Publications by authors named "Francesco Montorsi"

1,470 Publications

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Adjuvant immunotherapy in patients with high-risk muscle-invasive urothelial carcinoma: The potential impact of informative censoring.

Cancer 2022 May 12. Epub 2022 May 12.

Division of Hematology/Oncology, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York.

Background: The results of 2 studies exploring adjuvant immune checkpoint inhibition (aCPI) in high-risk muscle-invasive urothelial cancer have yielded conflicting results. A trial employing placebo as the control arm demonstrated a significant prolongation in disease-free survival (DFS) whereas a trial employing observation as the control arm (IMvigor010) demonstrated no prolongation in DFS with CPI. Here, the authors aimed to estimate the aCPI benefit and to model the potential impact of informative censoring on trial results.

Methods: Survival data from 1518 patients was reconstructed from Kaplan-Meier curves. A network meta-analysis approach was used to estimate aCPI benefit through the restricted mean disease-free survival time (RMDFST). To estimate the potential impact of informative censoring on IMvigor010, a simulation was performed. The minimum proportion of informative censoring on the observation arm that could account for the lack of observed improvement in DFS was estimated. Random variability from the time of censoring to progression was modeled using the exponential distribution.

Results: Patients receiving aCPI had better DFS: ΔRMDFST at 36 months of 2.2 (95% CI, 0.6-3.7, P = .006) months relative to observation/placebo. In IMvigor010, in the observation arm, 20.5% of patients were censored due to consent withdrawal, protocol violation and/or noncompliance, or lost to follow-up versus 8.2% in the treatment arm. On simulation, it was found that the lack of observed improvement in DFS could have resulted from as few as 14% of the censored patients on observation arm not being censored at random (simulated DFS with 14% informative censoring hazard ratio, 0.83; 95% CI, 0.69-0.99; P = .049).

Conclusions: Phase 3 trials comparing adjuvant therapies to observation are at risk for informative censoring that could potentially impact interpretation of study results.
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http://dx.doi.org/10.1002/cncr.34255DOI Listing
May 2022

Does previous prostate surgery affect multiparametric magnetic resonance imaging accuracy in detecting clinically significant prostate cancer? Results from a single institution series.

Prostate 2022 May 10. Epub 2022 May 10.

Division of Oncology/Unit of Urology, Urological Research Institute, IRCCS San Raffaele Hospital, Milan, Italy.

Background: Multiparametric MRI (mpMRI) has demonstrated high diagnostic accuracy for clinically significant PCa (csPCa). However, the accuracy of this test in men that received a previous prostatic surgery is still controversial. We aimed at assessing the effect of previous prostatic surgery on the detection of csPCa in a tertiary referral center.

Method: We relied on a cohort of 311 men with a positive mpMRI (prostate imaging - reporting and data system [PI-RADS] ≥ 3) who underwent a targeted (TBx) plus concomitant systematic random biopsy (SBx) at a single tertiary referral center between 2017 and 2020. The study outcome was to compare the detection of csPCa (Gleason score ≥ 3 + 4) between the two groups (no previous prostate surgery [Group 1] vs. previous prostate surgery [Group 2]). Multivariable logistic regression analysis (MVA) was used to assess the relationship between previous prostate surgery and the detection of csPCa at TBx, after taking into account potential clinical confounders.

Results: Overall, 24 (8%) patients received a previous prostate surgery before undergoing mpMRI. Median prostate-specific antigen density was 0.15 versus 0.08 ng/ml/cc, in Group 1 versus 2, respectively. The most frequent finding at mpMRI was in Group 1 versus 2, PI-RADS 4 (55%) versus PI-RADS 3 and 4 (42% each). The majority of patients were biopsy naïve in both Groups 1 (66%) and 2 (71%). The overall detection of csPCa in Group 1 versus 2 was 83% versus 75%, respectively. Differently, the detection of csPCa at TBx in Groups 1 versus 2 was 76% versus 71%, respectively. At MVA, previous prostate surgery (odds ratio: 0.65; p = 0.02) was significantly associated with lower csPCa detection at TBx, after accounting for potential confounders.

Conclusion: The presence of previous prostate surgery significantly decreases the accuracy of mpMRI in detecting csPCa. These results should be taken into account when assessing patients with a history of prostatic surgery and a suspicious lesion at mpMRI, to better select those who might avoid an unnecessary biopsy.
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http://dx.doi.org/10.1002/pros.24368DOI Listing
May 2022

Learning Curve Analysis for Intracorporeal Robot-assisted Radical Cystectomy: Results from the EAU Robotic Urology Section Scientific Working Group.

Eur Urol Open Sci 2022 May 2;39:55-61. Epub 2022 Apr 2.

Department of Urology, Radboud University Medical Center, Nijmegen, The Netherlands.

Background: The utilisation of robot-assisted radical cystectomy with intracorporeal reconstruction (iRARC) has increased in recent years. Little is known about the length of the learning curve (LC) for this procedure.

Objective: To study the length of the LC for iRARC in terms of 90-d major complications (MC90; Clavien-Dindo grade ≥3), 90-d overall complications (OC90, Clavien-Dindo grades 1-5), operating time (OT), estimated blood loss (EBL), and length of hospital stay (LOS).

Design Setting And Participants: This was a retrospective analysis of all consecutive iRARC cases from nine European high-volume hospitals with ≥100 cases. All patients had bladder cancer for which iRARC was performed, with an ileal conduit or neobladder as the urinary diversion.

Outcome Measurements And Statistical Analysis: Outcome parameters used as a proxy for LC length were the number of consecutive cases needed to reach a plateau level in two-piece mixed-effects models for MC90, OC90, OT, EBL, and LOS.

Results And Limitations: A total of 2186 patients undergoing iRARC between 2003 and 2018were included. The plateau levels for MC90 and OC90 were reached after 137 cases (95% confidence interval [CI] 80-193) and 97 cases (95% CI 41-154), respectively. The mean MC90 rate at the plateau was 14% (95% CI 7-21%). The plateau level was reached after 75 cases (95% CI 65-86) for OT, 88 cases (95% CI 70-106) for EBL, and 198 cases (95% CI 130-266) for LOS. A major limitation of the study is the difference in the balance of urinary diversion types between centres.

Conclusions: This multicentre retrospective analysis for the iRARC LC among nine European centres showed that 137 consecutive cases were needed to reach a stable MC90 rate.

