Publications by authors named "Sisto Perdona"

115 Publications

Discrepancy of p16 immunohistochemical expression and HPV RNA in penile cancer. A multiplex in situ hybridization/immunohistochemistry approach study.

Infect Agent Cancer 2021 Mar 31;16(1):22. Epub 2021 Mar 31.

Pathology Unit, Department of Mental and Physical Health and Preventive Medicine, University of Campania "L. Vanvitelli", Complesso di Santa Patrizia, Via Luciano Armanni, 5, 80138, Naples, Italy.

Background: The high-risk human papillomavirus (HPV) infection represents one of the main etiologic pathways of penile carcinogenesis in approximately 30-50 % of cases. Several techniques for the detection of HPV are currently available including Polymerase chain reaction-based techniques, DNA and RNA in situ hybridization (ISH), p16 immunohistochemistry (IHC). The multiplex HPV RNA ISH/p16 IHC is a novel technique for the simultaneous detection of HPV E6/E7 transcripts and p16INK4a overexpression on the same slide in a single assay. The main aim of this study was to evaluate the discrepancy of p16 IHC expression relatively to HPV RNA ISH in penile cancer tissue.

Methods: We collected a series of 60 PCs. HPV has been analysed through the RNA ISH, p16 IHC and the multiplex HPV RNA ISH/p16 IHC.

Results: The multiplex HPV RNA ISH /p16 IHC results in the series were in complete agreement with the previous results obtained through the classic p16 IHC and HPV RNA scope carried out on two different slides. The multiplex HPV RNA ISH /p16 IHC showed that HPV positivity in our series is more frequently in usual squamous cell carcinoma than in special histotypes (19 out of 60 - 15 %- versus 6 out of 60 - 10 %-), in high-grade than in moderate/low grade carcinomas (6 out of 60 - 10 %- versus 4 out of 60 - 6.7 %-). In addition, our data revealed that in 5 out of 20 cases with p16 high intensity expression is not associated with HPV RNA ISH positivity.

Conclusions: Our findings emphasize that the use of p16 as a surrogate of HPV positivity was unsuccessful in approximatively 8 % of cases analysed in our series. Indeed, p16 IHC showed a sensitivity of 100 % and a specificity of 71 %, with a positive predictive value (PPV) of 54 % and a negative predictive value of 100 %; when considering high intensity, p16 IHC showed a sensitivity of 100 %, a specificity of 89 %, with a PPV of 75 % and NPV of 100 %. Since HPV positivity could represent a relevant prognostic and predictive value, the correct characterization offered by this approach appears to be of paramount importance.
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http://dx.doi.org/10.1186/s13027-021-00361-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8011184PMC
March 2021

Systemic combining inflammatory score (SCIS): a new score for prediction of oncologic outcomes in patients with high-risk non-muscle-invasive urothelial bladder cancer.

Transl Androl Urol 2021 Feb;10(2):626-635

Urology Section, Department of Surgery, University of Catania, Catania, Italy.

Background: An accurate and early diagnosis of bladder cancer (BC) is essential to offer patients the most appropriate treatment and the highest cure rate. For this reason, patients need to be best stratified by class and risk factors. We aimed to develop a score able to better predict cancer outcomes, using serum variables of inflammation.

Methods: A total of 1,510 high-risk non-muscle invasive bladder cancer (NMIBC) patients were included in this retrospective observational study. Patients with pathologically proven T1 HG/G3 at first TURBT were included. Systemic combined inflammatory score (SCIS) was calculated according to systemic inflammatory markers (SIM), modified Glasgow prognostic score (mGPS), and prognostic nutritional index (PNI) dichotomized (final score from 0 to 3).

Results: After 48 months of follow-up (IQR 40.0-73.0), 727 patients recurred (48.1%), 485 progressed (32.1%), 81 died for cancer (7.0%), and 163 died for overall causes (10.8%). Overall, 231 (15.3%) patients had concomitant Cis, 669 (44.3%) patients had multifocal pathology, 967 (64.1%) patients had tumor size >3 cm. Overall, 357 (23.6%) patients received immediate-intravesical therapy, 1,356 (89.8%) received adjuvant intravesical therapy, of which 1,382 (91.5%) received BCG, 266 (17.6%) patients received mitomycin C, 4 (0.5%) patients received others intravesical therapy. Higher SCIS was independently predictive of recurrence (hazard ratio HR 1.5, 1.3 and 2.2) and cancer specific mortality for SCIS 0 and 3 (HR: 1.61 and 2.3), and overall mortality for SCIS 0 and 3 (HR: 2.4 and 3.2). Conversely, SCIS was not associated with a higher probability of progression.

Conclusions: The inclusion of the SCIS in clinical practice is simple to apply and can help improve the prediction of cancer outcomes. It can identify patients with high-grade BC who are more likely to experience disease mortality.
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http://dx.doi.org/10.21037/tau-20-1272DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7947442PMC
February 2021

Subcellular Localization of uc.8+ as a Prognostic Biomarker in Bladder Cancer Tissue.

Cancers (Basel) 2021 Feb 8;13(4). Epub 2021 Feb 8.

Institute of Genetics and Biophysics "A. Buzzati Traverso", National Research Council (CNR), 80131 Naples, Italy.

Non-coding RNA transcripts originating from Ultraconserved Regions (UCRs) have tissue-specific expression and play relevant roles in the pathophysiology of multiple cancer types. Among them, we recently identified and characterized the ultra-conserved-transcript-8+ (uc.8+), whose levels correlate with grading and staging of bladder cancer. Here, to validate uc.8+ as a potential biomarker in bladder cancer, we assessed its expression and subcellular localization by using tissue microarray on 73 human bladder cancer specimens. We quantified uc.8+ by in-situ hybridization and correlated its expression levels with clinical characteristics and patient survival. The analysis of subcellular localization indicated the simultaneous presence of uc.8+ in the cytoplasm and nucleus of cells from the Low-Grade group, whereas a prevalent cytoplasmic localization was observed in samples from the High-Grade group, supporting the hypothesis of uc.8+ nuclear-to-cytoplasmic translocation in most malignant tumor forms. Moreover, analysis of uc.8+ expression and subcellular localization in tumor-surrounding stroma revealed a marked down-regulation of uc.8+ levels compared to the paired (adjacent) tumor region. Finally, deep machine-learning approaches identified nucleotide sequences associated with uc.8+ localization in nucleus and/or cytoplasm, allowing to predict possible RNA binding proteins associated with uc.8+, recognizing also sequences involved in mRNA cytoplasm-translocation. Our model suggests uc.8+ subcellular localization as a potential prognostic biomarker for bladder cancer.
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http://dx.doi.org/10.3390/cancers13040681DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7914980PMC
February 2021

Association of statin use and oncological outcomes in patients with first diagnosis of T1 high grade non-muscle invasive urothelial bladder cancer: results from a multicentre study.

Minerva Urol Nefrol 2021 Jan 13. Epub 2021 Jan 13.

Department of Medical, Oral and Biotechnological Sciences, G. d'Annunzio University of Chieti, Urology Unit, SS. Annunziata Hospital, Chieti, Italy.

Introduction: We aimed to test the hypothesis that the immune-modulatory effect of statins may improve survival outcomes in patients with non-muscle invasive bladder cancer (NMIBC). We focused on a cohort of patients diagnosed with high risk NMIBC, that were treated with intravesical BCG immunotherapy.

