefit of VisioCyt® for diagnosing urothelial carcinoma. METHODS: VISIOCYT1 was a French prospective clinical trial conducted in 14 centers. The trial enrolled adults undergoing endoscopy for suspected bladder cancer or to explore the lower urinary tract. Participants were allocated either Group 1: with bladder cancer, i.e., with positive cystoscopy or with negative cystoscopy but positive cytology, or Group 2: without bladder cancer. Before cystoscopy and histopathology, slides were prepared for cytology and the VisioCyt® test from urine samples. The diagnostic performance of VisioCyt® was assessed using sensitivity (primary objective, 70% lower-bound threshold) and specificity (75% lower-bound threshold). Sensitivity was also assessed by tumor grade and T-staging. VisioCyt® and cytology performance were evaluated relative to the histopathological assessments. RESULTS: Between October 2017 and December 2019, 391 participants (170 in Group 1 and 149 in Group 2) were enrolled. VisioCyt®'s sensitivity was 80.9% (95% CI 73.9-86.4%) and specificity was 61.8% (95% CI 53.4-69.5%). In high-grade tumors, the sensitivity was 93.7% (95% CI 86.0-97.3%) and in low-grade tumors 66.7% (95% CI 55.2-76.5%). Sensitivity by T-staging, compared to the overall sensitivity, was higher in high-grade tumors and lower in low-grade tumors. CONCLUSION: VisioCyt® is a promising diagnostic tool for urothelial cancers with improved sensitivities for high-grade tumors and notably for low-grade tumors.

Oncocytoma on renal mass biopsy: is it still the same histology when surgery is performed? Results from UroCCR-104 study.

PURPOSE: To describe clinical features of patients with oncocytoma on renal biopsy (RMB), correlation with final histology on surgically treated patients, and predictive factors of discrepancy between RMB and final histology. METHODS: This was a retrospective study conducted in the framework of the UroCCR project (NCT03293563). All tumors with oncocytoma on RMB were selected and all pathological reports were reviewed. Patients with the RMB simultaneously performed with a focal treatment, synchronous bilateral tumors and ambiguous RMB report were excluded. Discrepancy between RMB and definitive histology was evaluated using a uni- and multivariable logistic regression analyses model. RESULTS: Overall, 119 tumors with oncocytoma on RMB, from 15 centers, were included. Of those, 54 (45.4%) had upfront surgery and 65 (54.6%) had active surveillance (AS). In renal masses with initial active surveillance, with a median follow-up of 28 months, 23 (19.3%) underwent surgery, 4 (3.4%) received focal treatment and 38 (31.9%) remained on AS. On final pathology, only 51 of the 75 surgically treated tumors (68.0%) had oncocytoma, while 24 presented malignant tumors (mainly chromophobe carcinoma (19.2%), and hybrid oncocytic/chromophobe tumor (HOCT) (6.8%)) leading to a discrepancy of 32.0% between RMB and final pathology. The only predictive factor of a discrepancy between RMB and definitive histology was a biopsy done outside of the center (Odds ratio: 3.22 [95%-confidence interval: 1.08-9.61], p = 0.03). CONCLUSION: Despite the increase of RMB in more and more centers, histologic discrepancy between RMB and definitive histology remains significant. This information should be discussed with patients and taken into consideration before treatment decision.

Nephrometry scores to predict oncological outcomes following partial nephrectomy (UroCCR Study 70).

