Localised non-metastatic sarcomatoid renal cell carcinoma: a 31-year externally verified study.

OBJECTIVE: To evaluate post-nephrectomy outcomes and predictors of cancer-specific survival (CSS) between patients with localised sarcomatoid renal cell carcinoma (sRCC) and those with Grade 4 RCC (non-sRCC), as most sRCC research focuses on advanced or metastatic disease with limited studies analysing outcomes of patients with localised non-metastatic sRCC. PATIENTS AND METHODS: A total of 564 patients with localised RCC underwent partial or radical nephrectomy between June 1988 to March 2019 for sRCC (n = 204) or World Health Organization/International Society of Urological Pathology Grade 4 non-sRCC (n = 360). The CSS at every stage between groups was assessed. Phase III ASSURE clinical trial data were used to externally validate the CSS findings. The Mann-Whitney U-test and chi-squared test compared outcomes and the Kaplan-Meier method evaluated CSS, overall survival (OS) and recurrence-free survival. Clinicopathological features associated with RCC death were evaluated using Cox proportional hazards regression. RESULTS: The median follow-up was 31.5 months. The median OS and CSS between the sRCC and Grade 4 non-sRCC groups was 45 vs 102 months and 49 vs 152 months, respectively (P < 0.001). At every stage, sRCC had worse CSS compared to Grade 4 non-sRCC. Notably, pT1 sRCC had worse CSS than pT3 Grade 4 non-sRCC. Negative predictors of CSS were sarcomatoid features, non-clear cell histology, positive margins, higher stage (pT3/pT4), and use of minimally invasive surgery (MIS). ASSURE external verification showed worse CSS in patients with sRCC (hazard ratio [HR] 1.63, 95% confidence interval [CI] 1.12-2.36; P = 0.01), but not worse outcomes in MIS surgery (HR 1.39, 95% CI 0.75-2.56; P = 0.30). CONCLUSIONS: Localised sRCC had worse CSS compared to Grade 4 non-sRCC at every stage. Negative survival predictors included positive margins, higher pathological stage, use of MIS, and non-clear cell histology. sRCC is an aggressive variant even at low stages requiring vigilant surveillance and possible inclusion in adjuvant therapy trials.

Prognostic Factors for Survival in Patients Undergoing Surveillance After Cytoreductive Nephrectomy.

PURPOSE: The clinical course of patients being placed on surveillance in a cohort of systemic therapy-naïve patients who undergo cytoreductive nephrectomy is not well documented. Thus, we evaluated the clinical course of patients placed on surveillance following cytoreductive nephrectomy and identified predictors of survival. MATERIALS AND METHODS: In this large single-institution study, we retrospectively analyzed metastatic renal cell carcinoma patients who underwent cytoreductive nephrectomy followed by surveillance. Predictors of survival were evaluated using the Kaplan-Meier method with a log-rank test. Patients were risk stratified based on IMDC (International mRCC Database Consortium) and number of metastatic sites (Rini score), with IMDC score ≤1 and ≤2 metastatic organ sites considered favorable risk. Primary end point was systemic therapy-free survival. Secondary end points included intervention-free survival, cancer-specific survival, and overall survival. RESULTS: Median systemic therapy-free survival was 23.6 months (95% CI: 15.1-40.6), intervention-free survival was 11.8 months (95% CI: 8.0-18.4), cancer-specific survival was 54.2 months (95% CI: 46.2-71.4), and overall survival 52.4 months (95% CI: 40.3-66.8). Favorable-risk patients compared to unfavorable-risk patients had longer systemic therapy-free survival (50.6 vs 11.1 months, P < .01), survival (25.2 vs 7.3, P < .01), and cancer-specific survival (71.4 vs 46.2 months, P = .02). CONCLUSIONS: Using risk stratification based on IMDC and number of metastatic sites, surveillance in favorable-risk patients can be utilized for a period without the initiation of systemic therapy. This approach can delay patients' exposure to the side effects of systemic therapy.

