Large quantities of data are now available to medical researchers; however, observational studies are plagued by bias and confounding. Additionally, much of this research only speculates on variable associations, leaving prospective randomized clinical trials as the sole purveyors of claims about causal relations between variables. There has been a growing movement of causal inference that uses new techniques to investigate causality using observational data. These techniques include the implementation of directed acyclic graphs, which allow researchers to explicitly and reproducibly define the causal relationships between study variables, thus making statistical analysis more robust. Directed acyclic graphs further allow researchers to identify confounding and other sources of bias and to discover causal effects among complex networks of variables. This review aims to introduce these techniques to the general urology and urologic oncology research communities in order to provide a basic understanding of causal inference and analysis and call for integration of these practices more generally in research methodology.

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.

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.

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.

Objective: To define the value of a digital rectal exam (DRE) in the prostate‐magnetic resonance imaging (MRI) era. Prostate MRI is increasingly used in men with elevated prostate‐specific antigen (PSA) prior to biopsy.Methods: A retrospective study was performed in men with elevated PSA undergoing MRI followed by MRI fusion with systematic biopsy and men with elevated PSA/active surveillance with negative MRI followed by biopsy. Baseline clinicopathologic characteristics and DRE findings were collected. We examined performance of a positive DRE on sensitivity and specificity of diagnosing clinically significant prostate cancer (CSPC).Results: A total of 339 patients had elevated PSA and positive MRI followed by MRI fusion guided with systematic biopsy. Pre‐biopsy DRE was documented in 286/339 patients, who were included in further analysis. About 81.6% positive, 78.7% questionable, and 55.8% negative DRE patients had CSPC. Positive DRE had 21.8% sensitivity and 91.3% specificity for CSPC. Positive or questionable DRE had 42.1% sensitivity and 81.5% specificity. Among 148 men with non‐CSPC (GG1)‐targeted biopsy, 28 had systematic biopsy with CSPC. About 5/28 had positive DRE and 8/28 had positive or questionable DRE. Twenty‐seven patients were included who had elevated PSA/on active surveillance with negative MRI and biopsy done within 2 years. About 77.8% had negative, 7.4% had questionable, and 14.8% men had positive DRE. About 7.4% had CSPC and all had a negative DRE.Conclusions: Our study provides limited evidence for the value of a DRE. However, it does show occasional benefit in detecting GG2 or higher disease and given the lack of cost and side effects, should still be considered.