Publications by authors named "Maria C Mir"

37 Publications

Trimodal therapy in muscle invasive bladder cancer management.

Minerva Urol Nefrol 2020 Dec;72(6):650-662

Department of Urology, Instituto Valenciano de Oncologia (IVO), Valencia, Spain -

Introduction: Radical cystectomy (RC) is the current mainstay for muscle-invasive bladder cancer (MIBC). Concerns regarding morbidity, mortality and quality of life have favored the introduction of bladder sparing strategies. Trimodal therapy, combining transurethral resection, chemotherapy and radiotherapy is the current standard of care for bladder preservation strategies in selected patients with MIBC.

Evidence Acquisition: A comprehensive search of the Medline and Embase databases was performed. A total of 19 studies were included in a systematic review of bladder sparing strategies in MIBC management was carried out following the preferred reporting items for systematic reviews and meta-analysis (PRISMA).

Evidence Synthesis: The overall median complete response rate after trimodal therapy (TMT) was 77% (55-93). Salvage cystectomy rate with TMT was 17% on average (8-30). For TMT, the 5-year cancer-specific survival and overall survival rates range from 42-82% and 32-74%, respectively. Currently data supporting neoadjuvant or adjuvant chemotherapy in bladder sparing approaches are emerging, but robust definitive conclusions are still lacking. Gastrointestinal toxicity rates are low around 4% (0.5-16), whereas genitourinary toxicity rates reached 8% (1-24). Quality of life outcomes are still underreported.

Conclusions: Published data and clinical experience strongly support trimodal therapy as an acceptable bladder sparing strategy in terms of oncological outcomes and quality of life in selected patients with MIBC. A strong need exists for specialized centers, to increase awareness among urologists, to discuss these options with patients and to stress the increased participation of patients and their families in treatment path decision-making.
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http://dx.doi.org/10.23736/S0393-2249.20.04018-7DOI Listing
December 2020

Robot-assisted Radical Nephrectomy: A Systematic Review and Meta-analysis of Comparative Studies.

Eur Urol 2020 Nov 17. Epub 2020 Nov 17.

Division of Urology, Department of Surgery, Virginia Commonwealth University, Richmond, Virginia, USA. Electronic address:

Context: Radical nephrectomy (RN) is the gold standard treatment for large and locally advanced renal tumors. Although robot-assisted radical nephrectomy (RRN) is being increasingly adopted, it remains unclear whether it offers benefits over standard laparoscopic radical nephrectomy (LRN) or open radical nephrectomy (ORN).

Objective: To compare the outcomes of robotic surgery to those of laparoscopic and open surgery in patients undergoing RN for renal cell carcinoma (RCC).

Evidence Acquisition: A systematic search was performed across MEDLINE, EMBASE, and Web of Science for retrospective and prospective studies comparing RRN to LRN or ORN. A meta-analysis evaluated perioperative safety, effectiveness, survival, and cost-effectiveness outcomes. The weighted mean difference (WMD) and odds ratio (OR) were used to compare continuous and dichotomous variables, respectively. Quality was assessed using the Newcastle-Ottawa scale. Sensitivity analyses were performed to assess the robustness of the estimates.

Evidence Synthesis: Twelve studies involving 64 221 patients were identified and included in the analysis. Compared to LRN, RRN was associated with statistically significant longer operative time (WMD 37.44 min; p =  0.03), shorter length of stay (WMD -0.84 days; p =  0.02) and higher total costs (WMD US$4700; p < 0.001). Compared to ORN, RRN was associated with shorter length of stay (WMD -3.06 days; p =  0.002), fewer overall complications (OR 0.56; p <  0.001), lower estimated blood loss (WMD -702 ml; p =  0.01), and higher total hospital costs (WMD US$4520; p =  0.004). There was high heterogeneity across all analyses.

Conclusions: In patients undergoing RN for RCC, RRN seems to offer some key advantages compared to ORN, including shorter hospitalization and fewer complications. Compared to LRN, RRN provides similar surgical outcomes but at higher total costs. These findings should be interpreted within the limitations of this type of analysis, given high heterogeneity between studies and poor robustness for most outcomes. Randomized clinical studies with long-term follow-up are needed to obtain more definitive results.

Patient Summary: In patients with renal cell carcinoma, robot-assisted radical nephrectomy shows perioperative advantages compared to open radical nephrectomy, but not compared to laparoscopic radical nephrectomy.
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http://dx.doi.org/10.1016/j.eururo.2020.10.034DOI Listing
November 2020

Surgical Management and Outcomes of Renal Tumors Arising from Horseshoe Kidneys: Results from an International Multicenter Collaboration.

Eur Urol 2021 Jan 16;79(1):133-140. Epub 2020 Sep 16.

Department of Urology, University Hospitals Leuven, Leuven, Belgium. Electronic address:

Background: Despite being the most frequent renal fusion anomaly, tumors arising from horseshoe kidneys (HSKs) are extremely rare and management guidance is lacking.

Objective: To evaluate the perioperative, oncological, and functional outcomes of surgically treated HSK tumors.

Design, Setting, And Participants: A retrospective, multicenter cohort study of 43 HSK tumors in 40 patients was conducted, and technical description of the surgical approach has been provided.

Surgical Procedure: Surgical resection of renal tumors arising from HSKs was performed either via open surgery or via minimally invasive surgery (MIS).

Measurements: We analyzed patient and tumor characteristics as well as surgical technique, and functional and oncological outcomes.

Results And Limitations: Eight patients were treated by MIS and 32 by open surgery. One patient (2.5%) experienced an intraoperative complication and 13 patients (32.5%) experienced postoperative complications, of which three (7.5%) were Clavien-Dindo ≥3 complications. Surgical margins were positive in two tumors (4.7%). The most frequent histology was clear-cell renal cell carcinoma (46.5%). The median follow-up was 51 (interquartile range [IQR] 17-73) mo. The 5-yr overall, cancer-specific, and recurrence-free survival rates were 81.2%, 86.8%, and 83.1%, respectively. The percent decreases in estimated glomerular filtration rate at discharge and the last follow-up were 15% (IQR 4-26%) and 17% (IQR 1-31%), respectively. Limitations include the cohort's retrospective nature, heterogeneity, and small sample size.

Conclusions: Surgical management of tumors in HSKs can be approached via both open surgery and MIS, with maximal preservation of functional renal parenchyma. In this cohort, rates of complications, positive surgical margins, and renal functional decrease were acceptable, considering the anatomical complexity of these kidneys and tumors. These tumors display great variation in histological subtypes. Meticulous presurgical planning, taking advantage of advanced imaging techniques, can aid in achieving good outcomes.

Patient Summary: We evaluated the surgical management of renal tumors in horseshoe kidneys, which are very rare. Although these procedures are highly complex, outcomes are acceptable. Modern imaging techniques are often required in presurgical planning.
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http://dx.doi.org/10.1016/j.eururo.2020.09.012DOI Listing
January 2021

Triggers for delayed intervention in patients with small renal masses undergoing active surveillance: a systematic review.

