Inflammatory myofibroblastic tumor of the urinary bladder: A systematic review of the literature and report of a case.

Introduction: Inflammatory myofibroblastic tumors (IMTs) are intermediate-grade lesions that frequently recur and rarely metastasize. There are currently no guidelines on the management of bladder IMTs. This systematic review aims to describe the clinical presentation and compare the management options for bladder IMTs. Methods: A PubMed/Medline search was conducted, according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, using the following Mesh terms: ("inflammatory myofibroblastic") AND ("tumor") OR ("tumor") AND ("bladder") AND ("case report"). A total of 75 case reports were included in the analysis. Results: The mean age of the patients was 36 years. 65% of the cases initially presented with hematuria. 68% of the tumors stained positive for anaplastic lymphoma kinase, and 20% invaded the muscularis. Patients underwent either transurethral resection of the bladder tumor (TURBT) only (34%), TURBT followed by complementary partial cystectomy (16%), or TURBT followed by radical cystectomy (4%). 36% and 9% of the cases underwent partial and radical cystectomy after the initial diagnosis, respectively. Cystectomies were performed using an open (74%), laparoscopic (14%), robotic-assisted (10%), or unknown (2%) approach. At a mean follow-up of 14 months, the recurrence and metastasis rates were about 9% and 4%, respectively. In addition, we present the case of a 49-year-old woman with a bladder IMT who underwent TURBT followed by laparoscopic partial cystectomy. The patient remains tumor free postoperatively (follow-up period of 12 months). Conclusion: A complete surgical excision of the bladder IMT is crucial for the optimal management of these cases. Proper differentiation of this tumor from sarcoma or leiomyosarcoma leads to the best outcomes.

Impact of bladder cancer family history on the prognosis of patients with non-muscle invasive bladder cancer treated with Bacillus Calmette-Guerin (BCG).

BACKGROUND: To evaluate the impact of having first-degree relatives (FDR) with bladder cancer (BC) among non-muscle invasive bladder cancer (NMIBC) patients treated with Bacillus Calmette - Guérin (BCG) on their oncological outcomes. METHODS: The National Phase II BCG/Interferon (IFN) trial database from 125 sites in the U.S.A. (1999-2001) and multi-institutional databases from France (FR) and Lebanon (LB) (2000-2021) were queried for NMIBC patients treated with BCG. Cox regression models were used to evaluate the effect of BC family history on tumor recurrence and progression in their relatives. RESULTS: There were 867 patients in the U.S.A. cohort and 1232 patients in the FR/LB cohort. Almost 8% of patients in both cohorts had FDR with BC. Patients in the FR/LB cohort were more likely to have carcinoma in situ tumors (CIS) (41% vs. 24%, p < 0.01). Having FDR with BC was not significantly associated with tumor recurrence or progression in the U.S.A. cohort. Conversely, on multivariable analysis FDR history was significantly associated with a 2.10 times increased risk of recurrence (p < 0.01) and a 3.01 times increased risk of progression (p < 0.01) in the FR/LB cohort. CONCLUSION: A family history of BC could have an important impact on the response to BCG.

Combination intravesical chemotherapy for non-muscle invasive bladder cancer (NMIBC) as first-line or rescue therapy: where do we stand now?

INTRODUCTION: The combination of intravesical gemcitabine (Gem) with docetaxel (Doce) or with mitomycin C (MMC) has been used in the primary setting as an alternative to Bacillus Calmette-Guerin (BCG) to treat high-risk (HR) and intermediate-risk (IR) non-muscle invasive bladder cancer (NMIBC), as well in the rescue setting for patients in whom BCG has failed. AREA COVERED: Efficacy and safety of Gem/Doce and Gem/MMC to treat NMIBC in BCG-naive and failure settings. EXPERT OPINION: In the BCG-naive setting, Gem/Doce was the primary alternative combination therapy reported, with a weighted mean of 12- and 24-month recurrence-free survival (RFS) of 79% and 77% for HR disease and 84% and 76% for IR disease, respectively. In the HR BCG-failure setting, the weighted mean of 12- and 24-month RFS was 60% and 42% for Gem/Doce and 63% and 40% for Gem/MMC. While patients without BCG exposure and papillary disease only benefit the most from Gem/Doce, there is also reasonable efficacy in BCG refractory disease and CIS. Combination therapy is well tolerated, with grade III toxicity reported in less than 1% of patients. Unlike single-agent chemotherapy, intravesical Gem/Doce is considered effective and safe regardless of risk-stratification.

