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In the current era of immune checkpoint inhibitors (ICIs), the role and optimal timing of a nephrectomy in patients with metastatic renal cell carcinoma (mRCC) remain unknown.To assess the oncological outcomes of patients who responded to ICI-based treatments and were subsequently treated with a delayed nephrectomy.This national retrospective evaluation included 30 patients with mRCC who underwent a nephrectomy after a complete response (CR) or a major partial response (80%) to ICI treatment at metastatic sites.Partial or radical nephrectomy after a favorable response to ICI treatment.Disease-free survival (DFS), progression-free survival (PFS), overall survival (OS), and potential discontinuation of systemic treatment were assessed.ICI-based treatments included ipilimumab-nivolumab (40%), ICI + tyrosine kinase inhibitor (10%), and nivolumab (50%). A delayed nephrectomy was performed after a median ICI treatment duration of 10 mo. In 19 cases (63.3%), surgeons faced difficulties due to adhesions or inflammatory changes. A complete pathological response was observed in 16.7% of patients. After a median follow-up of 19.5 mo after nephrectomy, 76.7% of patients achieved DFS. At 1 yr, 66.7% of patients were free from systemic treatment. The PFS and OS rates were, respectively, 96.7% and 100% at 1 yr, and 78.3% and 86.1% at 2 yr. Patients with a CR at metastatic sites had a better prognosis than those with a major partial response, in terms of DFS (p = 0.022) and PFS (p = 0.014).Despite potentially challenging surgery, a delayed nephrectomy for patients who responded to ICI treatment provided promising oncological outcomes, and the majority of patients could discontinue systemic treatment.In this study, we evaluated the clinical outcome in patients who responded well to immunotherapy, and subsequently underwent kidney ablation surgery. Three-quarters of patients experienced no recurrence, and in most cases, medical treatment could be discontinued.

Supplementary Figure from Escherichia coli–Specific CXCL13-Producing TFH Are Associated with Clinical Efficacy of Neoadjuvant PD-1 Blockade against Muscle-Invasive Bladder Cancer

Biomarkers guiding the neoadjuvant use of immune-checkpoint blockers (ICB) are needed for patients with localized muscle-invasive bladder cancers (MIBC). Profiling tumor and blood samples, we found that follicular helper CD4+ T cells (TFH) are among the best therapeutic targets of pembrolizumab correlating with progression-free survival. TFH were associated with tumoral CD8 and PD-L1 expression at baseline and the induction of tertiary lymphoid structures after pembrolizumab. Blood central memory TFH accumulated in tumors where they produce CXCL13, a chemokine found in the plasma of responders only. IgG4+CD38+ TFH residing in bladder tissues correlated with clinical benefit. Finally, TFH and IgG directed against urothelium-invasive Escherichia coli dictated clinical responses to pembrolizumab in three independent cohorts. The links between tumor infection and success of ICB immunomodulation should be prospectively assessed at a larger scale.Significance:In patients with bladder cancer treated with neoadjuvant pembrolizumab, E. coli–specific CXCL13 producing TFH and IgG constitute biomarkers that predict clinical benefit. Beyond its role as a biomarker, such immune responses against E. coli might be harnessed for future therapeutic strategies.This article is highlighted in the In This Issue feature, p. 2221

Relationship between GPR126 mutation status and standard clinical pathological and biological parameters in bladder cancer

Survival curves of two patients groups according to GPR126 overexpression status in the series of 59 MIBC. x-axes represents the time (months). y-axes represents A : Recurrence-free-survival ; B: Overall survival. p=value is the result of log-rank test.