Patient Summary: We carried out a multicentre analysis of the surgical learning curve for robot-assisted removal of the bladder and bladder reconstruction in patients with bladder cancer. We found that 137 consecutive cases were needed to reach a stable rate of serious complications.
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http://dx.doi.org/10.1016/j.euros.2022.03.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9068730PMC
May 2022

Quality-of-Life Outcomes in Female Patients With Ileal Conduit or Orthotopic Neobladder Urinary Diversion: 6-Month Results of a Multicenter Prospective Study.

Front Oncol 2022 12;12:855546. Epub 2022 Apr 12.

Department of Human Sciences, Verona University, Verona, Italy.

Radical cystectomy (RC) often affects patients' life as this surgery is a traumatic and invasive event for the patients, with drawbacks on their daily, social, working, and sex life. Such changes in the quality of life (QoL) of patients are commonly studied through retrospective clinical evaluations and rarely with longitudinal studies. To date, studies focusing on functional outcomes, sexual function, and health-related QoL for female patients are lacking. We evaluated 37 patients using EORTC QLQ-C30 (QLQ-30) and Short-Form 36 (SF-36) questionnaires, before and after surgery, at 3 and 6 months of follow-up. The mean values for the emotional functioning in QLQ-C30 as well as the mental health in SF-36 were significantly higher in the ONB group compared to the IC group at 3 months of follow-up. These differences were not significant at 6 months of follow-up. At 6 months of follow-up, the ONB group showed a higher mean score in the physical and role functioning than the IC group. Although there was a statistically significant age difference at baseline of the two groups, none of the results are correlated with age, as demonstrated by Spearman's analysis. The ONB seems to represent the most advantageous solution compared to the IC in terms of QOL at the 6-month follow-up.
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http://dx.doi.org/10.3389/fonc.2022.855546DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9067240PMC
April 2022

Are finasteride-related penile curvature/Peyronie's disease Adverse Event Reports worthy of further clinical investigation? Disproportionality analysis based on both the Food and Drug Administration (FDA) and the European Medicines Agency (EMA) pharmacovigilance databases.

Int J Impot Res 2022 May 5. Epub 2022 May 5.

Università Vita-Salute San Raffaele, Milan, Italy.

A limited number of studies have described patients on finasteride showing findings which were consistent with Peyronie's disease (PD). We aimed to detect a pharmacovigilance signal of possible association between finasteride and PD-related clinical features. The Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS) database was queried to identify the ten drugs which were associated the most with the adverse drug reactions (ADRs) recorded as "penile curvature" and/or "Peyronie's disease". A similar analysis, including the same drugs, was carried out for the EMA (European Medicines Agency) EudraVigilance (EV) database. Descriptive data have been analyzed, and Proportional Reporting Ratios (PRRs) have been computed against the other nine drugs of the database. Overall, 860 reports of "penile curvature" and/or "Peyronie's disease", were identified in the FAERS database, 214 of which (24.9%) were associated with finasteride. Most reports (56.9%) were submitted by healthcare professionals. Where a treatment-indication was stated, the vast majority of reports (176/210; 83.8%) were associated with androgenetic alopecia. The outcome of most ADRs was "serious" (82.2%), with 96 ADRs resulting in levels of permanent disability. For 97/214 individual cases, penile curvature/PD reports were not part of a syndromic cluster suggestive of post-finasteride syndrome (PFS). The PRR resulted 6.6 (95% CI: 5.6-7.8) and 11.8 (95% CI: 9.08-15.33), respectively, in the FAERS and in the EV databases. Notwithstanding the related limitations and biasing factors of pharmacovigilance studies based on spontaneous reporting, the PRR values here identified should be interpreted as strong signals of disproportionality. These findings, per se, are however not useful to confirm any causal association. Clinical studies are needed to investigate on the possible role for finasteride in causing PD-related clinical features, an hypothesis which remains highly speculative due to the very questionable quality of present data.
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http://dx.doi.org/10.1038/s41443-022-00568-2DOI Listing
May 2022

Life expectancy in metastatic urothelial bladder cancer patients according to race/ethnicity.

Int Urol Nephrol 2022 May 4. Epub 2022 May 4.

Cancer Prognostics and Health Outcomes Unit, Division of Urology, University of Montréal Health Center, Montréal, QC, Canada.

Purpose: to compare observed overall survival vs age-adjusted lifetable (LT) derived life expectancy (LE) in metastatic urothelial bladder cancer (MBCa) patients according to race/ethnicity.

Methods: We identified Caucasian, African American, Hispanic/Latino and Asian metastatic urothelial bladder cancer patients from 2004 to 2011 within the Surveillance, Epidemiology and End Results database. Social Security Administration tables were used to compute 5 year LE. LT-derived LE was compared to observed overall survival OS. Additionally, we relied on Poisson regression plots to display cancer-specific mortality (CSM) relative to other-cause mortality (OCM) for each race/ethnicity.

Results: Overall, 2286 MBCa patients were identified. Of those, 1800 (79%) were Caucasian vs 212 (9.3%) African American vs 189 (8.3%) Hispanic/Latino vs 85 (3.7%) Asians. The median age at diagnosis was 71 years for Asians vs 70 for Caucasians vs 67 for Hispanic/Latinos vs 67 for African Americans. African Americans showed the biggest difference between observed OS and LT-predicted LE at five years (- 83.8%), followed by Hispanic/Latinos (- 81%), Caucasians (- 77%) and Asian patients (- 69%). In Poisson regression plots, Hispanic/Latinos displayed the highest cancer-specific mortality rate (88%), while African/Americans showed the highest other cause mortality rate (12%). Conversely, Asian patients displayed the lowest CSM rate (83%) and second lowest OCM rate (7%).

Conclusions: African Americans showed the least favorable survival profile in MBCa, despite being youngest at diagnosis. Contrarily, Asians displayed the best survival profile in MBCa, despite being oldest at diagnosis.
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http://dx.doi.org/10.1007/s11255-022-03221-5DOI Listing
May 2022

Oncologic Surveillance After Radical Nephroureterectomy for High-risk Upper Tract Urothelial Carcinoma.

Eur Urol Oncol 2022 Apr 30. Epub 2022 Apr 30.

Department of Urology, Vita-Salute San Raffaele University, Milan, Italy.

Background: The appropriate surveillance protocol after radical nephroureterectomy (RNU) for upper tract urothelial carcinoma (UTUC) is still poorly addressed.

Objective: To evaluate the appropriate intensity and duration of oncologic surveillance following RNU, according to a prior history of bladder cancer (BCa).

Design, Setting, And Participants: We identified 1378 high-risk UTUC patients, according to the European Association of Urology (EAU) guidelines, from a prospectively maintained database involving eight European referral centers. Surveillance protocol was based on cystoscopies and cross-sectional imaging, as per the EAU guidelines.

