Publications by authors named "Renzo Colombo"

151 Publications

Protocol of the Italian Radical Cystectomy Registry (RIC): a non-randomized, 24-month, multicenter study comparing robotic-assisted, laparoscopic, and open surgery for radical cystectomy in bladder cancer.

BMC Cancer 2021 Jan 11;21(1):51. Epub 2021 Jan 11.

Department of Urology, Policlinico Abano Terme, Abano Terme, PD, Italy.

Background: Bladder cancer is the ninth most common type of cancer worldwide. In the past, radical cystectomy via open surgery has been considered the gold-standard treatment for muscle invasive bladder cancer. However, in recent years there has been a progressive increase in the use of robot-assisted laparoscopic radical cystectomy. The aim of the current project is to investigate the surgical, oncological, and functional outcomes of patients with bladder cancer who undergo radical cystectomy comparing three different surgical techniques (robotic-assisted, laparoscopic, and open surgery). Pre-, peri- and post-operative factors will be examined, and participants will be followed for a period of up to 24 months to identify risks of mortality, oncological outcomes, hospital readmission, sexual performance, and continence.

Methods: We describe a protocol for an observational, prospective, multicenter, cohort study to assess patients affected by bladder neoplasms undergoing radical cystectomy and urinary diversion. The Italian Radical Cystectomy Registry is an electronic registry to prospectively collect the data of patients undergoing radical cystectomy conducted with any technique (open, laparoscopic, robotic-assisted). Twenty-eight urology departments across Italy will provide data for the study, with the recruitment phase between 1st January 2017-31st October 2020. Information is collected from the patients at the moment of surgical intervention and during follow-up (3, 6, 12, and 24 months after radical cystectomy). Peri-operative variables include surgery time, type of urinary diversion, conversion to open surgery, bleeding, nerve sparing and lymphadenectomy. Follow-up data collection includes histological information (e.g., post-op staging, grading, and tumor histology), short- and long-term outcomes (e.g., mortality, post-op complications, hospital readmission, sexual potency, continence etc).

Discussion: The current protocol aims to contribute additional data to the field concerning the short- and long-term outcomes of three different radical cystectomy surgical techniques for patients with bladder cancer, including open, laparoscopic, and robot-assisted. This is a comparative-effectiveness trial that takes into account a complex range of factors and decision making by both physicians and patients that affect their choice of surgical technique.

Trial Registration: ClinicalTrials.gov , NCT04228198 . Registered 14th January 2020- Retrospectively registered.
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http://dx.doi.org/10.1186/s12885-020-07748-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7802145PMC
January 2021

Perioperative and oncologic outcomes of open radical nephrectomy and inferior vena cava thrombectomy with liver mobilization and Pringle maneuver for Mayo III level tumor thrombus: single institution experience.

Minerva Urol Nefrol 2020 Nov 27. Epub 2020 Nov 27.

Department of Urology, IRCCS, San Raffaele Scientific Institute, Milan, Italy -

Background: Scarce data are available regarding the technique and outcomes for patients with RCC and Mayo III caval thrombi. To report surgical and oncological outcomes of RCC patients with Mayo III thrombi treated with radical nephrectomy and thrombectomy after liver mobilization (LM) and Pringle Manoeuvre (PM).

Methods: Retrospective analysis of surgical technique, outcomes and cancer control in 19 patients undergoing LM and PM in a single tertiary care institution.

Results: Overall, 78% of the patients had performance status ECOG 1 and 58% had a comorbidity index >2. Median surgical time was 305 minutes (IQR 264-440). Intraoperative complications were reported for 39% of patients and postoperative ones for 58% (only Grade 1 and 2). Intensive Care Unit support was necessary in 16% of the cases. Median length of hospital stay was 9 days (IQR 7-11). Thirty- and 90-day mortality were 5% and 15%. Twoyear overall survival and cancer-specific survival were 60% and 62%, respectively.

Conclusions: We reported surgical techniques, intra and perioperative complications and follow-up in the largest cohort of RCC patients requiring LM and PM.
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http://dx.doi.org/10.23736/S0393-2249.20.03844-8DOI Listing
November 2020

Prediction of the Need for an Extended Lymphadenectomy at the Time of Radical Cystectomy in Patients with Bladder Cancer.

Eur Urol Focus 2020 Oct 2. Epub 2020 Oct 2.

Department of Urology, Urological Research Institute, Vita-Salute University, San Raffaele Scientific Institute, Milan, Italy.

Background: A prospective randomized trial (LEA AUO AB 25/02) found no survival benefit in extended compared with limited pelvic lymph node dissection (PLND) templates in bladder cancer (BCa) patients treated with radical cystectomy (RC). However, the rate of lymph node invasion (LNI) in the standard and extended templates was lower than estimated.

Objective: To assess the accuracy of preoperative clinical and pathological parameters to predict LNI and to develop a model to preoperatively select candidates for the extended PLND templates.

Design, Setting, And Participants: A total of 903 BCa patients treated at a single institution were retrospectively identified. The primary outcome was to identify preoperatively the risk of LNI to tailor the type of PLND. The extended PLND templates consisted in the removal of pelvic lymph nodes together with the common iliac, presacral, para-aortocaval, interaortocaval, and paracaval sites up to the inferior mesenteric artery.

Intervention: A total of 903 BCa patients were treated with RC and bilateral extended PLND templates.

Outcome Measurements And Statistical Analysis: Several models predicting LNI were evaluated using the area under the receiver operating characteristic curve (AUC), calibration plots and decision curve analyses. A nomogram predicting LNI in the extended pattern was developed and validated internally.

Results And Limitations: Overall, 55 patients (6.1%) had LNI in the extended PLND templates at RC. The median number of nodes removed was 19 (interquartile range: 13-26). A model including age, clinical T stage, clinical node stage, lymphovascular invasion, and presence of carcinoma in situ at the last transurethral resection before RC was developed. The AUC of this model is 73%. Using a cutoff of 3%, 108 extended PLNDs (12%) would be spared and only two LNIs (3%) would be missed. The main limitations of our model are the retrospective nature of the data, lack of external validation, and low rate of LNI.

Conclusions: This is the first proposed model to predict LNI in the extended PLND templates. This model might help urologists identify which patients might benefit from an extended PLND at the time of RC, reserving a standard PLND for all the others.

Patient Summary: We developed the first nomogram to predict lymph node invasion (LNI) in the extended pelvic lymph node dissection templates in bladder cancer patients treated with radical cystectomy. The adoption of our model to identify candidates for the extended pelvic lymph node dissection templates could avoid up to 12% of these procedures at the cost of missing only 3% of patients with LNI.
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http://dx.doi.org/10.1016/j.euf.2020.09.009DOI Listing
October 2020

Adjuvant chemotherapy is ineffective in patients with bladder cancer and variant histology treated with radical cystectomy with curative intent.

World J Urol 2020 Jul 25. Epub 2020 Jul 25.

Klinik für Urologie, Luzerner Kantonsspital, Lucerne, Switzerland.

Objectives: Adjuvant chemotherapy (ACT) is recommended for non-organ-confined bladder cancer (BCa) after radical cystectomy (RC) and pelvic lymph node dissection (PLND), but there are sparse data regarding its specific efficacy in patients with histological variants. The aim of our study was to evaluate the role of ACT on survival outcomes in patients with variant histology in a large multicenter cohort.

