Non-Metastatic Clear Cell Renal Cell Carcinoma Immune Cell Infiltration Heterogeneity and Prognostic Ability in Patients Following Surgery.

Predicting which patients will progress to metastatic disease after surgery for non-metastatic clear cell renal cell carcinoma (ccRCC) is difficult; however, recent data suggest that tumor immune cell infiltration could be used as a biomarker. We evaluated the quantity and type of immune cells infiltrating ccRCC tumors for associations with metastatic progression following attempted curative surgery. We quantified immune cell densities in the tumor microenvironment and validated our findings in two independent patient cohorts with multi-region sampling to investigate the impact of heterogeneity on prognostic accuracy. For non-metastatic ccRCC, increased CD8+ T cell infiltration was associated with a reduced likelihood of progression to metastatic disease. Interestingly, patients who progressed to metastatic disease also had increased percentages of exhausted CD8+ T cells. Finally, we evaluated the spatial heterogeneity of the immune infiltration and demonstrated that patients without metastatic progression had CD8+ T cells in closer proximity to ccRCC cells. These data strengthen the evidence for CD8+ T cell infiltration as a prognostic biomarker in non-metastatic ccRCC and demonstrate that multi-region sampling may be necessary to fully characterize immune infiltration within heterogeneous tumors. Tumor CD8+ T cell infiltration should be investigated as a biomarker in adjuvant systemic therapy clinical trials for high-risk non-metastatic RCC.

Contemporary Patients Have Better Perioperative Outcomes Following Cytoreductive Nephrectomy: A Multi-institutional Analysis of 1272 Consecutive Patients.

OBJECTIVE: To evaluate factors associated with perioperative outcomes in a multi-institutional cohort of patients treated with cytoreductive nephrectomy (CN). METHODS: Data were analyzed for metastatic renal cell carcinoma patients treated with CN at 6 tertiary academic centers from 2005 to 2019. Outcomes included: Clavien-Dindo complications, mortality, length of hospitalization, 30-day readmission rate, and time to systemic therapy. Univariate and multivariable models evaluated associations between outcomes and prognostic variables including the year of surgery. RESULTS: A total of 1272 consecutive patients were treated with CN. Patients treated in 2015-2019 vs 2005-2009 had better performance status (P<.001), higher pathologic N stage (P = .04), more frequent lymph node dissections (P<.001), and less frequent presurgical therapy (P = .02). Patients treated in 2015-2019 vs 2005-2009 had lower overall and major complications from surgery, 22% vs 39%, P<.001% and 10% vs 16%, P = .03. Mortality at 90days was higher for patients treated 2005-2009 vs 2015-2019; 10% vs 5%, P = .02. After multivariable analysis, surgical time period was an independent predictor of major complications and 90-day mortality following cytoreductive surgery. CONCLUSION: Postoperative major complications and mortality rates following CN are significantly lower in patients treated within the most recent time period.

Understanding the Tumor Immune Microenvironment in Renal Cell Carcinoma.

Scientific understanding of how the immune microenvironment interacts with renal cell carcinoma (RCC) has substantially increased over the last decade as a result of research investigations and applying immunotherapies, which modulate how the immune system targets and eliminates RCC tumor cells. Clinically, immune checkpoint inhibitor therapy (ICI) has revolutionized the treatment of advanced clear cell RCC because of improved outcomes compared to targeted molecular therapies. From an immunologic perspective, RCC is particularly interesting because tumors are known to be highly inflamed, but the mechanisms underlying the inflammation of the tumor immune microenvironment are atypical and not well described. While technological advances in gene sequencing and cellular imaging have enabled precise characterization of RCC immune cell phenotypes, multiple theories have been suggested regarding the functional significance of immune infiltration in RCC progression. The purpose of this review is to describe the general concepts of the anti-tumor immune response and to provide a detailed summary of the current understanding of the immune response to RCC tumor development and progression. This article describes immune cell phenotypes that have been reported in the RCC microenvironment and discusses the application of RCC immunophenotyping to predict response to ICI therapy and patient survival.

Predicting Adherent Perinephric Fat Using Preoperative Clinical and Radiological Factors in Patients Undergoing Partial Nephrectomy.

