Photodynamic cystoscopy for bladder cancer diagnosis and for NMIBC follow-up: An overview of systematic reviews and meta-analyses.

INTRODUCTION: Currently, bladder cancer detection is based on cytology and cystoscopy. White light cystoscopy (WLC) is an invasive procedure and may under-detect flat lesions. Blue light cystoscopy (BLC) and narrow band imaging (NBI) cystoscopy are new modalities that could improve the detection of non-muscle invasive bladder cancer (NMIBC) and its recurrence or progression to muscle invasive bladder cancer. We present a systematic review on BLC and NBI cystoscopy for bladder cancer diagnosis and NMIBC follow-up. MATERIAL AND METHODS: All available systematic reviews and meta-analyses on cystoscopy published in PubMed® between May 2010 and March 2021 were identified and reviewed. The main endpoints were clinical performance for bladder cancer diagnosis and for recurrence or progression detection during NMIBC follow-up, and additional value compared with cytology and/or WLC. RESULTS: Most of the meta-analyses and systematic reviews published suggest a better sensitivity of BLC and NBI cystoscopy compared to WLC, particularly for the detection of flat lesions (CIS). NBI- and BLC-guided TURBT could decrease the recurrence rates. However, their clinical utility to reduce progression rate and increase survival is still unclear. CONCLUSIONS: BLC and NBI cystoscopy are efficient techniques for bladder cancer diagnosis and NMIBC follow-up. However, their clinical benefit remains to be confirmed.

French AFU Cancer Committee Guidelines - Update 2022-2024: Non-muscle-invasive bladder cancer (NMIBC).

OBJECTIVE: To update the ccAFU recommendations for the management of bladder tumours that do not infiltrate the bladder muscle (NBMIC). METHODS: A systematic review (Medline) of the literature from 2020 to 2022 was performed, taking account of the diagnosis, treatment options and surveillance of NMIBC, while evaluating the references with their levels of evidence. RESULTS: The diagnosis of NMIBC (Ta, T1, CIS) is made after complete full-thickness tumour resection. The use of bladder fluorescence and the indication of a second look (4-6 weeks) help to improve the initial diagnosis. The EORTC score is used to assess the risk of recurrence and/or tumour progression. Through the stratification of patients in low, intermediate and high-risk categories, adjuvant treatment can be proposed: intravesical chemotherapy (immediate postoperative, initiation regimen) or BCG (initiation and maintenance regimen) instillations, or even the indication of cystectomy for BCG-resistant patients. CONCLUSION: Updating the ccAFU recommendations should contribute to improving patient management, as well as the diagnosis and treatment of NMIBC.

French AFU Cancer Committee Guidelines - Update 2022-2024: Muscle-Invasive Bladder Cancer (MIBC).

OBJECTIVE: To update the CCAFU recommendations for the management of muscle invasive bladder carcinoma (MIBC). METHODS: A systematic review (Medline) of the literature from 2020 to 2022 was performed taking account of the diagnosis, treatment options and surveillance of NMIBC and MIBC, while evaluating the references with their levels of evidence. RESULTS: MIBC is diagnosed after the most complete tumour resection possible. MIBC grading is based on CTU along with chest CT. Multiparametric pelvic MRI could be an alternative. Cystectomy with extensive lymphadenectomy is the gold standard treatment for non-metastatic MIBC. It should be preceded by platinum-based neoadjuvant chemotherapy in patients in good general health with satisfactory renal function. Enterocystoplasty is proposed in men and women in the absence of contraindications and when the urethral resection is negative on extemporaneous examination. Otherwise, transileal cutaneous ureterostomy is the recommended method of urinary diversion. Inclusion of all patients in an ERAS (Enhanced Recovery After Surgery) protocol is recommended. For metastatic MIBC, first line treatment with platinum-based chemotherapy (GC or MVAC) is recommended, if general health (PS>1) and renal function (clearance>60mL/min) so allow (only 50% of the cases). Pembrolizumab immunotherapy has demonstrated an overall survival benefit in second-line treatment. CONCLUSION: Updating the ccAFU recommendations should contribute to improving patient management, as well as the diagnosis and decision-making concerning MIBC treatment.