Patients And Methods: We included patients at first diagnosis of T1 high grade NMIBC after transurethral resection of bladder (TURB). All procedures were performed at 18 different tertiary institutions between January 2002 and December 2012. Univariable and multivariable models were used to test differences in terms of residual tumour, disease recurrence, disease progression and overall mortality (OM) rates.

Results: Overall, 1510 patients with T1 high grade NMIBC at TURB were included in our analyses. Of these, 402 (26.6%) were statin users. At multivariable analysis, statin use was associated with a higher rates of high grade BC at re-TURB (OR: 1.37, 95%CI: 1.04-1.78; p=0.022), while at follow-up it was not independently associated with OM (HR: 0.71, 95%CI: 0.50-1.03; p=0.068) and disease progression rates (HR: 0.97, 95%CI: 0.79-1.19; p=0.753). Conversely, statin use has been shown to be independently associated with a lower risk of recurrence (HR:0.80, 95%CI: 0.67-0.95; p=0.009). The median recurrence-free survival was 47 (95%CI 40-49) months for those classified as non-statin users vs. 53 (95%CI 48-68) months in those classified as statin users.

Conclusions: Statin daily intake do not compromise oncological outcomes in high risk NMIBC patients treated with BCG. Moreover, statin may have a beneficial effect on recurrence rates in this cohort of patients.
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http://dx.doi.org/10.23736/S0393-2249.20.04076-XDOI Listing
January 2021

Observational study on the effects of a topical formulation in patients with premature ejaculation.

Arch Ital Urol Androl 2020 Dec 18;92(4). Epub 2020 Dec 18.

Division of Urology, IRCCS Fondazione G. Pascale, Naples.

Premature ejaculation (PE) has been defined as the inability to control or delay ejaculation, resulting in dissatisfaction or distress of the patient. Although PE is the most frequent sexual dysfunction, it is still underdiagnosed. An accurate clinical history is the best diagnostic approach that, in the majority of cases, is enough to differentiate between primary and acquired PE. Nowadays, treatment is not curative but is effective in increasing the intravaginal ejaculatory latency time (IELT), improving the sexual satisfaction of the couple [...].
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http://dx.doi.org/10.4081/aiua.2020.4.328DOI Listing
December 2020

The clinical and translational research activities at the INT - IRCCS "Fondazione Pascale" cancer center (Naples, Italy) during the COVID-19 pandemic.

Infect Agent Cancer 2020 Nov 23;15(1):69. Epub 2020 Nov 23.

Istituto Nazionale Tumori IRCCS Fondazione Pascale, Naples, Italy.

COVID-19 pandemic following the outbreak in China and Western Europe, where it finally lost the momentum, is now devastating North and South America. It has not been identified the reason and the molecular mechanisms of the two different patterns of the pulmonary host responses to the virus from a minimal disease in young subjects to a severe distress syndrome (ARDS) in older subjects, particularly those with previous chronic diseases (including diabetes) and cancer. The Management of the Istituto Nazionale Tumori - IRCCS "Fondazione Pascale" in Naples (INT-Pascale), along with all Health professionals decided not to interrupt the treatment of those hospitalized and to continue, even if after a careful triage in order not to allow SARS-CoV-2 positive subjects to access, to take care of cancer patients with serious conditions. Although very few (n = 3) patients developed a symptomatic COVID-19 and required the transfer to a COVID-19 area of the Institute, no patients died during the hospitalization and completed their oncology treatment. Besides monitoring of the patients, all employees of the Institute (physicians, nurses, researchers, lawyers, accountants, gatekeepers, guardians, janitors) have been tested for a possible exposure. Personnel identified as positive, has been promptly subjected to home quarantine and subdued to health surveillance. One severe case of respiratory distress has been reported in a positive employees and one death of a family member. Further steps to home monitoring of COVID-19 clinical course have been taken with the development of remote Wi-Fi connected digital devices for the detection of early signs of respiratory distress, including heart rate and oxygen saturation.In conclusion cancer care has been performed and continued safely also during COVID-19 pandemic and further remote home strategies are in progress to ensure the appropriate monitoring of cancer patients.
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http://dx.doi.org/10.1186/s13027-020-00330-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7681193PMC
November 2020

Outcomes of Robot-assisted Partial Nephrectomy for Clinical T3a Renal Masses: A Multicenter Analysis.

Eur Urol Focus 2020 Nov 25. Epub 2020 Nov 25.

Department of Urology, UC San Diego School of Medicine, La Jolla, CA, USA. Electronic address:

Background: Use of partial nephrectomy (PN) in T3 renal cell carcinoma (RCC) is controversial.

Objective: To evaluate quality outcomes of robot-assisted PN (RAPN) for clinical T3a renal masses (cT3aRM).

Design, Setting, And Participants: This was a retrospective multicenter analysis of patients with cT3aN0M0 RCC who underwent RAPN.

Intervention: RAPN.

Outcome Measurements And Statistical Analysis: The primary endpoint was a trifecta composite outcome of negative surgical margins, warm ischemia time (WIT) ≤25 min, and no perioperative complications. The optimal outcome was defined as achieving this trifecta and ≥90% preservation of the estimated glomerular filtration rate (eGFR) and no stage upgrading of chronic kidney disease. Multivariable analysis (MVA) identified risk factors associated with lack of the optimal outcome. Kaplan-Meier analysis was conducted for survival outcomes.

Results And Limitations: Analysis was conducted for 157 patients (median follow-up 26 mo). The median tumor size was 7.0 cm (interquartile range [IQR] 5.0-7.8) and the median RENAL score was 9 (IQR 8-10). Median estimated blood loss (EBL) was 242 ml (IQR 121-354) and the median WIT was 19 min (IQR 15-25). A total of 150 patients (95.5%) had negative margins. Complications were noted in 25 patients (15.9%), with 4.5% having Clavien grade 3-5 complications. The median change in eGFR was 7 ml/min/1.72 m, with ≥90% eGFR preservation in 55.4%. The trifecta outcome was achieved for 64.3% and the optimal outcome for 37.6% of the patients. MVA revealed that greater age (odds ratio [OR] 1.06; p = 0.002), increasing RENAL score (OR 1.30; p = 0.035), and EBL >300 ml (OR 5.96, p = 0.006) were predictive of failure to achieve optimal outcome. The 5-yr recurrence-free survival, cancer-specific survival, and overall survival, were 82.1%, 93.3%, and 91.3%, respectively. Limitations include the retrospective design.

Conclusions: RAPN for select cT3a renal masses is feasible and safe, with acceptable quality outcomes. Further investigation is requisite to delineate the role of RAPN in cT3a RCC.

Patient Summary: Robot-assisted partial nephrectomy in patients with stage 3a kidney cancer provided acceptable survival, functional, and morbidity outcomes in the hands of experienced surgeons, and may be considered as an option when clinically indicated.
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http://dx.doi.org/10.1016/j.euf.2020.10.011DOI Listing
November 2020

Outcomes of minimally invasive partial nephrectomy among very elderly patients: report from the RESURGE collaborative international database.

Cent European J Urol 2020 8;73(3):273-279. Epub 2020 Sep 8.

Unit of Urology, Division of Experimental Oncology, Urological Research Institute (URI), IRCCS Ospedale San Raffaele, Milan, Italy.