Intraoperative complication of radical cystectomy for muscle-invasive bladder cancer: does the surgical approach matter? A retrospective multicenter study using the EAUiaiC classification.

PURPOSE: Despite surgical and anesthetic progress, radical cystectomy for bladder cancer remains one of the most morbid surgeries in urology. The objective of our study was to describe intraoperative complications and to assess the impact of surgical approach on morbidity. METHODS: We retrospectively reviewed medical records of patients treated by radical cystectomy for localized muscle invasive bladder cancer between 2015 and 2020, following the Martin et al. criteria for complications reports. All intraoperative adverse events were graded according to the EAUiaiC scores. Multivariate regression models were used to determine predicting factors of complications. RESULTS: A total of 318 patients were included for analysis. Among them, 17 patients (5.4%) presented an intraoperative complication. No preoperative oncological or clinical factor was associated with the occurrence of an intraoperative complication. Surgical approach had no impact on morbidity. Both overall survival (HR 2.02; CI95% 0.87-4.68; p = 0.101) and recurrence-free survival (HR 1.856; CI95% 0.804-4.284; p = 0.147) were not associated with intraoperative complication. CONCLUSION: Radical cystectomy remains a highly morbid surgery and surgical approach did not improve the complication rate. Perioperative morbidity has a significant impact on patient survival. The association between intraoperative and postoperative complications illustrates the cumulative effect of perioperative events that are associated with survival.

Comparison of oncological, surgical, and functional outcomes between radical retropubic and radical perineal prostatectomy: A multi-institutional study.

INTRODUCTION: To investigate the safety, oncologic, surgical, and functional outcomes of RPP and RRP for localized prostate cancer (Pca), especially focusing on RPP. MATERIALS AND METHODS: From March 2005 to January 2021, we retrospectively reviewed the records of 685 patients undergoing RPP (n = 320) or RRP (n = 365) for localized Pca. Surgical and functional outcomes, and complications were compared. Oncological outcomes were also compared using Kaplan-Meier survival analysis. RESULTS: A higher biochemical recurrence rate were noted in RRP than in RPP group (28.8% vs 21.6%, respectively; p = 0.03). A local recurrence was detected in a few numbers of patients (4.4%) with no statistically significant differences by surgical groups (p = 0.71). No significant differences were observed in the cancer-specific survival and the overall survival according to the surgical approach. Positive surgical margins were similar in the two techniques.In comparison to RRP, patients undergoing RPP have less postoperative pain, decreased transfusion rate, and less catheterization time. Complete continence was achieved in 96.9% of the RPP group at 18 and 24 months versus 91.8% and 92.3% in the RRP group at 18 and 24 months, respectively (p = 0.005 and p = 0.01, respectively). At 18 months of follow-up, the nerve-sparing technique was performed equally between the two groups, the mean of erectile function domain improved more in RPP than RRP (12.71 vs 10.42 respectively, p < 0.001). Medical and surgical complication rates were higher for RRP than RPP. CONCLUSIONS: RPP showed acceptable oncologic outcomes and excellent functional outcomes when compared to RRP.

Oncological Outcomes of Distal Ureterectomy for High-Risk Urothelial Carcinoma: A Multicenter Study by The French Bladder Cancer Committee.

Upper urinary tract urothelial carcinoma (UTUC) is an uncommon disease and its gold-standard treatment is radical nephroureterectomy (RNU). Distal ureterectomy (DU) might be an alternative for tumors of the distal ureter but its indications remain unclear. Here, we aimed to evaluate the oncological outcomes of DU for UTUC of the pelvic ureter. We performed a multicenter retrospective analysis of patients with UTUC who underwent DU. The primary endpoint was 5-year cancer-specific survival (CSS), followed by overall survival (OS), intravesical recurrence-free (IVR) and homolateral urinary tract recurrence-free (HUR) survivals as secondary endpoints. Univariate and multivariate Cox regressions were performed to assess factors associated with outcomes. 155 patients were included, 91% of which were high-risk. 5-year CSS was 84.4%, OS was 71.9%, IVR-free survival was 43.6% and HUR-free survival was 74.4%. Multifocality, high grade and tumor size were the most significant predictors of survival endpoints. Of note, neither hydronephrosis nor pre-operative diagnostic ureteroscopy/JJ stent were associated with any of the endpoints. Perioperative morbidity was minimal. In conclusion, DU stands as a possible alternative to RNU for UTUC of the pelvic ureter. Close monitoring is mandatory due to the high risk of recurrence in the remaining urinary tract.

