Mitochondrial complex I promotes kidney cancer metastasis.

Most kidney cancers are metabolically dysfunctional1-4, but how this dysfunction affects cancer progression in humans is unknown. We infused 13C-labelled nutrients in over 80 patients with kidney cancer during surgical tumour resection. Labelling from [U-13C]glucose varies across subtypes, indicating that the kidney environment alone cannot account for all tumour metabolic reprogramming. Compared with the adjacent kidney, clear cell renal cell carcinomas (ccRCCs) display suppressed labelling of tricarboxylic acid (TCA) cycle intermediates in vivo and in ex vivo organotypic cultures, indicating that suppressed labelling is tissue intrinsic. [1,2-13C]acetate and [U-13C]glutamine infusions in patients, coupled with measurements of respiration in isolated human kidney and tumour mitochondria, reveal lower electron transport chain activity in ccRCCs that contributes to decreased oxidative and enhanced reductive TCA cycle labelling. However, ccRCC metastases unexpectedly have enhanced TCA cycle labelling compared with that of primary ccRCCs, indicating a divergent metabolic program during metastasis in patients. In mice, stimulating respiration or NADH recycling in kidney cancer cells is sufficient to promote metastasis, whereas inhibiting electron transport chain complex I decreases metastasis. These findings in humans and mice indicate that metabolic properties and liabilities evolve during kidney cancer progression, and that mitochondrial function is limiting for metastasis but not growth at the original site.

Perioperative nivolumab versus observation in patients with renal cell carcinoma undergoing nephrectomy (PROSPER ECOG-ACRIN EA8143): an open-label, randomised, phase 3 study.

BACKGROUND: The standard of care for patients with intermediate-to-high risk renal cell carcinoma is partial or radical nephrectomy followed by surveillance. We aimed to investigate use of nivolumab before nephrectomy followed by adjuvant nivolumab in patients with high-risk renal cell carcinoma to determine recurrence-free survival compared with surgery only. METHODS: In this open-label, randomised, phase 3 trial (PROSPER EA8143), patients were recruited from 183 community and academic sites across the USA and Canada. Eligible patients were aged 18 years or older with an Eastern Cooperative Oncology Group performance status of 0-1, with previously untreated clinical stage T2 or greater or Tany N+ renal cell carcinoma of clear cell or non-clear cell histology planned for partial or radical nephrectomy. Selected patients with oligometastatic disease, who were disease free at other disease sites within 12 weeks of surgery, were eligible for inclusion. We randomly assigned (1:1) patients using permuted blocks (block size of 4) within stratum (clinical TNM stage) to either nivolumab plus surgery, or surgery only followed by surveillance. In the nivolumab group, nivolumab 480 mg was administered before surgery, followed by nine adjuvant doses. The primary endpoint was investigator-reviewed recurrence-free survival in patients with renal cell carcinoma assessed in all randomly assigned patients regardless of histology. Safety was assessed in all randomly assigned patients who started the assigned protocol treatment. This trial is registered with ClinicalTrials.gov, NCT03055013, and is closed to accrual. FINDINGS: Between Feb 2, 2017, and June 2, 2021, 819 patients were randomly assigned to nivolumab plus surgery (404 [49%]) or surgery only (415 [51%]). 366 (91%) of 404 patients assigned to nivolumab plus surgery and 387 (93%) of 415 patients assigned to surgery only group started treatment. Median age was 61 years (IQR 53-69), 248 (30%) of 819 patients were female, 571 (70%) were male, 672 (88%) were White, and 77 (10%) were Hispanic or Latino. The Data and Safety Monitoring Committee stopped the trial at a planned interim analysis (March 25, 2022) because of futility. Median follow-up was 30·4 months (IQR 21·5-42·4) in the nivolumab group and 30·1 months (21·9-41·8) in the surgery only group. 381 (94%) of 404 patients in the nivolumab plus surgery group and 399 (96%) of 415 in the surgery only group had renal cell carcinoma and were included in the recurrence-free survival analysis. As of data cutoff (May 24, 2023), recurrence-free survival was not significantly different between nivolumab (125 [33%] of 381 had recurrence-free survival events) versus surgery only (133 [33%] of 399; hazard ratio 0·94 [95% CI 0·74-1·21]; one-sided p=0·32). The most common treatment-related grade 3-4 adverse events were elevated lipase (17 [5%] of 366 patients in the nivolumab plus surgery group vs none in the surgery only group), anaemia (seven [2%] vs nine [2%]), increased alanine aminotransferase (ten [3%] vs one [<1%]), abdominal pain (four [1%] vs six [2%]), and increased serum amylase (nine [2%] vs none). 177 (48%) patients in the nivolumab plus surgery group and 93 (24%) in the surgery only group had grade 3-5 adverse events due to any cause, the most common of which were anaemia (23 [6%] vs 19 [5%]), hypertension (27 [7%] vs nine [2%]), and elevated lipase (18 [5%] vs six [2%]). 48 (12%) of 404 patients in the nivolumab group and 40 (10%) of 415 in the surgery only group died, of which eight (2%) and three (1%), respectively, were determined to be treatment-related. INTERPRETATION: Perioperative nivolumab before nephrectomy followed by adjuvant nivolumab did not improve recurrence-free survival versus surgery only followed by surveillance in patients with high-risk renal cell carcinoma. FUNDING: US National Institutes of Health National Cancer Institute and Bristol Myers Squibb.