The association between modifiable perioperative parameters and renal function after nephrectomy.

OBJECTIVE: To evaluate the association between intraoperative anaesthetic parameters, primarily intraoperative hypotension, and postoperative renal function in patients undergoing nephrectomy. PATIENTS AND METHODS: We reviewed data from 3240 consecutive patients who underwent nephrectomy between 2010 and 2018. Anaesthetic parameters evaluated included duration of hypotension, tachycardia, hypothermia, volatile anaesthetic use and mean arterial pressure in the post-anaesthesia care unit. Outcomes included acute kidney injury (AKI) and estimated glomerular filtration rate (eGFR) within the first year after nephrectomy. Associations between anaesthetic parameters and outcomes were evaluated with multivariable logistic regression and generalised estimating equation, respectively, adjusted for predictors of renal function after nephrectomy. RESULTS: Before nephrectomy, 677 (21%) patients had moderate-severe chronic kidney disease. A quarter of patients (n = 809) had postoperative AKI and 35% (n = 746) had Stage ≥3 chronic kidney disease 12-months after surgery. Only 12% of patients (n = 386) had >5 min of intraoperative hypotension. While not statistically significant, longer duration of intraoperative hypotension was associated with slightly higher rates of AKI (odds ratio [OR] per 10-min 1.14, 95% confidence interval [CI] 0.98, 1.32). Prolonged hypothermia was associated with increased rate of AKI (OR per 10-min 1.02, 95% CI 1.00, 1.04), and decreased eGFR (change in eGFR per 10-min -0.19, 95% CI -0.27, -0.12); however, these results have limited clinical significance. CONCLUSIONS: Under current practice, intraoperative anaesthetic parameters are tightly maintained, restricting the significance of their effect on postoperative renal function. Future studies should evaluate whether haemodynamic parameters during the early postoperative period, when they are monitored less frequently, are associated with renal functional outcome.

Evolving biological associations of upfront cytoreductive nephrectomy in metastatic renal cell carcinoma.

BACKGROUND: Systemic responses to cytoreductive nephrectomy (CN) in the management of metastatic renal cell carcinoma (mRCC) are variable and difficult to anticipate. The authors aimed to determine the association of CN with modifiable International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) risk factors and oncological outcomes. METHODS: Consecutive patients with mRCC referred for potential CN (2009-2019) were reviewed. The primary outcome was overall survival (OS); variables of interest included undergoing CN and the baseline number of modifiable IMDC risk factors (anemia, hypercalcemia, neutrophilia, thrombocytosis, and reduced performance status). For operative cases, the authors evaluated the effects of IMDC risk factor dynamics, measured 6 weeks and 6 months after CN, on OS and postoperative treatment disposition. RESULTS: Of 245 treatment-naive patients with mRCC referred for CN, 177 (72%) proceeded to surgery. The CN cases had fewer modifiable IMDC risk factors (P = .003), including none in 71 of 177 patients (40.1%); fewer metastases (P = .011); and higher proportions of clear cell histology (P = .012). In a multivariable analysis, surgical selection, number of IMDC risk factors, metastatic focality, and histology were associated with OS. Total risk factors changed for 53.8% and 57.2% of the patients from the preoperative period to 6 weeks and 6 months after CN, respectively. Adjusted for preoperative IMDC risk scores, an increase in IMDC risk factors at 6 weeks and 6 months was associated with adverse OS (hazard ratio [HR], 1.57; 95% confidence interval [CI], 1.13-2.19; P = .007; HR, 2.52; 95% CI, 1.74-3.65; P < .001). CONCLUSIONS: IMDC risk factors are dynamic clinical variables that can improve after upfront CN in select patients, and this suggests a systemic benefit of cytoreduction, which may confer clinically meaningful prognostic implications.

A qualitative framework of non-selection factors for cytoreductive nephrectomy.