Materials And Methods: We retrospectively evaluated data of 3963 patients with BCa treated with RC and bilateral PLND with curative intent at several institutions between 1999 and 2018. The histological type was classified into six groups: pure urothelial carcinoma (PUC) or squamous, sarcomatoid, micropapillary, glandular and neuroendocrine differentiation. Multivariable competing risk analysis was applied to assess the role of ACT on recurrence and cancer-specific mortality (CSM) in each histological subtype.

Results: Of the 3963 patients included in the study, 23% had variant histology at RC specimen and 723 (18%) patients received ACT. ACT was found to be significantly associated with reduced risk of recurrence (sub-hazard ratio [SHR]: 0.55, confidence interval [CI] 0.42-0.71, p < 0.001) and CSM (SHR: 0.58, CI 0.44-0.78, p < 0.001) in the PUC only, while no histological subtype received a significant benefit on survival outcomes (all p > 0.05) from administration of ACT. The limitation of the study includes the retrospective design, the lack of a central pathology review and the number of ACT cycles.

Conclusion: In our study, the administration of ACT was associated with improved survival outcomes in PUC only. No histological subtype found a benefit in overall recurrence and CSM from ACT.
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http://dx.doi.org/10.1007/s00345-020-03362-1DOI Listing
July 2020

The Value of Multiparametric Magnetic Resonance Imaging Sequences to Assist in the Decision Making of Muscle-invasive Bladder Cancer.

Eur Urol Oncol 2020 Jun 27. Epub 2020 Jun 27.

Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milano, Italy. Electronic address:

Interim data from the PURE-01 study, using pembrolizumab before radical cystectomy in muscle-invasive bladder cancer (MIBC), suggested that multiparametric magnetic resonance imaging (mpMRI) was able to predict the pathologic response. Owing to the availability of novel effective therapies in MIBC, the possibility to assess tumor response easily has become exceedingly important. The primary objective of the present study was to evaluate the association between individual and combined MRI sequences, and the pathologic response in the final PURE-01 population. Images were internally evaluated and the diagnostic performance was analyzed for separate sequences, along with their combination. From February 2017 to December 2019, 143 patients were enrolled in PURE-01, and 123 with suitable paired imaging assessments before and after pembrolizumab tests (N = 246 mpMRI in total) were analyzed in relation to the pathologic response. The area under the curve (AUC) of the combination of all sequences to predict ypT0ypN0 response was 0.74. By excluding dynamic contrast enhancement (DCE) assessment, the AUC was 0.74. When looking at ypT ypN0 response, the AUC was 0.87 in both cases. Without DCE, 95% of patients with no evidence of disease resulted in ypT ypN0 and 65% ypT0ypN0 responders. In conclusion, the final results confirmed the reliability of mpMRI and suggested the opportunity to avoid intravenous gadolinium contrast to personalize bladder-sparing strategies in radiologically complete responders. PATIENT SUMMARY: We evaluated the reliability of multiparametric bladder magnetic resonance imaging to predict the pathologic response to pembrolizumab administered before radical cystectomy in muscle-invasive bladder cancer. We observed that this radiologic examination is promising in the attempt to identify opportunities to spare the bladder in selected, radiologically defined complete responders. We also observed that the use of intravenous gadolinium contrast can be avoided in future studies. ClinicalTrials.gov, number NCT02736266.
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http://dx.doi.org/10.1016/j.euo.2020.06.004DOI Listing
June 2020

Hospital care in Departments defined as COVID-free: A proposal for a safe hospitalization protecting healthcare professionals and patients not affected by COVID-19.

Arch Ital Urol Androl 2020 Apr 24;92(2). Epub 2020 Apr 24.

Musumeci GECAS Clinic, Gravina di Catania, Catania.

The COVID-19 pandemic influenced the normal course of clinical practice leading to significant delays in the delivery of healthcare services for patients non affected by COVID-19. In the near future, it will be crucial to identify facilities capable of providing health care in compliance with the safety of healthcare professionals, administrative staff and patients. All the staff involved in the project of a Covid-free hospital should be subjected to a diagnostic swab for COVID-19 before the beginning of healthcare activity and then periodically in order to avoid the risk of contamination of patients during the process of care. The modifications of various activities involved in the process of care are described: outpatient care, reception of inpatients, inpatient ward and operating room. For outpatient care, modality of appointment procedure, characteristics of waiting room and personal protective equipment (PPE) for healthcare professionals and administrative staff are presented. Reception of inpatients shall be conditional on a negative swab for COVID-19 obtained with a drive-in procedure. The management of the operating room represents the most crucial step of the patient's care process. The surgical team should be restricted and monitored with periodic swabs; surgical procedures should be performed by experienced surgeons according to standard procedures; surgical training experimental treatments and research protocols should be suspended. Adequate personal protective equipment and measures to reduce aerosolization in the operating room (closed circuits, continuous cycle insufflators, fume extraction) should be adopted. Prevention of possible transmission of the virus during procedures in open, laparoscopic and endoscopic surgery is to use a multi-tactic approach, which includes correct filtration and ventilation of the operating room, the use of appropriate PPE (FFP3 plus surgical mask and protective visor for all the staff working in the operating room) and smoke evacuation devices with a suction and filter system.   on behalf of the UrOP Executive Committee Giuseppe Ludovico, Angelo Cafarelli, Ottavio De Cobelli, Ferdinando De Marco, Giovanni Ferrari, Stefano Pecoraro, Angelo Porreca, Domenico Tuzzolo.
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http://dx.doi.org/10.4081/aiua.2020.2.67DOI Listing
April 2020

Predicting the Pathologic Complete Response After Neoadjuvant Pembrolizumab in Muscle-Invasive Bladder Cancer.

J Natl Cancer Inst 2021 Jan;113(1):48-53

Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.

Background: In the PURE-01 study (NCT02736266), we aimed to evaluate the ability to predict the pathologic complete response (pT0N0) after pembrolizumab by using clinical and tumor biomarkers.

Methods: In an open-label, single-arm, phase 2 study, 3 courses of 200 mg pembrolizumab preceding radical cystectomy were administered in patients with T2-4aN0M0 muscle-invasive bladder cancer. The analyses included a comprehensive genomic profiling and programmed cell-death-ligand-1 (PD-L1)-combined positive score assessment (CPS; Dako 22C3 antibody) of pre- and posttherapy samples. Multivariable logistic regression analyses evaluated baseline clinical T stage and tumor biomarkers in association with pT0N0 response. Corresponding coefficients were used to develop a calculator of pT0N0 response based on the tumor mutational burden (TMB), CPS, and the clinical T stage. Decision-curve analysis was also performed. All statistical tests were 2-sided.

Results: From February 2017 to June 2019, 112 patients with biomarker data were enrolled (105 with complete TMB and CPS data). Increasing TMB and CPS values featured a linear association with logistic pT0N0 probabilities (P = .02 and P = .004, respectively). For low TMB values (≤11 mut/Mb, median value, n = 53), pT0N0 probability was not associated with increasing CPS. Conversely, for high TMB values (>11 mut/Mb, n = 52), pT0N0 was statistically significantly associated with higher CPS (P = .004). The C index of the pT0N0 probability calculator was 0.77. On decision-curve analysis, the net benefit of the model was higher than the "treat-all" option within the clinically meaningful threshold probabilities of 40%-50%.