Robot-assisted nephroureterectomy: surgical and mid-term oncological outcomes in over 1100 patients (ROBUUST 2.0 collaborative group).

OBJECTIVE: To analyse surgical, functional, and mid-term oncological outcomes of robot-assisted nephroureterectomy (RANU) in a contemporary large multi-institutional setting. PATIENTS AND METHODS: Data were retrieved from the ROBotic surgery for Upper tract Urothelial cancer STtudy (ROBUUST) 2.0 database, an international, multicentre registry encompassing data of patients with upper urinary tract urothelial carcinoma undergoing curative surgery between 2015 and 2022. The analysis included all consecutive patients undergoing RANU except those with missing data in predictors. Detailed surgical, pathological, and postoperative functional data were recorded and analysed. Oncological time-to-event outcomes were: recurrence-free survival (RFS), metastasis-free survival (MFS), cancer-specific survival (CSS), and overall survival (OS). Survival analysis was performed using the Kaplan-Meier method, with a 3-year cut-off. A multivariable Cox proportional hazard model was built to evaluate predictors of each oncological outcome. RESULTS: A total of 1118 patients underwent RANU during the study period. The postoperative complications rate was 14.1%; the positive surgical margin rate was 4.7%. A postoperative median (interquartile range) estimated glomerular filtration rate decrease of -13.1 (-27.5 to 0) mL/min/1.73 m2 from baseline was observed. The 3-year RFS was 59% and the 3-year MFS was 76%, with a 3-year OS and CSS of 76% and 88%, respectively. Significant predictors of worse oncological outcomes were bladder-cuff excision, high-grade tumour, pathological T stage ≥3, and nodal involvement. CONCLUSIONS: The present study contributes to the growing body of evidence supporting the increasing adoption of RANU. The procedure consistently offers low surgical morbidity and can provide favourable mid-term oncological outcomes, mirroring those of open NU, even in non-organ-confined disease.

Clinical application of radiomics for the prediction of treatment outcome and survival in patients with renal cell carcinoma: a systematic review.

PURPOSE: The management of renal cell carcinoma (RCC) relies on clinical and histopathological features for treatment decisions. Recently, radiomics, which involves the extraction and analysis of quantitative imaging features, has shown promise in improving RCC management. This review evaluates the current application and limitations of radiomics for predicting treatment and oncological outcomes in RCC. METHODS: A systematic search was conducted in Medline, EMBASE, and Web of Science databases or studies that used radiomics to predict response to treatment and survival outcomes in patients with RCC. The study quality was assessed using the Radiomics Quality Score (RQS) tools. RESULTS: The systematic review identified a total of 27 studies, examining 6,119 patients. The most used imaging modality was contrast-enhanced abdominal CT. The reviewed studies extracted between 19 and 3376 radiomics features, including Histogram, Texture, Filter, or transformation method. Radiomics-based risk stratification models provided valuable insights into treatment response and oncological outcomes. All developed signatures demonstrated at least modest accuracy (AUC range: 0.55-0.99). The studies included in this analysis reported heterogeneous results regarding radiomics methods. The range of Radiomics Quality Score (RQS) was from - 5 to 20, with a mean RQS total of 9.15 ± 7.95. CONCLUSION: Radiomics has emerged as a promising tool in the management of RCC. It offers the potential for improved risk stratification and response assessment. However, future trials must demonstrate the generalizability of findings to prospective cohorts before progressing towards clinical translation.