Outcome Measurements And Statistical Analysis: First, we evaluated the noncumulative risk of bladder and other-site recurrences (including distant metastasis and locoregional relapse) against the follow-up time points, as suggested by the current EAU guidelines. Second, in an effort to identify the time points when the risk of other-cause mortality (OCM) exceeded that of recurrence and follow-up might be discontinued, we relied on adjusted Weibull regression.

Results And Limitations: The median follow-up was 4 yr. A total of 427 and 951 patients with and without a prior BCa history, respectively, were considered. At 5-yr, the time point after which cystoscopies should be performed semiannually, the bladder recurrence risk was 10%; at 4 yr, the bladder recurrence risk was 13%. At 2 yr, the time point after which imaging should be obtained semiannually, the nonbladder recurrence risk was 42% in case of nonprior BCa and 47% in case of prior BCa; at 4 yr, the nonbladder recurrence risk was 23%. Among patients without a prior BCa history, individuals younger than 60 yr should continue both cystoscopies and imaging beyond 10 yr from RNU, 70-79-yr-old patients should continue only imaging beyond 10 yr, while patients older than 80 yr might discontinue oncologic surveillance because of an increased risk of OCM. Limitations include the fact that patients were treated and surveilled over a relatively long period of time.

Conclusions: We suggest intensifying the frequency of imaging to semiannual till the 4th year after RNU, the time point after which the risk of recurrence was almost halved. Cystoscopies could be obtained annually from the 4th year given a similar risk of recurrence at 4 and 5 yr after RNU. Oncologic surveillance could be discontinued in some cases in the absence of a prior BCa history.

Patient Summary: In this study, we propose a revision of the current guidelines regarding surveillance protocols following radical nephroureterectomy. We also evaluated whether oncologic surveillance for high-risk upper tract urothelial carcinoma could be discontinued and, if so, in what circumstances.
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http://dx.doi.org/10.1016/j.euo.2022.04.003DOI Listing
April 2022

Neoadjuvant chemotherapy does not increase peri-operative morbidity following radical cystectomy.

World J Urol 2022 Apr 30. Epub 2022 Apr 30.

Department of Urology, Institut Mutualiste Montsouris and Université Paris Descartes, Paris, France.

Objective: To determine whether use of neoadjuvant chemotherapy (NAC) is associated with a higher risk of post-operative complications following radical cystectomy (RC) for bladder cancer (BCa).

Materials And Methods: We retrospectively reviewed records of patients undergoing RC for non-metastatic urothelial BCa at 13 tertiary care centres from 2007-2019. Patients who received NAC ('NAC + RC' group) were compared with those who underwent upfront RC ('RC alone' group) for intra-operative variables, incidence of post-operative complications as per the Clavien-Dindo classification (CDC) and rates of re-admission and re-intervention. Multivariable logistic regression analysis was performed to determine predictors of CDC overall and CDC major (grade III-V) complications. We also analysed the trend of NAC utilization over the study period.

Results: Of the 3113 patients included, 968 (31.1%) received NAC while the remaining 2145 (68.9%) underwent upfront RC for BCa. There was no significant difference between the NAC + RC and RC alone groups with regards to 30-day CDC overall (53.2% vs 54.6%, p = 0.4) and CDC major (15.5% vs 16.5%, p = 0.6) complications. The two groups were comparable for the rate of surgical re-intervention (14.6% in each group) and re-hospitalization (19.6% in NAC + RC vs 17.9% in RC alone, p = 0.2%) at 90 days. On multivariable regression analysis, NAC use was not found to be a significant predictor of 90-day CDC overall (OR 1.02, CI 0.87-1.19, p = 0.7) and CDC major (OR 1.05, CI 0.87-1.26, p = 0.6) complications. We also observed that the rate of NAC utilization increased significantly (p < 0.001) from 11.1% in 2007 to 41.2% in 2019, reaching a maximum of 48.3% in 2018.

Conclusion: This large multicentre analysis with a substantial rate of NAC utilization showed that NAC use does not lead to an increased risk of post-operative complications following RC for BCa. This calls for increasing NAC use to allow patients to avail of its proven oncologic benefit.
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http://dx.doi.org/10.1007/s00345-022-04012-4DOI Listing
April 2022

Morbidity and mortality in men: Role of androgens.

Best Pract Res Clin Endocrinol Metab 2022 Apr 22:101662. Epub 2022 Apr 22.

Division of Experimental Oncology/Unit of Urology, URI, IRCCS Ospedale San Raffaele, Milan, Italy; University Vita-Salute San Raffaele, Milan, Italy. Electronic address:

In this narrative review we provide an overview of the current literature on male hypogonadism and related comorbidities, also depicting the role of testosterone therapy (TTh) in the various settings. Male hypogonadism has been associated with major comorbidities such as type 2 diabetes mellitus, obesity and cardiovascular diseases, promoting a vicious cycle that may lead to further hypogonadism. The biological underpinnings of this association are currently under investigations, but clearly emerges the relevance of the hypothalamic-pituitary-gonadal axis. Hypogonadism has also been associated with increased risk of mortality. As such, TTh has the potential to oppose these patterns and improve cardiovascular and metabolic health in hypogonadal men. Clinical and observational data suggest that in males with hypogonadism, TTh, together with lifestyle changes and diabetes medications, may improve glycemia, reduce risk of progression to diabetes and provides positive effects on cardiovascular risk. Conversely, available data does not fully support any increased risk of prostate cancer in men under TTh. Of clinical relevance, a possible harmful role of hypogonadal status in men with COVID-19 eventually emerged.
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http://dx.doi.org/10.1016/j.beem.2022.101662DOI Listing
April 2022

A Novel RGD-4C-Saporin Conjugate Inhibits Tumor Growth in Mouse Models of Bladder Cancer.

Front Oncol 2022 11;12:846958. Epub 2022 Apr 11.

Urological Research Institute, Division of Experimental Oncology, IRCCS San Raffaele Scientific Institute, Milano, Italy.

