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.

The Selection for Cytoreductive Nephrectomy (SCREEN) Score: Improving Surgical Risk Stratification by Integrating Common Radiographic Features.

BACKGROUND: Careful patient selection is critical when considering cytoreductive nephrectomy (CN) for metastatic renal cell carcinoma (mRCC) but few studies have investigated the prognostic value of radiologic features that measure tumor burden. OBJECTIVE: To develop a prognostic model to improve CN selection with integration of common radiologic features with known prognostic factors associated with mortality in the first year following surgery. DESIGN, SETTINGS, AND PARTICIPANTS: Data were analyzed for consecutive patients with mRCC treated with upfront CN at five institutions from 2006 to 2017. Univariable and multivariable models were used to evaluate radiographic features and known risk factors for associations with overall survival. Relevant factors were used to create the SCREEN model and compared to the International mRCC Database Consortium (IMDC) model for predictive accuracy and clinical usefulness. RESULTS AND LIMITATIONS: A total of 914 patients with mRCC were treated with upfront CN during the study period. Seven independently predictive variables were used in the SCREEN score: three or more metastatic sites, total metastatic tumor burden ≥5 cm, bone metastasis, systemic symptoms, low serum hemoglobin, low serum albumin, and neutrophil/lymphocyte ratio ≥4. Predictive accuracy measured as the area under the receiver operating characteristic curves was 0.76 for the SCREEN score and 0.55 for the IMDC model. Decision curve analysis showed that the SCREEN model was useful beyond the IMDC classifier for threshold first-year mortality probabilities between 15% and 70%. CONCLUSIONS: The SCREEN score had higher predictive accuracy for first-year mortality compared to the IMDC scheme in a multi-institutional cohort and may be used to improve CN selection. PATIENT SUMMARY: This study provides a model to improve selection of patients with metastatic kidney cancer who may benefit from surgical removal of the primary kidney tumor. We found that radiographic measurements of the tumor burden predicted the risk of death in the first year after surgery. The model can be used to improve decision-making by these patients and their physicians.

Shorter Ureters Lead to Fewer Strictures Following Cystectomy and Urinary Diversion.

OBJECTIVE: To identify the impact of length of distal ureteral resection on the risk of benign uretero-enteric anastomotic stricture (UEAS) formation following cystectomy and urinary diversion. METHODS: A database of patients who underwent cystectomy and urinary diversion from 2015 to 2022 was analyzed. Distal ureteral resections were sent for final pathology. The length of resected ureter was collected from pathology reports. Benign UEAS were confirmed with renal scintigraphy, antegrade nephrostogram, or endoscopic evaluation. The relationship between stricture formation and clinical parameters were assessed using T-tests, chi-square tests, and multivariable analysis. RESULTS: A total of 366 patients underwent cystectomy and urinary diversion. Of the cohort, 35 (9.5%) patients developed UEAS. Median time to stricture formation was 12.5months (IQR 4-30). Of the 711 uretero-enteric anastomoses, 40 (5.6%) ultimately formed a UEAS. Median distal ureteral resection was significantly longer among ureteral anastomoses which did not form a UEAS (2.3 cm vs 1.65 cm, P = .028). Multivariable logistic regression adjusting for surgical approach, prior radiation, ureteral side, and urinary diversion type demonstrated that longer distal ureteral resections were inversely associated with odds of UEAS formation (OR 0.73, 95% CI 0.58-0.92). Multivariable Cox regression analysis similarly showed that length of distal ureteral resection was inversely associated with time to stricture formation (HR 0.78, 95% CI 0.62-0.98). CONCLUSION: The etiology of benign UIA strictures is multifactorial. Vascular compromise is a critical hypothesis. We found that longer distal ureteral resections (and thus shorter ureters) were associated with a significantly lower risk of stricture formation in cystectomy patients.

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.

Impact of Agent Orange Exposure on Non-muscle Invasive Bladder Cancer Outcomes.