PURPOSE: Partial nephrectomy (PN) for large or complex renal tumors can be difficult and associated with a higher risk of recurrence than radical nephrectomy. We aim to evaluate the clinical useful of nephrometry scores for predicting oncological outcomes in a large cohort of patients who underwent PN for renal cell carcinomas. METHODS: Our analysis included patients who underwent PN for renal cell carcinoma in 21 French academic centers (2010-2020). RENAL, PADUA, and SPARE scores were calculated based on preoperative imaging. Uni- and multivariate cox models were performed to identify predictors of recurrence-free survival and overall survival. The area under the curve (AUC) was used to identify models with the highest discrimination. Decision curve analyses (DCAs) determined the net benefit associated with their use. RESULTS: A total of 1927 patients were analyzed with a median follow-up of 32 months (14-45). RENAL score (p = 0.01), age (p = 0.002), histological type (p = 0.001), high nuclear grade (p = 0.001), necrotic component (p < 0.001), and positive margins (p = 0.005) were significantly related to recurrence in multivariate analyses. The discriminative performance of the 3 radiological scores was modest (65, 63, and 63%, respectively). All 3 scores showed good calibration, which, however, deteriorated with time. Decision curve analysis of the three models for the prediction of overall and recurrence-free survival was similar for all three scores and of limited clinical relevance. CONCLUSION: The association between nephrometry scores and oncological outcomes after NP is very weak. The use of these scores for predicting oncological outcomes in routine practice is therefore of limited clinical value.

A multicenter comparative matched-pair analysis of percutaneous tumor ablation and robotic-assisted partial nephrectomy of T1b renal cell carcinoma (AblatT1b study-UroCCR 80).

OBJECTIVE: Renal cell carcinomas represent the sixth- and tenth-most frequently diagnosed cancer in men and women. Recently, percutaneous-guided thermal ablations have proved to be as effective as partial nephrectomy and safer for treating small renal masses (i.e., < 3 cm). This study compared the perioperative and recurrence outcomes of percutaneous thermal ablation (TA) and robotic-assisted partial nephrectomy (RAPN) for the treatment of T1b renal cell carcinomas (4.1-7 cm). METHODS: Retrospective data from 11 centers on the national database, between 2010 and 2020, included 81 patients treated with thermal ablation (TA) and 308 patients treated with RAPN for T1b renal cell carcinoma, collected retrospectively and matched for tumor size, histology results, and the RENAL score. TA included cryoablation and microwave ablation. Endpoints compared the rate between the two groups: local recurrence, metastases, complications, renal function decrease, and length of hospitalization. RESULTS: After matching, 75 patients were included in each group; mean age was 76.6 (± 9) in the TA group and 61.1 (± 12) in the RAPN group, including 69.3% and 76% men respectively. The local recurrence (LR) rate was significantly higher in the TA group than in the PN group (14.6% vs 4%; p = 0.02). The LR rate was 20% (1/5) after microwave ablation, 11.1% (1/9) after radiofrequency ablation, and 14.7% (9/61) after cryoablation. The major complication rate (Clavien-Dindo ≥ 3) was higher following PN than after TA (5.3% vs 0%; p < 0.001). Metastases, eGFR decrease, and length of hospitalization did not differ significantly between the two groups. CONCLUSIONS: The local recurrence rate was significantly higher after thermal ablation; however, thermal ablation resulted in significantly lower rates of complications. Thermal ablation and robotic-assisted partial nephrectomy are effective treatments for T1b renal cancer; however, the local recurrence rate was higher after thermal ablation. KEY POINTS: • The local recurrence rate was significantly higher in the thermal ablation group than in the partial nephrectomy group. • The major complication rate (Clavien-Dindo ≥ 3) was higher following PN than after TA (5.3% vs. 0%; p < 0.001).

Nivolumab, nivolumab-ipilimumab, and VEGFR-tyrosine kinase inhibitors as first-line treatment for metastatic clear-cell renal cell carcinoma (BIONIKK): a biomarker-driven, open-label, non-comparative, randomised, phase 2 trial.