Minerva Urol Nefrol 2020 Aug;72(4):389-407

European Society of Residents in Urology (ESRU), Arnhem, the Netherlands.

Introduction: Patients with small renal masses (SRM) can be exposed to overdiagnosis and overtreatment. As such, active surveillance (AS) is recommended by all Guidelines for selected patients. However, it remains underutilized. One key reason is the lack of consensus on the factors prompting delayed intervention (DI). Herein we provide an updated overview of the triggers for DI in patients with SRMs initially undergoing AS.

Evidence Acquisition: A systematic review of the English-language literature was performed according to the PRISMA statement recommendations using the MEDLINE, Cochrane Central Register of Controlled Trials and Web of Science databases.

Evidence Synthesis: Overall, 10 prospective studies including 1870 patients were included. Median patient age ranged between 64 and 75 years, while median tumor size between 1.7 cm to 2.3 cm. The proportion of cystic SRMs ranged from 0% to 30%. Baseline renal tumor biopsy was performed in 7-45.2% of patients. Among these, malignant histology was found in 28.5%-83.3% of cases. Overall, the median growth rate of SRMs ranged between 0.10 and 0.27 cm/year. The proportion of patients undergoing DI ranged between 7% and 44%, after a median AS period of 12-27 months. The most commonly performed type of DI was surgery. Of resected SRMs, 0% to 30% were benign. The actual triggers for DI were either tumor-related (renal mass growth, stage progression, development of local complications/symptoms) or patient-related (patient preference, improved medical conditions, or qualification for other surgical procedures). At a median follow-up of 21.7 - 57-6 months, the proportion of patients experiencing metastatic disease, cancer-specific and other-cause mortality was 0-3.1%, 0-4% and 0-45.6%, respectively.

Conclusions: The available evidence shows that both tumor-related and patient-related factors are ultimate triggers for DI in patients with SRMs undergoing AS. However, the level of evidence is still low and further research is needed to individualize AS strategies according to both tumor biology and patient-related characteristics and values.
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http://dx.doi.org/10.23736/S0393-2249.20.03870-9DOI Listing
August 2020

Rates and Predictors of Perioperative Complications in Cytoreductive Nephrectomy: Analysis of the Registry for Metastatic Renal Cell Carcinoma.

Eur Urol Oncol 2020 08 12;3(4):523-529. Epub 2020 May 12.

Department of Urology, University Hospitals Leuven, Leuven, Belgium.

Background: Cytoreductive nephrectomy (CN) plays an important role in the treatment of a subgroup of metastatic renal cell carcinoma (mRCC) patients.

Objective: We aimed to evaluate morbidity associated with this procedure and identify potential predictors thereof to aid patient selection for this procedure and potentially improve patient outcomes.

Design, Setting, And Participants: Data from 736 mRCC patients undergoing CN at 14 institutions were retrospectively recorded in the Registry for Metastatic RCC (REMARCC).

Outcome Measurements And Statistical Analysis: Logistic regression analysis was used to identify predictors for intraoperative, any-grade (AGCs), low-grade, and high-grade (HGCs) postoperative complications (according to the Clavien-Dindo classification) as well as 30-d readmission rates.

Results And Limitations: Intraoperative complications were observed in 69 patients (10.9%). Thrombectomy (odds ratio [OR] 1.38, 95% confidence interval [CI] 1.08-1.75, p = 0.009) and adjacent organ removal (OR 2.7, 95% CI 1.38-5.30) were significant predictors of intraoperative complications at multivariable analysis. Two hundred seventeen patients (29.5%) encountered AGCs, while 45 (6.1%) encountered an HGC, of whom 10 (1.4%) died. Twenty-four (3.3%) patients had multiple postoperative complications. Estimated blood loss (EBL; OR 1.49, 95% CI 1.08-2.05, p = 0.01) was a significant predictor of AGCs at multivariable analysis. CN case load (OR 0.13, 95% CI 0.03-0.59, p = 0.009) and EBL (OR 2.93, 95% CI 1.20-7.15, p = 0.02) were significant predictors solely for HGCs at multivariable analysis. Forty-one patients (11.5%) were readmitted within 30 d of surgery. No significant predictors were identified. Results were confirmed in a subanalysis focusing solely on patients treated in the contemporary targeted therapy era.

Conclusions: Morbidity associated with CN is not negligible. Predictors of high-grade postoperative morbidity are predominantly indicators of complex surgery. EBL is a strong predictor of postoperative complications. CN case load correlates with lower high-grade morbidity and highlights the benefit of centralization of complex surgery. However, risks and benefits should be balanced when considering CN in mRCC patients.

Patient Summary: We studied patients with metastatic renal cancer to evaluate the outcomes associated with the surgical removal of the primary kidney tumor. We found that this procedure is often complex and adverse events are not uncommon. High intraoperative blood loss and a small number of cases performed at the treating center are associated with a higher rate of postoperative complications.
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http://dx.doi.org/10.1016/j.euo.2020.04.006DOI Listing
August 2020

Impact of sex on response to neoadjuvant chemotherapy in patients with bladder cancer.

Urol Oncol 2020 07 11;38(7):639.e1-639.e9. Epub 2020 Feb 11.

Department of Urology, Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria; Department of Urology, University of Texas Southwestern Medical Center, Dallas, TX; Departments of Urology, Weill Cornell Medical College, New York, New York; Department of Urology, Second Faculty of Medicine, Charles University, Prague, Czech Republic; Institute for Urology and Reproductive Health, I.M. Sechenov First Moscow State Medical University, Moscow, Russia. Electronic address:

Objective: To assess the effect of patient's sex on response to neoadjuvant chemotherapy (NAC) in patients with clinically nonmetastatic muscle-invasive bladder cancer (MIBC).

Methods: Complete pathologic response, defined as ypT0N0 at radical cystectomy, and downstaging were evaluated using sex-adjusted univariable and multivariable logistic regression modeling. We used interaction terms to account for age of menopause and smoking status. The association of sex with overall survival and cancer-specific survival was evaluated using Cox regression analyses.

Results: A total of 1,031 patients were included in the analysis, 227 (22%) of whom were female. Female patients had a higher rate of extravesical disease extension (P = 0.01). After the administration of NAC, ypT stage was equally distributed between sexes (P = 0.39). On multivariable logistic regression analyses, there was no difference between the sexes or age of menopause with regards to ypT0N0 rates or downstaging (all P > 0.5). On Cox regression analyses, sex was associated with neither overall survival (hazard ratio 1.04, 95% confidence interval 0.75-1.45, P = 0.81) nor cancer-specific survival (hazard ratio 1.06, 95% confidence interval 0.71-1.58, P = 0.77).