Resume Introduction L’information transmise au diagnostic de Tumeur de vessie non infiltrant le muscle (TVNIM) est variable. Or, les patients bien informes sont plus impliques dans les decisions partagees. L’objectif de cette etude etait d’evaluer l’information percue par le patient au moment du diagnostic de TVNIM. Materiel La cohorte francaise VICAN consiste en un echantillon representatif de 4174 patients pris en charge pour un cancer et survivants a 5 ans. Les donnees reportees par les patients ont ete collectees prospectivement par entretiens telephoniques et auto-questionnaires. Parmi les 118 patients pris en charge pour une TVNIM, le terme utilise au diagnostic pour definir la pathologie et l’impact sur la qualite de vie (questionnaires SF12, EORTC-QLQ-C30 et echelle HAD) et sur l’observance (suivi cystoscopique a 1 an selon les donnees du SNIIR-AM) ont ete evalues. Resultats Seuls 26,8 % des patients ont declare avoir entendu le terme “Cancer” a l’annonce du diagnostic de TVNIM. A l’inverse, 73,2 % d’entre eux ont reporte l’utilisation d’autres termes, incluant “Tumeur” (22,0 %), “Polype” (24,8 %) et “Carcinome” (17,1 %). Il n’y avait pas de difference en termes de qualite de vie, physique et mentale, ni d’anxiete ressentie, en fonction du terme utilise. L’observance etait significativement meilleure chez les patients pour qui le mot « Cancer » a ete utilise. Conclusion Trois quarts des patients ayant une TVNIM n’avaient pas integre la notion de “Cancer” au diagnostic. La terminologie utilisee au diagnostic n’influence pas la qualite de vie mais semble impacter l’observance et l’adhesion aux protocoles de soins. Niveau de preuve 3.

CIS of the bladder is associated with a high risk of progression. In the case of BCG failure, radical cystectomy should be performed. For patients who refuse or are ineligible, bladder-sparing alternatives are evaluated. This study aims to investigate the efficacy of Hyperthermic IntraVesical Chemotherapy (HIVEC) depending on the presence or absence of CIS. This retrospective, multicenter study was conducted between 2016 and 2021. Patients with non-muscle-invasive bladder cancer (NMIBC) with BCG failure received 6–8 adjuvant instillations of HIVEC. The co-primary endpoints were recurrence-free survival (RFS) and progression-free survival (PFS). A total of 116 consecutive patients met our inclusion criteria of whom 36 had concomitant CIS. The 2-year RFS rate was 19.9% and 43.7% in patients with and without CIS, respectively (p = 0.52). Fifteen patients (12.9%) experienced progression to muscle-invasive bladder cancer with no significant difference between patients with and without CIS (2-year PFS rate = 71.8% vs. 88.8%, p = 0.32). In multivariate analysis, CIS was not a significant prognostic factor in terms of recurrence or progression. In conclusion, CIS may not be considered a contraindication to HIVEC, as there is no significant association between CIS and the risk of progression or recurrence after treatment.

International audience; Purpose: Curative radio-chemotherapy is recognized as a standard treatment option for muscle-invasive bladder cancer (MIBC). Nevertheless, the technical aspects for MIBC radiotherapy are heterogeneous with a lack of practical recommendations.Methods and materials: In 2018, a workshop identified the need for two cooperative groups to develop consistent, evidence-based guidelines for irradiation technique in the delivery of curative radiotherapy. Two radiation oncologists performed a review of the literature addressing several topics relative to radical bladder radiotherapy: planning computed tomography acquisition, target volume delineation, radiation schedules (total dose and fractionation) and dose delivery (including radiotherapy techniques, image-guided radiotherapy (IGRT) and adaptive treatment modalities). Searches for original and review articles in the PubMed and Google Scholar databases were conducted from January 1990 until March 2020. During a meeting conducted in October 2020, results on 32 topics were presented and discussed with a working group involving 15 radiation oncologists, 3 urologists and one medical oncologist. We applied the American Urological Association guideline development's method to define a consensus strategy.Results: A consensus was obtained for all 34 except 4 items. The group did not obtain an agreement on CT enhancement added value for planning, PTV margins definition for empty bladder and full bladder protocols, and for pelvic lymph-nodes irradiation. High quality evidence was shown in 6 items; 8 items were considered as low quality of evidence.Conclusion: The current recommendations propose a homogenized modality of treatment both for routine clinical practice and for future clinical trials, following the best evidence to date, analyzed with a robust methodology. The XXX group formulates practical guidelines for the implementation of innovative techniques such as adaptive radiotherapy.

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.

The management of metastatic renal cell carcinoma (mRCC) is evolving rapidly. In the era of antiangiogenic treatments, the Carmena trial showed no benefit of upfront cytoreductive nephrectomy compared to sunitinib alone for patients with intermediate or poor prognosis. The Surtime trial suggests that deferred nephrectomy after initiation of systemic therapy may be a better strategy. In the current era of immune checkpoint inhibitors, the role and optimal timing of nephrectomy is still unknown. Delayed nephrectomy after response to systemic therapy seems to be an interesting approach, especially for residual kidney disease in patients with radiological complete response at metastatic sites, and may achieve good oncological outcomes in selected patients. However, due to the technical complexity and complication rates, post-immunotherapy surgery should be performed in expert centres. Surgery could also be integrated into the management of mRCC metastases and surgical resection may be discussed in selected cases.