French AFU Cancer Committee Guidelines - Update 2022-2024: Upper urinary tract urothelial cancer (UTUC).

INTRODUCTION: The aim was to propose an update of the French Urology Association Cancer Committee (ccAFU) Recommendations on the management of upper urinary tract urothelial carcinomas (UUT-UC). METHODS: A systematic Medline search was performed between 2020 and 2022, taking account of the diagnosis, treatment options and follow-up of UUT-UC, while evaluating the references with their levels of evidence. RESULTS: The diagnosis of this rare pathology is based on CTU acquisition during excretion and flexible ureterorenoscopy with histological biopsies. Radical nephroureterectomy (RNU) remains the gold standard for surgical treatment. Nevertheless conservative treatment can be discussed for low risk lesions: tumour of low-grade, with no infiltration on imaging, unifocal<2cm, eligible for full treatment therefore requiring close endoscopic surveillance by flexible ureteroscopy in compliant patients. After RNU, postoperative instillation of chemotherapy is recommended to reduce the risk of recurrence in the bladder. Adjuvant chemotherapy has shown clinical benefits compared to surveillance after RNU for tumours (pT2-T4 N0-3 M0). CONCLUSION: These updated recommendations should contribute to improving not only patients' level of care, but also the diagnosis and decision-making concerning treatment for UUT-UC.

[Guidelines from the cancer (CC-AFU) and infection disease (CI-AFU) committees of the French Association of Urology for the management of adverse events and complications of BCG]. / Recommandations des Comités de cancérologie (CC-AFU) et d'infectiologie (CI-AFU) de l'Association française d'urologie pour la prise en charge effets indésirables et complications du BCG.

INTRODUCTION: Intravesical instillations of BCG are recommended for the treatment of high-risk non-muscle-invasive bladder cancer. However, their prolonged use remains limited by the associated potentially serious adverse effects or complications. The purpose of this article was to provide updated recommendations for the diagnosis and management of adverse events (AEs) or complications of intravesical BCG instillations. MATERIALS AND METHODS: Review of the literature in Medline (http://www.ncbi.nlm.nih.gov) and Embase (http://www.embase.com) using the following MeSH keywords or a combination of these keywords: "bladder," "BCG," "complication," "toxicity," "adverse events," "prevention," and "treatment". RESULTS: AEs or complications of BCG included genitourinary and systemic symptoms. The most common complications (cystitis, moderate fever) should be treated symptomatically and may require adjustment to allow patients to have the most complete BCG treatment possible. Serious complications are rare but must be identified promptly because of the life-threatening nature of the disease. Their management is based on the combination of anti-tuberculosis treatments, anti-inflammatory drugs and the definitive discontinuation of BCG. CONCLUSION: The management of BCG AEs requires early identification, rational and effective treatment if necessary, and discussion of the continuation of treatment for each situation.

[Guidelines from the cancer committee of the French Association of Urology (CC-AFU) for adequate intravesical instillations of Mitomycin C, Epirubicin, and BCG for non-muscle invasive bladder cancer]. / Recommandations du Comité de cancérologie de l'Association Française d'Urologie (CC-AFU) pour la bonne pratique des instillations intravésicales de mitomycine C, d'épirubicine et de BCG pour le traitement des tumeurs de la vessie n'infiltrant pas le muscle (TVNIM).