Although toxin may have some advantages compared to chemotherapeutic drugs in cancer therapy, e.g. a potent cytotoxic activity and a reduced risk of resistance, their successful application in the treatments to solid tumors still remains to be fully demonstrated. In this study, we genetically modified the structure of the plant-derived single-chain ribosome inactivating protein saporin (SAP) by fusing its N-terminus to the ACDCRGDCFCG peptide (RGD-4C), an αv-integrin ligand, and explored the anti-tumor activity of the resulting protein (called RGD-SAP) and , using a model of muscle invasive bladder cancer. We found that the RGD-4C targeting domain enhances the cytotoxic activity of SAP against various tumor cell lines, in a manner dependent on αv-integrin expression levels. In a subcutaneous syngeneic model of bladder cancer, RGD-SAP significantly reduced tumor growth in a dose-dependent manner. Furthermore, systemic administration of RGD-SAP in combination with mitomycin C, a chemotherapeutic drug currently used to treat patients with bladder cancer, increased the survival of mice bearing orthotopic bladder cancer with no evidence of systemic toxicity. Overall, the results suggest that RGD-SAP represents an efficient drug that could be exploited, either alone or in combination with the state-of-the-art therapies, for the treatment of bladder cancer and, potentially, of other solid tumors.
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http://dx.doi.org/10.3389/fonc.2022.846958DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9035931PMC
April 2022

Time-Resolved Optical Pump-Resonant X-ray Probe Spectroscopy of 4-Thiouracil: A Simulation Study.

J Chem Theory Comput 2022 May 27;18(5):3075-3088. Epub 2022 Apr 27.

Department of Chemistry, University of California, Irvine, California 92697-2025, United States.

We theoretically monitor the photoinduced ππ* → π* internal conversion process in 4-thiouracil (4TU), triggered by an optical pump. The element-sensitive spectroscopic signatures are recorded by a resonant X-ray probe tuned to the sulfur, oxygen, or nitrogen K-edge. We employ high-level electronic structure methods optimized for core-excited electronic structure calculation combined with quantum nuclear wavepacket dynamics computed on two relevant nuclear modes, fully accounting for their quantum nature of nuclear motions. We critically discuss the capabilities and limitations of the resonant technique. For sulfur and nitrogen, we document a pre-edge spectral window free from ground-state background and rich with ππ* and π* absorption features. The lowest sulfur K-edge shows strong absorption for both ππ* and π*. In the lowest nitrogen K-edge window, we resolve a state-specific fingerprint of the ππ* and an approximate timing of the conical intersection via its depletion. A spectral signature of the π* transition, not accessible by UV-vis spectroscopy, is identified. The oxygen K-edge is not sensitive to molecular deformations and gives steady transient absorption features without spectral dynamics. The ππ*/π* coherence information is masked by more intense contributions from populations. Altogether, element-specific time-resolved resonant X-ray spectroscopy provides a detailed picture of the electronic excited-state dynamics and therefore a sensitive window into the photophysics of thiobases.
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http://dx.doi.org/10.1021/acs.jctc.2c00064DOI Listing
May 2022

Survival trends in chemotherapy exposed metastatic bladder cancer patients and chemotherapy effect across different age, sex, and race/ethnicity.

Urol Oncol 2022 Apr 14. Epub 2022 Apr 14.

Cancer Prognostics and Health Outcomes Unit, Division of Urology, University of Montréal Health Center, Montréal, Québec, Canada.

Purpose: To test for survival differences in metastatic urothelial carcinoma of the urinary bladder (mUCUB) patients, according to years of diagnosis, age, sex, and race/ethnicity over time and for the effect of chemotherapy on overall mortality (OM).

Materials And Methods: Within the Surveillance, Epidemiology, and End Results (2000-2016), we identified 6860 mUCUB patients. Of those, 3,249 were exposed to chemotherapy. Kaplan-Meier plots and Cox regression models focused on OM. First, we tested the effect of years of diagnosis (historical [2000-2005] vs. intermediate [2006-2011] vs. contemporary [2012-2016]) in chemotherapy exposed mUCUB patients. Second, we tested the effect of chemotherapy in all mUCUB patients.

Results: In chemotherapy exposed mUCUB patients according to historical vs. intermediate vs. contemporary years, median overall survival was 11 vs. 13 vs. 14 months respectively, which translated into hazard ratios (HR) of 0.86 (P = 0.005) and 0.75 (P < 0.001) in intermediate and contemporary vs. historical, respectively. Subgroup analyses in <70 years old, males and Caucasians were in agreement regarding statistically significant differences between historical vs. intermediate vs. contemporary, respectively. In multivariable Cox regression models fitted in the entire mUCUB cohort, chemotherapy exposure reduced OM (HR: 0.46; P < 0.001). Virtually the same results were recorded in age, sex, and race/ethnicity subgroups analyses.

Conclusions: Contemporary chemotherapy exposed mUCUB patients exhibited better survival than their historical and intermediate counterparts. Chemotherapy reduced mortality by half, across all patient types.
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http://dx.doi.org/10.1016/j.urolonc.2022.03.014DOI Listing
April 2022

Contemporary seminal vesicle invasion rates in NCCN high-risk prostate cancer patients.

Prostate 2022 Apr 11. Epub 2022 Apr 11.

Cancer Prognostics and Health Outcomes Unit, Division of Urology, University of Montréal Health Center, Montréal, Québec, Canada.

Background: Contemporary seminal vesicle invasion (SVI) rates in National Cancer Comprehensive Network (NCCN) high-risk prostate cancer (PCa) patients are not well known but essential for treatment planning. We examined SVI rates according to individual patient characteristics for purpose of treatment planning.

Materials And Methods: Within Surveillance, Epidemiology, and End Results (SEER) database (2010-2015), 4975 NCCN high-risk patients were identified. In the development cohort (SEER geographic region of residence: South, North-East, Mid-West, n = 2456), we fitted a multivariable logistic regression model predicting SVI. Its accuracy, calibration, and decision curve analyses (DCAs) were then tested versus previous models within the external validation cohort (SEER geographic region of residence: West, n = 2519).

Results: Out of 4975 patients, 28% had SVI. SVI rate ranged from 8% to 89% according to clinical T stage, prostate-specific antigen (PSA), biopsy Gleason Grade Group and percentage of positive biopsy cores. In the development cohort, these variables were independent predictors of SVI. In the external validation cohort, the current model achieved 77.6% accuracy vs 73.7% for Memorial Sloan Kettering Cancer Centre (MSKCC) vs 68.6% for Gallina et al. Calibration was better than for the two alternatives: departures from ideal predictions were 6.0% for the current model vs 9.8% for MSKCC vs 38.5% for Gallina et al. In DCAs, the current model outperformed both alternatives. Finally, different nomogram cutoffs allowed to discriminate between low versus high SVI risk patients.