BACKGROUND: We previously reported a 35-gene expression classifier identifying four clear-cell renal cell carcinoma groups (ccrcc1 to ccrcc4) with different tumour microenvironments and sensitivities to sunitinib in metastatic clear-cell renal cell carcinoma. Efficacy profiles might differ with nivolumab and nivolumab-ipilimumab. We therefore aimed to evaluate treatment efficacy and tolerability of nivolumab, nivolumab-ipilimumab, and VEGFR-tyrosine kinase inhibitors (VEGFR-TKIs) in patients according to tumour molecular groups. METHODS: This biomarker-driven, open-label, non-comparative, randomised, phase 2 trial included patients from 15 university hospitals or expert cancer centres in France. Eligible patients were aged 18 years or older, had an Eastern Cooperative Oncology Group performance status of 0-2, and had previously untreated metastatic clear-cell renal cell carcinoma. Patients were randomly assigned (1:1) using permuted blocks of varying sizes to receive either nivolumab or nivolumab-ipilimumab (ccrcc1 and ccrcc4 groups), or either a VEGFR-TKI or nivolumab-ipilimumab (ccrcc2 and ccrcc3 groups). Patients assigned to nivolumab-ipilimumab received intravenous nivolumab 3 mg/kg plus ipilimumab 1 mg/kg every 3 weeks for four doses followed by intravenous nivolumab 240 mg every 2 weeks. Patients assigned to nivolumab received intravenous nivolumab 240 mg every 2 weeks. Patients assigned to VEGFR-TKIs received oral sunitinib (50 mg/day for 4 weeks every 6 weeks) or oral pazopanib (800 mg daily continuously). The primary endpoint was the objective response rate by investigator assessment per Response Evaluation Criteria in Solid Tumors version 1.1. The primary endpoint and safety were assessed in the population who received at least one dose of study drug. This trial is registered with ClinicalTrials.gov, NCT02960906, and with the EU Clinical Trials Register, EudraCT 2016-003099-28, and is closed to enrolment. FINDINGS: Between June 28, 2017, and July 18, 2019, 303 patients were screened for eligibility, 202 of whom were randomly assigned to treatment (61 to nivolumab, 101 to nivolumab-ipilimumab, 40 to a VEGFR-TKI). In the nivolumab group, two patients were excluded due to a serious adverse event before the first study dose and one patient was excluded from analyses due to incorrect diagnosis. Median follow-up was 18·0 months (IQR 17·6-18·4). In the ccrcc1 group, objective responses were seen in 12 (29%; 95% CI 16-45) of 42 patients with nivolumab and 16 (39%; 24-55) of 41 patients with nivolumab-ipilimumab (odds ratio [OR] 0·63 [95% CI 0·25-1·56]). In the ccrcc4 group, objective responses were seen in seven (44%; 95% CI 20-70) of 16 patients with nivolumab and nine (50% 26-74) of 18 patients with nivolumab-ipilimumab (OR 0·78 [95% CI 0·20-3·01]). In the ccrcc2 group, objective responses were seen in 18 (50%; 95% CI 33-67) of 36 patients with a VEGFR-TKI and 19 (51%; 34-68) of 37 patients with nivolumab-ipilimumab (OR 0·95 [95% CI 0·38-2·37]). In the ccrcc3 group, no objective responses were seen in the four patients who received a VEGFR-TKI, and in one (20%; 95% CI 1-72) of five patients who received nivolumab-ipilimumab. The most common treatment-related grade 3-4 adverse events were hepatic failure and lipase increase (two [3%] of 58 for both) with nivolumab, lipase increase and hepatobiliary disorders (six [6%] of 101 for both) with nivolumab-ipilimumab, and hypertension (six [15%] of 40) with a VEGFR-TKI. Serious treatment-related adverse events occurred in two (3%) patients in the nivolumab group, 38 (38%) in the nivolumab-ipilimumab group, and ten (25%) patients in the VEGFR-TKI group. Three deaths were treatment-related: one due to fulminant hepatitis with nivolumab-ipilimumab, one death from heart failure with sunitinib, and one due to thrombotic microangiopathy with sunitinib. INTERPRETATION: We demonstrate the feasibility and positive effect of a prospective patient selection based on tumour molecular phenotype to choose the most efficacious treatment between nivolumab with or without ipilimumab and a VEGFR-TKI in the first-line treatment of metastatic clear-cell renal cell carcinoma. FUNDING: Bristol Myers Squibb, ARTIC.

Artificial intelligence to improve cytology performances in bladder carcinoma detection: results of the VisioCyt test.