Conclusion: Our study generates the hypothesis that NAC equalizes the preoperative disparity in pathologic stage between males and females suggesting a possible differential response between sexes. This might be the explanation underlying the comparable survival outcomes between sexes despite females presenting with more advanced tumor stage.
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http://dx.doi.org/10.1016/j.urolonc.2020.01.010DOI Listing
July 2020

The prognostic value of the neutrophil-to-lymphocyte ratio in patients with muscle-invasive bladder cancer treated with neoadjuvant chemotherapy and radical cystectomy.

Urol Oncol 2020 01 31;38(1):3.e17-3.e27. Epub 2019 Oct 31.

Department of Urologic Sciences, University of British Columbia, Vancouver, BC, Canada. Electronic address:

Introduction: The neutrophil-to-lymphocyte ratio (NLR) is an attractive marker because it is derived from routine bloodwork. NLR has shown promise as a prognostic factor in muscle invasive bladder cancer (MIBC) but its value in patients receiving neoadjuvant chemotherapy (NAC) before radical cystectomy (RC) is not yet established. Since NLR is related to an oncogenic environment and poor antitumor host response, we hypothesized that a high NLR would be associated with a poor response to NAC and would remain a poor prognostic indicator in patients receiving NAC.

Methods: A retrospective analysis was performed on patients with nonmetastatic MIBC (cT2-4aN0M0) who received NAC prior to RC between 2000 and 2013 at 1 of 19 centers across Europe and North America. The pre-NAC NLR was used to split patients into a low (NLR ≤ 3) and high (NLR > 3) group. Demographic and clinical parameters were compared between the groups using Student's t test, chi-squared, or Fisher's exact test. Putative risk factors for disease-specific and overall survival were analyzed using Cox regression, while predictors of response to NAC (defined as absence of MIBC in RC specimen) were investigated using logistic regression.

Results: Data were available for 340 patients (199 NLR ≤ 3, 141 NLR > 3). Other than age and rate of lymphovascular invasion, demographic and pretreatment characteristics did not differ significantly. More patients in the NLR > 3 group had residual MIBC after NAC than the NLR ≤ 3 group (70.8% vs. 58.3%, P = 0.049). NLR was the only significant predictor of response (odds ratio: 0.36, P = 0.003) in logistic regression. NLR was a significant risk factor for both disease-specific (hazard ratio (HR): 2.4, P = 0.006) and overall survival (HR:1.8, P = 0.02).

Conclusion: NLR > 3 was associated with a decreased response to NAC and shorter disease-specific and overall survival. This suggests that NLR is a simple tool that can aid in MIBC risk stratification in clinical practice.
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http://dx.doi.org/10.1016/j.urolonc.2019.09.023DOI Listing
January 2020

Phase II trial of continuous treatment with sunitinib in patients with high-risk (BCG-refractory) non-muscle invasive bladder cancer.

Invest New Drugs 2019 12 24;37(6):1231-1238. Epub 2019 Jun 24.

Cleveland Clinic, Glickman Urological and Kidney Institute, 9500 Euclid Avenue/R35, Cleveland, OH, 44195, USA.

Purpose Sunitinib is a vascular endothelial growth factor receptor (VEGFR) inhibitor with antitumor activity against bladder cancer. We hypothesized that treatment with sunitinib may decrease progression or recurrence in non-muscle invasive bladder cancer (NMIBC) refractory to intra-vesical BCG. Patients and Methods This is a single-arm phase II study of sunitinib in patients (pts) with NMIBC who progressed after BCG. Treatment included sunitinib 37.5 g daily for 12 weeks followed by 12± 2-week cystoscopy and surveillance for one year. The primary endpoint was the complete response rate at 12 months. Secondary endpoints included recurrence free survival (RFS), progression free survival (PFS), overall survival (OS), and safety of sunitinib. Correlative studies on effects of sunitinib on myeloid derived suppressor cells (MDSC) and humoral immune responses were also performed. This trial was registered on ClinicalTrials.gov, number NCT01118351. Results Between June 2011 and September 2011, 15/19 pts. completed 12 weeks of therapy. The remaining 4 pts. had treatment related adverse events leading to discontinuation of sunitinib with one patient withdrawing consent. On the 12-week cystoscopy, 44% (8/18) of the pts. showed remission, 50% (9/18) progression and 1/18 recurrence. Overall, 22% (4/18) of pts. remained free of progression for >12 months. Grade (G) 4 toxicities were noted in 2 pts. (anemia and thrombocytopenia) while G3 were noted in 58%. Sunitinib resulted in reversal of MDSC mediated immunosuppression. Conclusions In NMIBC refractory to BCG, treatment with sunitinib was safe but not associated with improved clinical outcomes. The immune effects of sunitinib deserve further investigation.
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http://dx.doi.org/10.1007/s10637-018-00716-wDOI Listing
December 2019

Systematic Review of the Management of Local Kidney Cancer Relapse.

Eur Urol Oncol 2018 12 13;1(6):512-523. Epub 2018 Jul 13.

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

Context: Management of locally recurrent renal cancer is complex.

Objective: In this systematic review we analyse the available literature on the management of local renal cancer recurrence.

Evidence Acquisition: A systematic search (PubMed, Web of Science, CINAHL, Clinical Trials, and Scopus) of English literature from 2000 to 2017 was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines.

Evidence Synthesis: The search identified 1838 articles. Of those, 36 were included in the evidence synthesis. The majority of the studies identified were retrospective and not controlled. Local recurrence after thermal ablation (TA) may be managed with repeat TA. Alternatively, salvage nephrectomy is possible. However, a higher rate of complications should be expected than after primary nephrectomy. Salvage nephrectomy and TA represent treatment options for local recurrence after partial nephrectomy. Local retroperitoneal recurrence after radical nephrectomy is ideally treated with surgical resection, for which minimally invasive approaches might be applicable to select patients. For large recurrences, addition of intraoperative radiation may improve local control. Local tumour destruction appears to be more beneficial than systemic therapy alone for local recurrences.

Conclusions: Management of local renal cancer relapse varies according to the clinical course and prior treatments. The available data are mainly limited to noncontrolled retrospective series. After nephron-sparing treatment, TA represents an effective treatment with low morbidity. For local recurrence after radical nephrectomy, the low-level evidence available suggests superiority of surgical excision relative to systemic therapy or best supportive care. As a consequence, surgery should be prioritised when feasible and applicable.

Patient Summary: In renal cell cancer, the occurrence and management of local recurrence depend on the initial treatment. This cancer is a disease with a highly variable clinical course. After initial organ-sparing treatment, thermal ablation offers good cancer control and low rates of complications. For recurrence after radical nephrectomy, surgical excision seems to provide the best long-term cancer control and it is superior to medical therapy alone.
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http://dx.doi.org/10.1016/j.euo.2018.06.007DOI Listing
December 2018

Randomized phase II trial of neoadjuvant everolimus in patients with high-risk localized prostate cancer.