Role of neoadjuvant chemotherapy in patients with locally advanced and clinically positive nodes Upper Tract Urothelial Carcinoma treated with Nephroureterectomy: real-world data from the ROBUUST 2.0 Registry.

PURPOSE: To assess the impact of neoadjuvant and adjuvant chemotherapy on survival outcomes, within a large multicenter cohort of Upper tract urothelial carcinoma patients treated with Nephroureterectomy. METHODS: A multicenter retrospective analysis utilizing the Robotic surgery for Upper Tract Urothelial Cancer Study registry was performed. Baseline, preoperative, perioperative, and pathologic variables of three groups of patients receiving surgery only, neoadjuvant or adjuvant chemotherapy were compared. Categorical and continuous variables among the three subgroups were compared with Chi square and ANOVA tests. The impact of perioperative chemotherapy on survival outcomes was assessed with the Kaplan Meier method. Univariable and multivariable Cox regression analyses were performed to identify predictors of survival. RESULTS: Overall, 1,994 patients were included. Overall and Clavien grade ≥3 complications rates were comparable among the three subgroups (p = 0.65 and p = 0.92). At Kaplan Meier analysis, neoadjuvant chemotherapy significantly improved cancer-specific survival (p = 0.03) and overall survival (p = 0.03) probabilities of patients with cT ≥ 3 tumors and of those with positive cN (p = 0.03 and p = 0.02). On multivariable analysis, neoadjuvant chemotherapy was independently associated with an improvement of cancer-specific survival in cT ≥ 3 patients (HR 0.44; p = 0.04), and of both cancer-specific survival (HR 0.50; p = 0.03) and overall survival (HR 0.53; p = 0.02) probabilities in positive cN patients. CONCLUSIONS: This large multicenter retrospective analysis suggests significant survival benefit in Upper tract urothelial carcinoma patients with either locally advanced or clinically positive nodes disease receiving neoadjuvant chemotherapy. These findings can be regarded as "hypothesis generating", stimulating future trials focusing on such advanced stages.

Perioperative systemic therapy, current paradigm and ongoing clinical trials in upper tract urothelial cancer.

PURPOSE OF REVIEW: To provide of comprehensive overview of existing and future paradigms for perioperative systemic therapy in the treatment of upper tract urothelial carcinoma. RECENT FINDINGS: Contemporary treatment paradigms for the management of upper tract urothelial carcinoma focus on use of neoadjuvant cisplatin based chemotherapy for high grade disease primarily based on two small single arm phase II clinical trials. More robust evidence from a phase III randomized clinical trial exists for the use of adjuvant platinum based chemotherapy for invasive disease after radical nephroureterectomy, but there are significant concerns about renal function and platinum eligibility after nephroureterectomy. There are currently ongoing clinical trials for nonplatinum based perioperative systemic therapies including checkpoint inhibitors/immunotherapy as well as antibody-drug conjugates, but currently no recommendation can be made for these approaches. SUMMARY: Current evidence supports neoadjuvant cisplatin chemotherapy in the setting of high grade disease or concern for significant renal dysfunction after radical nephroureterectomy or platinum based adjuvant chemotherapy in eligible patients with advanced disease after surgery. While there is no established role for nonplatinum based therapies yet, multiple ongoing trials exploring use of immunotherapies and antibody-drug conjugates as monotherapy or combination may provide new therapeutic options in this population.

Clinical value of cholinesterase in patients treated with radical nephroureterectomy for upper urinary tract carcinoma.

PURPOSE: To evaluate the prognostic value and the clinical impact of preoperative serum cholinesterase (ChoE) levels on decision-making in patients treated with radical nephroureterectomy (RNU) for clinically non-metastatic upper tract urothelial cancer (UTUC). METHODS: A retrospective review of an established multi-institutional UTUC database was performed. We evaluated preoperative ChoE as a continuous and dichotomized variable using a visual assessment of the functional form of the association of ChoE with cancer-specific survival (CSS). We used univariable and multivariable Cox regression models to establish its association with recurrence-free survival (RFS), CSS, and overall survival (OS). Discrimination was evaluated using Harrell's concordance index. Decision curve analysis (DCA) was used to assess the impact on clinical decision-making of preoperative ChoE. RESULTS: A total of 748 patients were available for analysis. Within a median follow-up of 34 months (IQR 15-64), 191 patients experienced disease recurrence, and 257 died, with 165 dying of UTUC. The optimal ChoE cutoff identified was 5.8 U/l. ChoE as continuous variable was significantly associated with RFS (p < 0.001), OS (p < 0.001), and CSS (p < 0.001) on univariable and multivariable analyses. The concordance index improved by 8%, 4.4%, and 7% for RFS, OS, and CSS, respectively. On DCA, including ChoE did not improve the net benefit of standard prognostic models. CONCLUSION: Despite its independent association with RFS, OS, and CSS, preoperative serum ChoE has no impact on clinical decision-making. In future studies, ChoE should be investigated as part of the tumor microenvironment and assessed as part of predictive and prognostic models, specifically in the setting of immune checkpoint-inhibitor therapy.