The aim of the study was to perform a comprehensive investigation of clinical outcomes of robot-assisted partial nephrectomy (RAPN) or laparoscopic partial nephrectomy (LPN) in elderly patients presenting with a renal mass. The REnal SURGery in Elderly (RESURGE) collaborative database was queried to identify patients aged 75 or older diagnosed with cT1-2 renal mass and treated with RAPN or LPN. Study outcomes were: overall complications (OC); warm ischemia time (WIT) and 6-month estimated glomerular filtration rate (eGFR); positive surgical margins (PSM), disease recurrence (REC), cancer-specific mortality (CSM) and other-cause mortality (OCM). Descriptive statistics, Kaplan-Meier, smoothed Poisson plots and logistic and linear regression models (MVA) were used. Overall, 216 patients were included in this analysis. OC rate was 34%, most of them being of low Clavien grade. Median WIT was 17 minutes and median 6-month eGFR was 54 ml/min/1.73 m. PSM rate was 5%. After a median follow-up of 20 months, the 5-year rates of REC, CSM and OCM were 4, 4 and 5%, respectively. At MVA predicting perioperative morbidity, RAPN relative to LPN (odds ratio [OR] 0.33; p <0.0001) was associated with lower OC rate. At MVA predicting functional outcomes, RAPN relative to LPN was associated with shorter WIT (estimate [EST] -4.09; p <0.0001), and with higher 6-month eGFR (EST 6.03; p = 0.01). In appropriately selected patients with small renal masses, minimally-invasive PN is associated with acceptable perioperative outcomes. The use of a robotic approach over a standard laparoscopic approach can be advantageous with respect to clinically relevant outcomes, and it should be preferred when available.
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http://dx.doi.org/10.5173/ceju.2020.0179DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7587491PMC
September 2020

From clinical trials to clinical use of checkpoint inhibitors for patients with metastatic urothelial cancer.

Immunotherapy 2021 Jan 12;13(1):67-77. Epub 2020 Oct 12.

Department of Urology & Gynecology, Istituto Nazionale Tumori 'Fondazione G Pascale' IRCCS, Napoli, Italy.

Monoclonal antibodies targeting the checkpoint inhibitors (CPIs), programmed cell death protein-1 or programmed cell death ligand-1, are changing the landscape of urothelial carcinoma therapeutics. Overall, clinical studies in metastatic or advanced urothelial cancer showed that CPIs provided a slight improvement in survival and a relevant advantage in safety, compared with chemotherapy. After reviewing published and ongoing trials, the authors discuss expected answers to unmet needs, with a special attention to the research of biological markers for patients with urothelial cancer eligible for treatment with CPIs in this article.
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http://dx.doi.org/10.2217/imt-2020-0128DOI Listing
January 2021

Massive intra-abdominal recurrence after robotic-assisted radical cystectomy: A case report and critical appraisal of literature.

Urologia 2021 Feb 18;88(1):21-24. Epub 2020 Sep 18.

Department of Urology, AORN Antonio Cardarelli, Naples, Italy.

Introduction: Over the years, the robotic surgery is gaining increasing importance in the treatment of bladder cancer. Some doubts remain about the oncological safety of robotic approach and alerts have been raised about the occurrence of atypical recurrences, including peritoneal carcinomatosis and port-site metastasis.

Case Presentation: The patient referred to our Emergency Department because of acute confusional state probably due to severe anemia and sepsis. A left nephroureterectomy, left hemicolectomy with end colostomy and the surgical excision of the huge mass was performed through a xipho-pubic incision associated to another left peri-stomal incision. The histological specimen analysis showed a high-grade sarcoma, not otherwise specified (sarcoma, NOS-type), measuring 29 cm × 8 cm × 5 cm in diameters. The left kidney and ureter were not infiltrated by the neoplasm while serosa membranes and muscular layers of left colon were infiltrated by the mass. The patient died because of a cardiac arrest 4 days after surgery.

Discussion: RARC is a safe and feasible alternative to open radical cystectomy (ORC) with satisfactory operative time, little blood loss, and low transfusion rates. Despite this, RARC is associated with a low, but not neglectable, risk of atypical metastases like peritoneal implants and port-site metastasis. Although a small amount (7%) of RARC were performed in non-urothelial variants of bladder cancer, the sarcomatoid one can be related to a greater risk of atypical recurrence and special precaution should be taken to reduce potential causes of tumor seeding.
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http://dx.doi.org/10.1177/0391560320957235DOI Listing
February 2021

Molecular characterization of a bladder pleomorphic rhabdomyosarcoma in an adult patient.

Pathol Res Pract 2020 Aug 28;216(8):153033. Epub 2020 May 28.

Pathology Unit, Istituto nazionale tumori-irccs-fondazione g. pascale, Naples, Italy.

Pleomorphic rhabdomyosarcoma (PRMS) is a rare but highly aggressive soft tissue tumor, accounting for 3% of soft tissue sarcomas. PRMS is the most frequent subtype of RMS in adulthood and it is mainly located in the large muscles of the extremities, particularly the lower limbs and the trunk, more rarely in other locations especially in the bladder. At our knowledge, only six cases of adult pleomorphic rhabdomyosarcoma of the bladder have been reported in the literature. In this study, we report a case of PRMS of bladder with a very poor prognosis. In fact, the patient died a month after surgery. The tumor was characterized by poorly differentiated, medium-sized sometimes rhabdoid cells, mixed with large-sized and pleomorphic elements with evident anisonucleosis, and with large areas of necrosis. We used an extensive immunohistochemical panel to exclude other tumors much more frequently reported at this site. The positivity for myogenic markers such as actin, desmin, myogenin and MyoD1 allowed the correct diagnosis. Furthermore, since preliminary studies highlighted a series of specific molecular alterations in PMRS cell lines, we analyzed a panel of specific mutations and gene rearrangements by RT-PCR and FISH methods. We showed a copy gains of CCND1 and MALT genes in our samples, suggesting an accurate molecular characterization of PRMS to establish a better management of patients and new therapeutic opportunities.
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http://dx.doi.org/10.1016/j.prp.2020.153033DOI Listing
August 2020

Circulating preoperative testosterone level predicts unfavourable disease at radical prostatectomy in men with International Society of Urological Pathology Grade Group 1 prostate cancer diagnosed with systematic biopsies.

World J Urol 2020 Jul 18. Epub 2020 Jul 18.

Department of Translational Medical Sciences, University of Naples "Federico II", 8031, Naples, Italy.

Purpose: The association between circulating total testosterone (T) levels and clinically significant PCa is still a matter of debate. In this study, we evaluated whether serum testosterone levels may have a role in predicting unfavorable disease (UD) and biochemical recurrence (BCR) in patients with clinically localized (≤ cT2c) ISUP grade group 1 PCa at biopsy.

Methods: 408 patients with ISUP grade group 1 prostate cancer, undergone to radical prostatectomy and T measurement were included. The outcome of interest was the presence of unfavourable disease (UD) defined as ISUP grade group [Formula: see text] 3 and/or pT [Formula: see text] 3a.

Results: Statistically significant differences resulted between serum testosterone values and ISUP grade groups (P < 0.0001). Significant correlation was found analyzing testosterone values versus age (P < 0.0001), and versus PSA (P = 0.008). BCR-free survival was significantly decreased in patients with low levels of testosterone (P = 0.005). These findings were confirmed also in the ISUP 1-2 subgroups (P = 0.01). ROC curve analysis showed that T outperformed PSA in predicting UD (AUC 0.718 vs AUC 0.525; P < 0.001) and was and independent risk factor for BCR.