OBJECTIVE: To explore the utility of artificial intelligence (AI) using the VisioCyt® test (VitaDX International, Rennes, France) to improve diagnosis of bladder carcinoma using voided urine cytology. PATIENTS AND METHODS: A national prospective multicentre trial (14 centres) was conducted on 1360 patients, divided in two groups. The first group included bladder carcinoma diagnosis with different histological grades and stages, and the second group included control patients based on negative cystoscopy and cytology results. The first step of this VISIOCYT1 trial focussed on algorithm development and the second step on validating this algorithm. A total of 598 patients were included in this first step, 449 patients with bladder tumours (219 high-grade and 230 low-grade) and 149 as negative controls. The VisioCyt test was compared to voided urine cytology performed by experienced uro-pathologists from each centre. RESULTS: Overall sensitivity was highly improved by the VisioCyt test compared to cytology (84.9% vs 43%). For high-grade tumours the VisioCyt test sensitivity was 92.6% vs 61.1% for the uro-pathologists. Regarding low-grade tumours, VisioCyt test sensitivity was 77% vs 26.3% for the uro-pathologists. CONCLUSION: In comparison to routine cytology, the results of the first phase of the VISIOCYT1 trial show very clear progress in terms of sensitivity, which is particularly visible and interesting for low-grade tumours. If the validation cohort confirms these results, it could lead to the VisioCyt test being considered as a very useful aid for pathologists. Moreover, as this test is in fact software based on AI, it should become more and more efficient as more data are collected.

Essential elements of anaesthesia practice in ERAS programs.

PURPOSE: Enhanced recovery pathways vary amongst institutions but include key components for anesthesiologists, such as haemodynamic optimization, use of short-acting drugs (and monitoring), postoperative nausea and vomiting (PONV) prophylaxis, protective ventilation, and opioid-sparing multimodal analgesia. METHODS: After critical appraisal of the literature, studies were selected with particular attention being paid to meta-analyses, randomized controlled trials, and large prospective cohort studies. For each item of the perioperative treatment pathway, available English literature was examined and reviewed. RESULTS: Patients should be permitted to drink clear fluids up to 2 h before anaesthesia and surgery. Oral carbohydrate loading should be used routinely. All patients may have an individualized plan for fluid and haemodynamic management that matches the monitoring needs with patient and surgical risk. Minimizing the side effects of anaesthetics and analgesics using short-acting drugs with careful perioperative monitoring should be encouraged. Protective ventilation with alveolar recruitment maneuvers is required. Preventive use of a combination with 2-3 antiemetics in addition to propofol-based total intravenous anaesthesia (TIVA) is most likely to reduce PONV. While the ideal analgesia regimen remains to be determined, it is clear that a multimodal opioid-sparing analgesic strategy has significant benefits. CONCLUSION: Careful evaluation of single patient and planning of the anesthetic care are mandatory to join the ERAS philosophy. Optimal fluid management, use of short-acting drugs, prevention of PONV, protective ventilation, and multimodal analgesia are the cornerstones of the anaesthesia management within ERAS protocols.

Self-reported functional assessment after treatment for prostate cancer: 5-year results of the prospective cohort VICAN.

Objective: We aimed to assess the long-term association of therapeutic strategies with urinary, sexual function and health-related quality of life (HR-QoL) for 5-year prostate cancer (PC) survivors. Materials & methods: The VICAN survey consisted of self-reported data prospectively collected, including living conditions, treatment side effects and quality of life (QoL) of cancer survivors. Results: Among the 434 PC survivors, 52.8% reported urinary incontinence (UI) and 55.8% reported erectile dysfunction (ED). Patients treated with radical prostatectomy with salvage radiotherapy reported significantly more UI (p = 0.014) and more ED (p = 0.012) compared with other strategies. UI was significantly associated with physical and mental health-related QoL (p = 0.045 and p = 0.049, respectively). Conclusion: Self-assessed functional outcomes 5 years after PC diagnosis remain poor and could have an impact on health-related QoL.

Patients treated for prostate cancer may have long-term consequences due to the treatment they receive ­ in particular urinary incontinence (UI) and erectile dysfunction (ED). We analyzed self-reported data from 434 patients diagnosed with prostate cancer 5 years earlier, focusing especially on treatment side effects and the impact on patient quality of life. Of these patients, 52.8% reported UI and 55.8% reported ED. Patients treated with surgery plus radiotherapy reported significantly more UI and more ED compared with other treatment strategies. We have also shown that UI has an impact on physical and mental quality of life of these patients. In conclusion, functional recovery 5 years after prostate cancer diagnosis remains poor and requires implementation of new, long-term management strategies for cancer survivors.