Invest New Drugs 2019 06 30;37(3):559-566. Epub 2019 Apr 30.

Department of Solid Tumor Oncology and Urology, Cleveland Clinic Taussig Cancer Institute, Cleveland, OH, USA.

Background Despite definitive local therapy, patients with high-risk prostate cancer have a significant risk for local and distant failure. To date, no systemic therapy given prior to surgery has been shown to improve outcomes. The phosphatidilinositol 3-kinase/AKT/mTOR pathway is commonly dysregulated in men with prostate cancer. We sought to determine the clinical efficacy and safety of the mTOR/TORC1 inhibitor everolimus in men with high-risk prostate cancer undergoing radical prostatectomy. Methods This is a randomized phase II study of everolimus at two different doses (5 and 10 mg daily) given orally for 8 weeks before radical prostatectomy in men with high-risk prostate cancer. The primary endpoint was the pathologic response (histologic P0, margin status, extraprostatic extension) and surgical outcomes. Secondary endpoints included changes in serum PSA level and treatment effects on levels of expression of mTOR, p4EBP1, pS6 and pAKT. Results Seventeen patients were enrolled: nine at 10 mg dose and eight at 5 mg dose. No pathologic complete responses were observed and the majority of patients (88%) had an increase in their PSA values leading to this study being terminated early due to lack of clinical efficacy. Treatment-related adverse events were similar to those previously reported with the use of everolimus in other solid tumors and no additional surgical complications were observed. A significant decrease in the expression of p4EBP1 was noted in prostatectomy samples following treatment. Conclusions Neoadjuvant everolimus given at 5 mg or 10 mg daily for 8 weeks prior to radical prostatectomy did not impact pathologic responses and surgical outcomes of patients with high-risk prostate cancer. Trial registration NCT00526591 .
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http://dx.doi.org/10.1007/s10637-019-00778-4DOI Listing
June 2019

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

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

Optimization of renal function preservation during robotic partial nephrectomy.

Ther Adv Urol 2019 Jan-Dec;11:1756287218815819. Epub 2019 Jan 8.

VCU Health and Division of Urology, Department of Surgery, McGuire VA Medical Center, 1200 East Broad St, Richmond, VA 23249, USA.

Over the past few years, the role of robotic-assisted partial nephrectomy (RPN) has exponentially grown. Multiple recognized factors contribute to postoperative renal function in patients undergoing RPN. The aim of this review is to identify these potential factors, and to evaluate strategies that may help optimize the goal of renal function preservation. A nonsystematic literature review was performed to retrieve the most recent evidence on factors contributing to renal function post-RPN. Analyzed elements include baseline factors (tumor complexity and patient characteristics), intraoperative (surgical) factors (control of the renal hilum and type of ischemia, resection technique, renorrhaphy technique), and pharmacotherapeutics. In conclusion, the advantages of robotic surgery in the setting of partial nephrectomy (PN) are becoming well established. Maximal preservation of renal function remains a priority goal of the procedure, and it is influenced by a plethora of factors. Adequate patient selection using radiomics, control of comorbidities, utilization of evidence-based intraoperative techniques/strategies, and postoperative care are key components of postoperative preservation of renal function. Further investigations regarding these factors and their effects on long-term renal function are necessary and will continue to aid in guiding appropriate patient care.
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http://dx.doi.org/10.1177/1756287218815819DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6329014PMC
January 2019

Nutrition for cystectomy with pelvic lymph nodes dissection: perioperative considerations.

Minerva Urol Nefrol 2016 Apr 3;68(2):150-60. Epub 2016 Mar 3.

Department of Urology, Urology Institute, Case Western Reserve University, Cleveland, OH, USA -

Assessment of nutritional status by an objective measure such as NRS-2002 or sarcopenia in the preoperative workup of major abdominal surgeries helps identify patients at risk for increased surgical morbidity and mortality. Preoperative and immediate postoperative nutritional supplements have demonstrated to decrease risk of complications and length of stay. Enhancing the immune system with immunonutrition has also been suggested as major player in this setting. In this review on nutritional considerations in the perioperative setting of radical cystectomy, we will describe several tools available to improve the complications rates and mortality surrounding this procedure.
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April 2016

Current Paradigm for Ischemia in Kidney Surgery.

J Urol 2016 06 22;195(6):1655-63. Epub 2016 Jan 22.

Department of Urology, University of Miami Miller School of Medicine and Sylvester Comprehensive Cancer Center, Miami, Florida; Urology Clinic, Department of Medical, Surgical and Health Science, University of Trieste, Trieste, Italy (NP). Electronic address:

Purpose: Partial nephrectomy is the accepted standard of care for treatment of patients with small renal masses. The primary goal while performing partial nephrectomy is cancer control with a secondary important goal of maximizing renal function preservation with minimal perioperative morbidity. Recent studies have highlighted the importance of renal parenchymal quality and quantity postoperatively rather than duration of ischemia in determining long-term renal function. We review the available data regarding perioperative renal function optimization with special interest in ischemia during partial nephrectomy, highlighting the controversies and establishing future lines of investigation.

Materials And Methods: We performed a comprehensive literature review for the years 1970 to 2014 via MEDLINE(®), PubMed(®) and the Cochrane Library. Review was consistent with the PRISMA (Preferred Reporting Items for Systemic Reviews and Meta-Analyses) criteria. We used MeSH (Medical Subject Headings) terms for the search including "acute kidney injury/failure," "carcinoma, renal cell/carcinoma of kidney/neoplasm of kidney," "kidney failure, chronic/end-stage kidney disease," "ischemia-reperfusion" and "warm ischemia/cold ischemia." Relevant review articles were included. Abstracts from major urological/surgical conferences were reviewed. All studies included were performed in adults, were written in English and had an abstract available.

Results: Our traditional knowledge of renal ischemia is derived from animal studies, ie kidney transplant and retrospective partial nephrectomy series that indicate the risk of renal function impairment for every minute of ischemia. Careful evaluation of historical studies highlights flaws of the use of ischemia duration as a dichotomous marker (25 or 30 minutes) while predicting renal function outcomes. Recent studies have revealed no effect of duration of ischemia on ultimate kidney function in the short or long term. Quality and quantity of parenchyma preserved postoperatively are key predictors of ultimate renal function after partial nephrectomy. Traditionally partial nephrectomy has been performed with hilar occlusion to provide a relatively bloodless surgical field allowing effective oncologic control during tumor excision with secure management of blood vessels, collecting system and renal reconstruction. Selective clamping and nonclamping techniques have been proposed to avoid the perceived harmful effects of ischemia, although they convert a complex surgery into a more challenging procedure, potentially limiting the widespread use of partial nephrectomy for management of renal cancers. Promising urine and blood-based biomarkers (NGAL, KIM-1) in the context of critical care settings and global stress have been observed to predict acute kidney injury. Within the partial nephrectomy environment the usefulness of those markers needs to be further investigated. To date, no study has proved their usefulness in the setting of partial nephrectomy.