Conclusions: The study presents a composite biomarker-based pT0N0 probability calculator that reveals the complex interplay between TMB and CPS, added to the clinical T stage.
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http://dx.doi.org/10.1093/jnci/djaa076DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7781448PMC
January 2021

Sex-specific Alterations in the Urinary and Tissue Microbiome in Therapy-naïve Urothelial Bladder Cancer Patients.

Eur Urol Oncol 2020 12 25;3(6):784-788. Epub 2020 Apr 25.

Division of Experimental Oncology/Unit of Urology, Urological Research Institute, IRCCS Ospedale San Raffaele, Milan, Italy. Electronic address:

Comprehensive characterization of the urinary and urothelium-bound microbiomes in bladder cancer (BCa) and healthy state is essential to understand how these local microbiomes may play a role in BCa tumorigenesis and response to therapy, as well as to explain sex-based differences in BCa pathobiology. Performing 16 s rDNA microbiome analysis on 166 samples (urine and paired bladder tissues) from therapy-naïve BCa patients undergoing radical cystectomy and healthy controls, we defined (1) sex-specific microbiome differences in the urine and bladder tissue, and (2) representativeness of the tissue microenvironment by the voided urinary microbiome. The genus Klebsiella was more common in the urine of female BCa patients versus healthy controls, while no clinically relevant bacteria were found differently enriched in men. In tissues, the genus Burkholderia was more abundant in the neoplastic versus the non-neoplastic tissue in both sexes, suggesting a potential role in BCa pathobiology. Lastly, we found that the urinary microbiome shares >80% of the bacterial families present in the paired bladder tissue, making the urinary microbiome a fair proxy of the tissue bacterial environment. PATIENT SUMMARY: We identified specific bacteria present in the urine and tissues of male and female bladder cancer patients. These novel data represent a first step toward understanding the influence of the bladder microbiome on the development of bladder cancer and on the response to intravesical and systemic therapies.
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http://dx.doi.org/10.1016/j.euo.2020.04.002DOI Listing
December 2020

Impact of Molecular Subtyping and Immune Infiltration on Pathological Response and Outcome Following Neoadjuvant Pembrolizumab in Muscle-invasive Bladder Cancer.

Eur Urol 2020 06 9;77(6):701-710. Epub 2020 Mar 9.

Decipher Biosciences Inc., Vancouver, British Columbia, Canada. Electronic address:

Background: The PURE-01 study (NCT02736266) evaluated the use of pembrolizumab before radical cystectomy (RC) in muscle-invasive bladder cancer (MIBC).

Objective: To evaluate the ability of molecular signatures to predict the pathological complete response (CR: ypT0N0) and progression-free survival (PFS) after pembrolizumab and RC.

Design, Setting, And Participants: We analyzed the expression data from patients with T2-4aN0M0 MIBC enrolled in the PURE-01 study (N=84) and from patients of a retrospective multicenter cohort treated with cisplatin-based neoadjuvant chemotherapy (NAC; N=140).

Intervention: Neoadjuvant pembrolizumab or NAC and RC.

Outcome Measurements And Statistical Analysis: Immune signatures and molecular subtyping (The Cancer Genome Atlas, consensus model, and genomic subtyping classifier [GSC]) were evaluated in relation to CR and PFS. Multivariable logistic regression analyses for CR were used, adjusting for gender and clinical T stage.

Results And Limitations: The Immune190 signature was significant for CR on multivariable logistic regression analyses (p= 0.02) in PURE-01, but not in the NAC cohort (p= 0.7). Hallmark signatures for interferon gamma (IFNγ; p= 0.004) and IFNα response (p= 0.006) were also associated with CR for PURE-01, but not for NAC (IFNγ: p= 0.9 and IFNα: p= 0.8). In PURE-01, 93% of patients with the highest Immune190 scores (>1st quartile) had 2-yr PFS versus 79% of those with lower scores; no difference was observed in NAC patients, as well as for the other hallmarks in both groups. The neuroendocrine-like subtype had the worst 2-yr PFS in all three subtyping models (33%) and the GSC claudin-low subtype had the best, with no recurrences in 2 yr. Basal subtypes (across classifications) with higher Immune190 scores showed 100% 2-yr PFS after pembrolizumab therapy (p = 0.04, compared with basal-Immune190 low). Statistical analyses are limited by the small number of events and short follow-up.

Conclusions: Higher RNA-based immune signature scores were significantly associated with CR and numerically improved PFS outcomes after pembrolizumab, but not after NAC. These data emphasize that RNA profiling is a potential tool for personalizing neoadjuvant therapy selection.

Patient Summary: We used gene expression profiling to evaluate the association between immune gene expression and response to neoadjuvant immunotherapy, compared with standard chemotherapy, in patients with muscle-invasive bladder cancer (MIBC). We found a significant association between immune gene expression and response to pembrolizumab, but not chemotherapy. We conclude that gene expression profiling has the potential to guide personalized neoadjuvant therapy in MIBC.
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http://dx.doi.org/10.1016/j.eururo.2020.02.028DOI Listing
June 2020

Surgical Safety of Radical Cystectomy and Pelvic Lymph Node Dissection Following Neoadjuvant Pembrolizumab in Patients with Bladder Cancer: Prospective Assessment of Perioperative Outcomes from the PURE-01 Trial.

Eur Urol 2020 05 3;77(5):576-580. Epub 2020 Jan 3.

Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.

No data are available on the surgical safety of radical cystectomy (RC) and pelvic lymph node dissection (PLND) after the administration of checkpoint inhibitors. We aimed at reporting the first prospective rigorous assessment of perioperative outcomes after RC and extended PLND following neoadjuvant pembrolizumab in a contemporary cohort of patients with muscle-invasive bladder cancer (MIBC) enrolled in the PURE-01 trial. From February 2017 to June 2019, a total of 68 consecutive patients who received three courses of 200 mg pembrolizumab intravenously every 3 wk and were subsequently treated with either open or robot-assisted RC and PLND at a single high-volume tertiary referral center were identified. All men had prospectively collected data about intra- and postoperative outcomes. Postoperative complications were graded according to the Clavien-Dindo system. Perioperative data were prospectively and systematically collected during patient interviews at 90 d after surgery according to the European Association of Urology (EAU) Guidelines Panel recommendations on reporting and grading complications. Overall, 52 (77%) versus 16 (23%) patients underwent robot-assisted versus open RC, and 31 patients (46%) received an orthotopic neobladder. Median blood loss and length of stay were 150 ml and 12 d, respectively. Overall, 52 (77%), 47 (69%), and 22 (32%) patients experienced any-grade complications, grade ≥2 complications, and readmission at 90 d, respectively. High-grade complications (defined as Clavien-Dindo ≥3a) were observed in 23 patients (34%). The most frequent complications were fever (n = 35, 52%) and ileus (n = 21, 31%). None of the patients experienced perioperative mortality at 90 d. Our data represent the first prospective evidence supporting the surgical safety of RC and PLND in patients with N0M0 MIBC who received neoadjuvant immunotherapy with pembrolizumab. PATIENT SUMMARY: The current study represents the first prospective evidence supporting the surgical safety of radical cystectomy and pelvic lymph node dissection in patients with nonmetastatic bladder cancer who received neoadjuvant immunotherapy with pembrolizumab.
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http://dx.doi.org/10.1016/j.eururo.2019.12.019DOI Listing
May 2020

Multiparametric Magnetic Resonance Imaging as a Noninvasive Assessment of Tumor Response to Neoadjuvant Pembrolizumab in Muscle-invasive Bladder Cancer: Preliminary Findings from the PURE-01 Study.