PURPOSE: Cytoreductive nephrectomy (CN) benefits a subset of patients with metastatic renal cell carcinoma (mRCC), however proper patient selection remains complex and controversial. We aim to characterize urologists' reasons for not undertaking a CN at a quaternary cancer center. METHODS: Consecutive patients with mRCC referred to MSKCC urologists for consideration of CN between 2009 and 2019 were included. Baseline clinicopathologic characteristics were used to compare patients selected or rejected for CN. The reasons cited for not operating and the alternative management strategies recommended were extrapolated. Using an iterative thematic analysis, a framework of reasons for rejecting CN was designed. Kaplan-Meier estimates tested for associations between the reasons for not undertaking a CN and overall survival (OS). RESULTS: Of 297 patients with biopsy-proven mRCC, 217 (73%) underwent CN and 80 (27%) did not. Median follow-up of patients alive at data cut-off was 27.3 months. Non-operative patients were older (p = 0.014), had more sites of metastases (p = 0.008), harbored non-clear cell histology (p = 0.014) and reduced performance status (p < 0.001). The framework comprised seven distinct themes for recommending non-operative management: two patient-fitness considerations and five oncological considerations. These considerations were associated with OS; four of the oncological factors conferred a median OS of less than 12 months (p < 0.001). CONCLUSION: We developed a framework of criteria by which patients were deemed unsuitable candidates for CN. These new insights provide a novel perspective on surgical selection, could potentially be applicable to other malignancies and possibly have prognostic implications.

Immune checkpoint blockade in renal cell carcinoma.

Immune checkpoint blockade (ICB) is the foundation of current first-line therapies in patients with metastatic renal cell carcinoma (mRCC) with the potential for eliciting long-lasting remissions. With the expanding arsenal of ICB-based therapies, biomarkers of response are urgently needed to guide optimal therapeutic selection. We review the data behind ICB therapy in RCC, emerging biomarkers of response, and the evolving role of surgery in patients with mRCC.

Systemic Immunological Determinants of Oncological Outcomes After Surgery for Localized Renal Cell Carcinoma.

INTRODUCTION & OBJECTIVES: In systemic therapy trials, a decreasing neutrophil-to-lymphocyte ratio (NLR) after treatment for metastatic renal cell carcinoma (RCC) has been associated with improved oncologic outcomes. Paradoxically, for patients with localized RCC treated with upfront surgery the opposite effect has been reported. We thus aimed to evaluate NLR dynamics on localized RCC recurrence. MATERIALS AND METHODS: Treatment naïve patients with localized RCC managed surgically between 2005 and 2020 were included. Preoperative NLR was calculated within 6-weeks prior to surgery and postoperative NLR was calculated between 4 and twelve-weeks after surgery. Patients were followed for disease recurrence, noting metastatic sites and postoperative infections. Cox regression were used to determine whether the relative change in postoperative NLR was associated with metastasis-free survival (MFS) and cancer-specific survival (CSS), adjusted for preoperative NLR. RESULTS: In the cohort of 3310 patients, 996 (30%) had postoperative NLR available. These patients generally had more advanced disease, with 100 developing metastases and 38 dying from kidney cancer. Median MFS follow-up was 4.4 years. Decreasing 2-month postoperative NLR was associated with non-statistically significant worse MFS and CSS (HR 0.79, 95% 0.50, 1.24, P = .3; HR 0.83, 95% C.I. 0.40, 1.73; P = .6). On sensitivity analysis, across all NLR measurements, with NLR as a time-dependent covariate, results were similar, with a declining NLR associated with adverse MFS (HR 0.85, 95% CI 0.69, 1.30, P-value = .10), though not meeting conventional levels of significance. CONCLUSION: In higher-risk localized RCC patients, postoperative NLR is not suitable as a biomarker for predicting recurrences.

A Targetable Myeloid Inflammatory State Governs Disease Recurrence in Clear-Cell Renal Cell Carcinoma.