Conclusion: Our findings suggested that circulating total T was a significant predictor of UD at RP in patients with preoperative low- to intermediate-risk diseases, confirming the potential role of circulating androgens in preoperative risk assessment of PCa patients.
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http://dx.doi.org/10.1007/s00345-020-03368-9DOI Listing
July 2020

Outcomes and predictors of benign histology in patients undergoing robotic partial or radical nephrectomy for renal masses: a multicenter study.

Cent European J Urol 2020 23;73(1):33-38. Epub 2020 Mar 23.

Division of Urology, Virginia Commonwealth University Health System, Richmond, VA, USA.

Introduction: Theaim of this study was to assess preoperative factors associated with benign histology in patients undergoing surgical removal of a renal mass and to analyze outcomes of robotic partial nephrectomy (PN) and radical nephrectomy (RN) for these masses.

Material And Methods: Overall, 2,944 cases (543 benign and 2,401 malignant) who underwent robotic PN and RN between 2003-2018 at 10 institutions worldwide were included. The assessment of the predictors of benign histology was made at the final surgical pathology report. Descriptive statistics, Mann-Whitney U, Pearson's χ, and logistic regression analysis were used.

Results: Patients in the benign group were mostly female (61 vs. 33%; p <0.001), with lower body mass index (BMI) (26.0 vs. 27.1 kg/m; p <0.001). The benign group presented smaller tumor size (2.8 vs. 3.5 cm; p <0.001), R.E.N.A.L. score (6.0 vs. 7.0; p <0.001). There was a lower rate of hilar (11 vs.18%; p = 0.001), cT≥3 (1 vs. 4.5%; p <0.001) tumors in the benign group. There was a statistically significant higher rate of PN in the benign group (97 vs. 86%; p <0.001) as well as a statistically significant lower 30-day re-admission rate (2 vs. 5%; p = 0.081). Multivariable analysis showed male gender (OR: 0.52; p <0.001), BMI (OR: 0.95; p <0.001), and cT3a (OR: 0.22; p = 0.005) to be inversely associated to benign histology.

Conclusions: In 18% of cases, a benign histologic type was found. Only 3% of these tumors were treated with RN. Female gender, lower BMI, and higher T staging showed to be independent predictors of benign histology.
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http://dx.doi.org/10.5173/ceju.2020.0019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7203778PMC
March 2020

Type 2 diabetes mellitus predicts worse outcomes in patients with high-grade T1 bladder cancer receiving bacillus Calmette-Guérin after transurethral resection of the bladder tumor.

Urol Oncol 2020 05 12;38(5):459-464. Epub 2020 Mar 12.

Department of Emergency and Organ Transplantation, Urology, Andrology and Kidney Transplantation Unit, University of Bari, Bari, Italy.

Objectives: The aim of this multicenter study was to investigate the prognostic role of type 2 diabetes mellitus (T2DM) comorbidity in a large multi-institutional cohort of patients with primary T1HG/G3 non-muscle-invasive bladder cancer (NMIBC) treated with transurethral resection of the bladder (TURB).

Materials And Methods: A total of 1,172 patients with primary T1 HG/G3 who had NMIBC on re-TURB and who received adjuvant intravesical bacillus Calmette-Guérin therapy with maintenance were included. Endpoints were recurrence-free survival and progression-free survival.

Results: A total of 231 (19.7%) of patients had T2DM prior to TURB. Five-year recurrence-free survival estimates were 12.5% in patients with T2DM compared to 36% in patients without T2DM, P < 0.0001. Five-year PFS estimates were 60.5% in patients with T2DM compared to 70.2% in patients without T2DM, P = 0.003. T2DM was independently associated with disease recurrence (hazard ratio = 1.41; 95% confidence interval = 1.20-1.66, P < 0.001) and progression (hazard ratio = 1.27; 95% confidence interval = 0.99-1.63, P < 0.001), after adjusting for other known predictive factors such as tumor size, multifocality, T1G3 on re-TURB, body mass index, lymphovascular invasion, and neutrophil-to-lymphocytes ratio.

Conclusions: Given the potential implications for management, prospective validation of this finding along with translational studies designed to investigate the underlying biology of such an association are warranted.
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http://dx.doi.org/10.1016/j.urolonc.2020.02.016DOI Listing
May 2020

Effect of Obesity and Overweight Status on Complications and Survival After Minimally Invasive Kidney Surgery in Patients with Clinical T Renal Masses.

J Endourol 2020 03;34(3):289-297

Department of Medical, Oral and Biotechnological Sciences, Urology Unit, SS Annunziata Hospital, "G.D'Annunzio" University of Chieti, Chieti, Italy.

To evaluate the effect of obesity and overweight on surgical, functional, and survival outcomes in patients with large kidney masses after minimally invasive surgery. Within a multicenter multinational dataset, patients found to have ≥cT renal mass and treated with minimally invasive (laparoscopic or robotic) kidney surgery (radical or partial nephrectomy) during the period 2003 to 2017 were abstracted. They were stratified according to the body mass index classes as normal weight (18.5-24.9 kg/m), overweight (25.0-29.9 kg/m), and obese (≥30.0 kg/m). Mixed models and Cox proportional hazard regression tested differences in complication rates, estimated glomerular filtration rate (eGFR) change over time, overall mortality (OM), and disease recurrence (DR) rates. Of 812 patients, 30.6% were normal weight, 42.7% were overweight, and 26.7% obese. Overweight (odds ratio 0.82, 95% confidence interval [CI]: 0.51-1.31,  = 0.406) and obese patients (OR: 0.81, 95% CI: 0.44-1.47,  = 0.490) experienced similar complication rates than normal weight. Moreover, no statistically significant differences in eGFR were found for overweight ( = 0.129) or obese ( = 0.166) patients compared to normal weight. However, higher OM rates were recorded in overweight (hazard ratio [HR] 3.59, 95% CI: 1.03-12.51,  = 0.044), as well as in obese, patients (HR 7.83, 95% CI: 2.20-27.83,  = 0.002). Similarly, higher DR rates were recorded in obese (HR 2.76, 95% CI: 1.40-5.44,  = 0.003) patients. Obese and overweight patients do not experience higher complication rates or worse eGFR after minimally invasive kidney surgery, which therefore can be deemed feasible and safe also in this subset of patients. Nevertheless, obese and overweight patients seem to carry a higher risk of OM, and therefore, they should undergo a strict follow-up after surgery.
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http://dx.doi.org/10.1089/end.2019.0604DOI Listing
March 2020

Robotic versus other nephroureterectomy techniques: a systematic review and meta-analysis of over 87,000 cases.

World J Urol 2020 Apr 26;38(4):845-852. Epub 2019 Nov 26.

Division of Urology, VCU Health System, VCU Medical Center, PO Box 980118, Richmond, VA, 23298-0118, USA.

Purpose: To perform a systematic review and meta-analysis of the literature inherent robotic nephroureterectomy (RNU) and to compare its outcomes with those of other nephroureterectomy (NU) techniques.

Methods: A systematic literature search was performed up to April 2019 using PubMed, Embase®, and Web of Science. The Preferred Reporting Items for Systematic Review and Meta-analysis Statement was followed for study selection. The following data were extracted for each study: baseline features, surgical outcomes, oncological outcomes, and survival outcomes. Stata® 15.0 was used for statistical analysis.