Conclusions: Based on the available evidence, use of a single cutoff for duration of ischemia time as a dichotomous value for renal function outcomes in the setting of partial nephrectomy is flawed. Renal ischemia is a controversial topic with a shifted paradigm within the last decade. Current evidence has shown that patients with 2 kidneys undergoing nephron sparing surgery can tolerate ischemia times of more than 30 minutes without a clinically significant decline in renal function. Biomarkers predictive of renal tubular injury fail to predict acute kidney injury in the context of partial nephrectomy. Indications for partial nephrectomy could be significantly expanded as the safety of limited renal ischemia is now better understood.
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http://dx.doi.org/10.1016/j.juro.2015.09.099DOI Listing
June 2016

Current Clinical Applications of Testicular Cancer Biomarkers.

Urol Clin North Am 2016 Feb;43(1):119-25

Department of Urology, Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL 33136, USA. Electronic address:

Current use of testicular biomarkers for screening, diagnosis, and follow-up is reviewed in the context of potential clinical utility of these tests. This information will be of value to clinicians to determine patient suitability for certain treatments and will also assist in reviewing current literature regarding potential biomarkers that may be used for testicular cancer.
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http://dx.doi.org/10.1016/j.ucl.2015.08.011DOI Listing
February 2016

Comparison of 2 Computed Tomography-based Methods to Estimate Preoperative and Postoperative Renal Parenchymal Volume and Correlation With Functional Changes After Partial Nephrectomy.

Urology 2015 Jul;86(1):80-6

Imaging Institute, Cleveland Clinic, Cleveland, OH; Glickman Urological and Kidney Institute, Cleveland Clinic, Cleveland, OH. Electronic address:

Objective: To compare freehand scripting and semiautomated renal parenchymal volume measurements on preoperative or postoperative computed tomography scans and assess relationships between parenchymal volume loss and functional changes within the operated kidney after partial nephrectomy (PN).

Materials And Methods: Fifty patients (16 solitary kidneys, 34 bilateral kidneys) with renal tumors managed by PN with necessary studies for analysis were included. Freehand scripting and semiautomated threshold-based analysis were performed before and 4-12 months after PN to obtain preoperative normal parenchymal volumes, projected residual parenchymal volumes, and actual postoperative volumes. Glomerular filtration rate was determined by the Modification of Diet in Renal Disease 2 equation along with nuclear renal scan to provide split function for patients with 2 kidneys. Limits of agreement and Bland-Altman analyses were performed. The relationship between the amount of vascularized parenchyma preserved and renal function saved was correlated for each measurement method using Pearson correlation.

Results: The semiautomated method yielded estimates that were higher than freehand scripting by a mean of 14 cm(3) for estimation of preoperative normal parenchymal volume, 21 cm(3) for projected residual parenchymal volume, and 9 cm(3) for actual postoperative parenchymal volume. For the semiautomated method, correlation between the amount of normal parenchyma preserved and renal function saved was 0.52 (95% confidence interval [CI], 0.28-0.69; P <.001), and for the scripting method, correlation was 0.60 (95% CI, 0.39-0.76; P <.001).

Conclusion: Semiautomated and freehand scripting measurements of parenchymal volumes were relatively consistent before and after PN, although the semiautomated approach tended to yield volumes that were approximately 5%-10% higher on average. Measurement of parenchymal volume changes by both approaches correlated significantly with functional changes after PN.
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http://dx.doi.org/10.1016/j.urology.2015.04.029DOI Listing
July 2015

Analysis of Atrophy After Clamped Partial Nephrectomy and Potential Impact of Ischemia.

Urology 2015 Jun 16;85(6):1417-22. Epub 2015 Apr 16.

Department of Urology, Center for Urologic Oncology, Glickman Urological Kidney Institute, Cleveland Clinic, Cleveland, OH. Electronic address:

Objective: Ischemia is a potential contributor to decline of function after partial nephrectomy (PN), although loss of parenchymal mass related to excision and reconstruction appears to be a more significant factor. However, loss of parenchymal mass could also be due to global effects of ischemia leading to parenchymal atrophy. In this study, we evaluated parenchymal volumes in regions away from the operated site to assess for atrophy.

Materials And Methods: A total of 164 patients undergoing PN for whom detailed analysis of function and parenchymal mass within the operated kidney could be performed were assessed for opposite pole volume (OPV) before and 4-12 months after surgery. Tumor location was required to be ≥2 cm away from the opposite polar line to exclude local effects related to excision or reconstruction. OPV was estimated by software analysis, and the ratio of the estimates (OPV ratio = postoperative OPV to preoperative OPV) was used to assess for atrophy.

Results: Patient demographics and tumor characteristics were representative of conventional PN populations, and warm ischemia (n = 101; median, 21 minutes) and cold ischemia (n = 63; median, 26 minutes) were applied by surgeon discretion. OPVs before and after PN were 63.2 and 62.5 cm(3), respectively (P = .76). The median OPV ratio was 0.99 suggesting that significant atrophy did not occur. OPV ratio was 0.99 for warm ischemia cases and 0.99 for cold ischemia cases (P = .95).

Conclusion: Limited warm ischemia or hypothermia was not associated with significant parenchymal atrophy after PN, which suggests that parenchymal volume loss in this setting is primarily due to excision or reconstruction.
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http://dx.doi.org/10.1016/j.urology.2015.02.040DOI Listing
June 2015

Enhanced Recovery After Surgery protocols for radical cystectomy surgery: review of current evidence and local protocols.

ANZ J Surg 2015 Jul-Aug;85(7-8):514-20. Epub 2015 Mar 17.

Austin Health, The University of Melbourne, Melbourne, Victoria, Australia.

Background: Radical cystectomy (RC) remains a morbid procedure. The use of Enhanced Recovery After Surgery (ERAS) pathways has proven to reduce care time and post-operative complications after colorectal surgery. There is a high potential for reducing morbidity associated with RC by utilizing ERAS in this setting. The purpose of this review is to examine the current evidence for ERAS in preoperative, intra-operative and post-operative setting of care for RC patients and to propose ERAS evidence-based protocol for patients undergoing RC in the Australian and New Zealand environment.

Preoperative: Patient's medical optimization, avoidance of oral mechanical bowel preparation and emphasis on preoperative administration of high-energy carbohydrate drinks from colorectal literature has led to inclusion of these strategies in the preoperative considerations of ERAS in RC.

Intra-operative: Epidural analgesia has an integral role in reducing surgical stress response, improving analgesia and expediting functional recovery and should be included in ERAS RC protocols. Of relevance is 72 h maximum length of its duration. With regard to minimally invasive approach to RC, despite encouraging results from high-volume centres, high-level evidence in this field are lacking (ongoing clinical trials). Standardized anaesthetic protocols with particular emphasis on perioperative fluid management are essential components of ERAS protocols.