It is poorly understood how the tumor immune microenvironment influences disease recurrence in localized clear-cell renal cell carcinoma (ccRCC). Here we performed whole-transcriptomic profiling of 236 tumors from patients assigned to the placebo-only arm of a randomized, adjuvant clinical trial for high-risk localized ccRCC. Unbiased pathway analysis identified myeloid-derived IL6 as a key mediator. Furthermore, a novel myeloid gene signature strongly correlated with disease recurrence and overall survival on uni- and multivariate analyses and is linked to TP53 inactivation across multiple data sets. Strikingly, effector T-cell gene signatures, infiltration patterns, and exhaustion markers were not associated with disease recurrence. Targeting immunosuppressive myeloid inflammation with an adenosine A2A receptor antagonist in a novel, immunocompetent, Tp53-inactivated mouse model significantly reduced metastatic development. Our findings suggest that myeloid inflammation promotes disease recurrence in ccRCC and is targetable as well as provide a potential biomarker-based framework for the design of future immuno-oncology trials in ccRCC. SIGNIFICANCE: Improved understanding of factors that influence metastatic development in localized ccRCC is greatly needed to aid accurate prediction of disease recurrence, clinical decision-making, and future adjuvant clinical trial design. Our analysis implicates intratumoral myeloid inflammation as a key driver of metastasis in patients and a novel immunocompetent mouse model. This article is highlighted in the In This Issue feature, p. 2221.

Predictors of long-term renal function after kidney surgery for patients with preoperative chronic kidney disease.

INTRODUCTION: We evaluated the trajectory of estimated glomerular filtration rate (eGFR) after kidney surgery in patients with kidney cancer and chronic kidney disease (CKD). METHODS: We identified 1204 consecutive patients in our institutional database with preoperative CKD undergoing partial or radical nephrectomy from 1998-2016. Postoperative eGFR was tracked, with patients censored when receiving dialysis or kidney transplantation. A multivariable mixed-effects models assessed associations between preoperative baseline patient and tumor characteristics, and longitudinal eGFR. The Kaplan-Meier method and multivariable Cox regression were used to estimate overall survival, cancer-specific survival, and cumulative incidence of dialysis. RESULTS: Preoperatively, 892 (74.1%), 271 (22.5%), and 41 (3.4%) patients had CKD stage 3a, 3b, and 4/5, respectively. There were 55 patients dialyzed and 355 deaths (99 from kidney cancer). Median followup was 8.1 years, with 25 781 postoperative eGFR measurements. Factors associated with decreasing eGFR postoperatively included radical nephrectomy, male gender, older age, increased body mass index (BMI), and cardiovascular risk factors. We observed a significant interaction effect between time from surgery and preoperative CKD stage: the eGFR of stage 3a patients improved, while stage ≥3b declined (p<0.001). The two-year and five-year cumulative incidence of dialysis was 1.8% (1.1-2.6%) and 3.1% (2.2-4.2%), respectively. The cumulative incidence of dialysis, with death as a competing event, significantly differed by preoperative CKD stage. CONCLUSIONS: Preoperative CKD stage ≥3b is independently associated with a higher risk of declining renal function, dialysis, and mortality. With careful selection, patients with preoperative CKD withstand kidney surgery with low rates of dialysis.

Identifying Clear Cell Renal Cell Carcinoma Coexpression Networks Associated with Opioid Signaling and Survival.