Renal cell carcinoma with inferior vena cava thrombus: did we make progress in oncologic outcomes and complications?

PURPOSE OF REVIEW: Surgery for renal cell carcinoma (RCC) with inferior vena cava tumor thrombus (TT) remains one of the most complex surgeries performed with high rates of associated complications and perioperative mortality. Surgical techniques and neoadjuvant therapies have an important role to play in improving outcomes. This review provides a narrative analysis of recent literature on patients with RCC and TT. RECENT FINDINGS: Several imaging techniques are emerging that may improve diagnostic staging of tumor thrombus level. Robotic approaches to surgical resection for all thrombi levels is feasible and safe, while longer term outcomes for higher level thrombi continues to mature. Early data on neoadjuvant immunotherapy and radiotherapy have shown improvements in complication rates and intermediate term oncologic outcomes. SUMMARY: Data suggests that neoadjuvant therapies and minimally invasive techniques may improve outcomes in patients undergoing surgical resection for RCC with tumor thrombus. Larger multiinstitutional series are needed to confirm the benefit of these techniques as well as the durable long term oncologic outcomes.

Biological and prognostic implications of biopsy upgrading for high-grade upper tract urothelial carcinoma at nephroureterectomy.

OBJECTIVES: Technical limitations of ureteroscopic (URS) biopsy has been considered responsible for substantial upgrading rate in upper tract urothelial carcinoma (UTUC). However, the impact of tumor specific factors for upgrading remain uninvestigated. METHODS: Patients who underwent URS biopsy were included between 2005 and 2020 at 13 institutions. We assessed the prognostic impact of upgrading (low-grade on URS biopsy) versus same grade (high-grade on URS biopsy) for high-grade UTUC tumors on radical nephroureterectomy (RNU) specimens. RESULTS: This study included 371 patients, of whom 112 (30%) and 259 (70%) were biopsy-based low- and high-grade tumors, respectively. Median follow-up was 27.3 months. Patients with high-grade biopsy were more likely to harbor unfavorable pathologic features, such as lymphovascular invasion (p < 0.001) and positive lymph nodes (LNs; p < 0.001). On multivariable analyses adjusting for the established risk factors, high-grade biopsy was significantly associated with worse overall (hazard ratio [HR] 1.74; 95% confidence interval [CI], 1.10-2.75; p = 0.018), cancer-specific (HR 1.94; 95% CI, 1.07-3.52; p = 0.03), and recurrence-free survival (HR 1.80; 95% CI, 1.13-2.87; p = 0.013). In subgroup analyses of patients with pT2-T4 and/or positive LN, its significant association retained. Furthermore, high-grade biopsy in clinically non-muscle invasive disease significantly predicted upstaging to final pathologically advanced disease (≥pT2) compared to low-grade biopsy. CONCLUSIONS: High tumor grade on URS biopsy is associated with features of biologically and clinically aggressive UTUC tumors. URS low-grade UTUC that becomes upgraded to high-grade might carry a better prognosis than high-grade UTUC on URS. Tumor specific factors are likely to be responsible for upgrading to high-grade on RNU.

Outcomes of Lymph Node Dissection in Nephroureterectomy in the Treatment of Upper Tract Urothelial Carcinoma: Analysis of the ROBUUST Registry.