Results: Literature search identified 80 studies eligible for the meta-analysis and overall 87,291 patients were included in the analysis: open NU (ONU; n = 45,601), hand-assisted laparoscopic NU (HALNU; n = 442), laparoscopic NU (LNU n = 31,093), and RNU (n = 10,155). RNU was more likely to be performed in those patients with multifocal tumor location (proportion: 0.19; 95% CI 0.14, 0.24) and high-grade disease (proportion: 0.70; 95% CI 0.53, 0.68). The lowest EBL was recorded in the RNU group (weighted mean (WM) 163.31 mL; 95% CI 88.94, 237.68), whereas the highest was in the ONU group (414.99 mL; 95% CI 378.52, 451.46). Operative time was shorter for ONU (224.98 mL; 95% CI 212.26, 237.69). RNU had lower rate of intraoperative complications (0.02; 95% CI 0.01, 0.05). ONU showed higher odds of transfusions (0.20; 95% CI 0.15, 0.25). LOS was statistically significantly shorter for the RNU group (5.35 days; 95% CI 4.97, 5.82). HALNU seemed to present lower risk of PSM (0.02; 95% CI - 0.01, 0.05), and lower risk of recurrence (0.22; 95% CI 0.15, 0.30), metastasis (0.07; 95% CI 0.05, 0.10), and cancer-related death (0.03; 95% CI 0.01, 0.06). ONU showed the lowest 5 years cancer specific survival (proportion: 0.77; 95% CI 0.74, 0.80). No correlation was found between the surgical technique and recurrence-free and cancer-specific survival.

Conclusions: Evidence regarding RNU for the treatment of UTUC is increasing but it remains quite sparse and of low quality. Despite this, RNU seems to be safe, and to offer the advantages of a minimally invasive approach without impairing the oncological outcomes. Nevertheless, ONU, HALNU, and LNU still represent a valid, and commonly used surgical treatment option. As RNU becomes more popular, and concerns related to its use remain, the best surgical technique for NU remains to be determined.
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http://dx.doi.org/10.1007/s00345-019-03020-1DOI Listing
April 2020

Neuropathic painful complications due to endopelvic nerve lesions after robot-assisted laparoscopic prostatectomy: Three case reports.

Medicine (Baltimore) 2019 Nov;98(46):e18011

Uro-Gynecological Department.

Rationale: Robot-assisted laparoscopic prostatectomy (RALP) is the most frequent strategy used for the surgical remedy of patients with localized prostate cancer. Although there is awareness about potential patient positioning nerve injuries, iatrogenic nerve lesions are less described in the literature. Here, we report 3 cases of patients who presented with neuropathic painful complications due to RALP-associated nerve lesions.

Patient Concerns: A 62-year-old patient (case 1), a 72-year-old male (case 2), and a 57-year-old patient (case 3) presented at the clinic with symptoms of neuropathic pain after RALP surgery.

Diagnosis: Patients were diagnosed with a potential injury of different branches of the pudendal nerve (cases 1 and 2), and left obturator nerve (case 3).

Interventions: Patients underwent multimodal pharmacologic treatment through pregabalin, weak opioids, strong opioid, paracetamol, and adjuvants. In cases 2 and 3, a multidisciplinary approach was needed. As the patients responded to conservative treatment, invasive approaches were not necessary.

Outcomes: After treatment, the patients of case 1 showed pain relief after 4 days, paresthesia resolved in 15 days, whereas the anal crushing sensation lasted for approximately 1 month. In case 2, after 4 weeks of treatment, the patient experienced a considerable decrement in pain intensity with complete response after 4 months. In case 3, pain relief was achieved after 2 days, motor symptoms recovery after 2 weeks, and neuropathic features resolved completely after 5 weeks although the obturator sign resolved within 2 months.

Lessons: The RALP-associated neurologic injuries may occur even when performed by highly experienced surgeons. A better understanding of the potential iatrogenic nerve lesions can surely allow an improvement in the surgical technique. A multidisciplinary approach and early multimodal pain strategy are mandatory for managing these complications.
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http://dx.doi.org/10.1097/MD.0000000000018011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6867760PMC
November 2019

Robotic partial nephrectomy versus radical nephrectomy in elderly patients with large renal masses.

Minerva Urol Nefrol 2020 Feb 13;72(1):99-108. Epub 2019 Sep 13.

Division of Urology, Virginia Commonwealth University Health System, Richmond, VA, USA -

Background: Recent evidence suggests that the "oldest old" patients might benefit of partial nephrectomy (PN), but decision-making for this subset of patients is still controversial. Aim of this study is to compare outcomes of robotic partial (RPN) or radical nephrectomy (RRN) for large renal masses in patients older than 65 years.

Methods: We identified 417≥65 years old patients who underwent RRN or RPN for cT1b or ≥cT2 renal mass at 17 high volume centers. Propensity score match analysis was performed adjusting for age, ASA≥3, pre-operative eGFR, and clinical tumor size. Predictors of complications, functional and oncological outcomes were evaluated in multivariable logistic and Cox regression models.

Results: After propensity score analysis, 73 patients in the RPN group were matched with 74 in the RRN group. R.E.N.A.L. Score (9.6±1.7 vs. 8.6±1.7; P<0.001), and high complexity (56 vs. 15%; P=0.001) were higher in the RRN. Estimated blood loss was higher in the RPN group (200 vs. 100 mL; P<0.001). RPN showed higher rate of overall complications (38 vs. 23%; P=0.05), but not major complications (P=0.678). At last follow-up, RPN group showed better functional outcomes both in eGFR (55.4±22.6 vs. 45.7±15.7 mL/min; P=0.016) and lower eGFR variation (9.7 vs. 23.0 mL/min; P<0.001). The procedure type was not associated with recurrence free survival (RFS) (HR: 0.47; P=0.152) and overall mortality (OM) (0.22; P=0.084).

Conclusions: RPN in elderly patients with large renal masses provides acceptable surgical, and oncological outcomes allowing better functional preservation relative to RRN. The decision to undergo RPN in this subset of patients should be tailored on a case by case basis.
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http://dx.doi.org/10.23736/S0393-2249.19.03583-5DOI Listing
February 2020

Systemic Inflammatory Markers and Oncologic Outcomes in Patients with High-risk Non-muscle-invasive Urothelial Bladder Cancer.

Eur Urol Oncol 2018 10 13;1(5):403-410. Epub 2018 Jul 13.

Division of Urology, European Institute of Oncology, Milan, Italy.

Background: Serum levels of neutrophils, platelets, and lymphocytes have been recognized as factors related to poor prognosis for many solid tumors, including bladder cancer (BC).

Objective: To evaluate the prognostic role of the combination of the neutrophil/lymphocyte ratio (NLR), platelet/lymphocyte ratio (PLR), and lymphocyte/monocyte ratio (LMR) in patients with high-risk non-muscle-invasive urothelial BC (NIMBC).

Design, Setting, And Participants: A total of 1151 NMIBC patients who underwent first transurethral resection of the bladder tumor (TURBT) at 13 academic institutions between January 1, 2002 and December 31, 2012 were included in this analysis. The median follow-up was 48 mo.

Intervention: TURBT with intravesical chemotherapy or immunotherapy.

Outcome Measurements And Statistical Analysis: Multivariable Cox regression analysis was performed to identify factors predictive of recurrence, progression, cancer-specific mortality, and overall mortality. A systemic inflammatory marker (SIM) score was calculated based on cutoffs for NLR, PLR, and LMR.