Conclusions: More than a quarter of NCCN high-risk PCa patients harbored SVI. Since SVI positivity rate varies from 8% to 89%, the currently developed model offers a valuable approach to distinguish between low and high SVI risk patients.
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http://dx.doi.org/10.1002/pros.24350DOI Listing
April 2022

Metastasis Within Three Years from Radical Nephroureterectomy as a Potential Surrogate for Overall Survival.

Clin Genitourin Cancer 2022 Mar 10. Epub 2022 Mar 10.

Division of Oncology/Unit of Urology, URI, IRCCS Ospedale San Raffaele, Milan, Italy; Department of Urology, Luzerner Kantonsspital, Lucerne, Switzerland.

Introduction: The only phase III trial that evaluated the role of adjuvant chemotherapy following radical nephroureterectomy (RNU) for upper tract urothelial carcinoma (UTUC) was terminated early. Thus, eventual overall survival (OS) surrogacy, as per Prentice, cannot be assessed in this setting. We aimed to identify an intermediate clinical endpoint (ICE) that could serve as an OS surrogate after RNU for UTUC.

Patients And Methods: We retrospectively analyzed 823 high-grade UTUC patients treated with RNU at 8 tertiary referral centers. We explored the role of any recurrence (aR), defined as recurrence in the urinary tract or in the resection bed as well the presence of distant metastasis (DM), defined as metastatic disease outside the urinary tract and regional lymph nodes, on OS through a time-varying Cox regression analyses fitted at the landmark points of 1, 2, 3, and 4 years from RNU. Models' discrimination was assessed using Harrell's c index, after internal validation.

Results: Median follow-up for survivors was 5.6 years (interquartile range: 2.0-8.8). Overall, 391 and 212 patients experienced aR and DM, respectively. In a time-varying model, aR and DM were predictors of OS: hazard ratio [HR]:1.20, 95% confidence interval [CI]: 1.13-1.28 (P < .001) and HR:1.26, 95% CI: 1.18-1.34 (P < .001), respectively. Progression to DM within 3 years from RNU was the most informative ICE for predicting OS (c index: 0.81; HR: 4.40; 95%CI: 2.45-7.92; P < .001), compared to DM within 1, 2, and 4 years (c indexes: 0.74, 0.76, and 0.78, respectively). Progression to DM within 3 years from RNU was further found superior for predicting OS compared to aR at any landmark points.

Conclusions: Progression to DM within 3 years represents a potential OS surrogate for surgically-treated UTUC. This information could help in patient counseling, future study design and expedite results release of ongoing randomized controlled trials.
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http://dx.doi.org/10.1016/j.clgc.2022.03.007DOI Listing
March 2022

Grade and stage misclassification in intermediate unfavorable-risk prostate cancer radiotherapy candidates.

Prostate 2022 Apr 1. Epub 2022 Apr 1.

Division of Urology, Cancer Prognostics and Health Outcomes Unit, University of Montréal Health Center, Montréal, Québec, Canada.

Background: We tested for upgrading (Gleason grade group [GGG] ≥ 4) and/or upstaging to non-organ-confined stage ([NOC] ≥ pT3/pN1) in intermediate unfavorable-risk (IU) prostate cancer (PCa) patients treated with radical prostatectomy, since both change the considerations for dose and/or type of radiotherapy (RT) and duration of androgen deprivation therapy (ADT).

Methods: We relied on Surveillance, Epidemiology, and End Results (2010-2015). Proportions of (a) upgrading, (b) upstaging, or (c) upgrading and/or upstaging were tabulated and tested in multivariable logistic regression models.

Results: We identified 7269 IU PCa patients. Upgrading was recorded in 479 (6.6%) and upstaging in 2398 (33.0%), for a total of 2616 (36.0%) upgraded and/or upstaged patients, who no longer fulfilled the IU grade and stage definition. Prostate-specific antigen, clinical stage, biopsy GGG, and percentage of positive cores, neither individually nor in multivariable logistic regression models, discriminated between upgraded and/or upstaged patients versus others.

Conclusions: IU PCa patients showed very high (36%) upgrading and/or upstaging proportion. Interestingly, the overwhelming majority of those were upstaged to NOC. Conversely, very few were upgraded to GGG ≥ 4. In consequence, more than one-third of IU PCa patients treated with RT may be exposed to suboptimal dose and/or type of RT and to insufficient duration of ADT, since their true grade and stage corresponded to high-risk PCa definition, instead of IU PCa. Data about magnetic resonance imaging were not available but may potentially help with better stage discrimination.
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http://dx.doi.org/10.1002/pros.24349DOI Listing
April 2022

Survival after Radical Prostatectomy versus Radiation Therapy in High-Risk and Very High-Risk Prostate Cancer. Letter.

J Urol 2022 Mar 29:101097JU0000000000002680. Epub 2022 Mar 29.

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

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http://dx.doi.org/10.1097/JU.0000000000002680DOI Listing
March 2022

The Paradoxical Role of Body Mass Index in Patients with Muscle-invasive Bladder Cancer Receiving Neoadjuvant Immunotherapy.

Eur Urol Oncol 2022 Mar 10. Epub 2022 Mar 10.

Division of Experimental Oncology/Unit of Urology, Urological Research Institute, IRCCS San Raffaele Scientific Institute, Milan, Italy.

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http://dx.doi.org/10.1016/j.euo.2022.02.004DOI Listing
March 2022

Radiomic and gEnomic approaches for the enhanced DIagnosis of clear cell REnal Cancer (REDIRECt): a translational pilot methodological study.

Transl Androl Urol 2022 Feb;11(2):149-158

Unit of Urology, Division of Experimental Oncology, Urological Research Institute, IRCCS San Raffaele Scientific Institute, Vita-Salute San Raffaele University, Milan, Italy.

Background: The combination of radiomic and transcriptomic approaches for patients diagnosed with small clear-cell renal cell carcinoma (ccRCC) might improve decision making. In this pilot and methodological study, we investigate whether imaging features obtained from computed tomography (CT) may correlate with gene expression patterns in ccRCC patients.

Methods: Samples from 6 patients who underwent partial nephrectomy for unilateral non-metastatic ccRCC were included in this pilot cohort. Transcriptomic analysis was conducted through RNA-sequencing on tumor samples, while radiologic features were obtained from pre-operative 4-phase contrast-enhanced CT. To evaluate the heterogeneity of the transcriptome, after a 1,000 re-sampling via bootstrapping, a first Principal Component Analyses (PCA) were fitted with all transcripts and a second ones with transcripts deriving from a list of 369 genes known to be associated with ccRCC from The Cancer Genome Atlas (TCGA). Significant pathways in each Principal Components for the 50 genes with the highest loadings absolute values were assessed with pathways enrichment analysis. In addition, Pearson's correlation coefficients among radiomic features themselves and between radiomic features and transcripts expression values were computed.