OBJECTIVE: To explore the effect of Agent Orange (AO) exposure on bladder cancer (BCa) outcomes in patients receiving Bacillus Calmette-Guérin (BCG) for non-muscle invasive BCa (NMIBC). METHODS: We retrospectively examined the association between AO exposure in patients with NMIBC in national veterans affairs databases who were being treated with BCG. Patients were diagnosed with NMIBC from 2000 to 2010 with follow-up through 2018. Clinical, pathological, and demographic variables were compared by AO exposure. Associations of AO exposure with recurrence, progression, and cancer-specific survival were performed using Cox proportional hazard models after inverse propensity score weighting and competing risks adjustments. We also assessed the association of AO exposure on grade and stage via multivariable logistic regression models. RESULTS: A total of 7651 patients were identified of which 753 (9.8%) were exposed to AO. The median follow-up time was 130 months. The AO-exposed patients were younger (age 61 vs 71 years, P <.001), but had similar Charlson comorbidity scores and stage/grade distribution as the non-AO exposed patients. AO exposure was not associated with higher grade or stage. In our Cox multivariable analyses, AO exposure was not associated with worse recurrence (hazard ratio (HR) 0.89, 95% confidence interval (CI) 0.72-1.10, P = .29), progression (HR 1.08, 95% CI 0.86-1.36, P = .51), or cancer-specific survival (HR 1.31, 95% CI 0.92-1.87, P = .13). CONCLUSION: AO exposure was not associated with worse oncologic outcomes in patients receiving BCG for NMIBC. While this is reassuring, additional research is needed in other patient populations and disease states to determine if the effect is consistent.

Understanding and integrating cytoreductive nephrectomy with immune checkpoint inhibitors in the management of metastatic RCC.

Cytoreductive nephrectomy became accepted as standard of care for selected patients with metastatic renal cell carcinoma (mRCC) because of improved survival observed in patients treated with cytoreductive nephrectomy in combination with interferon-α in two randomized clinical trials published in 2001. Over the past two decades, novel systemic therapies have shown higher treatment response rates and improved survival outcomes compared with interferon-α. During this rapid evolution of mRCC treatments, systemic therapies have been the primary focus of clinical trials. Results from multiple retrospective studies continue to suggest an overall survival benefit for selected patients treated with nephrectomy in combination with systemic mRCC treatments, with the notable exception of one debated clinical trial. The optimal timing for surgery is unknown, and proper patient selection remains crucial to improving surgical outcomes. As systemic therapies continue to evolve, clinicians have an increasing need to understand how to incorporate cytoreductive nephrectomy into the management of mRCC.

Neddylation inhibition sensitises renal medullary carcinoma tumours to platinum chemotherapy.

BACKGROUND: Renal medullary carcinoma (RMC) is a highly aggressive cancer in need of new therapeutic strategies. The neddylation pathway can protect cells from DNA damage induced by the platinum-based chemotherapy used in RMC. We investigated if neddylation inhibition with pevonedistat will synergistically enhance antitumour effects of platinum-based chemotherapy in RMC. METHODS: We evaluated the IC50 concentrations of the neddylation-activating enzyme inhibitor pevonedistat in vitro in RMC cell lines. Bliss synergy scores were calculated using growth inhibition assays following treatment with varying concentrations of pevonedistat and carboplatin. Protein expression was assessed by western blot and immunofluorescence assays. The efficacy of pevonedistat alone or in combination with platinum-based chemotherapy was evaluated in vivo in platinum-naïve and platinum-experienced patient-derived xenograft (PDX) models of RMC. RESULTS: The RMC cell lines demonstrated IC50 concentrations of pevonedistat below the maximum tolerated dose in humans. When combined with carboplatin, pevonedistat demonstrated a significant in vitro synergistic effect. Treatment with carboplatin alone increased nuclear ERCC1 levels used to repair the interstrand crosslinks induced by platinum salts. Conversely, the addition of pevonedistat to carboplatin led to p53 upregulation resulting in FANCD2 suppression and reduced nuclear ERCC1 levels. The addition of pevonedistat to platinum-based chemotherapy significantly inhibited tumour growth in both platinum-naïve and platinum-experienced PDX models of RMC (p < .01). CONCLUSIONS: Our results suggest that pevonedistat synergises with carboplatin to inhibit RMC cell and tumour growth through inhibition of DNA damage repair. These findings support the development of a clinical trial combining pevonedistat with platinum-based chemotherapy for RMC.

SMARCB1 regulates the hypoxic stress response in sickle cell trait.