Results And Limitations: The 48-mo recurrence-free survival was 80.8%, 47.35%, 20.67%, and 17.06% for patients with an SIM score of 0, 1, 2, and 3, respectively (p<0.01, log-rank test) while the corresponding 48-mo progression free-survival was 92.0%, 75.67%, 72.85%, and 63.1% (p<0.01, log-rank test). SIM scores of 1, 2, and 3 were associated with recurrence (hazard ratio [HR] 3.73, 7.06, and 7.88) and progression (HR 3.15, 4.41, and 5.83). Limitations include the lack of external validation and comparison to other clinical risk models.

Conclusions: Patients with high-grade T1 stage NMIBC with high SIM scores have worse oncologic outcomes in terms of recurrence and progression. Further studies should be conducted to stratify patients according to SIM scores to identify individuals who might benefit from early cystectomy.

Patient Summary: In this study, we defined a risk score (the SIM score) based on the measurement of routine systemic inflammatory markers. This score can identify patients with high-grade bladder cancer not invading the muscular layer who are more likely to suffer from tumor recurrence and progression. Therefore, the score could be used to select patients who might benefit from early bladder removal.
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http://dx.doi.org/10.1016/j.euo.2018.06.006DOI Listing
October 2018

Partial versus radical nephrectomy in very elderly patients: a propensity score analysis of surgical, functional and oncologic outcomes (RESURGE project).

World J Urol 2020 Jan 1;38(1):151-158. Epub 2019 Apr 1.

Division of Urology, VCU Health, 1200 East Broad st, Richmond, VA, 23298, USA.

Purpose: To compare the outcomes of PN to those of RN in very elderly patients treated for clinically localized renal tumor.

Patients And Methods: A purpose-built multi-institutional international database (RESURGE project) was used for this retrospective analysis. Patients over 75 years old and surgically treated for a suspicious of localized renal with either PN or RN were included in this database. Surgical, renal function and oncological outcomes were analyzed. Propensity scores for the predicted probability to receive PN in each patient were estimated by logistic regression models. Cox proportional hazard models were estimated to determine the relative change in hazard associated with PN vs RN on overall mortality (OM), cancer-specific mortality (CSM) and other-cause mortality (OCM).

Results: A total of 613 patients who underwent RN were successfully matched with 613 controls who underwent PN. Higher overall complication rate was recorded in the PN group (33% vs 25%; p = 0.01). Median follow-up for the entire cohort was 35 months (interquartile range [IQR] 13-63 months). There was a significant difference between RN and PN in median decline of eGFR (39% vs 17%; p < 0.01). PN was not correlated with OM (HR = 0.71; p = 0.56), OCM (HR = 0.74; p = 0.5), and showed a protective trend for CSM (HR = 0.19; p = 0.05). PN was found to be a protective factor for surgical CKD (HR = 0.28; p < 0.01) and worsening of eGFR in patients with baseline CKD. Retrospective design represents a limitation of this analysis.

Conclusions: Adoption of PN in very elderly patients with localized renal tumor does not compromise oncological outcomes, and it allows better functional preservation at mid-term (3-year) follow-up, relative to RN. Whether this functional benefit translates into a survival benefit remains to be determined.
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http://dx.doi.org/10.1007/s00345-019-02665-2DOI Listing
January 2020

Outcomes of Partial and Radical Nephrectomy in Octogenarians - A Multicenter International Study (Resurge).

Urology 2019 Jul 23;129:139-145. Epub 2019 Mar 23.

Division of Urology, VCU Health, Richmond, VA. Electronic address:

Objective: To analyze the outcomes of partial nephrectomy (PN) and radical nephrectomy (RN) in octogenarian patients.

Methods: The RESURGE (REnal SUrgery in the Eldely) multi-institutional database was queried to identify patients ≥80 years old who had undergone a PN or RN for a renal tumor. Multivariable binary logistic regression estimated the association between type of surgery and occurrence of complications. Multivariable Cox regression model assessed the association between type of surgery and All-Causes Mortality.

Results: The study analyzed 585 patients (median age 83 years, IQR 81-84), 364 of whom (62.2%) underwent RN and 221 (37.8%) PN. Patients undergoing RN were older (P = .0084), had larger tumor size (P < .0001) and higher clinical stage (P < .001). At multivariable analysis for complications, the only significant difference was found for lower risk of major postoperative complications for laparoscopic RN compared to open RN (OR: 0.42; P = .04). The rate of significant (>25%) decrease of eGFR in PN and RN was 18% versus 59% at 1 month, and 23% versus 65% at 6 months (P < .0001). After a median follow-up time of 39 months, 161 patients (31%) died, of whom 105 (20%) due to renal cancer.

Conclusion: In this patient population both RN and PN carry a non-negligible risk of complications. When surgical removal is indicated, PN should be preferred, whenever technically feasible, as it can offer better preservation of renal function, without increasing the risk of complications. Moreover, a minimally invasive approach should be pursued, as it can translate into lower surgical morbidity.
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http://dx.doi.org/10.1016/j.urology.2019.03.009DOI Listing
July 2019

Near-infrared Fluorescence Imaging with Indocyanine Green in Robot-assisted Partial Nephrectomy: Pooled Analysis of Comparative Studies.

Eur Urol Focus 2020 05 21;6(3):505-512. Epub 2019 Mar 21.

Division of Urology, VCU Health System, Richmond, VA, USA. Electronic address:

Context: The use of near-infrared fluorescence (NIRF) imaging was described to facilitate selective clamping during robot-assisted partial nephrectomy (RAPN).

Objective: To perform a systematic review and cumulative analysis of available studies comparing the outcomes of RAPN with or without use of this technology (NIRF).

Evidence Acquisition: A systematic review of the literature was performed to identify relevant studies up to December 2018 through PubMed and EMBASE databases. A meta-analysis was conducted with the RevMan 5.3 software.

Evidence Synthesis: Six comparative studies were identified. Overall, 369 cases were included for the analysis (171 NIRF-RAPN and 198 standard RAPN). No significant difference was identified between groups in baseline characteristics, operating time, and estimated blood loss; however, a shorter clamping time was recorded for the NIRF-RAPN group. Functional outcomes revealed higher overall estimated glomerular filtration rate (eGFR) values in the NIRF-RAPN group at short-term (1-3 mo) postoperative follow-up (weighted mean difference [WMD]: 9.26ml/min; 95% confidence interval [CI]: 6.46, 12.06; p<0.001). In two studies, a renal scan-based assessment of split eGFR was available, and pooled analysis revealed higher split eGFR for NIRF-RAPN (WMD: 7.91ml/min; 95% CI: 4.26, 11.56; p < 0.001), and lower Δ % between preoperative and 1-mo eGFR (WMD: -7.84%; 95% CI: -8.85, -6.83; p<0.00001).

Conclusions: Current evidence regarding the use of NIRF-guided selective clamping during RAPN is based on a limited number of studies from high-volume institutions. Notwithstanding these limitations, NIRF-RAPN can be safely performed, and it might offer better short-term renal functional outcomes. It remains to be determined whether this can ultimately translate into a clinical benefit for patients undergoing RAPN, especially in the long term.

Patient Summary: We assessed the outcomes of robot-assisted partial nephrectomy (RAPN) performed with or without the use of near-infrared fluorescence (NIRF) imaging. NIRF-RAPN appeared to be a safe procedure with potential better short-term functional outcomes.
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http://dx.doi.org/10.1016/j.euf.2019.03.005DOI Listing
May 2020

Robotic versus laparoscopic radical nephrectomy: a large multi-institutional analysis (ROSULA Collaborative Group).

World J Urol 2019 Nov 7;37(11):2439-2450. Epub 2019 Feb 7.