Post-operative: Avoidance of routine nasogastric tube placement, early mobilization and multifaceted approach to optimization of gut function and elimination of post-operative ileus are the cornerstones of post-operative care in the setting of ERAS in RC patients.
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http://dx.doi.org/10.1111/ans.13043DOI Listing
October 2016

Decline in renal function after partial nephrectomy: etiology and prevention.

J Urol 2015 Jun 29;193(6):1889-98. Epub 2015 Jan 29.

Glickman Urological Kidney Institute, Cleveland Clinic, Cleveland, Ohio. Electronic address:

Purpose: Partial nephrectomy is the reference standard for the management of small renal tumors and is commonly used for localized kidney cancer. A primary goal of partial nephrectomy is to preserve as much renal function as possible. New baseline glomerular filtration rate after partial nephrectomy can have prognostic significance with respect to long-term outcomes. Recent studies provide an increased understanding of the factors that determine functional outcomes after partial nephrectomy as well as preventive measures to minimize functional decline. We review these advances, highlight ongoing controversies and stimulate further research.

Materials And Methods: A comprehensive literature review consistent with the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) criteria was performed from January 2006 to April 2014 using PubMed®, Cochrane and Ovid Medline. Key words included partial nephrectomy, renal function, warm ischemia, hypothermia, nephron mass, parenchymal volume, surgical approaches to partial nephrectomy, preoperative and intraoperative imaging, enucleation, hemostatic agents and energy based resection. Relevant reviews were also examined as well as their cited references. An additional Google Scholar search was conducted to broaden the scope of the review. Only English language articles were included in the analysis. The primary outcomes of interest were the new baseline level of function after early postoperative recovery, percent decline in function, potential etiologies and preventive measures.

Results: Decline in function after partial nephrectomy averages approximately 20% in the operated kidney, and can be due to incomplete recovery from the ischemic insult or loss of nephron mass related to parenchymal excision or collateral damage during reconstruction. Compensatory hypertrophy in the contralateral kidney after partial nephrectomy in adults is marginal and decline in global renal function for patients with 2 kidneys averages about 10%, although there is some variance based on tumor size and location. Irreversible ischemic injury can be minimized by pharmacological intervention or surgical approaches such as hypothermia, limited warm ischemia, or zero or segmental ischemia. Excessive loss of nephron mass can be minimized by improved preoperative or intraoperative imaging, use of a bloodless field, enucleation and vascular microdissection. Hemostatic agents or energy based resection that minimizes the need for parenchymal and capsular suturing can also optimize preservation of the vascularized nephron mass.

Conclusions: Our understanding of the decline in renal function after partial nephrectomy has advanced considerably, including better appreciation of its magnitude and impact in various settings, possible etiologies and potential preventive measures. Many controversies persist and this remains an important area of investigation.
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http://dx.doi.org/10.1016/j.juro.2015.01.093DOI Listing
June 2015

CD117⁺ cells in the circulation are predictive of advanced prostate cancer.

Oncotarget 2015 Jan;6(3):1889-97

Department of Molecular Cardiology, Joseph J. Jacobs Center for Thrombosis and Vascular Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA.

Circulating tumor cells (CTCs) are associated with cancer progression, aggressiveness and metastasis. However, the frequency and predictive value of CTCs in patients remains unknown. If circulating cells are involved in tumor aggressiveness and metastasis, then cell levels should decline upon tumor removal in localized cancer patients, but remain high in metastatic patients. Accordingly, proposed biomarkers CD117/c-kit, CD133, CXCR4/CD184, and CD34-positive cell percentages in the blood of patients undergoing radical prostatectomy for localized cancer were assessed by flow cytometry prior to intervention and 1-3 months postoperatively. Only circulating CD117⁺ cell percentages decreased after radical prostatectomy, increased with cancer progression and correlated with high PSA values. Notably, postoperative CD117⁺ levels did not decrease in patients experiencing biochemical recurrence. In a xenograft model, CD117-enriched tumors were more vascularized and aggressive. Thus, CD117 expression on CTCs promotes tumor progression and could be a biomarker for prostate cancer diagnosis, prognosis, and/or response to therapy.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4359340PMC
http://dx.doi.org/10.18632/oncotarget.2796DOI Listing
January 2015

Multicenter assessment of neoadjuvant chemotherapy for muscle-invasive bladder cancer.

Eur Urol 2015 Feb 23;67(2):241-9. Epub 2014 Sep 23.

Vancouver Prostate Centre, Vancouver, British Columbia, Canada. Electronic address:

Background: The efficacy of neoadjuvant chemotherapy (NAC) for muscle-invasive bladder cancer (BCa) was established primarily with methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC), with complete response rates (pT0) as high as 38%. However, because of the comparable efficacy with better tolerability of gemcitabine and cisplatin (GC) in patients with metastatic disease, GC has become the most commonly used regimen in the neoadjuvant setting.

Objective: We aimed to assess real-world pathologic response rates to NAC with different regimens in a large, multicenter cohort.

Design, Setting, And Participants: Data were collected retrospectively at 19 centers on patients with clinical cT2-4aN0M0 urothelial carcinoma of the bladder who received at least three cycles of NAC, followed by radical cystectomy (RC), between 2000 and 2013.

Intervention: NAC and RC.

Outcome Measurements And Statistical Analysis: The primary outcome was pathologic stage at cystectomy. Univariable and multivariable analyses were used to determine factors predictive of pT0N0 and ≤pT1N0 stages.

Results And Limitations: Data were collected on 935 patients who met inclusion criteria. GC was used in the majority of the patients (n=602; 64.4%), followed by MVAC (n=183; 19.6%) and other regimens (n=144; 15.4%). The rates of pT0N0 and ≤pT1N0 pathologic response were 22.7% and 40.8%, respectively. The rate of pT0N0 disease for patients receiving GC was 23.9%, compared with 24.5% for MVAC (p=0.2). There was no difference between MVAC and GC in pT0N0 on multivariable analysis (odds ratio: 0.89 [95% confidence interval, 0.61-1.34]; p=0.6).

Conclusions: Response rates to NAC were lower than those reported in prospective randomized trials, and we did not discern a difference between MVAC and GC. Without any evidence from randomized prospective trials, the best NAC regimen for invasive BCa remains to be determined.

Patient Summary: There was no apparent difference in the response rates to the two most common presurgical chemotherapy regimens for patients with bladder cancer.
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http://dx.doi.org/10.1016/j.eururo.2014.09.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4840190PMC
February 2015

Assessment of outcomes in partial nephrectomy incorporating detailed functional analysis.

Urology 2014 Nov 18;84(5):1128-33. Epub 2014 Sep 18.