INTRODUCTION: Intravesical instillations of mitomycin C, epirubicin and BCG are considered as the standard treatment for most patients diagnosed with non-muscle invasive bladder cancer. These guidelines aim to optimize the adjuvant intravesical treatment in order to increase the efficacy and lower the morbidity associated with its administration. METHODS: We conducted a daily practice survey, an online search of available national regulation recommendations and of published guidelines. A bibliography search in French and English using Medline® and Embase® with the keywords "BCG"; "mitomycin C"; "epirubicin"; "bladder"; "complication"; "toxicity"; "adverse reaction"; "prevention" and "treatment" was performed November 2021. RESULTS: Patient information should be given by the attending physician before the first intravesical instillation. A medical exam to look for specific contraindications is also mandatory to select adequate candidates. Intravesical instillations should be delivered in health-care centers where urologic endoscopic procedures are routinely performed. Attending urologist or specialized nurse should check for negative pretreatment urine test. Intravesical instillation can only be delivered after bladder catheter has been inserted in the bladder without any injury of the lower urinary tract. The pharmaceutical agent should be kept in the bladder for two hours. Finally, voiding within the 6hours following intravesical instillations should be done in the sitting position and the patient should drink at least 2 liters of water per day for 2 days. CONCLUSION: The delivery of intravesical instillations of mitomycin C, epirubicin and BCG should follow a standardized procedure for better efficacy and lower morbidity.

Reassessing the clinical spectrum associated with hereditary leiomyomatosis and renal cell carcinoma syndrome in French FH mutation carriers.

We addressed uncertainties regarding hereditary leiomyomatosis and renal cell carcinoma (HLRCC) by exploring all French cases, representing the largest series to date. Fumarate hydratase (FH) germline testing was performed with Sanger sequencing and qPCR/MLPA. Enzyme activity was measured when necessary. We carried out whenever possible a pathology review of RCC and S-(2-succino)-cysteine (2SC)/fumarate hydratase immunohistochemistry. We estimated survival using non-parametric Kaplan-Meier. There were 182 cases from 114 families. Thirty-seven RCC were diagnosed in 34 carriers (19%) at a median age of 40. Among the 23 RCC with pathology review, 13 were papillary type 2. There were 4 papillary RCC of unspecified type, 3 unclassified, 2 tubulocystic, and 1 collecting duct (CD) RCC, all 2SC+ and most (8/10) FH-. Of the remaining 14, papillary type 2, papillary unspecified, CD, and clear cell histologies were reported. The vast majority of RCC (82%) were metastatic at diagnosis or rapidly became metastatic. Median survival for metastatic disease was 18 months (95%CI: 11-29). 133 cases (73%) had a history of cutaneous leiomyomas, 3 developed skin leiomyosarcoma. Uterine leiomyomas were frequent in women (77%), but no sarcomas were observed. Only 2 cases had pheochromocytomas/paraganglioma. CONCLUSION: Our findings have direct implications regarding the identification and management of HLRCC patients.

Tumor heterogeneity of fibroblast growth factor receptor 3 (FGFR3) mutations in invasive bladder cancer: implications for perioperative anti-FGFR3 treatment.

BACKGROUND: Fibroblast growth factor receptor 3 (FGFR3) is an actionable target in bladder cancer. Preclinical studies show that anti-FGFR3 treatment slows down tumor growth, suggesting that this tyrosine kinase receptor is a candidate for personalized bladder cancer treatment, particularly in patients with mutated FGFR3. We addressed tumor heterogeneity in a large multicenter, multi-laboratory study, as this may have significant impact on therapeutic response. PATIENTS AND METHODS: We evaluated possible FGFR3 heterogeneity by the PCR-SNaPshot method in the superficial and deep compartments of tumors obtained by transurethral resection (TUR, n = 61) and in radical cystectomy (RC, n = 614) specimens and corresponding cancer-positive lymph nodes (LN+, n = 201). RESULTS: We found FGFR3 mutations in 13/34 (38%) T1 and 8/27 (30%) ≥T2-TUR samples, with 100% concordance between superficial and deeper parts in T1-TUR samples. Of eight FGFR3 mutant ≥T2-TUR samples, only 4 (50%) displayed the mutation in the deeper part. We found 67/614 (11%) FGFR3 mutations in RC specimens. FGFR3 mutation was associated with pN0 (P < 0.001) at RC. In 10/201 (5%) LN+, an FGFR3 mutation was found, all concordant with the corresponding RC specimen. In the remaining 191 cases, RC and LN+ were both wild type. CONCLUSIONS: FGFR3 mutation status seems promising to guide decision-making on adjuvant anti-FGFR3 therapy as it appeared homogeneous in RC and LN+. Based on the results of TUR, the deep part of the tumor needs to be assessed if neoadjuvant anti-FGFR3 treatment is considered. We conclude that studies on the heterogeneity of actionable molecular targets should precede clinical trials with these drugs in the perioperative setting.