Results: The transcriptomes of the analysed samples showed a high grade of heterogeneity. However, we found four radiogenomic patterns, in which the correlation between radiomic features and transcripts were statistically significant.

Conclusions: We showed that radiogenomic approach is feasible, however its clinical meaning should be further investigated.
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http://dx.doi.org/10.21037/tau-21-713DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8899146PMC
February 2022

The Mediterranean Diet as a Source of Bioactive Molecules with Cannabinomimetic Activity in Prevention and Therapy Strategy.

Nutrients 2022 Jan 21;14(3). Epub 2022 Jan 21.

Division of Experimental Oncology, Urological Research Institute, IRCCS San Raffaele Scientific Institute, 20132 Milano, Italy.

The endocannabinoid system is a complex lipid signaling network that has evolved to be a key regulator of pro-homeostatic pathways for the organism. Its involvement in numerous processes has rendered it a very suitable target for pharmacological studies regarding metabolic syndrome, obesity and other lifestyle-related diseases. Cannabinomimetic molecules have been found in a large variety of foods, most of which are normally present in the Mediterranean diet. The majority of these compounds belong to the terpene and polyphenol classes. While it is known that they do not necessarily act directly on the cannabinoid receptors CB1 and CB2, their ability to regulate their expression levels has already been shown in some disease-related models, as well as their ability to modulate the activity of other components of the system. In this review, evidence was gathered to support the idea that phytocannabinoid dietary intake may indeed be a viable strategy for disease prevention and may be helpful in maintaining the health status. In an era where personalized nutrition is becoming more and more a reality, having new therapeutic targets could become an important resource.
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http://dx.doi.org/10.3390/nu14030468DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8839035PMC
January 2022

Is Hypertension Associated with Worse Renal Functional Outcomes after Minimally Invasive Partial Nephrectomy? Results from a Multi-Institutional Cohort.

J Clin Med 2022 Feb 25;11(5). Epub 2022 Feb 25.

Department of Urologic Oncology, IRCCS "Regina Elena" National Cancer Institute, 00144 Rome, Italy.

Background: Hypertension (HTN) is a global public health issue. There are limited data regarding the effects of HTN in patients undergoing partial nephrectomy (PN) for renal tumors. To address this void, we tested the association between HTN and renal function after minimally invasive PN (MIPN).

Methods: Using a multi-institutional database (2007-2017), we identified patients aged ≥ 18 years with a diagnosis of cT1 renal tumors treated with MIPN. Kaplan-Meier plots and Cox regression models addressed newly-onset CKD stage ≥ 3b or higher (sCKD). All analyses were repeated after 1:1 propensity score matching (PSM).

Results: Overall, 2144 patients were identified. Of those, 35% ( = 759) were yes-HTN. Yes-HTN patients were older, more frequently male and more often presented with diabetes. Yes-HTN patients harbored higher RENAL nephrometry scores and higher cT stages than no-HTN patients. Conversely, yes-HTN patients exhibited lower preoperative eGFRs. In the overall cohort, five-year sCKD-free survival was 86% vs. 94% for yes-HTN vs. no-HTN, which translated into a multivariable HR of 1.67 (95% CI: 1.06-2.63, = 0.026). After 1:1 PSM, virtually the same results were observed (HR 1.86, 95% CI: 1.07-3.23, = 0.027).

Conclusions: Yes-HTN patients exhibited worse renal function after MIPN when compared to their no-HTN counterparts. However, these observations need to be further tested in a prospective cohort study.
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http://dx.doi.org/10.3390/jcm11051243DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8911097PMC
February 2022

Holmium: yttrium-aluminum-garnet laser with Moses: does it make a difference?

Curr Opin Urol 2022 May 9;32(3):324-329. Epub 2022 Mar 9.

Division of Experimental Oncology/Unit of Urology, URI, IRCCS Ospe-dale San Raffaele.

Purpose Of Review: Moses effect is an inherent physical principle of Ho:YAG laser functioning. Moses Technology is a pulse modulation modality of Ho:YAG laser, which became commercially available for the treatment of two urological conditions: urinary stones and benign prostatic obstruction. The purpose of this narrative review is to distinguish between Moses effect and Moses Technology, as well as to summarize the latest evidence on Moses Technology and its main application in the urological field.

Recent Findings: During laboratory lithotripsy, Moses Technology seems to reduce stone retropulsion and determine higher ablation volume compared with regular lithotripsy. However, this technology presents similar characteristics to long pulse Ho:YAG laser, and several studies showed no significant difference between Moses Technology and standard lasers. When used in prostate enucleation, Moses Technology promises to reduce operating time by increasing the efficiency of prostate resection and improve the hemostasis. Moreover, some studies state that it is possible to reduce the HoLEP morbidity. Despite this, the clinical impact of the time reduction remains uncertain and different studies either present relevant limitations or are burdened by significant bias.

Summary: Although Moses effect has been extensively described and characterized, and several studies have been published on the usage of Moses Technology for both laser lithotripsy and laser enucleation of the prostate with Holmium YAG, solid clinical evidence on the real improvement of surgical outcomes is still missing.
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http://dx.doi.org/10.1097/MOU.0000000000000979DOI Listing
May 2022

Diagnostic accuracy of preoperative lymph node staging of bladder cancer according to different lymph node locations: A multicenter cohort from the European Association of Urology - Young Academic Urologists.

Urol Oncol 2022 May 27;40(5):195.e27-195.e35. Epub 2022 Feb 27.

Department of Urology, Luzerner Kantonsspital, Lucerne, Switzerland; Clinica Luganese Moncucco, Lugano, Switzerland; Clinica S.Anna, Swiss Medical Group, Sorengo, Switzerland; Clinica Santa Chiara, Locarno, Switzerland.

Background: The preoperative lymph node (LN) staging of bladder cancer (BCa) addresses the subsequent therapeutic strategy and influences patient's prognosis. However, sparce evidence exists regarding the accuracy of conventional cross-sectional imaging, such as computed tomography or magnetic resonance imaging, in correctly detect LN status. We aimed to assess the diagnostic accuracy of conventional cross-sectional imaging in detecting preoperative LN involvement among BCa patients treated with radical cystectomy and pelvic lymph node dissection.