Enhanced Recovery after Surgery for Radical Cystectomy Decreases Postoperative Complications at Different Times.

INTRODUCTION: This study aimed to assess whether enhanced recovery after surgery (ERAS) improves, at different time points, postoperative complications in patients undergoing radical cystectomy. METHODS: We performed a retrospective monocentric study using prospectively maintained databases including all patients treated by radical cystectomy between January 2015 and July 2019. An ERAS protocol was applied in all patients from February 2018. We analyzed and compared between non-ERAS and ERAS groups early and 90-day postoperative complications and 90-day readmission. ERAS was analyzed to know its implication in fast recovery improvement over time. RESULTS: A total of 150 patients underwent radical cystectomy, 74 without ERAS and 76 with ERAS protocol. ERAS decreased significantly early (p = 0.039) and 90-day (0.012) postoperative complications. In multivariate analysis, ERAS was an independent factor associated with less early (OR: 0.48, 95% CI: 0.25-0.96; p = 0.37) and 90-day (OR: 0.31, 95% CI: 0.14-0.68; p = 0.004) postoperative complications. There was no significant difference between groups for 90-day readmission (p = 0.349). Mean length of stay did not differ significantly between ERAS and non-ERAS groups (12.7 ± 6.2 and 13.1 ± 5.7 days, respectively; p = 0.743). DISCUSSION/CONCLUSION: Our study shows that ERAS has an early positive impact that lasts over time on postoperative complications. ERAS implementation has decreased early and 90-day postoperative complications without increasing 90-day readmission. In our cohort, length of stay was not improved with ERAS protocol.

Metastatic hormone sensitive prostate cancer: local treatment strategies.

PURPOSE: The landscape of the management of metastatic prostate cancer is changing rapidly and there is growing interest in the local treatment of the primary in these patients. The effect of local treatment on the outcome of metastatic prostate cancer patients was addressed based on retrospective analysis but now also based on prospective randomized trials. This article provides an overview of the currently available literature in this field. METHODS: A literature review was done searching the Medline database for English language articles using the keywords "metastatic prostate cancer", and "local treatment", "radiotherapy", "prostatectomy". The data of prospective randomized studies and the data of case-control studies or retrospective analysis were summarized in a narrative fashion. RESULTS: Data from two prospective randomized trials exploring the effect of local treatment of the prostate in hormone-sensitive metastatic prostate cancer showed no improvement of overall survival in the individual overall cohorts as well as in the pooled analysis (HR 0.92, 95% CI 0.81-1.04). There was an improvement of failure-free survival (pooled analysis HR 0.76, 95% CI 0.69-0.0.84). There was also an improved overall survival associated with radiotherapy in patients with < 5 metastases and with low volume disease. Data from prospective non-randomized or retrospective studies are inconclusive and underlies major selection biases. CONCLUSION: Based on prospective randomized trials, local treatment by radiotherapy does not improve the overall survival in unselected metastatic prostate cancer patients. An effect can be seen in low volume patients or patients with < 5 metastases.

PD-L1 expression and pattern of immune cells in pre-treatment specimens are associated with disease-free survival for HR-NMIBC undergoing BCG treatment.