Eur Urol 2020 05 25;77(5):636-643. Epub 2019 Dec 25.

Fondazione IRCCS Istituto Nazionale dei Tumori, Milano, Italy.

Background: In the PURE-01 study, pembrolizumab was given preoperatively before radical cystectomy in clinical T2-4aN0M0 patients. An accurate clinical response assessment may be useful for developing new perioperative strategies in these patients.

Objective: To evaluate the association between bladder multiparametric magnetic resonance imaging (mpMRI) findings after pembrolizumab and the pathological complete response (CR; pT0).

Design, Setting, And Participants: Patients were staged using bladder mpMRI whereby radiologists were asked to characterize the following parameters: residual disease at T1- and T2-weighted images (step 1: yes/no), presence of hyperintense spots within the bladder wall on diffusion-weighted imaging (step 2: yes/no), and presence of pathological contrast enhancement (step 3: yes/no), before and after three cycles of pembrolizumab. Examinations were internally assessed by two senior radiologists and externally evaluated by a third senior radiologist.

Intervention: To evaluate bladder tumor response after neoadjuvant pembrolizumab, mpMRI was used.

Outcome Measurements And Statistical Analysis: The primary objective was to predict the pT0 after neoadjuvant pembrolizumab by relying on the mpMRI findings. Cohen's kappa statistics was used to assess interobserver variability. Univariable analyses for pT0 were performed including internal and external post-therapy mpMRI steps.

Results And Limitations: From February 2017 to October 2018, 82 patients (164 total mpMRI assessments) were analyzed. The agreement between the internal and external mpMRI assessments after therapy was acceptable (κ values ranging from 0.5 to 0.76). Each mpMRI step was significantly associated with pT0 in both internal and external assessments. In patients with CR/no evidence of residual disease (NED) in all internally evaluated mpMRI steps (N = 37), the pT0 was seen in 23 (62%), compared with 19 of 26 externally evaluated NED patients (73%).

Conclusions: In post-pembrolizumab muscle-invasive bladder cancer, mpMRI sequence assessment had acceptable interobserver variability and represented the basis for the proposal of a radiological CR/NED status definition predicting the pT0 response to pembrolizumab. After validation of these findings with external datasets, we propose this tool for developing bladder-sparing immunotherapy maintenance therapies.

Patient Summary: Assessment of the extent of disease in patients with muscle-invasive bladder cancer using conventional imaging yields serious limitations. In the PURE-01 study, we evaluated the potential of bladder multiparametric magnetic resonance imaging (MRI) to predict the pathological complete response to neoadjuvant pembrolizumab. After validation with larger datasets, the proposed stepwise assessment incorporating multiparametric MRI sequences will be used at our center to develop bladder-sparing approaches in future studies.
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http://dx.doi.org/10.1016/j.eururo.2019.12.016DOI Listing
May 2020

Updated Results of PURE-01 with Preliminary Activity of Neoadjuvant Pembrolizumab in Patients with Muscle-invasive Bladder Carcinoma with Variant Histologies.

Eur Urol 2020 04 8;77(4):439-446. Epub 2019 Nov 8.

San Raffaele Hospital and Scientific Institute, Milan, Italy; Vita-Salute San Raffaele University, Milan, Italy.

Background: Patients with predominant variant histology (VH) of bladder tumors, defined as involving >50 % of the tumor specimens, are typically excluded from clinical trials, and for these patients, the efficacy of standard chemotherapy is limited.

Objective: To evaluate the activity of preoperative pembrolizumab in patients with muscle-invasive bladder carcinoma (MIBC) and VH, enrolled in PURE-01 study (NCT02736266).

Design, Setting, And Participants: In the open-label, single-arm, phase 2 PURE-01 study, three courses of 200 mg pembrolizumab preceding radical cystectomy (RC) were administered in T2-4aN0M0 MIBC patients. The amended study design included patients with predominant VH.

Intervention: Neoadjuvant pembrolizumab and RC.

Outcome Measurements And Statistical Analysis: Pathological complete response (pT0) in intention-to-treat population was the primary endpoint. Biomarker analyses included programmed cell-death ligand-1 (PD-L1) expression using the combined positive score (CPS; Dako 22C3 antibody) and comprehensive genomic profiling (FoundationOne assay). Multivariable logistic regression analyses (MVAs) evaluated the histological category (predominant VH vs nonpredominant VH vs pure urothelial carcinoma), tumor mutational burden (TMB) and CPS in association with the pathological response.

Results And Limitations: From February 2017 to June 2019, 114 patients were enrolled; 34 (30%) of them presented with VH, including 19 (17%) with predominant VH. In total, the pT0 rate was 37% (95% confidence interval [CI]: 28-46) and the pT ≤ 1 rate was 55% (95% CI: 46-65). The majority of predominant VH patients presented with squamous-cell carcinoma (SCC; N = 7), and six of seven (86%) had downstaging to pT ≤ 1, with one pT0; two of three lymphoepithelioma-like (LEL) variants had a pT0 response. None of the remaining nine predominant VHs had a response. On MVA, TMB and CPS were associated with both the pT0 and the pT ≤ 1 response, regardless of tumor histology.

Conclusions: The updated PURE-01 results confirm the activity of neoadjuvant pembrolizumab in MIBC. Patients with SCC and LEL features may be suitable for neoadjuvant immunotherapy trials. CPS and TMB are the key response predictors irrespective of the histological subtypes.

Patient Summary: In the PURE-01 study, we have preliminarily evaluated the activity of neoadjuvant pembrolizumab in patients with predominant variant histology (VH). Of these patients, those harboring squamous-cell carcinoma or a lymphoepithelioma-like variant feature had major, although preliminary, pathological responses compared with those with other predominant VHs. Expression of programmed cell-death ligand-1 and tumor mutational burden may predict the pathological response to pembrolizumab, and provide a rationale for selecting patients according to these features instead of the histological bladder cancer subtypes.
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http://dx.doi.org/10.1016/j.eururo.2019.10.026DOI Listing
April 2020

Complication rate after cystectomy following pelvic radiotherapy: an international, multicenter, retrospective series of 682 cases.

World J Urol 2020 Aug 6;38(8):1959-1968. Epub 2019 Nov 6.

Department of Urology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

Purpose: Conflicting evidence exists on the complication rates after cystectomy following previous radiation (pRTC) with only a few available series. We aim to assess the complication rate of pRTC for abdominal-pelvic malignancies.

Methods: Patients treated with radical cystectomy following any previous history of RT and with available information on complications for a minimum of 1 year were included. Univariable and multivariable logistic regression models were used to assess the relationship between the variable parameters and the risk of any complication.