PURPOSE: We sought to evaluate outcomes of lymph node dissection (LND) in patients with upper tract urothelial carcinoma. MATERIALS AND METHODS: We performed a multicenter retrospective analysis utilizing the ROBUUST (for RObotic surgery for Upper Tract Urothelial Cancer Study) registry for patients who did not undergo LND (pNx), LND with negative lymph nodes (pN0) and LND with positive nodes (pN+). Primary and secondary outcomes were overall survival (OS) and recurrence-free survival (RFS). Multivariable analyses evaluated predictors of outcomes and pathological node positivity. Kaplan-Meier analyses (KMAs) compared survival outcomes. RESULTS: A total of 877 patients were analyzed (LND performed in 358 [40.8%]/pN+ in 73 [8.3%]). Median nodes obtained were 10.2 for pN+ and 9.8 for pN0. Multivariable analyses noted increasing age (OR 1.1, p <0.001), pN+ (OR 3.1, p <0.001) and pathological stage pTis/3/4 (OR 3.4, p <0.001) as predictors for all-cause mortality. Clinical high-grade tumors (OR 11.74, p=0.015) and increasing tumor size (OR 1.14, p=0.001) were predictive for lymph node positivity. KMAs for pNx, pN0 and pN+ demonstrated 2-year OS of 80%, 86% and 42% (p <0.001) and 2-year RFS of 53%, 61% and 35% (p <0.001), respectively. KMAs comparing pNx, pN0 ≥10 nodes and pN0 <10 nodes showed no significant difference in 2-year OS (82% vs 85% vs 84%, p=0.6) but elicited significantly higher 2-year RFS in the pN0 ≥10 group (60% vs 74% vs 54%, p=0.043). CONCLUSIONS: LND during nephroureterectomy in patients with positive lymph nodes provides prognostic data, but is not associated with improved OS. LND yields ≥10 in patients with clinical node negative disease were associated with improved RFS. In high-grade and large tumors, lymphadenectomy should be considered.

NCCN Guidelines® Insights: Bladder Cancer, Version 2.2022.

The NCCN Guidelines for Bladder Cancer provide recommendations for the diagnosis, evaluation, treatment, and follow-up of patients with bladder cancer and other urinary tract cancers (upper tract tumors, urothelial carcinoma of the prostate, primary carcinoma of the urethra). These NCCN Guidelines Insights summarize the panel discussion behind recent important updates to the guidelines regarding the treatment of non-muscle-invasive bladder cancer, including how to treat in the event of a bacillus Calmette-Guérin (BCG) shortage; new roles for immune checkpoint inhibitors in non-muscle invasive, muscle-invasive, and metastatic bladder cancer; and the addition of antibody-drug conjugates for metastatic bladder cancer.

SPARC is a key mediator of TGF-ß-induced renal cancer metastasis.

Aberrant expression of transforming growth factor-ß1 (TGF-ß1) is associated with renal cell carcinoma (RCC) progression by inducing cancer metastasis. However, the downstream effector(s) in TGF-ß signaling pathway is not fully characterized. In the present study, the elevation of secreted protein acidic and rich in cysteine (SPARC) as a TGF-ß regulated gene in RCC was identified by applying differentially expressed gene analysis and microarray analysis, we further confirmed this result in several RCC cell lines. Clinically, the expression of these two genes is positively correlated in RCC patient specimens. Furthermore, elevated SPARC expression is found in all the subtypes of RCC and positively correlated with the RCC stage and grade. In contrast, SPARC expression is inversely correlated with overall and disease-free survival of patients with RCC, suggesting SPARC as a potent prognostic marker of RCC patient survival. Knocking down SPARC significantly inhibits RCC cell invasion and metastasis both in vitro and in vivo. Similarly, in vitro cell invasion can be diminished by using a specific monoclonal antibody. Mechanistically, SPARC activates protein kinase B (AKT) pathway leading to elevated expression of matrix metalloproteinase-2 that can facilitate RCC invasion. Altogether, our data support that SPARC is a critical role of TGF-ß signaling network underlying RCC progression and a potential therapeutic target as well as a prognostic marker.

Prognostic role of the systemic immune-inflammation index in upper tract urothelial carcinoma treated with radical nephroureterectomy: results from a large multicenter international collaboration.

PURPOSE: To investigate the prognostic role of the preoperative systemic immune-inflammation index (SII) in patients with upper tract urothelial carcinoma (UTUC) treated with radical nephroureterectomy (RNU). MATERIALS AND METHODS: We retrospectively analyzed our multi-institutional database to identify 2492 patients. SII was calculated as platelet count × neutrophil/lymphocyte count and evaluated at a cutoff of 485. Logistic regression analyses were performed to investigate the association of SII with muscle-invasive and non-organ-confined (NOC) disease. Cox regression analyses were performed to investigate the association of SII with recurrence-free, cancer-specific, and overall survival (RFS/CSS/OS). RESULTS: Overall, 986 (41.6%) patients had an SII > 485. On univariable logistic regression analyses, SII > 485 was associated with a higher risk of muscle-invasive (P = 0.004) and NOC (P = 0.03) disease at RNU. On multivariable logistic regression, SII remained independently associated with muscle-invasive disease (P = 0.01). On univariable Cox regression analyses, SII > 485 was associated with shorter RFS (P = 0.002), CSS (P = 0.002) and OS (P = 0.004). On multivariable Cox regression analyses SII remained independently associated with survival outcomes (all P < 0.05). Addition of SII to the multivariable models improved their discrimination of the models for predicting muscle-invasive disease (P = 0.02). However, all area under the curve and C-indexes increased by < 0.02 and it did not improve net benefit on decision curve analysis. CONCLUSIONS: Preoperative altered SII is significantly associated with higher pathologic stages and worse survival outcomes in patients treated with RNU for UTUC. However, the SII appears to have relatively limited incremental additive value in clinical use. Further study of SII in prognosticating UTUC is warranted before routine use in clinical algorithms.

