Treatment of muscle-invasive bladder cancer in patients without comorbidities and fit for surgery: Trimodality therapy vs radical cystectomy. Development of GRADE (Grades of Recommendation, Assessment, Development and Evaluation) recommendation by the Italian Association of Radiotherapy and Clinical Oncology (AIRO).

AIM: To compare trimodality therapy (TMT) versus radical cystectomy (RC) and develop GRADE (Grades of Recommendation, Assessment, Development and Evaluation) Recommendation by the Italian Association of Radiotherapy and Clinical Oncology (AIRO) for treatment of muscle-invasive bladder cancer (MIBC). MATERIAL AND METHODS: Prospective and retrospective studies comparing TMT and RC for MIBC patients were included. Qualitative and quantitative evaluation of evidence was made. RESULTS: Ten studies were included in the analysis. Pooled analysis showed salvage cystectomy and pathological complete response rates after TMT of 12 % and 72-77.5 %, respectively. Pooled rates of G3-G4 GU toxicity and serious toxicity rate were 18 vs 3% and 45 vs 29 % for patients undergoing TMT vs RC, respectively. The panel assessed a substantial equivalence in terms of OS and CSS at 5 years between TMT and RC. CONCLUSIONS: TMT could be suggested as an alternative treatment to RC in non-metastatic MIBC patients, deemed fit for surgery.

Tumor Infiltrating Neutrophils Are Enriched in Basal-Type Urothelial Bladder Cancer.

BACKGROUND: Urothelial bladder cancers (UBCs) are distinct in two main molecular subtypes, namely basal and luminal type. Subtypes are also diverse in term of immune contexture, providing a rationale for patient selection to immunotherapy. METHODS: By digital microscopy analysis of a muscle-invasive BC (MIBC) cohort, we explored the density and clinical significance of CD66b+ tumor-associated-neutrophils (TAN) and CD3+ T cells. Bioinformatics analysis of UBC datasets and gene expression analysis of UBC cell lines were additionally performed. RESULTS: Basal type BC contained a significantly higher density of CD66b+ TAN compared to the luminal type. This finding was validated on TCGA, GSE32894 and GSE124305 datasets by computing a neutrophil signature. Of note, basal-type MIBC display a significantly higher level of chemokines (CKs) attracting neutrophils. Moreover, pro-inflammatory stimuli significantly up-regulate CXCL1, CXCL2 and CXCL8 in 5637 and RT4 UBC cell lines and induce neutrophil chemotaxis. In term of survival, a high density of T celsl and TAN was significantly associated to a better outcome, with TAN density showing a more limited statistical power and following a non-linear predicting model. CONCLUSIONS: TAN are recruited in basal type MIBC by pro-inflammatory CKs. This finding establishes a groundwork for a better understanding of the UBC immunity and its relevance.

How to improve patient selection for neoadjuvant chemotherapy in bladder cancer patients candidate for radical cystectomy and pelvic lymph node dissection.

PURPOSE: To improve patient selection for neoadjuvant chemotherapy (NAC) before radical cystectomy (RC) in bladder cancer patients (BCa). METHODS: Retrospective evaluation of 1057 patients with cT2-4N0M0 BCa treated with RC and pelvic lymph node dissection between 1990 and 2018 at 3 referral centers. Adverse pathologic features (APF) were defined as pT3-pT4/pN + disease at RC. A regression tree model (CART) was used to assess preoperative risk group classes. A multivariable logistic regression (MVA) was performed to identify predictors of APF at RC. RESULTS: Median age was 70 years and most of the patients were men (83%). Of the 1057 patients included in our study, 688 (65%) had APF. CART analysis was able to stratify patients into 3 risk groups: low (cT2 and single disease, odds ratio [OR] 0.62), intermediate (cT2 and multiple disease, OR 1.08), and high (cT3-cT4, OR 1.28). On MVA APF were associated with variant histology (odds ratio [OR] 3.97, 95% confidence interval [CI] 1.46-10.83, p = 0.007), multifocality at TUR (OR 2.56, CI 1.27-5.17, p = 0.09), completeness of resection (OR 0.47, CI 0.23-0.96, p = 0.04) and clinical extravesical disease (OR 3.42, CI 1.63-7.14, p = 0.001). CONCLUSION: We defined three pre-operative risk classes. Our results indicate that patients with a cT3-T4 disease are those who might benefit more from NAC whereas those with T2 single disease should be those to whom NAC probably shouldn't be proposed. Given the high rate of understaging in BCa patients, NAC can be proposed in selected cases of cT2/multifocal disease.