International audience; 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.

International audience; 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.

Summary Objective. - To update French guidelines for the management of bladder cancer specifically non-muscle invasive (NMIBC) and muscle-invasive bladder cancers (MIBC). Methods. - A Medline search was achieved between 2018 and 2020, notably regarding diagnosis, options of treatment and follow-up of bladder cancer, to evaluate different references with levels of evidence. Results. - Diagnosis of NMIBC (Ta, T1, CIS) is based on a complete deep resection of the tumor. The use of fluorescence and a second-look indication are essential to improve initial diagnosis. Risks of both recurrence and progression can be estimated using the EORTC score. A stratification of patients into low, intermediate and high risk groups is pivotal for recommending adjuvant treatment: instillation of chemotherapy (immediate post-operative, standard schedule) or intravesical BCG (standard schedule and maintenance). Cystectomy is recommended in BCG-refractory patients. Extension evaluation of MIBC is based on contrast-enhanced pelvic-abdominal and thoracic CT-scan. Multiparametric MRI can be an alternative. Cystectomy associated with extended lymph nodes dissection is considered the gold standard for non-metastatic MIBC. It should be preceded by cisplatin-based neoadjuvant chemotherapy in eligible patients. An orthotopic bladder substitution should be proposed to both male and female patients with no contraindication and in cases of negative frozen urethral samples; otherwise transileal ureterostomy is recommended as urinary diversion. All patients should be included in an Early Recovery After Surgery (ERAS) protocol. For metastatic MIBC, first-line chemotherapy using platin is recommended (GC or MVAC), when performans status (PS 60 mL/min) allow it (only in 50% of cases). In second line treatment, immunotherapy with pembrolizumab demonstrated a significant improvement in overall survival. Conclusion. - These updated French guidelines will contribute to increase the level of urological care for the diagnosis and treatment of patients diagnosed with NMIBC and MIBC.

summary Introduction. –The purpose was to propose an update of the French guidelines from the national committee ccAFU on upper tract urothelial carcinomas (UTUC). Methods. – A systematic Medline search was performed between 2018 and 2020, as regards diagnosis, options of treatment and follow-up of UTUC, to evaluate different references with levels of evidence. Results. – The diagnosis of this rare pathology is based on CT-scan acquisition during excretion and ureteroscopy with histological biopsies. Radical nephroureterectomy (RNU) remains the gold standard for surgical treatment, nevertheless a conservative endoscopic approach can be proposed for low risk lesion: unifocal tumor, possible complete resection and low grade and absence of invasion on CT-scan. Close monitoring with endoscopic follow-up (flexible ureteroscopy) in compliant patients is therefore necessary. After RNU, bladder instillation of chemotherapy is recommended to reduce risk of bladder recurrence. A systemic chemotherapy is recommended after RNU in pT2–T4 N0–3 M0 disease. Conclusion. – These updated guidelines will contribute to increase the level of urological care for diagnosis and treatment for UTUC.

This study evaluated the prognostic value of a panel of 29 oncogenes derived from the analysis of The Cancer Genome Atlas (TCGA data) or from the recent literature on bladder tumors on a well-characterized series of muscle-invasive bladder cancer (MIBC) and non-MIBC (NMIBC) samples and tried to identify molecular prognostic markers. Mutations of HRAS, FGFR3, PIK3CA and TERT were found in 2.9%, 27.2%, 14.9% and 76.7% of tumor samples, respectively. Concerning NMIBC, on multivariate analysis, RXRA and FGFR3 levels were associated with recurrence-free survival (RFS) (p = 0.0022 and p = 0.0069) and RXRA level was associated with progression to muscle-invasive disease (p = 0.0068). We identified a 3-gene molecular signature associated with NMIBC prognosis. FGFR3 overexpression was associated with reduced response to Bacillus Calmette–Guerin treatment (p = 0.037). As regards MIBC, on multivariate analysis, ERCC2 overexpression was associated with RFS (p = 0.0011) and E2F3 and EGFR overexpression were associated with overall survival (p = 0.014 and p = 0.035). RT-PCR findings were confirmed by IHC for FGFR3. Genomic alterations in MIBC revealed in TCGA data also concern NMIBC and seem to be associated with prognosis in terms of recurrence and progression. Correcting these alterations by targeted therapies seems a promising pharmacological approach.