Center for Urologic Oncology, Glickman Urological & Kidney Institute, Cleveland Clinic, Cleveland, OH. Electronic address:

Objective: To assess perioperative morbidity and margins after conventional clamped partial nephrectomy (PN) while also using volumetric analysis to differentiate the contributions of parenchymal volume loss and recovery from ischemia.

Materials And Methods: The study analyzed 163 patients who underwent PN with appropriate studies to allow analysis of function and parenchymal mass specifically in the operated kidney. Recovery from ischemia (glomerular filtration rate saved/volume saved) would be 100% if all nephrons recovered from ischemia. Precision (postoperative parenchymal volume/predicted parenchymal volume, presuming loss of a 5-mm rim of parenchyma related to excision and reconstruction) reflects efforts to optimize the amount of vascularized parenchyma saved with the PN. Trifecta was defined as negative margins, no Clavien grade 3-5 or urologic complications, and both recovery ≥80% and precision ≥80%.

Results: An open procedure was performed in 82 patients (50%), and 59 (36%) had a solitary kidney. Warm ischemia was used in 96 patients (59%). The RENAL nephrometry score (radius, exophytic/endophytic properties of the tumor, nearness of tumor deepest portion to the collecting system or sinus, anterior/posterior descriptor, and the location relative to polar lines) was intermediate in 74 (45%) and high complexity in 38 (23%). Median recovery from ischemia was 95% and was ≥80% in 143 patients (88%). Median precision of excision/reconstruction was 93% and was ≥80% in 138 patients (85%). All tumors had negative surgical margins. Perioperative complications occurred in 13 patients (9%). Trifecta was achieved in 113 patients (69%). Multivariable analysis identified solitary kidney as the only significant predictor of trifecta.

Conclusion: Given careful patient selection and commensurate surgical expertise, excellent outcomes can be obtained with conventional clamped PN. Analysis of parenchymal volumes is necessary to facilitate comprehensive evaluation of functional outcomes after PN, allowing differentiation of nephron loss vs failure to recover from ischemia.
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http://dx.doi.org/10.1016/j.urology.2014.07.008DOI Listing
November 2014

Editorial Comment to Performance comparisons in major uro-oncological surgeries between the USA and Japan.

Int J Urol 2014 Nov 14;21(11):1150. Epub 2014 Jul 14.

Glickman Urological and Kidney Institute, Cleveland Clinic, Cleveland, Ohio, USA.

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http://dx.doi.org/10.1111/iju.12574DOI Listing
November 2014

Compensatory hypertrophy after partial and radical nephrectomy in adults.

J Urol 2014 Dec 12;192(6):1612-8. Epub 2014 Jun 12.

Glickman Urological Kidney Institute, Cleveland Clinic, Cleveland, Ohio. Electronic address:

Purpose: We assessed compensatory hypertrophy in the contralateral kidney after partial and radical nephrectomy in adults. We also examined predictive factors to facilitate more accurate estimation of global renal function after surgery.

Materials And Methods: We analyzed the records of 172 patients who underwent partial or radical nephrectomy with appropriate studies to determine function and parenchymal mass specifically in the operated and contralateral kidneys. All patients required renal scans to provide split renal function preoperatively and postoperatively. Parenchymal volume was measured by computerized tomography. All studies were done less than 2 months preoperatively and 4 to 12 months postoperatively.

Results: A total of 113 and 59 patients underwent partial and radical nephrectomy, and median tumor size was 3.5 and 7.0 cm, respectively (p <0.0001). Of patients treated with partial nephrectomy 19% had high complexity tumor compared to 80% of those treated with radical nephrectomy (p <0.0001). Median ipsilateral parenchymal volume was reduced 18% after partial nephrectomy and the median glomerular filtration rate in this kidney decreased 24.4%. The median contralateral kidney function increase after partial nephrectomy was 2.3% vs 21.1% after radical nephrectomy (p <0.0001). Median global function decreased 9.6% after partial nephrectomy vs 32.2% after radical nephrectomy (p <0.0001). A larger percent parenchymal volume loss (p = 0.0001) and fewer comorbidities (p = 0.0072) significantly correlated with greater compensatory hypertrophy in the contralateral kidney on multivariable analysis.

Conclusions: Compensatory hypertrophy in adults was limited after partial nephrectomy and it correlated significantly with the amount of parenchymal volume excised. Healthier patients also appeared to respond better. These results may allow for more accurate estimation of global renal function after partial and radical nephrectomy.
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http://dx.doi.org/10.1016/j.juro.2014.06.018DOI Listing
December 2014

Poorly functioning kidneys recover from ischemia after partial nephrectomy as well as strongly functioning kidneys.

J Urol 2014 Sep 19;192(3):665-70. Epub 2014 Mar 19.

Glickman Urological Kidney Institute, Cleveland Clinic, Cleveland, Ohio. Electronic address:

Purpose: Poorly functioning kidneys may not recover from ischemia as well as strongly functioning kidneys. This could impact surgical approaches to partial nephrectomy.

Materials And Methods: We analyzed the records of 155 consecutive patients treated with partial nephrectomy who underwent appropriate studies to facilitate analysis of function and parenchymal mass in the operated kidney, including computerized tomography and glomerular filtration rate measurement within 2 months preoperatively and 4 to 12 months postoperatively. Patients with a contralateral kidney also underwent renal scan in the same time frame to provide split renal function. Computerized tomography was done to measure functional parenchymal volume before and after partial nephrectomy. Recovery from ischemia, defined as percent glomerular filtration rate saved/percent volume saved, was considered 100% if all nephrons recovered from the ischemic insult.

Results: The median R.E.N.A.L. nephrotomy score was 8. Cold ischemia was used in 64 patients and limited warm ischemia was used in 91 (median 27 and 20 minutes, respectively). The median percent glomerular filtration rate saved in the operated kidney was 80% and the median parenchymal volume saved was 83%. The overall median rate of recovery from ischemia was 95%, including 100% for cold ischemia and 92% for limited warm ischemia. Recovery from ischemia was approximately 100% and was similar for all strata of preoperative estimated glomerular filtration rates in the operated kidney (p = 0.24), even in the warm ischemia subgroup.

Conclusions: Our results suggest that the quantity of parenchyma preserved is the main determinant of the postoperative glomerular filtration rate after partial nephrectomy as long as limited warm ischemia or hypothermia is used. Even poorly functioning kidneys recover well from the ischemic insult proportionate to the amount of parenchyma preserved.
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http://dx.doi.org/10.1016/j.juro.2014.03.036DOI Listing
September 2014

Autophagic flux determines cell death and survival in response to Apo2L/TRAIL (dulanermin).

Mol Cancer 2014 Mar 23;13:70. Epub 2014 Mar 23.

Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA.