Role of cultural analysis in patients with indwelling ureteral stent submitted to ureteroscopy for stones.

BACKGROUND: Aim of our study is to analyze the incidence of postoperative infectious complications and to assess its predictors in patients with indwelling ureteral stent treated with ureteroscopy (URS). METHODS: We retrospectively evaluated data of patients treated with URS from January 2017 to July 2018 at our center. We included 88 consecutive patients with available stent culture (SC) and urine culture (UC). Cefoxitin 2 g IV was given as prophylaxis in all patients with negative preoperative UC; otherwise, the choice of antibiotic was based on antibiogram. Ureteral stent was removed before URS procedure and analyzed. No postoperative antibiotic was given. Multivariable logistic regression analysis was built to assess preoperative predictors of postoperative infectious complications. RESULTS: Nineteen patients (22%) developed postoperative infectious complications and fever was the most common one. E. faecalis, which is not responsive to common prophylaxis schemes in force in our institution, was the most frequent pathogen isolated. Overall, 26% of patients were found to have a discordance between SC and UC. At multivariable logistic regression analysis preoperative SC positivity (Odds Ratio [OR]: 11.00, 95% Confidence Interval [CI]:1.08-111.41, P=0.04) was the only significant predictor of postoperative infectious complications. CONCLUSIONS: About one to five patients treated with URS developed an infectious complication and E. faecalis and E. coli were the most frequent pathogen isolated. A positive SC is the only independent risk factor for postoperative infection: consequently, an early SC analysis could allow a prompt antibiotic therapy in all patients with positive SC even if mildly symptomatic.

Hyper-Activation of STAT3 Sustains Progression of Non-Papillary Basal-Type Bladder Cancer via FOSL1 Regulome.

Urothelial bladder cancer (UBC) are classified into luminal and basal subtypes showing distinct molecular features and clinical behaviour. Recent in silico data have proposed the activation on the Signal Transducer and Activator of Transcription 3 (STAT3) as relevant transcription factor in UBC. To answer this question, we have combined the retrospective analysis of clinical samples, functional assays on cell lines, interrogation of public UBC datasets and a murine model of basal-type UBC. Immunohistochemistry on a retrospective UBC cohort uncovered that STAT3 Y705 phosphorylation (pSTAT3) is significantly increased in infiltrating basal-type UBC compared to luminal UBC. In vitro, STAT3 silencing in UBC cell lines significantly reduced tumor cell viability and invasion. Gene expression profile of UBC cell lines combined with the analysis of the Cancer Genome Atlas (TCGA) and GSE32894 UBC datasets showed that increased expression of a set of STAT3 targets predicts basal-type, propensity to local progression and worse prognosis. MYC and FOSL1 represent relevant STAT3 downstream targets, as validated by their co-localization in pSTAT3+ UBC cancer cells. These findings were largely reproduced in the BBN-induced murine model of basal-type UBC. Of note, FOSL1 protein resulted strongly expressed in the non-papillary UBC pathway and FOSL1-regulated transcripts were significantly enriched in the transition from NMIBC to MIBC, as indicated by the interrogation of the GSE32894 dataset. The blockade of the STAT3 pathway might represent a novel treatment option for these neoplasms. Monitoring pSTAT3 and the downstream targets, particularly FOSL1, could provide meaningful levels of UBC stratification.