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. 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. 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. 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.

Resume Introduction La thermo-chimiotherapie par HIVEC® est encore peu evaluee. Chez les patients refractaires au BCG, elle pourrait constituer une alternative a la cystectomie. L’objectif de notre etude etait d’evaluer la tolerance de l’HIVEC® chez les patients pris en charge pour une TVNIM refractaire ou contre-indiquee au BCG. Materiel Entre janvier 2017 et avril 2018, 22 patients pris en charge pour une TVNIM refractaire ou contre indiquee au BCG ont ete inclus dans notre etude. Le traitement a consiste en 6 instillations hebdomadaires de Mitomycine® chauffee a 43 °c. La tolerance du traitement a ete evaluee prospectivement a chaque instillation a l’aide d’un questionnaire (effets secondaires et IPSS). Resultats Parmi les 22 patients inclus, aucun n’a presente d’effet secondaire severe. Les effets secondaires mineurs etaient : imperiosites mictionnelles (40,1 %), brulures mictionnelles (40,1 %), hematurie macroscopique (4,5 %). Il n’y avait pas de difference significative en termes d’IPSS pre- et post-instillations (IPSS moyen : 10,8 versus 10,1, p = 0,77). Apres un suivi moyen de 11,2 mois, le taux de recidive etait de 27,3 % avec un delai moyen avant recidive de l’ordre de 7,36 mois. Deux patients (9,1 %) ont presente une progression vers l’infiltration musculaire. Quatre patients (18,2 %) ont finalement ete operes d’une cystectomie. Conclusion La thermo-chimiotherapie par HIVEC® est d’administration simple et bien toleree. Dans cette sous-population de patients refractaires, le taux de recidive a 1 an etait de 27,3 %. Ces donnees preliminaires meritent d’etre confirmees par des etudes prospectives multicentriques.

Simple Summary The goal of precision medicine is to deliver therapy matched to a relevant actionable genetic alteration (AGA) identified in the tumor. Few data are available regarding precision medicine in advanced urological cancers (AUC), the prognosis of which remains unfavorable. Sixty-four patients with refractory AUC were enrolled in the PERMED-01 clinical trial and underwent a tumor biopsy that was then profiled using sophisticated molecular analyses. The results were discussed in real-time during a weekly molecular tumor board meeting, and patients with a relevant AGA became candidates for an eventual matched therapy. A complete molecular profile was obtained in 77% of cases and an AGA was identified in 59%. Nineteen percent of patients received a matched therapy on progression, of which 42% showed a clinical benefit. The objective response, disease control rates, and the 6-year overall survival were higher in the ``matched therapy group'' than in the ``non-matched therapy group''. Introduction. The prognosis of advanced urological cancers (AUC) remains unfavorable, and few data are available regarding precision medicine. Methods: the PERMED-01 prospective clinical trial assessed the impact of molecular profiling in adults with refractory advanced solid cancer, in terms of number of patients with tumor actionable genetic alterations (AGA), feasibility, description of molecular alterations, treatment, and clinical outcome. We present here those results in the 64 patients enrolled with AUC. DNA extracted from a new tumor biopsy was profiled in real-time (targeted NGS, whole-genome array-comparative genomic hybridization), and the results were discussed during a weekly molecular tumor board meeting. Results: a complete molecular profile was obtained in 49 patients (77%). Thirty-eight (59%) had at least one AGA. Twelve (19%) received a matched therapy on progression, of which 42% had a PFS2/PFS1 ratio >= 1.3 versus 5% in the ``non-matched therapy group'' (n = 25). The objective response and disease control rates were higher in the ``matched therapy group'' (33% and 58%, respectively) than in the ``non-matched therapy group'' (13% and 22%), as was the 6-month OS (75% vs. 42%). Conclusion: the profiling of a newly biopsied tumor sample identified AGA in 59% of patients with AUC, led to ``matched therapy'' in 19%, and provided clinical benefit in 8%.