Background: Macroautophagy is a catabolic process that can mediate cell death or survival. Apo2 ligand (Apo2L)/tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) treatment (TR) is known to induce autophagy. Here we investigated whether SQSTM1/p62 (p62) overexpression, as a marker of autophagic flux, was related to aggressiveness of human prostate cancer (PCa) and whether autophagy regulated the treatment response in sensitive but not resistant PCa cell lines.

Methods: Immunostaining and immunoblotting analyses of the autophagic markers p62 [in PCa tissue microarrays (TMAs) and PCa cell lines] and LC3 (in PCa cell lines), transmission electron microscopy, and GFP-mCherry-LC3 were used to study autophagy induction and flux. The effect of autophagy inhibition using pharmacologic (3-methyladenine and chloroquine) and genetic [(short hairpin (sh)-mediated knock-down of ATG7 and LAMP2) and small interfering (si)RNA-mediated BECN1 knock-down] approaches on TR-induced cell death was assessed by clonogenic survival, sub-G1 DNA content, and annexinV/PI staining by flow cytometry. Caspase-8 activation was determined by immunoblotting.

Results: We found that increased cytoplasmic expression of p62 was associated with high-grade PCa, indicating that autophagy signaling might be important for survival in high-grade tumors. TR-resistant cells exhibited high autophagic flux, with more efficient clearance of p62-aggregates in four TR-resistant PCa cell lines: C4-2, LNCaP, DU145, and CWRv22.1. In contrast, autophagic flux was low in TR-sensitive PC3 cells, leading to accumulation of p62-aggregates. Pharmacologic (chloroquine or 3-methyladenine) and genetic (shATG7 or shLAMP2) inhibition of autophagy led to cell death in TR-resistant C4-2 cells. shATG7-expressing PC3 cells, were less sensitive to TR-induced cell death whereas those shLAMP2-expressing were as sensitive as shControl-expressing PC3 cells. Inhibition of autophagic flux using chloroquine prevented clearance of p62 aggregates, leading to caspase-8 activation and cell death in C4-2 cells. In PC3 cells, inhibition of autophagy induction prevented p62 accumulation and hence caspase-8 activation.

Conclusions: We show that p62 overexpression correlates with advanced stage human PCa. Pharmacologic and genetic inhibition of autophagy in PCa cell lines indicate that autophagic flux can determine the cellular response to TR by regulating caspase-8 activation. Thus, combining various autophagic inhibitors may have a differential impact on TR-induced cell death.
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http://dx.doi.org/10.1186/1476-4598-13-70DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3998041PMC
March 2014

Effectiveness of epidural versus alternate analgesia for pain relief after radical prostatectomy and correlation with biochemical recurrence in men with prostate cancer.

Res Rep Urol 2013 21;5:139-45. Epub 2013 Oct 21.

University of Melbourne, Department of Surgery, Austin Hospital, Melbourne, VIC, Australia ; Ludwig Institute for Cancer Research, Austin Hospital, Melbourne, VIC, Australia.

Objectives: Our objectives were to analyze the effectiveness of epidural anesthesia in patients who underwent open retropubic radical prostatectomy (RRP) at our institution over the past decade, and to examine subsequent oncologic outcomes, comparing those receiving with those not receiving epidural anesthesia.

Methods: A comprehensive database of all patients undergoing RRP from November 1996 to December 2006 was analyzed; 354 patients underwent RRP at our institution and were divided into those receiving or not receiving an epidural. An independent pain management team scoring technical success found epidural technique to be consistent. Oncological outcome was an endpoint of our study, comparing both analysis groups. We classed prostate-specific antigen (PSA) recurrence after RRP as a serum PSA ≥ 0.2 ng/mL at any stage of postoperative follow-up. Complications were recorded to 30 days using the modified Clavien system, and full statistical analyses were undertaken.

Results: Records were available for 239 men; we observed a decreased trend in the use of epidural for pain management, along with a decrease in average hospital stay and an overall epidural success rate of 64%. When dividing data into RRP with and without epidural, we found a median hospital stay of 7 days for patients receiving an epidural compared with 6 days for those not receiving an epidural. The differences were statistically significant (P < 0.048) and remained so after adjusting for complications (P < 0.0001). Regarding oncological outcome, PSA recurrence was further analyzed in this cohort. Percentage of recurrence was higher (14.8%) for patients receiving an epidural than for the non-epidural group (4.8%). The differences were statistically significant (P = 0.012).

Conclusion: Epidural analgesia increased length of hospital stay and technical problems related to the epidural. Furthermore, men receiving an epidural showed an increased recurrence of PSA. In light of our findings, epidurals are probably not indicated for men undergoing RRP. However, as minimally invasive techniques are becoming more widespread, and epidural analgesia is being used less frequently, large randomized controlled trials to definitively support our hypotheses are unlikely to be undertaken.
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http://dx.doi.org/10.2147/RRU.S49219DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3826925PMC
January 2014

Predictors of precision of excision and reconstruction in partial nephrectomy.

J Urol 2014 Jul 25;192(1):30-5. Epub 2013 Dec 25.

Glickman Urological Kidney Institute, Cleveland Clinic, Cleveland, Ohio. Electronic address:

Purpose: The precision of excision and reconstruction to optimize vascularized parenchymal preservation is a major determinant of renal function after partial nephrectomy. We assessed partial nephrectomy surgical precision using volumetric computerized tomography and analyzed predictive factors.

Materials And Methods: We analyzed the records of 122 patients treated with partial nephrectomy in whom detailed analysis of the precision of excision and reconstruction specific to the operated kidney could be performed. We used volumetric computerized tomography to measure functional parenchymal volume before and after partial nephrectomy in the operated kidney. The glomerular filtration rate in the operated kidney was determined by the MDRD2 (Modification of Diet in Renal Disease 2) equation along with renal scan in patients with a contralateral kidney. Surgical precision was defined as actual postoperative parenchymal volume/predicted postoperative parenchymal volume, presuming loss of a 5 mm rim of normal parenchyma related to excision and reconstruction.

Results: Median patient age was 61 years and 64 patients (52%) underwent an open procedure. Cold ischemia was used in 50 patients (median 26 minutes) and limited warm ischemia (median 20 minutes) was used in 72. The R.E.N.A.L. (radius, exophytic/endophytic, nearness of tumor to collecting system or sinus, anterior/posterior and location relative to polar line) nephrometry score indicated low, intermediate and high complexity in 43 (35%), 55 (45%) and 24 patients (20%), respectively. A total of 45 patients (37%) with a solitary kidney were included in analysis. The median precision of excision and reconstruction was 93%. The median preserved glomerular filtration rate was 80% in the operated kidney. A solitary kidney was the only significant predictor of excision and reconstruction precision on univariable and multivariable analysis.

Conclusions: A solitary kidney significantly impacted partial nephrectomy surgical precision. This was likely related to the recognized need to preserve as much renal parenchyma as possible to optimize renal function in the absence of a contralateral kidney.
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http://dx.doi.org/10.1016/j.juro.2013.12.035DOI Listing
July 2014