Left lobe of the prostate during clinical prostate cancer screening: the dark side of the gland for right-handed examiners.

BACKGROUND: The predictive value of the abnormality side during digital rectal examination (DRE) has never been studied, suggesting that physicians examined the left lobe of the gland as well as the right lobe. We aimed to assess the predictive value of the side of DRE abnormality for prostate cancer (PCa) detection and aggressiveness in right-handed urologists. METHODS: An analysis of a prospective database was carried out that included all consecutive men undergoing prostate biopsies between 2001 and 2012. The main end point was the predictive value of the abnormality side during DRE for cancer detection in clinically suspicious unilateral T2 disease. The diagnostic performance of left- versus right-sided abnormality was also assessed in terms of sensitivity, specificity and negative/positive predictive values. RESULTS: Overall, 308 patients had a suspicious unilateral clinical disease (detection rate 57.5%). The cancer detection rate was significantly higher in case of left-sided compared with right-sided clinical T2 stage (odds ratio 2.1). In case of left-sided disease, the number of positive cores, the rate of perineural invasion, the rate of primary grade 4 pattern and the percentage of cancer involvement per core were significantly higher compared with those reported for right-sided disease. The predictive value of abnormality laterality for cancer detection and aggressiveness remained statistically independent in multivariate models. The positive predictive value for cancer detection was 64.6 in case of suspicious left-sided disease versus 46.9 in case of right-sided disease. CONCLUSIONS: The risks of detecting PCa and aggressive disease on biopsy are significantly higher when DRE reveals a suspicious left-sided clinical disease as compared with right-sided disease. Right-handed physicians should be aware of this variance in diagnostic performance and potential underdetection of left-sided clinical disease, and should improve their examination of the left lobe of the gland by conducting longer exams or changing the patient's position.

Triple combination of bevacizumab, gemcitabine and platinum salt in metastatic collecting duct carcinoma.

BACKGROUND: Collecting duct carcinoma (CDC) is a rare and aggressive subtype of kidney cancer that responds to platinum-based chemotherapy. Recent phase II trials have established enhanced antitumor activity on combining bevacizumab with chemotherapy in patients with metastatic urothelial carcinoma, a tumor that shares many features with CDC. Our aim was to investigate whether combining bevacizumab with platinum-based chemotherapy might not also show promise in metastatic CDC (mCDC) patients. PATIENTS AND METHODS: Five previously untreated patients diagnosed with mCDC received bevacizumab (15 mg/kg) in combination with gemcitabine (1250 mg/m(2), D1-D8) and platinum salt (cisplatin 80 mg/m(2) or carboplatin AUC 5 mg/ml/min) every 3 weeks for up to six cycles. This was followed by bevacizumab maintenance therapy (15 mg/kg). RESULTS: All five patients (median age, 62 years; range 45-66 years) had an Eastern Cooperative Oncology Group PS of 0-1. They received the triple-drug combination for a median of four cycles (range, 2-6) and bevacizumab maintenance therapy for a median of three cycles (range, 0-17). There were three cases of partial response, one case of stable disease (20 months) and one case of complete remission after surgery of the only metastatic site. Median progression-free survival (PFS) was 15.1 months [95% confidence interval (CI) 5.6-20.4]. Median overall survival (OS) was 27.8 months (95% CI 12.4-unreached). Grades 3 or 4 adverse events were pulmonary embolism (n = 2), neutropenia (n = 2), thrombopenia (n = 1), asthenia (n = 1) and hypertension (n = 1). CONCLUSIONS: The addition of bevacizumab to platinum-based chemotherapy resulted in a longer PFS and longer OS than recorded in an earlier clinical trial of platinum-based chemotherapy alone. The triple combination was manageable. The French Collaborative Group (Groupe d'Etudes des Tumeurs Uro-Génitales) is planning a prospective multicenter phase II clinical trial of the triple combination in mCDC patients. CLINICAL TRIAL: BEVABEL/MO28644 (EudraCT: 2013-001179-19).