Biomarkers guiding the neoadjuvant use of immune-checkpoint blockers (ICB) are needed for patients with localized muscle-invasive bladder cancers (MIBC). Profiling tumor and blood samples, we found that follicular helper CD4+ T cells (TFH) are among the best therapeutic targets of pembrolizumab correlating with progression-free survival. TFH were associated with tumoral CD8 and PD-L1 expression at baseline and the induction of tertiary lymphoid structures after pembrolizumab. Blood central memory TFH accumulated in tumors where they produce CXCL13, a chemokine found in the plasma of responders only. IgG4+CD38+ TFH residing in bladder tissues correlated with clinical benefit. Finally, TFH and IgG directed against urothelium-invasive Escherichia coli dictated clinical responses to pembrolizumab in three independent cohorts. The links between tumor infection and success of ICB immunomodulation should be prospectively assessed at a larger scale. Significance: In patients with bladder cancer treated with neoadjuvant pembrolizumab, E. coli–specific CXCL13 producing TFH and IgG constitute biomarkers that predict clinical benefit. Beyond its role as a biomarker, such immune responses against E. coli might be harnessed for future therapeutic strategies. This article is highlighted in the In This Issue feature, p. 2221

Docetaxel has been shown to be an effective chemotherapy agent when combined with androgen deprivation therapy for hormone sensitive metastatic prostate cancer (CaP). Since very high risk CaP has a high rate of occult metastatic disease and early recurrence, we hypothesize that patients with very high risk locally advanced CaP may benefit from docetaxel-based neoadjuvant chemohormonal therapy (NCHT). Thus, we conducted a retrospective study to identify the outcome of these patients treated with NCHT followed by radical prostatectomy (RP).We retrospectively analyzed data from 177 consecutive patients who had very high risk locally advanced CaP between March 2014 and July 2017. Patients received 3 different therapies: (i) 60 men in NCHT group, (ii) 73 men in neoadjuvant hormonal therapy (NHT) group, and (iii) 44 men received immediate RP without neoadjuvant therapy (No-NT group). Surgical outcomes were analyzed and survival differences were compared by the Kaplan-Meier method.The NCHT group had statistically significant higher preoperative Prostate-Specific Antigen (PSA) (P0.002), higher Gleason score (P0.002), and more advanced clinical stage (P0.001) than other groups. After RP, 81% (42/52) of patients in NCHT group, 73% (51/70) of patients in NHT group, and 48% (21/44) of patients in No-NT group achieved an undetectable PSA (P0.001). A total of 14% (6/42) patients achieving a postoperative undetectable PSA experienced biochemical recurrence in the NCHT group, with median biochemical progression-free survival (bPFS) time of 19 months; 47% (24/51) experienced biochemical recurrence in the NHT group, with median bPFS time of 13 months; 81% (17/21) experienced biochemical recurrence in the No-NT group, with median bPFS time of 9 months (P0.001). The median follow-up time of 3 groups was 12.5 months in the NCHT group, 18.3 months in the NHT group, and 22.8 months in the No-NT group (P = 0.01).Despite having poorer prognostic factors, the NCHT group had better bPFS time after surgery compared to NHT and No-NT groups. Randomized controlled investigations are needed to validate these results and further follow-up is required for survival endpoints.

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).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.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.

OBJECTIVES The aim of our study was to assess the impact of blue light cystoscopy with hexaminolevulinate on residual tumor rates at second-look transurethral resection of the bladder (TURB). MATERIAL AND METHODS Among all patients undergoing TURB in our center between 2012 and 2017, 52 patients had a second-look after a first complete TURB with a delay