While opioids constitute the major component of perioperative analgesic regimens for surgery in general, a variety of evidence points to an association between perioperative opioid exposure and longer term oncologic outcomes. The mechanistic details underlying these effects are not well understood. In this study, we focused on clear cell renal cell carcinoma (ccRCC) and utilized RNA sequencing and outcome data from both The Cancer Genome Atlas, as well as a local patient cohort to identify survival-associated gene coexpression networks. We then projected drug-induced transcriptional profiles from in vitro cancer cells to predict drug effects on these networks and recurrence-free, cancer-specific, and overall survival. The opioid receptor agonist, leu-enkephalin, was predicted to have antisurvival effects in ccRCC, primarily through Th2 immune- and NRF2-dependent macrophage networks. Conversely, the antagonist, naloxone, was predicted to have prosurvival effects, primarily through angiogenesis, fatty acid metabolism, and hemopoesis pathways. Eight coexpression networks associated with survival endpoints in ccRCC were identified, and master regulators of the transition from the normal to disease state were inferred, a number of which are linked to opioid pathways. These results are the first to suggest a mechanism for opioid effects on cancer outcomes through modulation of survival-associated coexpression networks. While we focus on ccRCC, this methodology may be employed to predict opioid effects on other cancer types and to personalize analgesic regimens in patients with cancer for optimal outcomes. SIGNIFICANCE: This study suggests a possible molecular mechanism for opioid effects on cancer outcomes generally, with implications for personalization of analgesic regimens.

The Clinicopathologic and Molecular Landscape of Clear Cell Papillary Renal Cell Carcinoma: Implications in Diagnosis and Management.

BACKGROUND: Clear cell papillary renal cell carcinoma (CCPRCC) is a recently described tumor entity. Several questions remain about its epidemiology, molecular features, and clinical behavior. OBJECTIVE: To comprehensively evaluate clinicopathologic and molecular features of CCPRCC, and compare it with more common kidney cancer subtypes. DESIGN, SETTING, AND PARTICIPANTS: We identified 89 CCPRCC patients and compared their clinicopathologic features with 1120 localized clear cell renal cell carcinoma (ccRCC) and 129 type 1 papillary renal cell carcinoma (pRCC) patients. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Nonparametric statistical testing was used to compare relevant features between tumor types. Overall, cancer-specific survival (CSS) and metastasis-free survival estimates were calculated from initial diagnosis using the Kaplan-Meier method. Patients with ipsilateral multifocal disease were explored further. A subset of CCPRCC tumors underwent genomic analysis and were compared with other RCC subtypes. RESULTS AND LIMITATIONS: A higher proportion of female (45% vs 32%) and African-American (19% vs 3%) patients were observed in the CCPRCC cohort than in the ccRCC and pRCC cohorts. CCPRCC tumors also had increased odds of presenting with additional ipsilateral masses (odds ratio [OR]: 4.41 [confidence interval {CI}: 2.34, 8.15], p < 0.001) and bilateral disease (OR: 4.80 [CI: 2.40, 9.59], p < 0.001) compared with ccRCC tumors. On molecular analysis, CCPRCC tumors showed fewer somatic aberrations and a greater degree of mitochondrial DNA depletion. In multifocal CCPRCC tumors, histologic concordance among the different renal cell carcinoma masses was estimated at 44% (7/16), and none of the individuals presenting exclusively with CCPRCC tumors developed metastatic disease after 5 yr. In contrast, multifocal tumors with CCPRCC and other nonconcordant histologies were more likely to experience adverse outcomes (CSS, log rank p = 0.034). CONCLUSIONS: CCPRCC is characterized by distinct molecular and epidemiologic features that could be used to refine current diagnostic approaches. Although their clinical course is generally indolent, multifocal CCPRCC tumors represent a unique diagnostic challenge. In this context, single-mass biopsies could miss concomitant aggressive disease, with a potential negative impact on patient outcomes. Furthermore, high discordance rates in multifocal CCPRCC tumors have important clinical implications in management. PATIENT SUMMARY: We explored the molecular and clinical features of clear cell papillary renal cell carcinoma (CCPRCC) relative to other kidney cancer subtypes. While CCPRCC generally conveys a good prognosis, additional caution should be taken when it is diagnosed using biopsy if multiple kidney masses are present.

Somatic mutations as preoperative predictors of metastases in patients with localized clear cell renal cell carcinoma - An exploratory analysis.