The impact of completeness of last transurethral resection of bladder tumors on the outcomes of radical cystectomy.

PURPOSE: To evaluate the role of a complete transurethral resection of bladder tumors (c-TURBT) on oncological outcomes after radical cystectomy (RC) and its relationship with adverse pathological features. METHODS: We retrospectively analyzed data of 727 patients treated with RC and bilateral pelvic lymph node dissection at three tertiary referral centers. Possible c-TURBT was reported by the treating surgeon. Multivariable Cox regression analyses were used to assess the relationship of c-TURBT and survival outcomes after surgery in 1:1 propensity score-matched cohort adjusted for age and gender. Moreover, multivariable logistic regression (MVA) was built to predict the relationship between c-TURBT and pT3-T4 stages at RC, lymph node invasion (LNI) and positive soft tissue surgical margin (STSM). RESULTS: A total of 433 (60%) patients received a c-TURBT. 3.0% of patients with a c-TURBT achieved a pT0-pTa-pTis status vs. 2.0% of patients with incomplete TURBT. At multivariable Cox regression analyses, c-TURBT was not associated with survival outcomes. At MVA, incompleteness of TURBT was significantly associated with a pT3-T4 stage [odds ratio (OR) 8.04, 95% confidence interval (CI) 2.33-27.67, p = 0.001]. No significant association was found between c-TURBT, LNI and STSM. CONCLUSION: We found a low rate of achievement of pT0 stage at RC. An incomplete TURBT before RC represented a predictor of pT3-T4 stages, but no effect of a c-TURBT was shown on survival outcomes. Given the current inadequacy of clinical staging strategies with more than 50% of extravesical disease being under-staged, our results could improve patients selection for NAC, driving the decision-making in doubtful cases.

Prognostic role of delay before radical cystectomy: retrospective analysis of a single-centre cohort with 376 patients.

BACKGROUND: According to International Guidelines radical cystectomy (RC) should not be delayed over 90 days to prevent the risk of intercurrent progression and worse survival. Nevertheless, such a recommendation relies on a few retrospective studies reaching non-univocal conclusions. Aim of the present study was to investigate if the latency between diagnosis and cystectomy (LDC) is related to prognosis after RC. METHODS: Retrospective analysis of database collecting complete information on patients undergone RC at single institution since 2004. The cases with an LDC <15 or >360 days or submitted to neo-adjuvant chemotherapy or with distant metastasis were excluded. Uni- and multivariate analyses assessed the relationship between LDC upstaging, progression-free and overall survival. RESULTS: The data of 376 patients were analyzed; mean/median LDC was 83/76 days and 124 patients (33%) had LDC>90 days. LDC was shorter in younger patients with first diagnosis of more advanced BC at clinical staging; accordingly, patients with LDC<90 days had more advanced disease also at final pathology. Prevalence of pathological upstaging was 37%; in case of upstaging LDC was 75 days vs. 72 days (P=0.4629). Multivariable regression models adjusted for pathological local and lymph nodal stage showed that LDC, continuous or dichotomized at 30/60/90/120/180/240 days was not related to progression-free or overall survival. The retrospective design of study is the main limitation of the study. CONCLUSIONS: In our experience nor the risk of upstaging, neither survival after RC were related to LDC. Even if these results should not discourage any effort to perform surgery expeditiously, the window of opportunity for RC might not be delimited by a predetermined threshold.

Inhibition of Survivin Is Associated with Zoledronic Acid-induced Apoptosis of Prostate Cancer Cells.