BACKGROUND: The decision to perform a partial nephrectomy (PN) relies largely upon the complexity of the renal mass and its surrounding anatomy. The presence of adherent perinephric fat (APF) can increase surgical complexity and extend operative times. The accurate prediction of APF may improve surgical planning and aid in decision making for the surgical approach. OBJECTIVE: We sought to develop and externally validate a score that predicts APF based on preoperative clinical and radiological prognostic factors. DESIGN, SETTING, AND PARTICIPANTS: We retrospectively analyzed 495 consecutive patients who underwent open or minimally invasive PN. APF was defined as the presence of "dense," "adherent," or "sticky" perinephric fat at the time of dissection by the surgeon, and this did not require subcapsular dissection. Additionally, we analyzed an independent cohort of 285 patients for external validation. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: A score model was developed using multivariate logistic regression analysis. Calibration of the fitted model was assessed graphically with a plot of the predicted versus the actual probability of APF, and discrimination was assessed by calculating the area under the receiver operating characteristic curve. RESULTS AND LIMITATIONS: Of the 495 patients, 95 (19%) had APF. Patients with APF had longer operative (p=0.02) and arterial clamp (p=0.01) times than non-APF patients. On multivariate analyses, diabetes mellitus (p=0.009), posterior perinephric fat thickness (p<0.001), and perinephric stranding (p<0.001) were predictors of encountering APF in PN. A risk score ranging from 0 to 4 was developed based on these three variables to predict APF. The scoring system demonstrated good discrimination of 0.82 and 0.84 for the development and external validation cohorts, respectively. CONCLUSIONS: The APF score can accurately predict the presence of APF in patients with a small renal mass who are planning to undergo PN. This score could aid in pre- and intraoperative planning and impact the surgical approach. PATIENT SUMMARY: The presence of "sticky" fat surrounding the kidney in patients undergoing partial nephrectomy has previously been linked to longer operative times, intraoperative complications, and surgical conversion. In our study, we found that this feature is more often presented in patients with diabetes mellitus, and thicker and more inflammatory fat on renal imaging. Based on these findings, we developed a risk score that can accurately predict this feature before surgery, in order to improve surgical planning and better counsel the patients.

The Evolving Role of Metastasectomy for Patients with Metastatic Renal Cell Carcinoma.

Surgical metastasectomy continues to be utilized for patients with solitary or low-volume metastatic renal cell carcinoma (mRCC). Although few high-quality data are available to evaluate outcomes, local treatment is recommended when feasible because it may allow a subset of patients to delay or avoid systemic treatments. With the development of improved mRCC therapies, utilization of metastasectomy has increased because most patients have incomplete responses to systemic treatment of their metastases. This review discusses the rationale and history of metastasectomy, trends in utilization, prognostic factors for patient selection, site-specific considerations, alternatives for nonsurgical local treatment, and risk of morbidity associated with metastasectomy.

Comparing Outcomes for Patients with Clinical T1b Renal Cell Carcinoma Treated With Either Percutaneous Microwave Ablation or Surgery.

OBJECTIVE: To compare perioperative and oncologic outcomes for patients with clinical T1b renal cell carcinoma following treatment with microwave ablation (MW), partial nephrectomy (PN), or radical nephrectomy (RN). METHODS: Comprehensive clinical and pathologic data were collected for nonmetastatic renal cell carcinoma patients with cT1b tumors following MW, PN, or RN from 2000 to 2018. Local recurrence-free, metastasis-free, cancer-specific and overall survival were estimated using Kaplan-Meier method. Prognostic factors for complications and survival were determined using logistic regression and Cox hazard models, respectively. RESULTS: A total of 325 patients (40 MW, 74 PN, and 211 RN) were identified. Patients treated with MW were older with higher Charlson comorbidity indices compared to surgical patients. Median length of hospitalization was shorter for MW compared to surgical patients (1 day vs 4 days, P <.0001). Post-treatment estimated glomerular filtration rate decreased by median 4.5% for MW compared to 3.2% for PN (P = .58) and 29% for RN (P <.001). Median follow-up was 34, 35, and 49 months following MW, PN, and RN, respectively. Estimated 5-year local recurrence-free survival was 94.5% for MW vs 97.9% for PN (P = .34) and 99.2% for RN (P = .02). Two patients recurred after MW and underwent repeat ablation without subsequent recurrence. No difference in 5-year metastasis-free survival or cancer-specific survival was found among MW, PN, or RN. Four (10%) MW patients had high-grade complication. Only prior abdominal surgery predicted high-grade complication (OR 6.29, P = .017). CONCLUSION: Microwave ablation is a feasible alternative to surgery in select comorbid patients with clinical T1b renal cell carcinoma.

Percutaneous biopsy for risk stratification of renal masses.