OBJECTIVE: Recurrent genomic alterations in clear cell renal cell carcinoma (ccRCC) have been associated with treatment outcomes; however, current preoperative predictive models do not include known genetic predictors. We aimed to explore the value of common somatic mutations in the preoperative prediction of metastatic disease among patients treated for localized ccRCC. MATERIALS AND METHODS: After obtaining institutional review board approval, data of 254 patients with localized ccRCC treated between 2005 and 2015 who underwent genetic sequencing was collected. The mutation status of VHL, PBRM1, SETD2, BAP1 and KDM5C were evaluated in the nephrectomy tumor specimen, which served as a proxy for biopsy mutation status. The Raj et al. preoperative nomogram was used to predict the 12-year metastatic free probability (MFP). The study outcome was MFP; the relationship between MFP and mutation status was evaluated with Cox-regression models adjusting for the preoperative nomogram variables (age, gender, incidental presentation, lymphadenopathy, necrosis, and size). RESULTS: The study cohort included 188 males (74%) and 66 females (26%) with a median age of 58 years. VHL mutations were present in 152/254 patients (60%), PBRM1 in 91/254 (36%), SETD2 in 32/254 (13%), BAP1 in 19/254 (8%), and KDM5C in 19/254 (8%). Median follow-up for survivors was 8.1 years. Estimated 12-year MFP was 70% (95% CI: 63%-75%). On univariable analysis SETD2 (HR: 3.30), BAP1 (HR: 2.44) and PBRM1 (HR: 1.78) were significantly associated with a higher risk of metastases. After adjusting for known preoperative predictors in the existing nomogram, SETD2 mutations remained associated with a higher rate of metastases after nephrectomy (HR: 2.09, 95% CI: 1.19-3.67, P = 0.011). CONCLUSION: In the current exploratory analysis, SETD2 mutations were significant predictors of MFP among patients treated for localized ccRCC. Our findings support future studies evaluating genetic alterations in preoperative renal biopsy samples as potential predictors of treatment outcome.

Prevalence and Landscape of Actionable Genomic Alterations in Renal Cell Carcinoma.

PURPOSE: We report our experience with next-generation sequencing to characterize the landscape of actionable genomic alterations in renal cell carcinoma (RCC). EXPERIMENTAL DESIGN: A query of our institutional clinical sequencing database (MSK-IMPACT) was performed that included tumor samples from 38,468 individuals across all cancer types. Somatic variations were annotated using a precision knowledge database (OncoKB) and the available clinical data stratified by level of evidence. Alterations associated with response to immune-checkpoint blockade (ICB) were analyzed separately; these included DNA mismatch repair (MMR) gene alterations, tumor mutational burden (TMB), and microsatellite instability (MSI). Data from The Cancer Genome Atlas (TCGA) consortium as well as public data from several clinical trials in metastatic RCC were used for validation purposes. Multiregional sequencing data from the TRAcking Cancer Evolution through Therapy (TRACERx) RENAL cohort were used to assess the clonality of somatic mutations. RESULTS: Of the 753 individuals with RCC identified in the MSK-IMPACT cohort, 115 showed evidence of targetable alterations, which represented a prevalence of 15.3% [95% confidence interval (CI), 12.7%-17.8%). When stratified by levels of evidence, the alterations identified corresponded to levels 2 (11.3%), 3A (5.2%), and 3B (83.5%). A low prevalence was recapitulated in the TCGA cohort at 9.1% (95% CI, 6.9%-11.2%). Copy-number variations predominated in papillary RCC tumors, largely due to amplifications in the MET gene. Notably, higher rates of actionability were found in individuals with metastatic disease (stage IV) compared with those with localized disease (OR, 2.50; 95% CI, 1.16-6.16; Fisher's P = 0.01). On the other hand, the prevalence of alterations associated with response to ICB therapy was found to be approximately 5% in both the MSK-IMPACT and TCGA cohorts and no associations with disease stage were identified (OR, 1.35; 95% CI, 0.46-5.40; P = 0.8). Finally, multiregional sequencing revealed that the vast majority of actionable mutations occurred later during tumor evolution and were only present subclonally in RCC tumors. CONCLUSIONS: RCC harbors a low prevalence of clinically actionable alterations compared with other tumors and the evidence supporting their clinical use is limited. These aberrations were found to be more common in advanced disease and seem to occur later during tumor evolution. Our study provides new insights on the role of targeted therapies for RCC and highlights the need for additional research to improve treatment selection using genomic profiling.