[Oncological outcome of radical cystectomy for BCG failure compared to primary invasive disease]. / Résultats oncologiques de la cystectomie pour carcinome urothélial résistant au BCG comparés aux tumeurs invasives d'emblée.

INTRODUCTION AND OBJECTIVES: BCG therapy deeply modified prognosis of high-risk non muscle invasive (NMI) urothelial carcinomas. However, these tumors remain potentially lethal. The objective of this study was to compare oncological outcome of radical cystectomy (RC) for BCG failure to primary invasive (PI) tumors. MATERIAL AND METHODS: RC performed between 2001 and 2011 were retrospectively reviewed. Clinicopathological and follow-up data were compared between RC performed for: NMI high-grade recurrence under BCG therapy (ReNMI); MI recurrence (≥ T2) under BCG therapy (ReMI); primary invasive tumors (PI). The three groups were defined according to tumor status on last TUR before RC. All NMI high-grade bladder tumors at diagnosis had maintenance BCG immunotherapy. RESULTS: Two hundred patients were included, 155 PI, 21 ReNMI et 24 ReMI. Median follow up was 42 months (1.74-135.9). Mean BCG instillations number was 8 ± 4.2 versus 9.5 ± 4.3 for ReNMI and ReMI respectively (P=0.24). Upstaging (≥ pT2) occurred in 33% of ReNMI. The rate of pN+ was 24%, 42% and 30% for the ReNMI, ReMI et PI respectively (P=0.39). No differences were observed between the groups for lymphovascular invasion, extracapsular extension if pN+, soft tissue surgical margins and adjuvant chemotherapy. 5-year cancer specific survival (CSS) was 48% for the ReNMI, 18% for the ReMI and 47% for the PI (P=0.02). Progression to muscle invasion under BCG therapy was an independent pejorative prognostic factor for CSS (P=0.05). CONCLUSION: BCG failure led to poor prognosis, particularly when tumors progressed to muscle invasion. Recurrent NMI high-grade tumors seemed to have comparable prognosis than PI tumors because of the high amount of upstaging and nodal invasion. BCG failure is a therapeutic emergency.

[Prognostic impact of tumors localized at the prostatic apex]. / Impact pronostique des tumeurs localisées à l'apex prostatique.

OBJECTIVE: The apex is a particular region of the prostate in its surgical dissection and pathological analysis. We sought to evaluate the prognostic value of the apical localization of prostate tumors. METHOD: From 1988 to 2010, data pre- (age, clinical stage, preoperative PSA, biopsy Gleason score) and postoperative (prostate weight, pathologic stage TNM 2010, Gleason score, margin status) of 2765 total prostatectomies were collected prospectively. These data were compared according to existence or absence of tumor at the apex. The prognostic impact of tumor at the apex on biochemical recurrence-free survival (PSA>0.2 ng/mL) has been studied in univariate and multivariate models. RESULTS: One thousand eight hundred seventeen tumors had a location at the apex (65.7%). In univariate analysis, there was a significant difference in the clinical stage, the biopsy and pathological Gleason score, the result of curage, the pathological stage and the margin status between apical tumors and others. With a mean decline of 34.6 months, 502 patients had a biochemical recurrence (18.1%). Disease-free survival at 10 years was 60.7% for tumor at the apex versus 65.9% in other cases. The location at the apex was significantly associated with biochemical recurrence on univariate analysis (P=0.01). After adjustment for clinical and pathological stage, PSA level, Gleason score and surgical margins, the apex was not anymore a pejorative independent predictor (P=0.0087). CONCLUSION: The existence of tumor in the prostatic apex was associated with more aggressive tumoral criteria and was an independent and pejorative predictor of biochemical recurrence-free survival at 10 years in univariate analysis. The apical localization could be an additional argument in the decision of adjuvant therapy after prostatectomy.