The increased use of abdominal imaging has led to identification of more patients with incidental renal masses, and renal mass biopsy (RMB) has become a popular method to evaluate unknown renal masses prior to definitive treatment. Pathologic data obtained from biopsy may be used to guide decisions for treatment and may include the presence or absence of malignant tumor, renal cell cancer subtype, tumor grade and the presence of other aggressive pathologic features. However, prior to using RMB for risk stratification, it is important to understand whether RMB findings are equivalent to pathologic analysis of surgical specimens and to identify any potential limitations of this approach. This review outlines the advantages and limitations of the current studies that evaluate RMB as a guide for treatment decision in patients with unknown renal masses. In multiple series, RMB has demonstrated low morbidity and a theoretical reduction in cost, if patients with benign tumors are identified from biopsy and can avoid subsequent treatment. However, when considering the routine use of RMB for risk stratification, it is important to note that biopsy may underestimate risk in some patients by undergrading, understaging or failing to identify aggressive tumor features. Future studies should focus on developing treatment algorithms that integrate RMB to identify the optimal use in risk stratification of patients with unknown renal masses.

Preoperative multivariable prognostic models for prediction of survival and major complications following surgical resection of renal cell carcinoma with suprahepatic caval tumor thrombus.

OBJECTIVE: Surgical resection for renal cell carcinoma (RCC) with suprahepatic inferior vena cava tumor thrombus is associated with significant morbidity, yet there are currently no tools for preoperative prognostic evaluation. Our goal was to develop a preoperative multivariable model for prediction of survival and risk of major complications in patients with suprahepatic thrombi. METHODS: We identified patients who underwent surgery for RCC with suprahepatic tumor thrombus extension from 2000 to 2013 at 4 tertiary centers. A Cox proportional hazard model was used for analysis of overall survival (OS) and logistic regression was used for major complications within 90 days of surgery (Clavien ≥ 3A). Nomograms were internally calibrated by bootstrap resampling method. RESULTS: A total of 49 patients with level III thrombus and 83 patients with level IV thrombus were identified. During median follow-up of 24.5 months, 80 patients (60.6%) died and 46 patients (34.8%) experienced major complication. Independent prognostic factors for OS included distant metastases at presentation (hazard ratio = 2.52, P = 0.002) and Eastern Cooperative Oncology Group (ECOG) performance status (hazard ratio = 1.84, P<0.0001). Variables associated with increased risk of major complications on univariate analysis included preoperative systemic symptoms, level IV thrombus, and elevated preoperative alkaline phosphatase and aspartate transaminase levels; however, only systemic symptoms (odds ratio = 8.45, P<0.0001) was an independent prognostic factor. Preoperative nomograms achieved a concordance index of 0.72 for OS and 0.83 for major complications. CONCLUSIONS: We have developed and internally validated multivariable preoperative models for the prediction of survival and major complications in patients with RCC who have a suprahepatic inferior vena cava thrombus. If externally validated, these tools may aid in patient selection for surgical intervention.

NLR is predictive of upstaging at the time of radical cystectomy for patients with urothelial carcinoma of the bladder.

OBJECTIVE: To evaluate the ability of preoperative neutrophil-lymphocyte ratio (NLR) to predict pathologic upstaging and nonorgan-confined (NOC) (≥pT3) disease. METHODS AND MATERIALS: After institutional review board approval, the records of consecutive patients undergoing radical cystectomy (RC) for urothelial carcinoma from 2002 to 2012 at the University of Wisconsin Hospital were reviewed. A total of 102 patients with NLR within 100 days of surgery were eligible for analysis. The primary outcome was difference in stage from preoperative assessment to time of RC. Differences in preoperative NLR between groups were evaluated with an unequal variance t test. A univariate analysis assessed whether NLR, preoperative stage, grade, associated lymphovascular invasion, preoperative hydronephrosis, gender, previous pelvic radiotherapy, previous intravesical bladder cancer treatments, or nodal stage were related to upstaging. Multivariate analyses were performed to evaluate the relationship of NLR to upstaging and relative organ-confined (≤pT2) and NOC disease. RESULTS: Of 390 consecutive patients undergoing RC, 102 patients met study criteria. Overall, 55 (53.9%) patients were upstaged, 25 (25.5%) were unchanged, and 21 (20.6%) were downstaged. Fifty-one patients (50%) were upstaged to more advanced disease (≥pT3). NLR and preoperative hydronephrosis were significantly related to pathologic tumor staging. NLR, preoperative hydronephrosis, and preoperative tumor stage were significantly related to upstaging to NOC disease. Patients who were upstaged to≥pT3 demonstrated statistically significant greater NLRs (4.33±0.87) compared with patients who remained at≤pT2 stage (2.66±0.29) (P<0.001). CONCLUSIONS: Preoperative NLR is a simple measurement that can be used to identify high-risk patients who may be upstaged at the time of RC and may benefit from neoadjuvant chemotherapy.