Methods: We retrospectively analyzed data of 1,104 patients who underwent preoperative LN staging with computed tomography or magnetic resonance imaging and subsequent radical cystectomy with pelvic lymph node dissection for BCa between 1997 and 2017 at three tertiary referral centers. Patients receiving neoadjuvant chemotherapy were excluded. We assessed the concordance between clinical (cN) and pathological LN (pN) status, defined as the accuracy of imaging in detecting LN involvement using pathological specimen as reference; concordance was expressed according to Cohen's kappa coefficient. Location-based sub-analyses were performed, distinguishing among external iliac, intern iliac, obturator, common iliac, presacral and paraaortic LNs.

Results: Among 870 cN0 patients, 68.9% were confirmed pN0 at pathological report; while among 234 cN+ patients, 50.5% were found with LN metastases at pathological specimen. Overall, conventional imaging showed slight concordance (64.9%) between cN and pN stages (sensitivity: 30%; specificity: 84%). At sub-analysis, no agreement between cN and pN status was found in each LN location, with the only exception of common iliac LNs with slight concordance (37.5%). Common iliac LNs achieved the highest sensitivity and positive likelihood ratio (15% and 2.4, respectively) compared to other LN locations.

Conclusions: Overall, preoperative cross-sectional imaging exhibited a slight concordance between cN and pN status. Our location-based sub-analyses showed unsatisfactory results in each LN location- Thus, nomograms combining morphological patterns with serological and clinicopathological features are urgently required.
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http://dx.doi.org/10.1016/j.urolonc.2022.01.002DOI Listing
May 2022

Survival after radical prostatectomy versus radiation therapy in clinical node-positive prostate cancer.

Prostate 2022 05 28;82(6):740-750. Epub 2022 Feb 28.

Department of Urology, Cancer Prognostics and Health Outcomes Unit, Division of Urology, University of Montréal Health Center, Montréal , Québec, Canada.

Aim: To compare overall mortality (OM), cancer-specific mortality (CSM), and other cause mortality (OCM) rates between radical prostatectomy (RP) versus radiotherapy (RT) in clinical node-positive (cN1) prostate cancer (PCa).

Materials And Methods: Within Surveillance, Epidemiology, End Results (SEER) (2004-2016), we identified 4685 cN1 PCa patients, of whom 3589 (76.6%) versus 1096 (24.4%) were treated with RP versus RT. After 1:1 propensity score matching (PSM), Kaplan-Meier plots and Cox regression models tested the effect of RP versus RT on OM, while cumulative incidence plots and competing-risks regression (CRR) models addressed CSM and OCM between RP and RT patients. All analyses were repeated after the inverse probability of treatment weighting (IPTW). For CSM and OCM analyses, the propensity score was used as a covariate in the regression model.

Results: Overall, RT patients were older, harbored higher prostate-specific antigen values, higher clinical T and higher Gleason grade groups. PSM resulted in two equally sized groups of 894 RP versus 894 RT patients. After PSM, 5-year OM, CSM, and OCM rates were, respectively, 15.4% versus 25%, 9.3% versus 17%, and 6.1% versus 8% for RP versus RT (all p < 0.001) and yielded respective multivariate hazard ratios (HRs) of 0.63 (0.52-0.78, p < 0.001), 0.66 (0.52-0.86, p < 0.001), 0.71 (0.5-1.0, p = 0.05), all favoring RP. After IPTW, Cox regression models yielded HR of 0.55 (95% confidence interval [CI] = 0.46-0.66) for OM, and CRR yielded HRs of 0.49 (0.34-0.70) and 0.54 (0.36-0.79) for, respectively, CSM and OCM, all favoring RP (all p < 0.001).

Conclusions: RP may hold a CSM advantage over RT in cN1 PCa patients.
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http://dx.doi.org/10.1002/pros.24317DOI Listing
May 2022

Immediate radical cystectomy versus BCG immunotherapy for T1 high-grade non-muscle-invasive squamous bladder cancer: an international multi-centre collaboration.

World J Urol 2022 May 26;40(5):1167-1174. Epub 2022 Feb 26.

Department of Urology, Fundación Instituto Valenciano de Oncologia, Valencia, Spain.

Purpose: To compare cancer-specific mortality (CSM) and overall mortality (OM) between immediate radical cystectomy (RC) and Bacillus Calmette-Guérin (BCG) immunotherapy for T1 squamous bladder cancer (BCa).

Methods: We retrospectively analysed 188 T1 high-grade squamous BCa patients treated between 1998 and 2019 at fifteen tertiary referral centres. Median follow-up time was 36 months (interquartile range: 19-76). The cumulative incidence and Kaplan-Meier curves were applied for CSM and OM, respectively, and compared with the Pepe-Mori and log-rank tests. Multivariable Cox models, adjusted for pathological findings at initial transurethral resection of bladder (TURB) specimen, were adopted to predict tumour recurrence and tumour progression after BCG immunotherapy.

Results: Immediate RC and conservative management were performed in 20% and 80% of patients, respectively. 5-year CSM and OM did not significantly differ between the two therapeutic strategies (Pepe-Mori test p = 0.052 and log-rank test p = 0.2, respectively). At multivariable Cox analyses, pure squamous cell carcinoma (SqCC) was an independent predictor of tumour progression (p = 0.04), while concomitant lympho-vascular invasion (LVI) was an independent predictor of both tumour recurrence and progression (p = 0.04) after BCG. Patients with neither pure SqCC nor LVI showed a significant benefit in 3-year recurrence-free survival and progression-free survival compared to individuals with pure SqCC or LVI (60% vs. 44%, p = 0.04 and 80% vs. 68%, p = 0.004, respectively).

Conclusion: BCG could represent an effective treatment for T1 squamous BCa patients with neither pure SqCC nor LVI, while immediate RC should be preferred among T1 squamous BCa patients with pure SqCC or LVI at initial TURB specimen.
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http://dx.doi.org/10.1007/s00345-022-03958-9DOI Listing
May 2022

Variant histologies in bladder cancer: Does the centre have an impact in detection accuracy?

Urol Oncol 2022 Jun 23;40(6):273.e11-273.e20. Epub 2022 Feb 23.

Department of Urology, Policlinico San Martino Hospital, University of Genova, Genova, Italy.

Objective: To compare the accuracy in detecting variant histologies (VH) at transurethral resection of bladder (TURB) and radical cystectomy (RC) specimen among tertiary referral centres, in order to investigate potential reasons of discrepancies from the pathological point of view.