Scrotal calcinosis in a patient treated with isotretinoin: a rare entity.

Scrotal calcinosis is a rare disorder characterized by multiple papules or nodules of calcification in the scrotal skin. The pathogenesis of this disease is poorly understood. The condition presents as several brown to yellowish asymptomatic nodules on the scrotum. Excision followed by scrotal reconstruction is the treatment of choice. It leaves a good cosmetic result with low chances of recurrence. Newer treatments, such as ablative lasers, have been proposed with very good results. We describe the case of a 28-year-old patient with a history of severe acne treated with oral isotretinoin that presented for scrotal nodules. On laboratory examination, hypercalcemia was found with normal phosphorus, parathyroid hormone, and vitamin D hormone levels. Hypercalcemia was linked to his isotretinoin therapy. Serum calcium concentrations normalized after cessation of isotretinoin and hydration. Because the patient refused surgery, a biopsy of the lesion confirmed the diagnosis of scrotal calcinosis. Then the patient was referred to a cosmetic laser center to treat his condition.

The prognostic role of pre-cystectomy thrombocytosis in invasive bladder cancer.

PURPOSE: We aim to evaluate the impact of preoperative thrombocytosis on oncological outcomes in patients with bladder cancer (BC) who undergo radical cystectomy (RC). METHODS: Retrospective data collection of 1092 patients managed by RC for BC from 2 tertiary-care centers was performed. Elevated platelet count (PLT) was defined as > 450 × 109/L. Univariable and multivariable logistic regression analyses were used to investigate the impact of thrombocytosis on oncological outcomes. These outcomes were also compared using Kaplan-Meier survival analysis. RESULTS: The median follow-up was 50 months (32-64 months). Thrombocytosis was detected in 18.6% of the patients. The 3-year cancer-specific survival (CSS) for patients with normal PLT count was 92% which was higher than those with elevated PLT count (55%, P < 0.001). Similar results were found for the 6-year CSS with 82% for the no thrombocytosis group and 27% for the thrombocytosis group. Thrombocytosis was still significantly associated with poor prognosis for overall survival and recurrence-free survival (P < 0.001). In the multivariate analysis, CSS was significantly lower in patients with thrombocytosis (HR = 1.71, 95% CI = 1.22-2.39, P = 0.002). Patients with elevated PLT counts were also significantly more likely to receive adjuvant chemotherapy, to have a T stage > pT2b (P = 0.024), to have a positive lymph node, to have variant histology and positive resection margins, and to have concomitant carcinoma in situ (CIS) on final pathology (all P < 0.001). CONCLUSIONS: Preoperative thrombocytosis was valuable for predicting the oncological outcomes of patients undergoing RC for BC.

An update on the management algorithms of priapism during the last decade.

Priapism is a persistent penile erection lasting longer than 4 hours, that needs emergency management. This disorder can induce irreversible erectile dysfunction. There are three subtypes of priapism: ischemic, non-ischemic, and stuttering priapism. If the patient has ischemic priapism (IP) of less than 24-hours (h) duration, the initial management should be a corporal blood aspiration followed by instillation of phenylephrine into the corpus cavernosum. If sympathomimetic fails or the patient has IP from 24 to 48h, surgical shunts should be performed. It is recommended that distal shunts should be attempted first. If distal shunt failed, proximal, venous shunt, or T-shunt with tunneling could be performed. If the patient had IP for 48 to 72h, proximal and venous shunt or T-shunt with tunneling is indicated, if those therapies failed, a penile prosthesis should be inserted. Non-ischemic priapism (NIP) is not a medical emergency and many patients will recover spontaneously. If the NIP does not resolve spontaneously within six months or the patient requests therapy, selective arterial embolization is indicated. The goal of the management of a patient with stuttering priapism (SP) is the prevention of future episodes. Phosphodiesterase type 5 (PDE5) inhibitor therapy is considered an effective tool to prevent stuttering episodes but it is not validated yet. The management of priapism should follow the guidelines as the future erectile function is dependent on its quick resolution. This review briefly discusses the types, pathophysiology, and diagnosis of priapism. It will discuss an updated approach to treat each type of priapism.