Renal medullary carcinoma (RMC) is an aggressive kidney cancer that almost exclusively develops in individuals with sickle cell trait (SCT) and is always characterized by loss of the tumor suppressor SMARCB1. Because renal ischemia induced by red blood cell sickling exacerbates chronic renal medullary hypoxia in vivo, we investigated whether the loss of SMARCB1 confers a survival advantage under the setting of SCT. Hypoxic stress, which naturally occurs within the renal medulla, is elevated under the setting of SCT. Our findings showed that hypoxia-induced SMARCB1 degradation protected renal cells from hypoxic stress. SMARCB1 wild-type renal tumors exhibited lower levels of SMARCB1 and more aggressive growth in mice harboring the SCT mutation in human hemoglobin A (HbA) than in control mice harboring wild-type human HbA. Consistent with established clinical observations, SMARCB1-null renal tumors were refractory to hypoxia-inducing therapeutic inhibition of angiogenesis. Further, reconstitution of SMARCB1 restored renal tumor sensitivity to hypoxic stress in vitro and in vivo. Together, our results demonstrate a physiological role for SMARCB1 degradation in response to hypoxic stress, connect the renal medullary hypoxia induced by SCT with an increased risk of SMARCB1-negative RMC, and shed light into the mechanisms mediating the resistance of SMARCB1-null renal tumors against angiogenesis inhibition therapies.

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.

Cytoreductive Nephrectomy Following Immune Checkpoint Inhibitor Therapy Is Safe and Facilitates Treatment-free Intervals.

Patients with metastatic renal cell cancer (mRCC) who respond to upfront immune checkpoint inhibitor (ICI) combination therapies may be treated with cytoreductive nephrectomy (CN) to remove radiographically viable primary tumors. Early data for post-ICI CN suggested that ICI therapies induce desmoplastic reactions in some patients, increasing the risk of surgical complications and perioperative mortality. We evaluated perioperative outcomes for 75 consecutive patients treated with post-ICI CN at four institutions from 2017 to 2022. Our cohort of 75 patients had minimal or no residual metastatic disease but radiographically enhancing primary tumors after ICI and were treated with CN. Intraoperative complications were identified in 3/75 patients (4%) and 90-d postoperative complications in 19/75 (25%), including two patients (3%) with high-grade (Clavien ≥III) complications. One patient was readmitted within 30 d. No patients died within 90 d after surgery. Viable tumor was present in all but one specimen. Approximately half of the patients (36/75, 48%) remained off systemic therapy at last follow-up. These data suggest that CN following ICI therapy is safe and associated with low rates of major postoperative complications in appropriately selected patients at experienced centers. Post-ICI CN may facilitate observation without additional systemic therapy in patients without significant residual metastatic disease. Patient summary: Current first-line treatment for patients with kidney cancer that has spread to other sites (metastatic cancer) is immunotherapy. For cases in which metastatic sites respond to this therapy but primary tumor is still detected in the kidney, surgical treatment of the tumor is feasible and has a low rate of complications, and may delay the need for further chemotherapy.

Differentiation of benign from malignant solid renal lesions with MRI-based radiomics and machine learning.

BACKGROUND: Solid renal masses are often indeterminate for benignity versus malignancy on magnetic resonance imaging. Such masses are typically evaluated with either percutaneous biopsy or surgical resection. Percutaneous biopsy can be non-diagnostic and some surgically resected lesions are inadvertently benign. PURPOSE: To assess the performance of ten machine learning (ML) algorithms trained with MRI-based radiomics features in distinguishing benign from malignant solid renal masses. METHODS: Patients with solid renal masses identified on pre-intervention MRI were curated from our institutional database. Masses with a definitive diagnosis via imaging (for angiomyolipomas) or via biopsy or surgical resection (for oncocytomas or renal cell carcinomas) were selected. Each mass was segmented for both T2- and post-contrast T1-weighted images. Radiomics features were derived from the segmented masses for each imaging sequence. Ten ML algorithms were trained with the radiomics features gleaned from each MR sequence, as well as the combination of MR sequences. RESULTS: In total, 182 renal masses in 160 patients were included in the study. The support vector machine algorithm trained on radiomics features from T2-weighted images performed superiorly, with an accuracy of 0.80 and an area under the curve (AUC) of 0.79. Linear discriminant analysis (accuracy = 0.84 and AUC = 0.77) and logistic regression (accuracy = 0.78 and AUC = 0.78) algorithms trained on T2-based radiomics features performed similarly. ML algorithms trained on radiomics features from post-contrast T1-weighted images or the combination of radiomics features from T2- and post-contrast T1-weighted images yielded lower performance. CONCLUSION: Machine learning models trained with radiomics features derived from T2-weighted images can provide high accuracy for distinguishing benign from malignant solid renal masses. CLINICAL IMPACT: Machine learning models derived from MRI-based radiomics features may improve the clinical management of solid renal masses and have the potential to reduce the frequency with which benign solid renal masses are biopsied or surgically resected.