Results: 682 patients underwent pRTC after a previous RT (80.5% EBRT) for prostate, bladder (BC), gynecological or other cancers in 49.1%, 27.4%, 9.8% and 12.9%, respectively. Overall, 512 (75.1%) had at least one post-surgical complication, classified as Clavien ≥ 3 in 29.6% and Clavien V in 2.9%. At least one surgical complication occurred in 350 (51.3%), including bowel leakage in 6.2% and ureteric stricture in 9.4%. A medical complication was observed in 359 (52.6%) patients, with UTI/pyelonephritis being the most common (19%), followed by renal failure (12%). The majority of patients (86%) received an incontinent urinary diversion. In multivariable analysis adjusted for age, gender and type of RT, patients treated with RT for bladder cancer had a 1.7 times increased relative risk of experiencing any complication after RC compared to those with RT for prostate cancer (p = 0.023). The type of diversion (continent vs non-continent) did not influence the risk of complications.

Conclusion: pRTC carries a high rate of major complications that dramatically exceeds the rates reported in RT-naïve RCs.
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http://dx.doi.org/10.1007/s00345-019-02982-6DOI Listing
August 2020

Predictive factors of the absence of residual disease at repeated transurethral resection of the bladder. Is there a possibility to avoid it in well-selected patients?

Urol Oncol 2020 03 14;38(3):77.e1-77.e7. Epub 2019 Sep 14.

Division of Urology, Department of Surgical Sciences, San Giovanni Battista Hospital, University of Studies of Torino, Turin, Italy.

Purpose: To evaluate the predictive factors of pT0 at repeated transurethral resection of the bladder (re-TURB) in pT1 high-grade (HG) nonmuscle invasive bladder cancer in order to explore the possibility to avoid it in well-selected patients.

Methods: This multicenter retrospective study included patients with pT1HG nonmuscle invasive bladder cancer from 4 different centers who underwent a complete TURB. Re-TURB was defined as a second resection which involved the site of the first TURB performed within 2-6 weeks from the previous resection. A multivariable logistic-regression model was performed to evaluate the predictors of pT0 at re-TURB. A nomogram was built to calculate the probability of obtaining a negative histology at re-TURB. The performance of the nomogram and its net benefit were tested with the decision curve analysis.

Results: Overall, 321 patients were included in the study. On multivariable logistic regression, detrusor muscle in the specimen (HR 1.99, P = 0.02), concomitant carcinoma in situ (HR 0.29, P = 0.005) and resection performed with en-bloc technique (HR 7.71, P = 0.01) were independent predictors of pT0 at re-TURB. Decision curve analysis showed a net benefit for the nomogram for each probability over 0.35 compared to the strategy to perform a re-TURB in all pT1HG tumors.

Conclusions: The presence of detrusor muscle in TURB specimen, the absence of concomitant carcinoma in situ and the en-bloc resection were able to predict a negative histology at re-TURB, opening the door to the possibility to avoid it in an extremely well-selected cohort of patients. External validations and prospective studies are urgently needed.
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http://dx.doi.org/10.1016/j.urolonc.2019.08.010DOI Listing
March 2020

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

World J Urol 2020 May 28;38(5):1229-1233. Epub 2019 Aug 28.

Klinik für Urologie, Luzerner Kantonsspital, Lucerne, Switzerland.

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.
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http://dx.doi.org/10.1007/s00345-019-02916-2DOI Listing
May 2020

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

World J Urol 2019 Dec 25;37(12):2707-2714. Epub 2019 Mar 25.

Klinik für Urologie, Luzerner Kantonsspital, Lucerne, Switzerland.

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.
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http://dx.doi.org/10.1007/s00345-019-02734-6DOI Listing
December 2019

Evaluation of Cause of Death After Radical Cystectomy for Patients With Bladder Cancer: The Impact of Age at the Time of Surgery.

Clin Genitourin Cancer 2019 06 13;17(3):e541-e548. Epub 2019 Feb 13.

Unit of Urology/Division of Oncology, IRCCS Ospedale San Raffaele, URI Milan, Milan, Italy.

Introduction: Patients with bladder cancer treated with radical cystectomy (RC) have heterogeneous results in term of cancer-specific (CSM) and other cause mortality (OCM). Our aim is to assess the impact of age on cause of death after RC.

Patients And Methods: We retrospectively analyzed the data of 1222 patients treated with RC and bilateral pelvic lymph node dissection owing to nonmetastatic bladder cancer between 1990 and 2013. Patients were stratified according to age (< 59 vs. 60-69 vs. 70-79 vs. ≥ 80 years), tumor T stage at RC (pT0-T2 vs. pT3-T4), and tumor N stage at RC (pN+ vs. pN0). Competing-risks survival analyses were used to estimate CSM and OCM rates.

Results: With a median follow up of 6 years, 92 (7.5%) and 385 (31.5%) OCM and CSM were recorded. The 5-year CSM and OCM rates were 40% and 8.8%, respectively. After stratification according to disease stage and patient age, CSM emerged as the main cause of mortality in all patient subgroups. The 5-year OCM was 4.6%, 4.8%, 11%, and 32% for patients aged < 60 years versus 60 to 69 years versus 70 to 79 years versus ≥ 80 years, respectively. The 5-years CSM was 34%, 45%, 35%, and 56% for patients aged < 60 years versus 60 to 69 years versus 70 to 79 years versus ≥ 80 years, respectively. Similar findings were observed stratifying the population according to pathologic T and N stage.

Conclusion: CSM is the preponderant cause of death for all the patients, regardless of age or stage. In this regard, RC also seems to be a reasonable approach for octogenarians.
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http://dx.doi.org/10.1016/j.clgc.2019.02.001DOI Listing
June 2019

Translation and cultural adaptation of the Computer Vision Syndrome Questionnaire (CVS-Q) into Italian.

Med Lav 2019 Feb 22;110(1):37-45. Epub 2019 Feb 22.

University of Alicante.

Background: The original Spanish version of the Computer Vision Syndrome Questionnaire (CVS-Q©) is a validated instrument with good psychometric properties to measure the Computer Visual Syndrome (CVS) in workers exposed to video display terminals (VDT). The Italian version would facilitate research and its use in clinical practice the prevention of occupational hazards.

Objective: To culturally translate and adapt the CVS-Q© into Italian.

Methods: Study with 5 consecutive stages: Direct translation, Synthesis of translations, Retro-translation, Consolidation by a committee of experts and Pre-test. During the Pre-test, a cross-sectional pilot study was conducted on users of VDT (n=40) who completed the Italian version of the questionnaire. Socio-demographic information and exposure assessment to VDT was also collected, as well as on the difficulty to fill in the CVS-Q©.

Results: The final version into Italian of the CVS-Q© was obtained. The totality of the sample considered that it didn't present difficulty in its completion and 90% confirmed that no improvement was needed; so that the 15% required to make changes was not reached. The mean age of participants was of 35.80±16.28 (20-65 years), 57.5% were women and 67.5% used VDT at work. A prevalence of CVS of 62.5% was observed.

Conclusion: The CVS-Q© can be considered a tool easy to understand and manage for measuring the CVS in the population exposed to VDT in Italy.
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http://dx.doi.org/10.23749/mdl.v110i1.7499DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7809999PMC
February 2019

Radical Cystectomy in Pathological T4a and T4b Bladder Cancer Patients: Is There Any Space for Sub Stratification?

Urol Int 2019 29;102(3):269-276. Epub 2019 Jan 29.

Division of Oncology, Unit of Urology, IRCCS Ospedale San Raffaele, Milan, Italy.