Association of Energy Expenditure and Efficacy in Metastatic Renal Cell Carcinoma Patients Treated with Nivolumab.

Background: Nivolumab improved patients' survival in metastatic renal cell carcinoma (mRCC). We aimed to evaluate resting energy expenditure (REE) (i.e., patients' basal metabolism) to predict efficacy. Methods: We conducted a monocentric, observational study of mRCC patients receiving nivolumab between October 2015 and May 2020. REE was measured prior to initiating immunotherapy using indirect calorimetry to determine hypo, normo and hypermetabolism. Primary endpoint was 6-month, progression-free survival (PFS), and secondary endpoints were response rate, PFS and overall survival (OS). Results: Of the 51 consecutive patients, 15 (29%) were hypermetabolic, 24 (47%) normometabolic, and 12 (24%) hypometabolic. The 6-month PFS was 15% for hypermetabolic patients and 65% for non-hypermetabolic patients (p < 0.01). In the multivariate analysis, hypermetabolism was the only baseline factor predicting 6-month PFS (OR 9.91, 95%CI [1.62−60.55], p = 0.01). Disease progression was noted as the best response in 73% of hypermetabolic patients and 26% of non-hypermetabolic patients (p = 0.02). Median PFS was 2.8 and 8.7 months (p < 0.01), and median OS was 20.2 and 35.1 months (p = 0.13) in the hypermetabolic and non-hypermetabolic groups, respectively. Conclusions: Our study identifies an association between mRCC patients' energy expenditure and nivolumab efficacy. The measurement of REE by indirect calorimetry in routine practice could help identify patients at risk of nivolumab failure.

A Challenging Case of Ureteroiliac Artery Fistula Managed With an Endovascular Approach.

Ureteroarterial fistula (UAF) is a rare but life-threatening condition because of massive hemorrhage. Risk factors include degenerative vascular diseases, previous vascular surgery, pelvic radiation, chemotherapy, pelvic surgery, and prolonged ureteral stenting. The most common presentation of UAF is massive hematuria with hemorrhagic shock. The diagnosis is always difficult even with angiography. Endovascular repair with stenting and/or coiling is effective and safe. The surgical treatment should be used in recurrent UAF cases. We reported a rare case describing rapid management of a UAF in a patient who presented with hematuria even when we had no diagnosis on the initial CT scan. The patient was in shock. Deployment of a stent graft within the common iliac artery bypassing the UAF was performed. The patient improved rapidly.

Preexisting Autoantibodies and Immune Related Adverse Events in Metastatic Urothelial Carcinoma Patients Treated by Pembrolizumab.

INTRODUCTION: Immune checkpoint inhibitor are standard therapy in metastatic urothelial carcinoma. No predictive biomarker of immune related adverse events (iRAE) exists. Antinuclear antibodies (ANA) can be the sign of a subclinical autoimmune condition that could be enhanced by Immune checkpoint inhibitor. We decided to assess the predictive value of baseline autoantibodies and ANA for iRAE in metastatic urothelial carcinoma patients treated with pembrolizumab and explore their prognostic signification. PATIENTS AND METHOD: Data concerning patients treated in our institution between 2015 and 2020 with pembrolizumab for metastatic urothelial carcinoma with available baseline value of ANA and other autoantibodies was collected. ANA with titer >1/80 were defined positive. RESULTS: A total of 68 patients were included. Fifty-five (80%) had ANA >1/80 and among them 21 patients (30%) had ANA >1/160. Seven patients with ANA >160 (33%) presented iRAE vs. 5 patients (10%) in the rest of the population. Presence of ANA >160 was significantly associated with iRAE (P = .029) and limiting toxicity (P = .048) in univariate analysis. iRAE tend to occur earlier, before the third cycle, for patients with ANA >1/160 as compared to rest of the patients (28% vs. 6%, P = .052). Exploratory analysis did not reveal correlation between progression free survival or overall survival and ANA >1/160 in univariate or in multivariate analysis including the Bellmunt score (HR = 0.7, 95%CI [0.38-1.35], P = .5). CONCLUSION: The presence of ANA >1/160 is associated with iRAE and limiting toxicity of pembrolizumab.

Perspectives on the urological care in Parkinson's disease patients.