Models of Renal Cell Carcinoma Used to Investigate Molecular Mechanisms and Develop New Therapeutics.

Modeling renal cell carcinoma is critical to investigating tumor biology and therapeutic mechanisms. Multiple systems have been developed to represent critical components of the tumor and its surrounding microenvironment. Prominent in vitro models include traditional cell cultures, 3D organoid models, and microphysiological devices. In vivo models consist of murine patient derived xenografts or genetically engineered mice. Each system has unique advantages as well as limitations and researchers must thoroughly understand each model to properly investigate research questions. This review addresses common model systems for renal cell carcinoma and critically evaluates their performance and ability to measure tumor characteristics.

Increased body mass index is associated with operative difficulty during robot-assisted radical prostatectomy.

Objective: This study aimed to identify factors associated with surgeon perception of robot-assisted radical prostatectomy (RARP) difficulty. Patients and Methods: This study surveyed surgeons performing RARP between 2017 and 2018 and asked them to rate operative conditions and difficulty as optimal, good, acceptable, or poor. These answers were stratified as optimal or suboptimal for this study. Associations between surgeon responses and variables hypothesized to affect surgical difficulty, including anatomic factors such as pelvic diameter and prostate volume:pelvic diameter ratio, were assessed. Results: Between November 2017 and September 2018, a total of 100 patients were prospectively enrolled in the study of which 58 cases were rated as optimal and 42 were rated as suboptimal. Of the evaluated variables, only increasing clinical T stage (odds ratio [OR] 1.49, 95% confidence interval [CI] 1.03-2.15, p = 0.03) and increasing body mass index (BMI) (OR 1.14, 95% CI 1.03-1.26, p = 0.01) were associated with increased difficulty; 90-day complication rates were similar between the optimal and suboptimal cohorts (17.3% vs. 23.8%, respectively; p = 0.5). The number of patients with previous surgery, pelvic diameter, and prostate size:pelvic diameter ratio were not significantly different between cohorts (p > 0.05 for all). Operative time (ρ = 0.23, p = 0.02) and estimated blood loss (EBL) (ρ = 0.38, p = 0.0001) were correlated with suboptimal difficulty. Conclusion: The factors associated with surgeon-reported RARP difficulty were patient BMI and clinical T stage among surgeons with significant RARP experience. These data should be incorporated into surgical decision making and patient counseling prior to performing a RARP.

Association of High-Intensity Exercise with Renal Medullary Carcinoma in Individuals with Sickle Cell Trait: Clinical Observations and Experimental Animal Studies.

Renal medullary carcinoma (RMC) is a lethal malignancy affecting individuals with sickle hemoglobinopathies. Currently, no modifiable risk factors are known. We aimed to determine whether high-intensity exercise is a risk factor for RMC in individuals with sickle cell trait (SCT). We used multiple approaches to triangulate our conclusion. First, a case-control study was conducted at a single tertiary-care facility. Consecutive patients with RMC were compared to matched controls with similarly advanced genitourinary malignancies in a 1:2 ratio and compared on rates of physical activity and anthropometric measures, including skeletal muscle surface area. Next, we compared the rate of military service among our RMC patients to a similarly aged population of black individuals with SCT in the U.S. Further, we used genetically engineered mouse models of SCT to study the impact of exercise on renal medullary hypoxia. Compared with matched controls, patients with RMC reported higher physical activity and had higher skeletal muscle surface area. A higher proportion of patients with RMC reported military service than expected compared to the similarly-aged population of black individuals with SCT. When exposed to high-intensity exercise, mice with SCT demonstrated significantly higher renal medulla hypoxia compared to wild-type controls. These data suggest high-intensity exercise is the first modifiable risk factor for RMC in individuals with SCT.