Putative Drivers of Aggressiveness in TCEB1-mutant Renal Cell Carcinoma: An Emerging Entity with Variable Clinical Course.

BACKGROUND: TCEB1-mutant renal cell carcinoma (RCC) is a rare variant of RCC with clear-cell features. Owing to its unique morphological and molecular features it has recently been proposed as a separate entity. Initial series suggested an indolent, early-stage phenotype. Here we expand our clinical cohort and describe a more detailed genomic analysis looking for potential drivers of aggressiveness. DESIGN, SETTING, AND PARTICIPANTS: We identified five new cases in our institutional sequencing cohort, four of whom were found to have high-stage disease (American Joint Committee on Cancer stage III/IV). Twelve previously reported cases were pooled for comparison purposes (Sato, The Cancer Genome Atlas, TRACERx Renal). OUTCOME MEASURES AND STATISTICAL ANALYSIS: We used our previously validated pipeline to analyze somatic mutations and copy number alterations (CNAs) in seven tumor samples with available data and estimated the number of cancer cells bearing each somatic mutation. The oncogenic potential of mutations was assessed using OncoKB and two other algorithms. Mann-Whitney U tests were used to evaluate differences in genomic markers between stage groups. RESULTS AND LIMITATIONS: All tumors showed biallelic inactivation of the TCEB1 gene according to a combination of somatic mutation and CNA analyses. Mutations were always found in residues involved in hydrophobic interactions with VHL. We found that high-stage tumors had additional oncogenic mutations (median 1, interquartile range [IQR] 1-1 vs 2, IQR 2-2; median difference 1, 95% confidence interval [CI] 1-1; p= 0.002) and showed whole-genome doubling events. They also seemed to have a higher burden of somatic CNAs (median fraction CNA genome 0.10, IQR 0.10-0.15 vs 0.63, IQR 0.58-0.68), however, this finding did not reach statistical significance (median difference 0.49, 95% CI 0.33-0.63; p=0.052). CONCLUSIONS: TCEB1-mutant RCC can show variable behavior ranging from very indolent to aggressive. Specific molecular events leading to high genomic instability seem to be associated with aggressiveness. This study expands the clinical spectrum of TCEB1-mutant RCC. PATIENT SUMMARY: We present four cases of aggressive TCEB1-mutant renal cell carcinoma, a rare type of kidney cancer. In-depth analysis of the genomes of these tumors revealed certain abnormalities that might explain this aggressive behavior.

The Role of Cytoreductive Nephrectomy for Sarcomatoid Renal Cell Carcinoma: A 29-Year Institutional Experience.

OBJECTIVE: To assess which patients respond best following cytoreductive nephrectomy for renal cell carcinoma (RCC) with sarcomatoid dedifferentiation (sRCC) and whether outcomes are improving over time. METHODS: We identified 562 patients with metastatic RCC treated between 1989 and 2018 with cytoreductive nephrectomy. We reviewed baseline clinical and pathologic characteristics, including the presence of sRCC, and metastatic sites at time of nephrectomy. The primary study endpoint was overall survival (OS). Univariate and multivariate Cox-regression analyses were used to identify significant predictors of OS. RESULTS: The study cohort had 192 sRCC patients, with a median age of 59 years. Frequently involved metastatic locations were lung (n = 115), retroperitoneal nodes (n = 63), and axial skeleton (n = 43). Lung metastasis were more prevalent in clear cell histology (P = .0017) whereas nodal involvement was associated with nonclear cell subtypes (P = .0064). Median follow-up was 14 months. Estimated 2- and 5-year OS were 34.1% and 14.8%, respectively. On multivariate analysis, metastases to the liver (HR = 1.64; 95% CI 1.02-2.63; P = .04), lung (HR = 1.50; 95% CI 1.05-2.14; P = .03), retroperitoneal nodes (HR = 1.52; 95% CI 1.03-2.25; P = 0.04) and nonclear cell histology (HR = 1.61; 95% CI 1.10-2.35; P = .01) were associated with worse OS in the sRCC cohort. CONCLUSION: OS after cytoreductive nephrectomy for sRCC and non-sRCC is improving over time. In patients with sRCC, presentations with unifocal metastasis not involving the liver or lung, clear cell histology and node negative disease have better outcomes following cytoreductive nephrectomy and may yield greater benefit from the procedure.