PURPOSE: To assess the association between PD-L1 expression and disease-free survival (DFS) in High-Risk Non-Muscle Invasive Bladder Cancer (HR-NMIBC) patients treated with intravesical Bacillus Calmette-Guerin (BCG) instillations (IBI). METHODS: Retrospective study in five French centres between 2001 and 2015. Participants were 140 patients with histologically confirmed HR-NMIBC. All patients received induction and maintenance IBI. Pathological stage/grade, concomitant carcinoma in situ, lesion number and tumour size were recorded. CD3, CD8 and PD-L1 expression in tumour cells and in T cells in the tumour microenvironment (TME) was determined immunohistochemically. Median follow-up was 54.2 months. The primary outcome measure was DFS. Univariable and multivariable analyses were performed using the log rank test and Cox proportional hazards model. RESULTS: Of the 140 NMIBC, 52 (37.1%) were Ta, 88 (62.9%) were T1 and 100% were high grade. Median number of maintenance IBI was six (range 1-30). Twenty-five (17.9%) patients had recurrence/progression. In multivariable analysis, age (HR 1.07 [95% CI 1.02-1.13], p = 0.009), PD-L1 expression in tumour cells (HR per 10 units = 1.96 [95% CI 1.28-3.00], p = 0.02) and CD3/CD8 ratio (HR per 10 units = 3.38 [95% CI 1.61-7.11], p = 0.01) were significantly associated with DFS. However, using the cut-off corresponding for each PD-L1 antibodies, PD-L1 + status was not associated with DFS. CONCLUSION: Despite an association between PD-L1 expression and BCG failure in HR-NMIBC, the PD-L1 + status was not a prognostic factor in the response of BCG. Moreover, we confirmed the key role played by the IC within the microenvironment in BCG treatment. These findings highlighted the rationale to combine BCG and PD-L1/PD-1 antibodies in early bladder cancer.

Efficacy of HIVEC in patients with high-risk non-muscle invasive bladder cancer who are contraindicated to BCG and in patients who fail BCG therapy.

PURPOSE: To evaluate Hyperthermic-Intra-Vesical Chemotherapy (HIVEC) efficacy regarding 1-year disease-free survival (RFS) rate and bladder preservation rate in patients with High-risk Non-Muscle Invasive Bladder Cancer (NMIBC) who fail BCG therapy or are contraindicated to BCG. METHODS: Between June 2016 and October 2019, patients treated with HIVEC for mostly high-risk NMIBC who failed BCG or BCG-naive if BCG contraindicated have been included in our study. These patients had a theoretical indication for cystectomy but were ineligible for surgery or refused it. RESULTS: Fifty-three patients, median age 72 [39-93] years, were included in this study (n = 29 BCG-failure and n = 24 BCG-naive). The median follow-up was 18 months. The bladder preservation rate was 92.4%. The 12 months-RFS rate was 60.5%. The RFS rates for BCG-naive and BCG-failure groups were respectively 70% and 52.2% at 12 months. Three patients progressed to muscle infiltration, all in the BCG-failure group and all in the very high-risk EORTC group. Two of them developed metastatic disease and died from bladder cancer. CONCLUSION: Chemohyperthermia using HIVEC achieved a RFS rate of 60% at 1 year and enabled a bladder preservation rate of 92%. Given the low risk of progression in the BCG-naive group, HIVEC could be a good alternative. Conversely, for patients with very high-risk tumors that fail BCG, cystectomy should remain the standard of care and HIVEC may be discussed cautiously for patients who are not eligible for surgery and well informed of the risk of progression to muscle-invasive disease.

Comparison between Zumsteg classification and Briganti nomogram for the risk of lymph-node invasion before radical prostatectomy.

PURPOSE: To evaluate the performance of the Zumsteg classification to estimate the risk of lymph-node invasion (LNI) compared with the Briganti nomogram (BN) in prostatectomy patients with intermediate-risk prostate cancer (IRPC). METHODS: We included consecutive patients who had extended pelvic lymph-node dissection associated with radical prostatectomy for IRPC. To be classified favorable intermediate risk (FIR), patients could only have one intermediate-risk factor, fewer than 50% positive biopsies and no primary Gleason score of 4. RESULTS: On the 387 patients included, 149 (38.5%) and 238 (54.3%) were classified FIR and unfavorable intermediate risk (UIR), respectively, and 212 (54.8%) had a BN inferior to 5%. Thirty-eight patients (9.8%) had LNI: 6 FIR patients (4.0%) versus 32 UIR patients (13.4%) and 14 patients (6.6%) with a BN inferior to 5% versus 24 patients (13.7%) with a BN superior to 5%. Eight patients with a BN inferior to 5%, but classified UIR, had LNI. Sensitivity to detect LNI was higher with the Zumsteg classification than with the BN: 84.2% (CI 95% [68-93]) versus 63.2% (CI 95% [46-78]). Both screening tests were concordant to predict LNI (kappa coefficient of 0.076, p < 0.05 for Zumsteg and Briganti) CONCLUSIONS: Zumsteg classification appeared to be more sensitive and as effective (despite the impossibility to make decision curve analysis) than the BN to estimate the risk of LNI. Regarding the modest number of pN+ patients, further studies are needed to see the interest of proposing ePLND for UIR patients only.