Introduction: According to TNM staging, pathological T4ab are comprehensive of the invasion of prostate, seminal vesicles, uterus or vagina and pelvic or abdominal wall. However, few data are available on the perioperative and oncological outcomes of specific organ invasion.

Materials And Methods: A total of 917 consecutive bladder cancer (BCa) patients treated with radical cystectomy (RC) at a single institution between 1990 and 2015 were studies. Cox regression analyses were used to stratify pT4ab according to the site of invasion and survival.

Results: Overall, 176 (19.2%) and 40 (4.4%) patients harbored pT4a or pT4b disease. Specifically, 84 (9.2%) patients reported prostate and/or SVI invasion, 62 (6.8%) prostate only, 16 (1.7%) uterus, 14 (1.5%) vaginal, 24 (2.6%) pelvic wall, and 16 (1.7%) abdominal wall invasion. The median follow-up in pT4 patients was 48 months. The 1-year cancer-specific mortality (CSM) rates were 71, 65, 24, 50, 50, and 72%, for vaginal, uterus, prostate only, prostate and/or seminal vesicles, pelvic wall, and abdominal wall invasions, respectively. At multivariable Cox regression, the invasion of prostate only (hazard ratio [HR] 3.53), prostate and/or SVI (HR 4.98), uterus (HR 7.16), vagina (HR 6.12), pelvic (HR 11.81), abdominal (8.36) were associated with adverse CSM.

Conclusions: Our study described the differences in survival related to invasion site in pT4 patients, confirming poor survival expectancies in this subgroup. Patients with prostate invasion only seem to be associated with better survival than those affected by concomitant invasion of seminal vesicles. Uterus and vaginal invasions were associated with poor survival outcomes. Patients Summary: In this study, we looked at the outcome of locally advanced invasive BCa (stage pT4) in patients treated with RC at a tertiary referral hospital. We analyzed the differences in survival related to the specific organ invasion. We confirmed poor survival in this subgroup of patients. Only patients who had prostate invasion only seem to have a better survival.
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http://dx.doi.org/10.1159/000493899DOI Listing
December 2019

Pembrolizumab as Neoadjuvant Therapy Before Radical Cystectomy in Patients With Muscle-Invasive Urothelial Bladder Carcinoma (PURE-01): An Open-Label, Single-Arm, Phase II Study.

J Clin Oncol 2018 12 20;36(34):3353-3360. Epub 2018 Oct 20.

Andrea Necchi, Andrea Anichini, Daniele Raggi, Simona Massa, Maurizio Colecchia, Patrizia Giannatempo, Roberta Mortarini, Elena Farè, Francesco Monopoli, Antonella Messina, Roberto Salvioni, and Luigi Mariani, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico, Istituto Nazionale dei Tumori; Alberto Briganti, Roberta Lucianò, Marco Bianchi, Renzo Colombo, Andrea Gallina, Andrea Salonia, and Francesco Montorsi, Vita Salute San Raffaele University and Urological Research Institute, Istituto di Ricovero e Cura a Carattere Scientifico San Raffaele Hospital, Milan, Italy; Siraj M. Ali, Russell Madison, Jeffrey S. Ross, and Jon H. Chung, Foundation Medicine, Cambridge, MA; and Jeffrey S. Ross, Upstate Medical University, Syracuse, NY.

Purpose: To determine the activity of pembrolizumab as neoadjuvant immunotherapy before radical cystectomy (RC) for muscle-invasive bladder carcinoma (MIBC) for which standard cisplatin-based chemotherapy is poorly used.

Patients And Methods: In the PURE-01 study, patients had a predominant urothelial carcinoma histology and clinical (c)T≤3bN0 stage tumor. They received three cycles of pembrolizumab 200 mg every 3 weeks before RC. The primary end point in the intention-to-treat population was pathologic complete response (pT0). Biomarker analyses included programmed death-ligand 1 (PD-L1) expression using the combined positive score (CPS; Dako 22C3 pharmDx assay), genomic sequencing (FoundationONE assay), and an immune gene expression assay.

Results: Fifty patients were enrolled from February 2017 to March 2018. Twenty-seven patients (54%) had cT3 tumor, 21 (42%) cT2 tumor, and two (4%) cT2-3N1 tumor. One patient (2%) experienced a grade 3 transaminase increase and discontinued pembrolizumab. All patients underwent RC; there were 21 patients with pT0 (42%; 95% CI, 28.2% to 56.8%). As a secondary end point, downstaging to pT<2 was achieved in 27 patients (54%; 95% CI, 39.3% to 68.2%). In 54.3% of patients with PD-L1 CPS ≥ 10% (n = 35), RC indicated pT0, whereas RC indicated pT0 in only 13.3% of those with CPS < 10% (n = 15). A significant nonlinear association between tumor mutation burden (TMB) and pT0 was observed, with a cutoff at 15 mutations/Mb. Expression of several genes in pretherapy lesions was significantly different between pT0 and non-pT0 cohorts. Significant post-therapy changes in the TMB and evidence of adaptive mechanisms of immune resistance were observed in residual tumors.

Conclusion: Neoadjuvant pembrolizumab resulted in 42% of patients with pT0 and was safely administered in patients with MIBC. This study indicates that pembrolizumab could be a worthwhile neoadjuvant therapy for the treatment of MIBC when limited to patients with PD-L1-positive or high-TMB tumors.
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http://dx.doi.org/10.1200/JCO.18.01148DOI Listing
December 2018

Development of a Prediction Tool for Exclusive Locoregional Recurrence After Radical Cystectomy in Patients With Muscle-Invasive Bladder Cancer.

Clin Genitourin Cancer 2019 Feb 13;17(1):7-14.e3. Epub 2018 Sep 13.

Mount Sinai School of Medicine, Tisch Cancer Institute, New York, NY.

Background: Limited information is available about the pattern of relapse after perioperative chemotherapy with radical cystectomy (RC) vs. RC alone in muscle-invasive bladder cancer.

Patients And Methods: Data from 1082 patients of the Retrospective International Study of Invasive/Advanced Cancer of the Urothelium database, treated from February 1990 to December 2013 at 27 centers in the United States, Europe, Israel, and Canada, were collected. Locoregional relapse was defined as any pelvic lymph node or soft tissue-only recurrences. Cumulative incidence methods were used to estimate time to locoregional relapse (TTR). Cox regression analyses were performed and a nomogram for 12-month locoregional relapse-free survival (RFS) was developed. The nomogram was applied to an external data set (n = 1021).

Results: A total of 517 patients (47.8%) developed a relapse: 177 (16.4%) exclusive locoregional relapse. In multivariable analyses, perioperative chemotherapy was associated with longer TTR (P < .001). Other factors were nonurothelial histology (P = .013), pT-stage (P < .001), and surgical margins (P < .001). The concordance index of the model was 0.681 (95% bootstrapped confidence interval, 0.666-0.716). Risk group categories were obtained according to nomogram tertiles. Despite, overall, observed locoregional RFS in the validation cohort exceeding predicted results, for high-risk patients (80 points or less, lowest nomogram tertile) observed 12-month RFS was similar between development and validation cohorts (60.1% and 66.6%). The study is limited by its retrospective nature.