An evaluation of the role of tumor load in cytoreductive nephrectomy.

INTRODUCTION: New radiological tools can accurately provide preoperative three-dimensional spatial assessment of metastatic renal cell carcinoma (RCC). We aimed to determine whether the distribution, volume, shape, and fraction of RCC resected in a cytoreductive nephrectomy associates with survival. METHODS: We retrospectively reviewed 560 patients undergoing cytoreductive nephrectomy, performing a comprehensive volumetric analysis in eligible patients of all detectable primary and metastatic RCC prior to surgery. We used Cox regression analysis to determine the association between the volume, shape, fraction resected, and distribution of RCC and overall survival (OS). RESULTS: There were 62 patients eligible for volumetric analysis, with similar baseline characteristics to the entire cohort, and median survivor followup was 34 months. Larger primary tumors were less spherical, but not associated with different metastatic patterns. Increased primary tumor volume and tumor size, but not the fraction of tumor resected, were associated with inferior survival. The rank of tumors based on unidimensional size did not completely correspond to the rank by primary tumor volume, however, both measurements yielded similar concordance for predicted OS. Larger tumor volume was not associated with a longer postoperative time off treatment. CONCLUSIONS: Primary tumor volume was significant for predicting OS, while the fraction of disease resected did not appear to impact patient outcomes. Although rich in detail, our study is potentially limited by selection bias. Future temporal studies may help elucidate whether the primary tumor shape is associated with tumor growth kinetics.

Preoperative nomogram predicting 12-year probability of metastatic renal cancer - evaluation in a contemporary cohort.

OBJECTIVES: Preoperative models, based on patient and tumor characteristics, predict risk for adverse outcomes after nephrectomy. Changes in renal tumor characteristics over the last decades, warrant further evaluation using contemporary cohorts. We aimed to validate a previously published preoperative nomogram predicting 12-year metastasis-free probability after nephrectomy for localized renal tumors in a contemporary cohort. PATIENTS AND METHODS: After obtaining institutional review board approval, data of 1,760 patients who underwent nephrectomy for a localized renal mass between 2005 and 2011 were reviewed. Preoperative images were evaluated for the presence of tumor necrosis, lymphadenopathy, and tumor size. The study outcome was metastatic-free probability. Model discrimination was assessed with Gönen and Heller's concordance probability estimate, and calibration was evaluated. RESULTS: The cohort included 1,102 male and 658 female patients with a median age of 60 years. Most patients presented incidentally (84%). On imaging, 3% had evidence of lymphadenopathy, 55% had necrosis and median tumor diameter was 3.7 cm (interquartile range [IQR]: 2.5, 5.5). Median follow-up in non-metastatic patients was 7.7 years (IQR: 5.3, 9.7). Estimated 12-year metastatic-free probability was 88% (86%-90%). The model showed strong discrimination (concordance probability estimate [CPE]: 0.77), and fair calibration. The time-dependent receiver operating characteristic (ROC) curves showed strong discrimination at all-time points and the area under the curve (AUC) for year 12 was 0.83 (95% Confidence Interval: 0.78-0.89). CONCLUSIONS: We validated the preoperative nomogram of 12-year metastasis-free probability in a contemporary cohort despite different tumor characteristics. Future studies should evaluate the role of preoperative risk stratification in patient selection for neoadjuvant treatment.