Extent of positive surgical margins following radical prostatectomy: impact on biochemical recurrence with long-term follow-up.

BACKGROUND: To assess the prognostic value of the extent of positive surgical margins (PSM) following radical prostatectomy (RP) on biochemical recurrence (BR) with long-term follow-up. METHODS: This retrospective study analyzed 1275 RPs performed between January 1992 and December 2013 in two university centers in Marseille (France). The inclusion criteria were: follow-up > 24 months, undetectable postoperative prostate-specific antigen (PSA), no seminal vesicle (SV) invasion, no lymph node invasion confirmed by surgery (pN0) or imaging (pNx), and no neoadjuvant or adjuvant treatment. BR was defined by PSA level ≥ 0.2 ng/mL on two successive samples. We included 189 patients, divided into two groups: - Focal PSM (fPSM): single PSM (sPSM) ≤3 mm; - Extensive PSM (ePSM): sPSM with linear length > 3 mm or several margins regardless of the length. RESULTS: The median follow-up was 101 months (18-283) and the median age was 63 years (46-76). BR occurred in only 12.1% (14/115) of cases involving fPSM and in 54.1% (40/74) of cases involving ePSM. In the multivariate model, ePSM patients were significantly associated with increased BR compared to fPSM (hazard ratio [HR] = 6.11; 95% confidence interval [CI] = 3.25-11.49). The ePSM significantly decreased BR-free survival (p < 0.001) for every patient and every subgroup (pT2, pT3a, pG ≤6, and pG ≥7). The median BR time following RP was significantly shorter for ePSM patients than fPSM (57.2 vs. 89.2 months p < 0.001). CONCLUSION: With a median 8-year follow-up, ePSM was strongly associated with BR compared to fPSM. Therefore, it seems legitimate to monitor patients with fPSM. In cases of ePSM, adjuvant treatment appears effective.

Development of immunotherapy in bladder cancer: present and future on targeting PD(L)1 and CTLA-4 pathways.

PURPOSE: Over the past 3 decades, no major treatment breakthrough has been reported for advanced bladder cancer. Recent Food and Drug Administration (FDA) approval of five immune checkpoint inhibitors in the management of advanced bladder cancer represent new therapeutic opportunities. This review examines the available data of the clinical trials leading to the approval of ICIs in the management of metastatic bladder cancer and the ongoing trials in advanced and localized settings. METHODS: A literature search was performed on PubMed and ClinicalTrials.gov combining the MeSH terms: 'urothelial carcinoma' OR 'bladder cancer', and 'immunotherapy' OR 'CTLA-4' OR 'PD-1' OR 'PD-L1' OR 'atezolizumab' OR 'nivolumab' OR 'ipilimumab' OR 'pembrolizumab' OR 'avelumab' OR 'durvalumab' OR 'tremelimumab'. Prospectives studies evaluating anti-PD(L)1 and anti-CTLA-4 monoclonal antibodies were included. RESULTS: Evidence-data related to early phase and phase III trials evaluating the 5 ICIs in the advanced urothelial carcinoma are detailed in this review. Anti-tumour activity of the 5 ICIs supporting the FDA approval in the second-line setting are reported. The activity of PD(L)1 inhibitors in the first-line setting in cisplatin-ineligible patients are also presented. Ongoing trials in earlier disease-states including non-muscle-invasive and muscle-invasive bladder cancer are discussed. CONCLUSIONS: Blocking the PD-1 negative immune receptor or its ligand, PD-L1, results in unprecedented rates of anti-tumour activity in patients with metastatic urothelial cancer. However, a large majority of patients do not respond to anti-PD(L)1 drugs monotherapy. Investigations exploring the potential value of predictive biomarkers, optimal combination and sequences are ongoing to improve such treatment strategies.