BACKGROUND/AIM: Evidence suggests that zoledronic acid (ZA) exerts direct antitumor effects on cancer cells but the underlying mechanisms of these actions are unknown. This study investigated the possible involvement of survivin in the antiproliferative effects of ZA in prostate cancer. MATERIALS AND METHODS: 3-(4,5-dimethyl-2-thiazol)-2,5-diphenyl-2H-tetrazolium bromide (MTT) dye reduction assay was used to assess cell viability and acridine orange/ethidium bromide double staining to analyze cell death. Human Apoptosis Array evaluated the expression of apoptosis-related proteins. Survivin protein was measured by western blot technique and miR-203 levels were quantified by quantitative real-time polymerase chain reaction. RESULTS: ZA induced inhibition of cell proliferation and apoptosis activation, with down-regulation of survivin protein. A negative regulation at gene expression level may be hypothesized because we observed a significant decrease of survivin mRNA level and an increase of miR-203 expression after ZA exposure. CONCLUSION: This study provides evidence that ZA may directly inhibit cancer cell proliferation, identifying survivin as one of its downstream targets.

Comparison of Perioperative Morbidity of Radical Cystectomy With Neobladder Versus Ileal Conduit: A Matched Pair Analysis of 170 Patients.

BACKGROUND: The objective of this study was to evaluate if use of an ileal conduit (IC) versus a neobladder (NB) during radical cystectomy (RC) can play a role in the morbidity of the surgical procedure. PATIENTS AND METHODS: Since 2001 our institution has prospectively maintained a database of more than 500 patients who have undergone RC. The records of 258 patients who received an RC and IC and 121 who received an RC and NB were reviewed for the present study. Using a binary logistic regression model a propensity score was generated for the following factors: sex, age, smoking habit, Charlson score, American Society of Anesthesiology score, preoperative hydronephrosis, and pathologic T stage. Two groups of patients with similar propensity scores were created with a ratio of 1:1, one group who received an IC and another who received an NB. The following features were compared between the 2 groups: blood loss, intraoperative complication rate, time to oral intake resumption, postoperative complication rate (overall, Clavien classification 1-2, Clavien classification 3-5, related to RC, related to urinary reconstruction). RESULTS: In total, 170 patients were selected; 85 with NB, 85 with IC, and the 2 groups were well matched according to the desired features. No differences were noted for all of the compared features. CONCLUSION: The morbidity of RC does not seem to be affected by the choice of IC versus NB.

[ProACT (Adjustable Continence Therapy) implants in case of failure of other techniques for urinary incontinence]. / Reimpianto del sistema ProACT in caso di fallimento precoce nella cura dell'incontinenza urinaria dopo prostatectomia radicale.

BACKGROUND: Urinary incontinence after radical prostatectomy is one of the most feared problems. It can affect almost 40% of patients, with different degrees of severity according to each specific case. The aim of this work is to analyze our experience in ProACT (Adjustable Continence Therapy) implants, especially in case of failure of other techniques. METHODS: Between November 2007 and December 2010, 31 patients with post-radical prostatectomy incontinence underwent a ProACT implant. Eight patients had their device explanted (in local anesthesia): in two cases the device spontaneously broke, three of them migrated in the urethra (one patient received radiation therapy), another one was infected in the device site (one in BCG treatment for non-muscle invasive bladder cancer), two devices were wrongly placed. Seven of these patients had had their device replaced with success. Using pad score, incontinence was classified as mild, moderate and severe. Overall, the total amount of procedures, most of them fluoroscopic-guided in spinal anesthesia, were 38; the average duration of the surgery was 37.6 minutes. In one patient with impaired balloon volume due to monolateral device malfunction, we noticed good results in controlling incontinence; therefore, we successfully applied the same technique in other four cases with previous partial results. RESULTS: With a total amount of 28 implants, we had 17 (60.7%) complete responses, 6 (25%) partial and 4 (14.3%) failures. We had 4 post-radiotherapy implants: one was completely dry, two were in balloon adjustment, and one of them had a replacement due to urethral erosion of the first implant.
All patients with impaired balloon inflation were satisfied: one was completely dry and three had sensible improvement. CONCLUSIONS: The ProACT is a minimally invasive surgical therapy for post-radical prostatectomy urinary incontinence. Early failure is frequent and is mainly due to rupture and migration of the device. In these cases the solution can be the replacement, even with impaired balloon inflation.