Division of Urology, Virginia Commonwealth University School of Medicine, Richmond, VA, USA.

Objective: To compare the outcomes of robotic radical nephrectomy (RRN) to those of laparoscopic radical nephrectomy (LRN) for large renal masses.

Methods: This was a retrospective analysis of RRN and LRN cases performed for large (≥ cT2) renal masses from 2004 to 2017 and collected in the multi-institutional international database (ROSULA: RObotic SUrgery for LArge renal masses). Peri-operative, functional, and oncologic outcomes were compared between each approach. Descriptive analyses were performed and presented as medians with interquartile ranges. Inverse probability of treatment weighting-adjusted multivariable analyses were used to identify predictors of peri-operative complications. Kaplan-Meier analysis and Cox regression models were used to assess survival outcomes.

Results: A total of 941 patients (RRN = 404, LRN = 537) were identified. There was no difference in terms of gender, age, and clinical tumor size. Over the study period, RRN had an annual increase of 11.75% (95% CI [7.34, 17.01] p < 0.001) and LRN had an annual decline of 5.39% (95% CI [-6.94, -3.86] p < 0.001). Patients undergoing RRN had higher BMI (27.6 [IQR 24.8-31.1] vs. 26.5 [24.1-30.0] kg/m, p < 0.01). Operative duration was longer for RRN (185.0 [150.0-237.2] vs. 126 [90.8-180.0] min, p < 0.001). Length of stay was shorter for RRN (3.0 [2.0-4.0] vs. 5.0 [4.0-7.0] days, p < 0.001). RRN cases presented more advanced disease (higher pathologic staging [pT3-4 52.5 vs. 24.2%, p < 0.001], histologic grade [high grade 49.3 vs. 30.4%, p < 0.001], and rate of nodal disease [pN1 5.4 vs. 1.9%, p < 0.01]). Surgical approach did not represent an independent risk factor for peri-operative complications (OR 1.81 95% CI [0.97-3.39], adjusted p = 0.2). The main study limitation is the retrospective design.

Conclusions: This study represents the largest known multi-center comparison between RRN and LRN. The two procedures seem to offer similar peri-operative outcomes. Notably, RRN has been increasingly utilized, especially in the setting of more advanced and surgically challenging disease without increasing the risk of peri-operative complications.
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http://dx.doi.org/10.1007/s00345-019-02657-2DOI Listing
November 2019

Predictors of Residual T1 High Grade on Re-Transurethral Resection in a Large Multi-Institutional Cohort of Patients with Primary T1 High-Grade/Grade 3 Bladder Cancer.

J Cancer 2018 20;9(22):4250-4254. Epub 2018 Oct 20.

Division of Urology, European Institute of Oncology, Milan, Italy.

The aim of this multi-institutional study was to identify predictors of residual high-grade (HG) disease at re-transurethral resection (reTUR) in a large cohort of primary T1 HG/Grade 3 (G3) bladder cancer patients. A total of 1155 patients with primary T1 HG/G3 bladder cancer from 13 academic institutions that underwent a reTUR within 6 weeks after first TUR were evaluated. Logistic regression analysis was performed to assess the association of predictive factors with residual HG at reTUR. Residual HG cancer was found in 288 (24.9%) of patients at reTUR. Patients presenting residual HG cancer were more likely to have carcinoma in situ (CIS) at first resection (p<0.001), multiple tumors (p=0.02), and tumor size larger than 3 cm (p=0.02). Residual HG disease at reTUR was associated with increased preoperative neutrophil-to-lymphocytes ratio (NLR) (p=0.006) and body mass index (BMI)>=25 kg/m. On multivariable analysis, independent predictors for HG residual disease at reTUR were tumor size >3cm (OR = 1.37; 95% CI: 1.02-1.84, p=0.03), concomitant CIS (OR 1.92; 95% CI: 1.32-2.78, p=0.001), being overweight (OR= 2.08; 95% CI: 1.44-3.01, p<0.001) and obesity (OR 2.48; 95% CI: 1.64-3.77, p<0.001). A reTUR in high grade T1 bladder cancer is mandatory as about 25% of patients, presents residual high grade disease. Independent predictors to identify patients at risk of residual high grade disease after a complete TUR include tumor size, presence of carcinoma in situ, and BMI >=25 kg/m.
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http://dx.doi.org/10.7150/jca.26129DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6277616PMC
October 2018

Mutated Von Hippel-Lindau-renal cell carcinoma (RCC) promotes patients specific natural killer (NK) cytotoxicity.

J Exp Clin Cancer Res 2018 Dec 4;37(1):297. Epub 2018 Dec 4.

Functional Genomics, Istituto Nazionale per lo Studio e la Cura dei Tumori, Fondazione "G. Pascale"-IRCCS, Via Semmola, 80131, Naples, Italy.

Background: Previous evidence demonstrated that restoration of wild type VHL in human renal cancer cells decreased in vitro NK susceptibility. To investigate on the role of tumoral VHL status versus NK capability in renal cancer patients, 51 RCC patients were characterized for VHL mutational status and NK function.

Methods: VHL mutational status was determined by direct DNA sequencing on tumor tissue. NK cytotoxicity was measured against specific target cells K562, VHL-wild type (CAKI-1) and VHL-mutated (A498) human renal cancer cells through externalization of CD107a and IFN-γ production. Activating NK receptors, NKp30, NKp44, NKp46, NKG2D, DNAM-1, NCAM-1 and FcγRIIIa were evaluated through quantitative RT-PCR. RCC tumoral Tregs were characterized as CD4CD25CD127Foxp3 and Treg function was evaluated as inhibition of T-effector proliferation.

Results: VHL mutations were detected in 26/55 (47%) RCC patients. IL-2 activated whole-blood samples (28 VHL-WT-RCC and 23 VHL-MUT-RCC) were evaluated for NK cytotoxicity toward human renal cancer cells A498, VHL-MUT and CAKI-1, VHL-WT. Efficient NK degranulation and increase in IFN-γ production was detected when IL-2 activated whole-blood from VHL-MUT-RCC patients were tested toward A498 as compared to CAKI-1 cells (CD107aNK: 7 ± 2% vs 1 ± 0.41%, p = 0.015; IFN-γNK: 6.26 ± 3.4% vs 1.78 ± 0.9% respectively). In addition, IL-2 activated NKs induced higher CD107a exposure in the presence of RCC autologous tumor cells or A498 as compared to SN12C (average CD107aNK: 4.7 and 2.7% vs 0.3% respectively at 10E:1 T ratio). VHL-MUT-RCC tumors were NKp46 cells infiltrated and expressed high NKp30 and NKp46 receptors as compared to VHL-WT-RCC tumors. A significant lower number of Tregs was detected in the tumor microenvironment of 13 VHL-MUT-RCC as compared to 13 VHL-WT-RCC tumors (1.84 ± 0.36% vs 3.79 ± 0.74% respectively, p = 0.04). Tregs isolated from VHL-MUT-RCC patients were less suppressive of patients T effector proliferation compared to Tregs from VHL-WT-RCC patients (Teff proliferation: 6.7 ± 3.9% vs 2.8 ± 1.1%).

Conclusions: VHL tumoral mutations improve NKs effectiveness in RCC patients and need to be considered in the evaluation of immune response. Moreover therapeutic strategies designed to target NK cells could be beneficial in VHL-mutated-RCCs alone or in association with immune checkpoints inhibitors.
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http://dx.doi.org/10.1186/s13046-018-0952-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6278085PMC
December 2018

Validation of Neutrophil-to-lymphocyte Ratio in a Multi-institutional Cohort of Patients With T1G3 Non-muscle-invasive Bladder Cancer.