Conclusion: In the largest study, to our knowledge, that analyzed locoregional recurrences after RC, we propose a risk prediction tool for exclusive locoregional failures that might be suitable for clinical studies. Patients best suited for adjuvant radiotherapy might be those within the lowest nomogram tertile. Prospective trials are needed to validate findings.
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http://dx.doi.org/10.1016/j.clgc.2018.09.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6857172PMC
February 2019

Pattern of node metastases in patients treated with radical cystectomy and extended or superextended pelvic lymph node dissection due to bladder cancer.

Urol Oncol 2018 Jun 27;36(6):307.e9-307.e14. Epub 2018 Mar 27.

Unit of Urology/Division of Oncology; IRCCS Ospedale San Raffaele; URI, Milan, Italy.

Background: Pelvic lymph node dissection (PLND) has a diagnostic and therapeutic role during radical cystectomy in bladder cancer patients. However, at the time, no prospective data supports the value of extended PLND in improving survival expectances. We sought to describe incidence and location of node metastases in patients treated with extended and superextended PLND.

Methods: We evaluated 653 contemporary patients with clinically nonmetastatic high risk nonmuscle invasive or muscle-invasive bladder cancer treated with radical cystectomy and extended or superextended PLND without neoadjuvant chemotherapy at a single tertiary referral center between 1990 and 2013. Limited PLND is defined as the removal of obturator and internal iliac nodes. Standard included also the external iliac nodes. Extended includes also common and presacral nodes. Finally, superextended PLND includes all the nodes removed along the inferior mesenteric artery. We evaluated incidence of pathologically node metastases. Logistic regression analyses evaluate preoperative and pathologic characteristics to the risk of harboring node metastases in the extended and superextended template.

Results: Overall, 191 (29.3%) patients were found with pathologically node confirmed metastases. Of these, 56 (29.3%) patients were found with a single node metastasis, while 135 (70.7%) had multiple node metastases. The vast majority of patients were found with node metastases standard template (n = 172, 26.3%), on the other hand 30 (4.6%) and 21 (3.2%) patients had node metastases in extended and superextended templates, respectively. However, of these only 2 patients were found without concomitant lymph node metastases in the limited or standard templates. On multivariable analyses, cN+ status (odds ratio = 4.40, P<0.001) and cT3-4 vs. cT1-2 (odds ratio = 2.25, P<0.001) were associated with an increased risk of harboring node metastases in the extended or superextended template.

Conclusions: We found that the majority of patients harbored node disease in the limited or standard node dissection pattern. On the other hand, only a minority of patient were found with a disease in extended or superextended template without harboring a concomitant node disease in the limited pattern.
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http://dx.doi.org/10.1016/j.urolonc.2018.03.002DOI Listing
June 2018

Adjuvant recMAGE-A3 Immunotherapy After Cystectomy for Muscle-invasive Bladder Cancer: Lessons Learned from the Phase 2 MAGNOLIA Clinical Trial.

Eur Urol Focus 2019 09 21;5(5):849-852. Epub 2018 Feb 21.

EAU Research Foundation, Arnhem, The Netherlands. Electronic address:

The MAGNOLIA study, investigating the concept of perioperative immunotherapy in muscle- invasive bladder cancer, was prematurely terminated. The lessons learned that should be considered before initiating and conducting future clinical trials in this field are highlighted.
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http://dx.doi.org/10.1016/j.euf.2018.02.005DOI Listing
September 2019

Surgical treatment for clinical node-positive bladder cancer patients treated with radical cystectomy without neoadjuvant chemotherapy.

World J Urol 2018 Apr 24;36(4):639-644. Epub 2018 Jan 24.

Unit of Urology/Division of Oncology, IRCCS Ospedale San Raffaele, URI Milan, Milan, Italy.

Objective: Growing literature supports good survival expectancies in bladder cancer (BCa) patients affected by clinical node metastases (cN+) treated with multimodal therapy. We evaluated the role of adjuvant chemotherapy in cN+BCa patients treated with radical cystectomy (RC) and pelvic lymph node dissection (PLND) without neoadjuvant chemotherapy (NAC).

Methods: We evaluated a total of 192 patients with BCa and cN+. All patients were treated with RC and PLND without NAC between 2001 and 2013. Kaplan-Meier analyses and Cox regression analyses were used to assess the impact of adjuvant chemotherapy (ACT) on recurrence, cancer-specific mortality (CSM) and overall mortality (OM) after surgery.

Results: Overall, 99 patients (51.6%) were found without node metastases at RC, while 18 (9.4%), 58 (30.2%) and 17 (8.9%) patients were found pN1, pN2 and pN3, respectively. With a median follow-up of 48 months, in cN+ patients we recorded 5-year recurrence, CSM and OM of 55, 53 and 51%, respectively. Overall, 36 (18.8%) patients were treated with adjuvant chemotherapy. At univariable analyses, ACT was associated with improved overall survival [Hazard ratio (HR): 0.42, confidence interval (CI) 0.20-0.86, p = 0.02) in pN+ subgroup only. These results were confirmed at multivariable analyses, where ACT was associated with improved CSS (HR: 0.45, CI 0.21-0.89, p = 0.03) and OS (HR: 0.37, CI 0.17-0.81, p = 0.01).

Conclusions: We report good survival outcomes in cN+ patients treated with RC. The use of ACT after surgery increases survival expectancies, especially in those patients with pathological node disease. Our data need to be further evaluated in prospective setting.
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http://dx.doi.org/10.1007/s00345-018-2190-1DOI Listing
April 2018

Perioperative and Oncologic Outcomes of Nephrectomy and Caval Thrombectomy Using Extracorporeal Circulation and Deep Hypothermic Circulatory Arrest for Renal Cell Carcinoma Invading the Supradiaphragmatic Inferior Vena Cava and/or Right Atrium.

Eur Urol 2018 05 13;73(5):793-799. Epub 2017 Sep 13.

Unit of Urology, University Vita-Salute San Raffaele, IRCCS San Raffaele Scientific Institute, Milan, Italy; Division of Oncology, URI, Urological Research Institute, Renal cancer Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy. Electronic address:

Background: Radical nephrectomy (RN) and caval thrombectomy (CT) for renal cell carcinoma, with extracorporeal circulation (ECC) and deep hypothermic circulatory arrest (DHCA) is a challenging surgical approach.

Objective: To assess peri-operative and oncologic outcomes of renal cell carcinoma patients treated with RN and CT, using ECC and DHCA.

Design, Setting, And Participants: We retrospectively evaluated 46 patients who underwent RN and CT using ECC and DHCA.

Surgical Procedure: After retroperitoneal nodal dissection and RN, a cardiopulmonary bypass was placed and DHCA achieved. A combined approach through the abdomen and the thorax was described.

Measurements: Perioperative and long-term survival outcomes were reported.

Results And Limitations: Median operative time and length of hospital stay were 545min and 22 d. Overall, 33 patients (72%) did not require any additional interventional or surgical treatment. Thirty-day and 90-d mortality were 11% (5/46) and 15% (7/46). The 1-yr, 2-yr, and 3-yr cancer specific mortality (CSM)-free survival rates were 77%, 62%, and 56%, respectively. After stratification, according to metastatic status at diagnosis, CSM-free survival rates were significantly lower for cM1 patients compared with cM0 patients (1-yr 46% vs 93%, 2-yr 23% vs 81%, 3-yr 23% vs 73%, p<0.01). Our study is limited by its retrospective and uncomparative nature.