Risk Factors for Intravesical Recurrence after Minimally Invasive Nephroureterectomy for Upper Tract Urothelial Cancer (ROBUUST Collaboration).

PURPOSE: Intravesical recurrence (IVR) after radical nephroureterectomy (RNU) for upper tract urothelial carcinoma (UTUC) has an incidence of approximately 20%-50%. Studies to date have been composed of mixed treatment cohorts-open, laparoscopic and robotic. The objective of this study is to assess clinicopathological risk factors for intravesical recurrence after RNU for UTUC in a completely minimally invasive cohort. MATERIALS AND METHODS: We performed a multicenter, retrospective analysis of 485 patients with UTUC without prior or concurrent bladder cancer who underwent robotic or laparoscopic RNU. Patients were selected from an international cohort of 17 institutions across the United States, Europe and Asia. Univariate and multiple Cox regression models were used to identify risk factors for bladder recurrence. RESULTS: A total of 485 (396 robotic, 89 laparoscopic) patients were included in analysis. Overall, 110 (22.7%) of patients developed IVR. The average time to recurrence was 15.2 months (SD 15.5 months). Hypertension was a significant risk factor on multiple regression (HR 1.99, CI 1.06; 3.71, p=0.030). Diagnostic ureteroscopic biopsy incurred a 50% higher chance of developing IVR (HR 1.49, CI 1.00; 2.20, p=0.048). Treatment specific risk factors included positive surgical margins (HR 3.36, CI 1.36; 8.33, p=0.009) and transurethral resection for bladder cuff management (HR 2.73, CI 1.10; 6.76, p=0.031). CONCLUSIONS: IVR after minimally invasive RNU for UTUC is a relatively common event. Risk factors include a ureteroscopic biopsy, transurethral resection of the bladder cuff, and positive surgical margins. When possible, avoidance of transurethral resection of the bladder cuff and alternative strategies for obtaining biopsy tissue sample should be considered.

Real-World Application of Pre-Orchiectomy miR-371a-3p Test in Testicular Germ Cell Tumor Management.

PURPOSE: Current serum tumor markers for testicular germ cell tumor are limited by low sensitivity. Growing evidence supports the use of circulating miR-371a-3p as a superior marker for malignant (viable) germ cell tumor management. We evaluated the real-world application of serum miR-371a-3p levels in detecting viable germ cell tumor among patients undergoing partial or radical orchiectomy. MATERIALS AND METHODS: Serum samples were collected from 69 consecutive patients before orchiectomy. Performance characteristics of serum miR-371a-3p were compared with conventional serum tumor markers (⍺-fetoprotein/ß-human chorionic gonadotropin/lactate dehydrogenase) between patients with viable germ cell tumor and those without viable germ cell tumor on orchiectomy pathology. Relative miR-371a-3p levels were correlated with clinical course. The Kruskal-Wallis test and linear and ordinal regression models were used for analysis. RESULTS: For detecting viable germ cell tumor, combined conventional serum tumor markers had a specificity of 100%, sensitivity of 58% and AUC of 0.79. The miR-371a-3p test showed a specificity of 100%, sensitivity of 93% and AUC of 0.978. Median relative expression of miR-371a-3p in viable germ cell tumor cases was more than 6,800-fold higher than in those lacking viable germ cell tumor. miR-371a-3p levels correlated with composite stage (p=0.006) and, among composite stage I cases, independently associated with embryonal carcinoma percentage (p=0.0012) and tumor diameter (p <0.0001). Six patients underwent orchiectomy after chemotherapy and were correctly predicted to have presence or absence of viable germ cell tumor by the miR-371a-3p test. CONCLUSIONS: If validated, the miR-371a-3p test can be used in conjunction with conventional serum tumor markers to aid clinical decision making. A positive miR-371a-3p test in patients after preoperative chemotherapy or with solitary testes could potentially guide subsequent orchiectomy or observation.