Clin Genitourin Cancer 2018 12 6;16(6):445-452. Epub 2018 Jul 6.

Department of Urology, Medical University of Vienna, Vienna, Austria; Karl Landsteiner Institute of Urology and Andrology, Vienna, Austria; Department of Urology, University of Texas Southwestern Medical Center, Dallas, TX; Department of Urology, Weill Cornell Medical College, New York, NY.

Introduction: The aim of this multicenter study was to investigate the prognostic role of neutrophil-to-lymphocyte ratio (NLR) and to validate the NLR cutoff of 3 in a large multi-institutional cohort of patients with primary T1 HG/G3 non-muscle-invasive bladder cancer (NMIBC).

Patients And Methods: The study period was from January 2002 through December 2012. A total of 1046 patients with primary T1 HG/G3 who had NMIBC on re-transurethral bladder resection (TURB) who received adjuvant intravesical bacillus Calmette-Guérin therapy with maintenance from 13 academic institutions were included. Endpoints were time to disease, and recurrence-free (RFS), progression-free (PFS), overall (OS), and cancer-specific survival (CSS).

Results: A total of 512 (48.9%) of patients had NLR ≥ 3 prior to TURB. High pretreatment NLR was associated with female gender and residual T1HG/G3 on re-TURB. The 5-year RFS estimates were 9.4% (95% confidence interval [CI], 6.8%-12.4%) in patients with NLR ≥ 3 compared with 58.8% (95% CI, 54%-63.2%) in patients with NLR < 3; the 5-year PFS estimates were 57.1% (95% CI, 51.5%-62.2%) versus 79.2% (95% CI, 74.7%-83%; P < .0001); the 10-year OS estimates were 63.6% (95% CI, 55%-71%) versus 66.5% (95% CI, 56.8%-74.5%; P = .03); the 10-year CSS estimates were 77.4% (95% CI, 68.4%-84.2%) versus 84.3% (95% CI, 76.6%-89.7%; P = .004). NLR was independently associated with disease recurrence (hazard ratio [HR], 3.34; 95% CI, 2.82-3.95; P < .001), progression (HR, 2.18; 95% CI, 1.71-2.78; P < .001) and CSS (HR, 1.65; 95% CI, 1.02-2.66; P = .03). The addition of NLR to a multivariable model that included established features increased its discrimination for predicting of RFS (+6.9%), PFS (+1.8%), and CSS (+1.7%).

Conclusions: Pretreatment NLR ≥ 3 was a strong predictor for RFS, PFS, and CSS in patients with primary T1 HG/G3 NMIBC. It could help in the decision-making regarding intensity of therapy and follow-up.
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http://dx.doi.org/10.1016/j.clgc.2018.07.003DOI Listing
December 2018

An increased body mass index is associated with a worse prognosis in patients administered BCG immunotherapy for T1 bladder cancer.

World J Urol 2019 Mar 10;37(3):507-514. Epub 2018 Jul 10.

Department of Emergency and Organ Transplantation, Urology, Andrology and Kidney Transplantation Unit, University of Bari, Bari, Italy.

Purpose: The body mass index (BMI) may be associated with an increased incidence and aggressiveness of urological cancers. In this study, we aimed to evaluate the impact of the BMI on survival in patients with T1G3 non-muscle-invasive bladder cancer (NMIBC).

Methods: A total of 1155 T1G3 NMIBC patients from 13 academic institutions were retrospectively reviewed and patients administered adjuvant intravesical Bacillus Calmette-Guérin (BCG) immunotherapy with maintenance were included. Multivariable Cox regression analysis was performed to identify factors predictive of recurrence and progression.

Results: After re-TURBT, 288 patients (27.53%) showed residual high-grade NMIBC, while 867 (82.89%) were negative. During follow-up, 678 (64.82%) suffered recurrence, and 303 (30%) progression, 150 (14.34%) died of all causes, and 77 (7.36%) died of bladder cancer. At multivariate analysis, tumor size (hazard ratio [HR]:1.3; p = 0.001), and multifocality (HR:1.24; p = 0.004) were significantly associated with recurrence (c-index for the model:55.98). Overweight (HR: 4; p < 0.001) and obesity (HR:5.33 p < 0.001) were significantly associated with an increased risk of recurrence. Addition of the BMI to a model that included standard clinicopathological factors increased the C-index by 9.9. For progression, we found that tumor size (HR:1.63; p < 0.001), multifocality (HR:1.31; p = 0.01) and concomitant CIS (HR: 2.07; p < 0.001) were significant prognostic factors at multivariate analysis (C-index 63.8). Overweight (HR: 2.52; p < 0.001) and obesity (HR: 2.521 p < 0.001) were significantly associated with an increased risk of progression. Addition of the BMI to a model that included standard clinicopathological factors increased the C-index by 1.9.

Conclusions: The BMI could have a relevant role in the clinical management of T1G3 NMIBC, if associated with bladder cancer recurrence and progression. In particular, this anthropometric factor should be taken into account at initial diagnosis and in therapeutic strategy decision making.
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http://dx.doi.org/10.1007/s00345-018-2397-1DOI Listing
March 2019

High-Grade T1 on Re-Transurethral Resection after Initial High-Grade T1 Confers Worse Oncological Outcomes: Results of a Multi-Institutional Study.

Urol Int 2018 4;101(1):7-15. Epub 2018 Jul 4.

Department of Urology, Medical University of Vienna, Vienna, Austria.

Introduction: The aim of this multicenter study was to investigate the prognostic impact of residual T1 high-grade (HG)/G3 tumors at re-transurethral resection (TUR of bladder tumor) in a large multi-institutional cohort of patients with primary T1 HG/G3 bladder cancer (BC).

Patients And Methods: The study period was from January 2002 to -December 2012. A total of 1,046 patients with primary T1 HG/G3 and who had non-muscle invasive BC (NMIBC) on re-TUR followed by adjuvant intravesical Bacillus Calmette-Guerin (BCG) therapy with maintenance were included. Endpoints were time to disease recurrence, progression, and overall and cancer-specific death.

Results: A total of 257 (24.6%) patients had residual T1 HG/G3 tumors. The presence of concomitant carcinoma in situ, multiple and large tumors (> 3 cm) at first TUR were associated with residual T1 HG/G3. Five-year recurrence-free survival (RFS), progression-free survival (PFS), overall survival (OS), and cancer-specific survival (CSS) were 17% (CI 11.8-23); 58.2% (CI 50.7-65); 73.7% (CI 66.3-79.7); and 84.5% (CI 77.8-89.3), respectively, in patients with residual T1 HG/G3, compared to 36.7% (CI 32.8-40.6); 71.4% (CI 67.3-75.2); 89.8% (CI 86.6-92.3); and 95.7% (CI 93.4-97.3), respectively, in patients with NMIBC other than T1 HG/G3 or T0 tumors. Residual T1 HG/G3 was independently associated with RFS, PFS, OS, and CSS in multivariable analyses.

Conclusions: Residual T1 HG/G3 tumor at re-TUR confers worse prognosis in patients with primary T1 HG/G3 treated with maintenance BCG. Patients with residual T1 HG/G3 for primary T1 HG/G3 are very likely to fail BCG therapy alone.
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http://dx.doi.org/10.1159/000490765DOI Listing
January 2019