Parkinson's disease (PD) is recognized as the most common neurodegenerative disorder after Alzheimer's disease. Lower urinary tract symptoms are common in patients with PD, either storage symptoms (overactive bladder symptoms or OAB) or voiding symptoms. The most important diagnostic clues for urinary disturbances are provided by the patient's medical history. Urodynamic evaluation allows the determination of the underlying bladder disorder and may help in the treatment selection. Pharmacologic interventions especially anticholinergic medications are the first-line option for treating OAB in patients with PD. However, it is important to balance the therapeutic benefits of these drugs with their potential adverse effects. Intra-detrusor Botulinum toxin injections, electrical stimulation were also used to treat OAB in those patients with variable efficacy. Mirabegron is a ß3-agonist that can also be used for OAB with superior tolerability to anticholinergics. Desmopressin is effective for the management of nocturnal polyuria which has been reported to be common in PD. Deep brain stimulation (DBS) surgery is effective in improving urinary functions in PD patients. Sexual dysfunction is also common in PD. Phosphodiesterase type 5 inhibitors are first-line therapies for PD-associated erectile dysfunction (ED). Treatment with apomorphine sublingually is another therapeutic option for PD patients with ED. Pathologic hypersexuality has occasionally been reported in patients with PD, linked to dopaminergic agonists. The first step of treatment of hypersexuality consists of reducing the dose of dopaminergic medication. This review summarizes the epidemiology, pathogenesis, risk factors, genetic, clinical manifestations, diagnostic test, and management of PD. Lastly, the urologic outcomes and therapies are reviewed.

Feasibility and safety of targeted focal microwave ablation of the index tumor in patients with low to intermediate risk prostate cancer: Results of the FOSTINE trial.

OBJECTIVE: To assess the feasibility, safety and precision of organ-based tracking (OBT)-fusion targeted focal microwave ablation (FMA), in patients with low to intermediate risk prostate cancer. PATIENTS AND METHOD: Ten patients with a visible index tumor of Gleason score ≤3+4, largest diameter <20mm were included. Transrectal OBT-fusion targeted FMA was performed using an 18G needle. Primary endpoint was the evidence of complete overlap of the index tumor by ablation zone necrosis on MRI 7 days after ablation. Urinary and sexual function were assessed with IPSS, IIEF5 and MSHQ-EjD-SF. Oncological outcomes were assessed with PSA at 2 and 6 months, and re-biopsy at 6 months. RESULTS: Median [IQR] age was 64.5 [61-72] years and baseline PSA was 5 [4.3-8.1] ng/mL. Seven (70%) and 3 (30%) patients had a low and intermediate risk cancer, respectively. Median largest tumor axis was of 11 [9.0-15.0] mm. Median duration of procedure was of 82 [44-170] min. No patient reported any pain or rectal bleeding, and all 10 patients were discharged the next day. Seven days after ablation, total necrosis of the index tumor on MRI was obtained in eight (80% [95%CI 55%-100%]) patients. One patient was treated with radical prostatectomy. Re-biopsy at 6 months in the other 9 did not show evidence of cancer in 4 patients. IPSS, IIEF-5 and MSHQ-EjD-SF were not statistically different between baseline and 6 months follow up. CONCLUSIONS: OBT-fusion targeted FMA was feasible, precise, and safe in patients with low to intermediate risk localized prostate cancer.

Assessment of prognostic implication of a panel of oncogenes in bladder cancer and identification of a 3-gene signature associated with recurrence and progression risk in non-muscle-invasive bladder cancer.

This study evaluated the prognostic value of a panel of 29 oncogenes derived from the analysis of The Cancer Genome Atlas (TCGA data) or from the recent literature on bladder tumors on a well-characterized series of muscle-invasive bladder cancer (MIBC) and non-MIBC (NMIBC) samples and tried to identify molecular prognostic markers. Mutations of HRAS, FGFR3, PIK3CA and TERT were found in 2.9%, 27.2%, 14.9% and 76.7% of tumor samples, respectively. Concerning NMIBC, on multivariate analysis, RXRA and FGFR3 levels were associated with recurrence-free survival (RFS) (p = 0.0022 and p = 0.0069) and RXRA level was associated with progression to muscle-invasive disease (p = 0.0068). We identified a 3-gene molecular signature associated with NMIBC prognosis. FGFR3 overexpression was associated with reduced response to Bacillus Calmette-Guerin treatment (p = 0.037). As regards MIBC, on multivariate analysis, ERCC2 overexpression was associated with RFS (p = 0.0011) and E2F3 and EGFR overexpression were associated with overall survival (p = 0.014 and p = 0.035). RT-PCR findings were confirmed by IHC for FGFR3. Genomic alterations in MIBC revealed in TCGA data also concern NMIBC and seem to be associated with prognosis in terms of recurrence and progression. Correcting these alterations by targeted therapies seems a promising pharmacological approach.