Eosinophilic Vacuolated Tumor of the Kidney: A Review of Evolving Concepts in This Novel Subtype With Additional Insights From a Case With MTOR Mutation and Concomitant Chromosome 1 Loss.

Recent advances in molecular genetics have expanded our knowledge of renal tumors and enabled a better classification. These studies have revealed that renal tumors with predominantly "eosinophilic/oncocytic" cytoplasm include several novel biological subtypes beyond the traditionally well-recognized renal oncocytoma and an eosinophilic variant of chromophobe renal cell carcinoma. Herein, we present a comprehensive review of the eosinophilic vacuolated tumor (EVT) building upon a case report including radiology, histopathology, electron microscopy, and next-generation sequencing. EVTs are characterized by mTORC1 activation. We speculate that loss of chromosome 1 in EVT with MTOR mutation may be driven in part by an advantage conferred by loss of the remaining MTOR wild-type allele. mTORC1 is best known for its role in promoting protein translation and it is interesting that dilated cisterns of rough endoplasmic reticulum (ER) likely account for the cytoplasmic vacuoles seen by light microscopy. We present an integrated view of EVT as well as cues that can assist in the differential diagnosis.

Value of tumour-infiltrating immune cells in predicting response to intravesical BCG in patients with non-muscle-invasive bladder cancer: a systematic review and meta-analysis.

OBJECTIVE: To investigate the predictive value of tumour-infiltrating immune cells (TIICs) on oncological outcomes and response to BCG treatment in patients with non-muscle-invasive bladder cancer (NMIBC). MATERIALS AND METHODS: A systematic review and meta-analysis was performed using PubMed, Scopus and the Cochrane Library in July 2020 to identify relevant studies according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. The pooled recurrence-free survival (RFS) rate was calculated using a fixed-effect model. RESULTS: We retrieved 15 studies (including 791 patients) evaluating the effect of TIICs on oncological outcomes in patients with NMIBC treated with intravesical BCG. TIICs were reported to be a significant predictor of oncological outcomes and response to BCG treatment in 10 studies. Tumour-associated macrophages were associated with worse RFS (pooled hazard ratio 2.30, 95% confidence interval 1.64-3.22). CONCLUSIONS: Based on these data, TIICs are significant predictors of RFS and response to BCG treatment in patients with NMIBC; therefore, incorporation of TIICs into risk stratification models may help patients and physicians in the clinical decision-making process in order to achieve the maximum possible benefit from BCG treatment.

Perioperative outcomes and cost of robotic vs open simple prostatectomy in the modern robotic era: results from the National Inpatient Sample.

OBJECTIVES: To perform a comparative analysis of perioperative outcomes and hospitalisation cost between open (OSP) and robot-assisted simple prostatectomy (RASP) for treatment of benign prostatic hyperplasia (BPH) using the National Inpatient Sample (NIS) in the contemporary robotic era. MATERIALS AND METHODS: The NIS was queried for cases of OSP and RASP for the treatment of BPH between 2013 and 2016. Perioperative complications, unadjusted hospital cost and length of stay (LOS) were compared between RASP and OSP. Smoothed linear regression curves comparing hospitalisation cost by increasing LOS was stratified by surgical approach to identify point of cost equivalency between RASP and OSP. Multivariable linear regression analysis was used to construct a hospitalisation cost model to examine the contribution of the robotic approach and LOS to hospitalisation cost. RESULTS: The total analytical cohort included 2551 OSP and 704 RASP procedures. Patients undergoing RASP were younger, at a median (interquartile range [IQR]) age of 68 (63-73) vs 71 (65-77) years, and with less comorbidity (76.8% vs 86.5%, P < 0.01). RASP was associated with fewer total complications (11.1% vs 29.2%, P < 0.01) and a greater likelihood of routine discharge to home rather than another facility (88.9% vs 76.7%, P < 0.01). While LOS was shorter with RASP (median [IQR], 2 [1-3] vs 4 [3-6] days, P < 0.01), total unadjusted hospitalisation cost (in United States dollars) was greater (median [IQR], $10 855 [$7965-$15 675] vs $13 467 [$10 572-$17 722], P < 0.01). Presence of any complication increased both LOS and hospitalisation cost (P < 0.01). Linear regression modelling determined the point of cost equivalence between RASP staying a median of 2 days was an OSP case staying between 5 and 6 days. On multivariable regression analysis, the robotic approach contributed an additional $6175 (P < 0.01) to the cost model, whereas each additional day of hospitalisation contributed $1687 (P < 0.01), suggesting LOS would need to be 3-4 days shorter with RASP to offset surgical costs of the robot. CONCLUSIONS: While RASP appears to have significantly better perioperative complication rates with shorter LOS and likely discharge to home, total hospitalisation cost remained greater, likely related to upfront operative costs. While this retrospective study is limited by selection bias for patients undergoing RASP, the benefits of improved convalescence, discharge to home, and lower rate of perioperative complications appear to justify performance of RASP in an experienced pelvic robotic centre despite relatively greater hospitalisation cost if referral to an experienced holmium laser enucleation of the prostate centre is not feasible.