Conclusions: RN with CT using ECC and DHCA is a challenging procedure which requires a dedicated multidisciplinary working team to minimise complications and maximise patients' outcomes.

Patient Summary: Patients with kidney cancer and a thrombus within the inferior vena cava, which reaches above the diaphragm, can be treated with surgery. However, this kind of surgical treatment is challenging and requires a dedicated multidisciplinary team in order to accomplish the task.
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http://dx.doi.org/10.1016/j.eururo.2017.08.019DOI Listing
May 2018

Predicting local failure after radical cystectomy in patients with bladder cancer: Implications for the selection of candidates at adjuvant radiation therapy.

Urol Oncol 2017 12 5;35(12):672.e1-672.e6. Epub 2017 Sep 5.

Department of Urology, Urological Research Institute, Vita-Salute San Raffaele University, San Raffaele Scientific Institute, Milan, Italy.

Objective: To evaluate incidence and predictors of local failure (LF) after radical cystectomy (RC) due to bladder cancer.

Methods: We focused on 1,112 patients treated with RC, between 1990 and 2012, at a single center. LF was defined as imaging evidence of recurrence in the pelvic soft tissues or nodes below the aortic bifurcation at least 3 months before the detection of distant metastases. Competing risk analyses tested the relationship between clinical and pathological factors and the risk to develop LF. Regression tree analysis stratified patients into risk-groups based on their characteristics and the corresponding LF rate.

Results: Overall, 50 (4.5%) patients developed LF during a median follow-up period of 62 (35-92) months. On univariable competing risk regression analyses, pathological T stage (pT4 vs. pT3; hazard ratio [HR] = 2.55, P = 0.003), soft tissue surgical margin (STSM; HR = 2.95, P = 0.005), and variant histology (HR = 1.79, P = 0.03) were associated with an increased risk of developing LF. The cohort was stratified into 4 risk groups: very low (≤pT3a disease and pure urothelial histology), low (≤pT3a disease and variant histology), intermediate (pT4 disease), and high (positive STSM).

Conclusions: LF is an important event in RC patients. We developed a new risk model based on bladder cancer characteristics. Our findings could help with the identification of the best candidate for consideration of adjuvant radiotherapy.
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http://dx.doi.org/10.1016/j.urolonc.2017.08.013DOI Listing
December 2017

In reply to: Lawless et al. Stalk versus base invasion in pT1 papillary cancers of the bladder: improved substaging system predicting the risk of progression.

Histopathology 2018 01 27;72(2):361-362. Epub 2017 Oct 27.

Department of Urology, Ospedale San Raffaele, Milan, Italy.

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http://dx.doi.org/10.1111/his.13374DOI Listing
January 2018

Clinical Lymphadenopathy in Urothelial Cancer: A Transatlantic Collaboration on Performance of Cross-sectional Imaging and Oncologic Outcomes in Patients Treated with Radical Cystectomy Without Neoadjuvant Chemotherapy.

Eur Urol Focus 2018 03 23;4(2):245-251. Epub 2016 Nov 23.

Department of Urology, Mayo Clinic, Rochester, MN, USA. Electronic address:

Background: Data regarding clinical node metastases (cN+) in patients undergoing radical cystectomy (RC) are scarce.

Objective: To evaluate the performance of conventional imaging in detecting cN+ and analyze the impact of cN+ on survival among patients treated with RC without neoadjuvant chemotherapy (NAC).

Design, Setting, And Participants: Data from three independent centers of consecutive patients with bladder cancer treated with RC without NAC were analyzed. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: cN+ was defined as pelvic nodes >8mm or abdominal nodes >10mm in maximum short-axis diameter as detected via preoperative computed tomography or magnetic resonance imaging. Performance characteristics were evaluated considering pN+ disease as the reference standard. Multivariable Cox regression analyses were performed for prediction of survival.

Results And Limitations: Overall, 196 patients (7.1%) had cN+ disease before RC and pN+ status was confirmed for 122 of them (62.2%). cN+ status in the overall population had sensitivity of 18% and specificity of 96% with a calculated area under the curve of 57%. The median follow-up was 108 mo. On multivariable analyses, cN+pN+ (hazard ratio [HR] 1.84, 95% confidence interval [CI] 1.26-2.68) and cN-pN+ (HR 2.36, 95% CI 1.90-2.92) were predictors of CSM (both p<0.001). Conversely, cN+pN- status was not associated with worse survival outcomes (p > 0.2).

Conclusions: Our study confirms the poor accuracy of conventional preoperative imaging in assessing nodal disease status. cN status had no independent impact on survival when all confounders were evaluated, and potentially curative treatments should not be withheld on the basis of clinical nodal status alone.

Patient Summary: The accuracy of conventional imaging techniques for detection of pathologic lymph node-positive disease before radical cystectomy for bladder cancer is suboptimal. The presence of clinical lymph node positivity on preoperative imaging is not an independent predictor of oncologic outcomes, and if the node invasion is not confirmed at radical cystectomy, these patients may have good long-term outcomes.
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http://dx.doi.org/10.1016/j.euf.2016.11.005DOI Listing
March 2018

Feasibility and Clinical Roles of Different Substaging Systems at First and Second Transurethral Resection in Patients with T1 High-Grade Bladder Cancer.

Eur Urol Focus 2018 01 15;4(1):87-93. Epub 2016 Jun 15.

Department of Pathology, Azienda Ospedaliera Sant'Anna, Como, Italy.

Background: Decision making in T1 high-grade bladder cancer patients remains a challenging issue in urologic practice.

Objective: To assess the feasibility and potential prognostic role of three different substaging systems in specimens from both primary and second transurethral resection (TUR) of the bladder in T1 high-grade bladder cancer patients.

Design, Setting, And Participants: A total of 250 consecutive, confirmed pure transitional T1 high-grade bladder tumors submitted to second TUR entered the retrospective study.

Outcome Measurements And Statistical Analysis: Feasibility of two already clinically tested microstaging systems (anatomy-based T1a/T1b/T1c and micrometric T1m/T1e with 0.5-mm thresholds of invasion) and that of a micrometric substage designed by the authors and based on a 1-mm threshold of invasion (Rete Oncologica Lombarda [ROL] system) was assessed by five independent uropathologists on both first and second TUR specimens. Univariable Cox proportional hazards models were attempted to identify significant independent predictors of recurrence and progression after TUR. Kaplan-Meier curves were plotted to compare different substaging methods analyzing recurrence and progression.

Results And Limitations: The ROL system proved to be feasible in nearly all cases at both first and second TUR. Median follow-up was 60 mo. The univariate Cox regression analysis documented the ROL substage (ROL2 vs ROL1) to be the only statistically significant predictor of progression (hazard ratio: 2.01; 95% CI, 1.03-3.79; p<0.03). For the first time to our knowledge, the substage was investigated and used to assess T1 tumors found at second TUR, registering a high rate of feasibility.

Conclusions: T1 microstaging using different procedures is feasible on both primary- and second-TUR specimens. A high rate of feasibility may be expected for T1m/T1e and ROL systems. The clinical role of microstaging on second TUR remains to be defined.

Patient Summary: The Rete Oncologica Lombarda system showed feasible results in T1 high-grade bladder tumors. Our substratification was predictive of progression of disease.
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http://dx.doi.org/10.1016/j.euf.2016.06.004DOI Listing
January 2018