Patients And Methods: Clinical and histopathological data of TURB specimen and subsequent cystectomy specimen of 3,445 RC candidate patients have been retrospectively collected from 24 tertiary referral centres between 1980 and 2021. VH considered in the analysis were pure squamous cell carcinoma, urothelial carcinoma with squamous differentiation, pure adenocarcinoma, urothelial carcinoma with glandular differentiation, micropapillary bladder cancer (BCa), neuroendocrine BCa, and other variants. The degree of agreement between TURB and RC concerning the identification of VH was expressed as concordance, classified according to Cohen's kappa coefficient.

Results: A VH was reported in 17% of TURB specimens, 45% of which were not confirmed in RC. The lowest concordance rate was reported for micropapillary BCa with 11 out of 18 (61%) centres reporting no agreement, whereas neuroendocrine BCa achieved the highest concordance rate with only 3 centres (17%) reporting no agreement. Our results shows that even among centres with the advantage of a referent uropathologist the micropapillary variant is characterized by scarce accuracy between TURB and RC. Differences in TURB specimen acquisition by the urologist and in sampling methods among different centres are the main limitations of the study.

Conclusions: Accuracy of TURB in detecting VH is poor for certain VH, in particular for micropapillary BCa, with evident variation among centres. Novel diagnostic tools are required to better identify these VH and drive patients toward a personalized treatment.
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http://dx.doi.org/10.1016/j.urolonc.2022.01.008DOI Listing
June 2022

Triglycerides/Glucose Index Is Associated with Sperm Parameters and Sperm DNA Fragmentation in Primary Infertile Men: A Cross-Sectional Study.

Metabolites 2022 Feb 3;12(2). Epub 2022 Feb 3.

Division of Experimental Oncology, Unit of Urology, URI, IRCCS Ospedale San Raffaele, 20132 Milan, Italy.

Study Question: we aimed to investigate the relationship between the tyg index and both semen and hormonal characteristics in a cohort of primary infertile men. Summary answer: almost one in two primary infertile men presented with a triglycerides/glucose index (tyg) suggestive of insulin resistance (ir). overall, patients with tyg suggestive of ir showed worse clinical, hormonal, and semen parameters. What is already known: male factor infertility (MFI) is often associated with metabolic disorders such as diabetes mellitus and metabolic syndrome, where insulin resistance (IR) plays a relevant pathological role. Recently, TyG has been suggested as a user-friendly IR marker.

Study Design: serum hormones and the sperm DNA fragmentation index (SDF) were measured in every patient. The semen analysis was based on 2010 WHO reference criteria. Glucose and insulin levels were measured for every man after a 12-h overnight fast, and the homeostatic model assessment index (HOMA-IR) was then calculated and categorized using a 2.6 threshold. Similarly, fasting glucose and triglycerides levels were measured and the TyG index was calculated and categorized using an 8.1 threshold. Descriptive statistics and logistic regression models tested the association between the TyG and semen and hormonal characteristics.

Participants: complete demographic, clinical, and laboratory data from 726 consecutive white European primary infertile men were considered for this analysis. Main results and the role of chance: the median (IQR) age was 39 (35-43) years. A TyG and HOMA suggestive for IR was found in 339 (46.6%) and 154 (21.2%) men, respectively. During the Spearman's test, the TyG index was highly correlated with HOMA-IR (rho = 0.46, < 0.001). Compared to men with a normal TyG, men with TyG > 8.1 were older, had greater BMI and CCI scores, and lower total testosterone and sperm concentration, but higher DFI, and presented a greater proportion of NOA (all < 0.01). The multivariable logistic regression analysis showed that men with TyG > 8.1 were at higher risk of SDF > 30 (OR 1.92 (CI: 1.2-2.9)) and NOA (OR 1.78 (CI: 1.1-2.8)). Wider implications of the findings: the Tyng index may act as a reliable marker of IR in the clinical work-up of primary infertile men in real-life settings.
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http://dx.doi.org/10.3390/metabo12020143DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8875300PMC
February 2022

Prostate Cancer: Is There Still a Role for Systematic Biopsies? Yes.

Eur Urol Open Sci 2022 Apr 10;38:10-11. Epub 2022 Feb 10.

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

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http://dx.doi.org/10.1016/j.euros.2021.06.016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8844839PMC
April 2022

Immunotherapy versus chemotherapy as first-line treatment for advanced urothelial cancer: A systematic review and meta-analysis.

Cancer Treat Rev 2022 Mar 10;104:102360. Epub 2022 Feb 10.

Division of Experimental Oncology/Unit of Urology, URI, Urological Research Institute, IRCCS San Raffaele Scientific Institute, Milan, Italy; Vita-Salute San Raffaele University, Milan, Italy.

Background: Pembrolizumab and atezolizumab have recently been approved for the first-line treatment of patients with advanced urothelial carcinoma (aUC) who are not eligible for cisplatin-based chemotherapy and whose tumors have high PD-L1 expression; however, the use of these immunotherapeutic agents relative to standard of care chemotherapy has ongoing concerns. The aim of this present study is to compare the effectiveness of single-agent immune-oncology (IO) compounds versus platinum-based chemotherapy in the first-line setting of aUC.

Methods: A comprehensive search for phase III trials on IO versus chemotherapy was conducted in PubMed, EMBASE, Web of Science, and Scopus databases from 01/2016 to 05/2021. An algorithm to obtain survival data from published Kaplan-Meier curves was used to reconstruct overall survival (OS) data. After demonstrating violation of the proportional hazard assumption, we used the difference in restricted mean survival time (ΔRMST) to compare OS.

Results: OS data from 2,068 individuals from 3 phase III trials investigating the role of IO vs chemotherapy were reconciled. Overall, patients receiving IO [n = 1,013 (49%)] or chemotherapy [n = 1,055 (51%)] had similar OS with a 24-month ΔRMST of -0.4 (95% CI: -1.1, 0.4; p = 0.2) months. In the cisplatin-ineligible population, patients receiving IO [n = 509 (49%)] or chemotherapy [n = 530 (51%)] had similar OS with a 24-month ΔRMST of 0.1 (95% CI: -0.9, 1.2; p = 0.7) months. In the cisplatin-ineligible population with PD-L1-high tumors, patients receiving IO [n = 226 (50%)] or chemotherapy [n = 226 (50%)] had similar OS with a 24-month ΔRMST of 1.1 (95% CI: -0.5, 2.7; p = 0.1) months.

Conclusion: We found no OS benefit for patients treated with first-line immune checkpoint inhibition compared to chemotherapy among the overall population, cisplatin-ineligible patients, and PD-L1-high patients.
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http://dx.doi.org/10.1016/j.ctrv.2022.102360DOI Listing
March 2022
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