Prospective evaluation of blue-light flexible cystoscopy with hexaminolevulinate in non-muscle-invasive bladder cancer.

OBJECTIVES: To evaluate the utility of blue-light flexible cystoscopy (BLFC) for surveillance of non-muscle-invasive bladder cancer (NMIBC). PATIENTS AND METHODS: Prospective cohort of consecutive patients who underwent office-based BLFC for NMIBC. Clinical information was collected including cystoscopic findings and pathological data. RESULTS: A total of 322 cases were performed on 190 patients. The mean age was 71 years and 83% were men. The highest stage prior to BLFC was Ta, carcinoma in situ (CIS), T1, and T2 in 45.3%, 18.4%, 30% and 2%, respectively. Prior to BLFC, 16.8%, 60.5%, and 16.8% were low grade (LG), high grade (HG), and CIS, respectively. Intravesical bacille Calmette-Guérin and intravesical chemotherapy were used in 54.2% and 18.4%, respectively. White-light cystoscopy (WLC) and BLFC were both normal in 173 (53.7%) of cases. WLC was normal and BLFC was abnormal in 26 (8%) cases. Of these, 15 had office-based biopsy and cancer was detected in 13 (87%; six CIS, four HG Ta, three LG Ta). Both WLC and BLFC were positive in 83 (25.8%) cases and 33% had additional tumours found. Cancer was found in 27 (75%) of WLC+/BLFC+ who underwent office-based biopsy including 19 LG Ta, six HG Ta, and two CIS. CONCLUSIONS: Incorporation of BLFC in clinical practice has potential advantages of finding cancer in cases with normal WLC. BLFC detected additional cancers in 33% of patients with positive WLC and BLFC, which can improve surveillance and performance of office-based biopsy. Further research is needed to determine cost-effectiveness and impact on recurrence rates.

Impact of circulating microRNA test (miRNA-371a-3p) on appropriateness of treatment and cost outcomes in patients with Stage I non-seminomatous germ cell tumours.

OBJECTIVES: To determine whether utilisation of a serum microRNA (miRNA) test could improve treatment appropriateness and cost-effectiveness for patients with Stage I non-seminomatous germ cell tumours (NSGCTs). PATIENTS AND METHODS: A decision tree model was built to investigate treatment course, clinical and cost outcomes for patients with Stage IA (T1N0M0S0) and IB (T2-4N0M0S0) NSGCT. The model compared outcomes and cost of standard approach using histopathology, conventional serum tumour markers and radiographic staging (standard model) to a miRNA-based approach using the standard model + post-orchidectomy serum miR-371a-3p (marker model). Probabilities of expected treatment and outcomes were based on presence/absence of cancer upon entering into the model. Overtreatment was defined as adjuvant chemotherapy or primary retroperitoneal lymph node dissection in a patient without cancer. Undertreatment was defined as initial surveillance for a patient with cancer. RESULTS: Utilising the miRNA marker-based approach, 26% of patients avoid overtreatment and 8% avoid undertreatment in Stage IA NSGCT; 27% avoid overtreatment and 23% avoid undertreatment in Stage IB disease. Appropriate treatment decision-making increased from 65% to 94% and 50% to 92% for Stage IA and IB, respectively. The miRNA-based approach remained cost-effective over a wide range of performance characteristics with savings of ~$1400 (American dollars)/patient for both Stage IA and IB disease. CONCLUSION: A miRNA-based approach may potentially select patients with Stage I NSGCT for correct treatment in a cost-effective manner. Identification of residual teratoma-only remains an issue. Prospective studies are necessary to validate these findings.