Tumor diameter response in patients with metastatic clear cell renal cell carcinoma is associated with overall survival.

OBJECTIVE: Tumor shrinkage of at least 10% after presurgical targeted molecular therapy (TMT) in renal cell carcinoma (RCC) patients has been associated with better overall survival (OS) outcomes. We characterized primary and metastatic tumor diameter response and OS in patients with metastatic clear cell RCC (ccRCC) who received preoperative TMT, immunotherapy, or both followed by deferred cytoreductive nephrectomy (dCN). MATERIALS AND METHODS: Patients with metastatic ccRCC (n = 198) who underwent preoperative therapy and dCN from 2005 to 2019 were identified retrospectively. Longest primary and metastatic tumor diameters were calculated using cross-sectional images obtained before systemic therapy and dCN using the Response Evaluation Criteria in Solid Tumors. Patients were stratified by tumor shrinkage of at least 10% in the primary and/or metastatic tumors after systemic therapy. The Kaplan-Meier method was used to estimate OS, and Cox proportional hazards models were used to assess the association of patient characteristics with OS. RESULTS: In total, 31.31% of patients had only metastatic tumor shrinkage (MTS) ≥ 10%, 8.08% had only primary tumor shrinkage (PTS) ≥ 10%, 32.32% had PTS and MTS ≥ 10%, and 28.28% had PTS/MTS < 10%. The median OS, number of patients with tumor shrinkage ≥ 10%, and International Metastatic Database Consortium (IMDC) scores were similar among the 3 systemic therapy groups (all P ≥ 0.80). Patients with MTS ≥ 10%, PTS ≥ 10%, and PTS/MTS ≥ 10% had significantly longer median OS compared to patients with PTS/MTS < 10% (P < 0.01). Patients with intermediate-risk IMDC scores had significantly longer median OS compared to patients in the poor-risk group. After adjusting for preoperative therapy and IMDC risk group, MTS ≥ 10%, PTS ≥ 10%, and PTS/MTS ≥ 10% were associated with better OS outcomes (HR 0.48 95% CI 0.32-0.73, P < 0.001; HR 0.48, 95% CI 0.23-0.98, P = 0.04; HR 0.44, 95% CI 0.29-0.67, P < 0.001, respectively). CONCLUSIONS: Intermediate risk score and shrinkage of at least 10% in the primary tumor, metastases, or both were associated with better OS outcomes in patients with metastatic ccRCC who underwent dCN independent of the type of preoperative systemic therapy.

Sarcomatoid features and lymph node-positive disease in chromophobe renal cell carcinoma.

PURPOSE: The presence of sarcomatoid features and/or lymph node-positive disease may be associated with a worse prognosis in chromophobe renal cell carcinoma (ChRCC). We sought to better characterize patients' long-term outcomes with these features compared with those without these features. MATERIALS AND METHODS: We identified 300 patients treated for sporadic, unilateral, nonmetastatic ChRCC between 1993 and 2019. Clinical and pathologic features were summarized, and cancer-specific survival (CSS) and recurrence-free survival (RFS) were analyzed using Kaplan-Meier plots. Cox regression analysis was performed to determine factors associated with recurrence. Patients with sarcomatoid features and/or nodal disease were grouped as high-risk in a secondary analysis. RESULTS: The median age was 60 years, 43.7% were female, 29.3% had pT3/T4 disease, 3.3% had sarcomatoid features, and 4% had pathologic N1 disease. Sixteen patients were categorized as high-risk based on the presence of sarcomatoid features (n = 4), pathologic N1 disease (n = 6), or both (n = 6). There were 22 recurrences; the recurrence rate in the low-risk group was 4.9% and 50% in the high-risk group. 10-year RFS was 91.4% in the low-risk group and 34.4% in the high-risk group (P < 0.001). 10-year CSS was 96.4% in the low-risk group and 54.3% in the high-risk group (P < 0.001). In multivariable analysis, sarcomatoid features (HR 5.5, CI 1.5-20.2, P = 0.01) and pN1 disease (HR 16.5, CI 5.3-51.4, P < 0.0001) were independently associated with RFS. CONCLUSIONS: The presence of sarcomatoid features and/or lymph node-positive disease portends a poor prognosis in ChRCC. Further studies evaluating the impact of novel therapeutic agents in these patients are warranted.