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

Numerous pangenomic studies identified protein-coding genes and signaling pathways involved in bladder carcinogenesis. However, noncoding somatic alterations remain unexplored. A recent study revealed a mutational hotspot in intron 6 of GPR126 gene in 2.7% of a large breast cancer series. As GPR126 is highly expressed in bladder tissues, we investigated here the prevalence and the prognostic significance of these mutations in bladder cancer. We analyzed a cohort of 103 bladder cancers including 44 nonmuscle-invasive bladder cancers (NMIBC) and 59 muscle-invasive bladder cancers (MIBC). GPR126 mutations were analyzed by high-resolution melting and Sanger sequencing, and GPR126 expression levels were assessed using real-time quantitative RT-PCR. In NMIBC, somatic GPR126 noncoding mutations occurred in 47.7% of samples and were negatively associated with GPR126 mRNA levels. GPR126 mutations had higher frequencies in nonsmoker patients and were associated with a prior history of NMIBC. GPR126 overexpression was detected in 70.5% of samples. GPR126 mutation and overexpression status were not associated with outcome. In MIBC, somatic GPR126 mutations occurred in 44.1% of samples. Mutations were more frequent in females. GPR126 overexpression was detected in 27.1% of the sample. A trend toward significance was observed between GPR126 overexpression and better outcome. We identified the second most frequent mutational hotspot after TERT promoter (∼70%) in bladder cancer, with a mutation rate of approximately 50%. Implications: The GPR126 intronic mutational hotspot could be a promising clinical biomarker candidate to monitor tumor burden using circulating tumor DNA in bladder cancer.

Introduction: Digestive metastases (DMs) from renal cell cancer (RCC) are rare. Over the past decade, the overall survival of metastatic RCC (mRCC) has been improved by tyrosine kinase inhibitors (TKIs) and immune checkpoint inhibitors. The main objective of this study was to assess the incidence of metastases of the digestive tract in this new field of treatment. The secondary objectives were to evaluate the clinical characteristics, prognosis, treatments used for DMs, and median time between the diagnosis of RCC or mRCC and DMs.Materials and Methods: A retrospective analysis of data collected from all patients with mRCC between 2007 (the time of TKI was a standard of care) and 2019 was carried out at the Paoli-Calmettes Institute (Marseille, France). Computer research software using artificial intelligence (ConSoRe®) was used to identify patients and assess their characteristics.Results: Between January 2007 and December 2019, 11 out of 660 (1.6%) mRCC patients had metastases of the gastrointestinal tract. The median age was 62 years. Of the 11 patients, 81.8% experienced digestive bleeding or anemia. Only 2 patients were asymptomatic. The metastases were mainly duodenal (50%) and gastric (41.6%). The median time from cancer diagnosis and from metastatic disease to gastrointestinal metastasis was 4.3 years (3 months−19.2 years) and 2.25 years (0 days−10.2 years), respectively. Local treatment was performed in 38.5% of cases by endoscopy (60%), surgery (20%) and radiotherapy (40%) with success rates of 33, 100, and 50%, respectively. Etiological treatment was modified following the discovery of DM in 84.6% of the cases. The median survival was 1 year from the diagnosis of DM (13 days−9.4 years). Two patients were still alive 2.9 and 9.4 years after the diagnosis of DM.Conclusion: This is the largest monocentric retrospective analysis of DM in patients with RCC. It seems to be a rare and late event in the course of the disease. Local treatment combined with systemic treatment could improve survival. In the context of prolonged survival with the new based immunotherapy treatments in mRCC, we suggest that unexplained anemia or persistent digestive symptoms could be explored by endoscopy.

BACKGROUND Sarcopenia is suspected to influence the complication rates in patients undergoing radical cystectomy (RC). The aim of our study was to assess variations in sarcopenia in patients scheduled for neoadjuvant cisplatin-based chemotherapy (NAC) and RC for muscle invasive bladder cancer (MIBC) and to explore the impact of sarcopenia on complications linked to NAC or surgery. METHODS Between 2012 and 2017, 82 consecutive patients who underwent NAC and RC for cT2-T4 N0 MIBC were retrospectively selected. Using CT scan before and after NAC, Lumbar Skeletal Muscle Index (SMI) was assessed by two observers. We defined severe sarcopenia as SMI