Giant Primary Scrotal Lipoma: A Rare Entity with Diagnostic Pitfalls.

Primary scrotal lipomas are rare. We describe the case of a 47-year-old male with a giant scrotal lipoma who underwent a surgical excision. We report the clinical and radiological approach as well as the treatment of this atypical benign tumor.

Pharmacokinetic/Pharmacodynamic Relationship of Enzalutamide and Its Active Metabolite N-Desmethyl Enzalutamide in Metastatic Castration-Resistant Prostate Cancer Patients.

INTRODUCTION: Enzalutamide (ENZA) is an oral androgen receptor inhibitor approved by the Food and Drug Administration and the European Medicines Agency for the treatment of metastatic and nonmetastatic castration-resistant prostate cancer (CRPC). ENZA is extensively metabolized by cytochrome P450 3A4 into N-desmethyl ENZA (NDE), an active metabolite. We aimed to explore the pharmacokinetic/pharmacodynamic relationship for ENZA and NDE in metastatic CRPC patients from a real-world setting. PATIENTS AND METHODS: Trough plasma concentration (Ctrough) of ENZA and NDE were assayed using liquid chromatography coupled with UV detection. The relationship between ENZA, NDE, and composite (ENZA with NDE) plasma concentration and requirement of ENZA dose reduction was investigated using the Mann-Whitney test. A survival univariate analysis was conducted to explore association between progression-free survival (PFS), overall survival (OS), and plasma Ctrough (ENZA, NDE, and composite). RESULTS: Twenty-two metastatic CRPC patients treated with ENZA (median age, 75.5 years; 13 patients (59%) with Eastern Cooperative Oncology Group status 0-1) were prospectively included. Mean plasma Ctrough of ENZA and NDE were 12.4 ± 3.0 µg/mL and 8.8 ± 2.1 µg/mL, respectively. Neither PFS nor OS were statistically associated with ENZA, NDE, or composite plasma Ctrough. In 4 patients (18%) who required ENZA dose reduction because of severe clinical toxicity, an increased ENZA plasma Ctrough was observed compared with 18 remaining patients (16.1 ± 2.4 µg/mL vs. 11.6 ± 2.6 µg/mL, respectively; P = .027). CONCLUSION: The low interindividual variability in ENZA and NDE Ctrough and the lack of relationship with survival do not support the need for plasma drug monitoring. Severe asthenia might be related to higher exposure and could be improved by decreasing ENZA dosing.

Tim-3 Expression on Tumor-Infiltrating PD-1+CD8+ T Cells Correlates with Poor Clinical Outcome in Renal Cell Carcinoma.

Inhibitory receptors expressed by T cells mediate tolerance to tumor antigens, with coexpression of these receptors exacerbating this dysfunctional state. Using the VectraR automated multiparametric immunofluorescence technique, we quantified intratumoral CD8+ T cells coexpressing the inhibitory receptors PD-1 and Tim-3 from patients with renal cell carcinoma (RCC). A second validation cohort measured the same parameters by cytometry. The percentage of tumor-infiltrating CD8+ T cells coexpressing PD-1 and Tim-3 correlated with an aggressive phenotype and a larger tumor size at diagnosis. Coexpression of PD-1 and Tim-3 above the median conferred a higher risk of relapse and a poorer 36-month overall survival. Notably, other CD8+T-cell subsets did not exert a similar effect on overall survival. Moreover, only the PD-1+Tim-3+ subset of CD8+ T cells exhibited impaired function after stimulation. Our findings establish intratumoral Tim-3+PD1+CD8+ T cells as critical mediators of an aggressive phenotype in RCC. Use of the Vectra tool may be useful to identify similarly critical prognostic and predictive biomarkers in other tumor types and their response to immunotherapy. Cancer Res; 77(5); 1075-82. ©2016 AACR.