Objectifs L’etude aUROre vise a decrire les caracteristiques et la prise en charge de patients atteints de cancer renal avance ou metastatique non prealablement traite, en fonction de l’expression de PD-L1. Dans ce cadre, une etude exploratoire de concordance inter-observateur de l’evaluation du statut PD-L1 a ete realisee sur une cohorte de 250 patients selectionnes dans la base de donnees clinico-biologique nationale du reseau UroCCR ( http ://www.uroccr.fr ). Methodes A partir du tissu tumoral colore avec l’anticorps PD-L1 SP142, trois pathologistes–dont deux formateurs dans l’evaluation PD-L1, ci-apres « experts » – ont determine independamment le statut PD-L1 (pourcentage de surface occupee par des cellules immunitaires exprimant PD-L1 – seuil de positivite ≥ 1 %). Une phase d’evaluation a porte sur 60 cas, suivie d’une 2e phase sur 190 cas apres concertation entre les pathologistes. Les objectifs sont de mesurer la concordance du statut PD-L1 entre pathologistes sur les 190 cas (coefficients de Kappa [+ 95 % IC]) et d’evaluer l’impact de la concertation a la fin de la 1ere phase sur le taux de concordance de la 2e. Resultats Sur les 190 cas, 179 sont consideres evaluables par les 3 pathologistes ( Tableau 1 ). Une concordance parfaite entre les 3 pathologistes est observee pour 123 cas (68,7 % ; Kappa de Fleiss de 0,58 [0,49–0,67], Tableau 2 ). La concordance est plus elevee entre les 2 experts (88,3 %, Kappa de Cohen de 0,77 [0,67–0,86]) qu’entre ceux de niveaux de formation differents (73,2 % [0,47 (0,35–0,59)] et 76,0 % [0,52 (0,41–0,64)]). La comparaison avec les 60 premiers cas (57 evaluables) montre une nette amelioration de la concordance sur le statut PD-L1 (+35,0 %), et du coefficient de concordance (+123 % [0,26 (0,09–0,43), Kappa de Fleiss]). Cette amelioration est plus elevee entre pathologistes de niveaux de formations differents (+236 % [0,14 (0,02–0,26)] et +77 % [0,30 (0,08–0,52)]) qu’entre les 2 experts (+45 % [0,53 (0,33–0,72)]). Conclusion La concordance inter-observateur est moderee a elevee (Landis, 1977 ; Fleiss, 1981) et croit avec le niveau de formation des pathologistes. Une nette amelioration est observee apres concertation entre pathologistes, particulierement pour le moins entraines. Ces resultats confortent la necessite de formations adaptees et du partage d’experience entre anatomopathologistes pour l’interpretation optimale du statut PD-L1 dans les echantillons tumoraux.

Objectifs Dans certaines indications imperatives, le traitement focal peut etre discute pour des tumeurs de plus de 4 cm. L’objectif de notre etude etait d’evaluer les resultats fonctionnels et oncologiques de la cryoablation percutanee pour tumeurs malignes de stade T1b (≥ 4 cm) en situation imperative. Methodes Il s’agit d’une etude retrospective multicentrique a partir des patients traites par cryoablation TDM-guidee percutanee entre 2013 et 2018. Les patients pris en charge pour une indication imperative (definie par au moins un des criteres suivants : rein unique, patients comorbides non eligibles a la chirurgie, fonction renale alteree), avec une tumeur maligne histologiquement prouvee mesurant entre 4,1 et 7,0 cm ont ete identifies. Nous avons analyse les taux d’efficacite (definie sur les criteres IRM a 1 mois), la survie sans progression (SSP), les complications (selon la classification de Clavien–Dindo) et la perte fonctionnelle renale (estimee par le debit de filtration glomerulaire [DFG]). Resultats Vingt-trois patients consecutifs ont ete inclus. Le diametre tumoral moyen etait de 45,6 ± 6,2 mm. Le score RENAL moyen etait de 8,1 ± 1,8. Le taux d’efficacite de la technique etait de 86,3 %, et de 100 % apres retraitement. Trois patients avec un resultat initial incomplet ont ete traites avec succes par une deuxieme cryoablation. La SSP etait de 85,7 % a 6 mois, 66,7 % a 12 mois et 66,7 % a 24 mois. Un patient avec une recidive locale a 12 mois a ete traite par nephrectomie elargie. Le taux de complications etait de 4,3 % (1 complication de grade ≥ II). La perte moyenne de DFG etait de 4,4 ± 8,5 ml/min/1,73 m2, avec une diminution significativement plus importante en cas de tumeur centro-hilaire (p Conclusion La cryoablation des tumeurs renales de stade T1b est techniquement faisable, avec un faible taux de complications et des Resultats fonctionnels favorables. D’un point de vue oncologique, 2/3 des patients sont sans recidive a 2 ans. Des etudes a plus long terme sont necessaires pour confirmer ces resultats.