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Background: Further stratification of the risk of recurrence of clear-cell renal cell carcinoma (ccRCC) with venous tumor thrombus (VTT) will facilitate selection of candidates for adjuvant therapy., Objective: To assess the impact of tumor grade discrepancy (GD) between the primary tumor (PT) and VTT in nonmetastatic ccRCC on disease-free survival (DFS), overall survival (OS), and cancer-specific survival (CSS)., Design, Setting, and Participants: This was a retrospective analysis of a multi-institutional nationwide data set for patients with pT3N0M0 ccRCC who underwent radical nephrectomy and thrombectomy., Outcomes Measurements and Statistical Analysis: Pathology slides were centrally reviewed. GD, a bidirectional variable (upgrading or downgrading), was numerically defined as the VTT grade minus the PT grade. Multivariable models were built to predict DFS, OS, and CSS., Results and Limitations: We analyzed data for 604 patients with median follow-up of 42 mo (excluding events). Tumor GD between VTT and PT was observed for 47% (285/604) of the patients and was an independent risk factor with incremental value in predicting the outcomes of interest (all p < 0.05). Incorporation of tumor GD significantly improved the performance of the ECOG-ACRIN 2805 (ASSURE) model. A GD-based model (PT grade, GD, pT stage, PT sarcomatoid features, fat invasion, and VTT consistency) had a c index of 0.72 for DFS. The hazard ratios were 8.0 for GD = +2 (p < 0.001), 1.9 for GD = +1 (p < 0.001), 0.57 for GD = -1 (p = 0.001), and 0.22 for GD = -2 (p = 0.003) versus GD = 0 as the reference. According to model-converted risk scores, DFS, OS, and CSS significantly differed between subgroups with low, intermediate, and high risk (all p < 0.001)., Conclusions: Routine reporting of VTT upgrading or downgrading in relation to the PT and use of our GD-based nomograms can facilitate more informed treatment decisions by tailoring strategies to an individual patient's risk of progression., Patient Summary: We developed a tool to improve patient counseling and guide decision-making on other therapies in addition to surgery for patients with the clear-cell type of kidney cancer and tumor invasion of a vein., (Copyright © 2023 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Background: The aging population and the incidence of renal cell carcinoma (RCC) are increasing worldwide. Over 25% of newly diagnosed LRM (localized renal masses) occur in patients over the eighth decade of life. The decision-making and treatment approach to LRM in this population represents a clinical dilemma due to inherited decreased functional reserve and competing mortality risks. Current literature reports conflicting evidence regarding age as a risk factor for worst surgical outcomes. As such, we aimed to evaluate the contemporary morbidity of elective surgery for LRM among elderly patients, focusing on intraoperative and postoperative complications., Methods: After Ethical Committee approval, we queried our prospectively maintained databases to identify patients with preoperative eGFR ≥60 ml/min/1.73 m [(David and Bloom, 2022) 22 and a normal contralateral kidney who underwent partial or radical nephrectomy (PN or RN) for a single cT1-T2N0M0 LRM between 1/2015-12/2021 at four high-volume European Academic Institutions. Patients were categorized by age groups: <50 yrs (young) vs. 50-75 (middle-aged) yrs vs.> 75 yrs (elderly). Postoperative complications were recorded according to Clavien-Dindo (CD) classification. The primary objectives were the proportion of patients experiencing intraoperative (IOC), any grade (AGC), and high-grade postoperative complications (HGC), defined as CD grade 3-5., Results: Overall, 2469/3076 (80.2%) patients met the inclusion criteria. Of these, 363 (14.7%) were young, 1682 (68.1%) were middle-aged, and 424 (17.2%) were elderly. Compared to middle-aged and young patients, elderly patients had a higher median Charlson Comorbidity Index (6 vs. 4 vs. 0, p < 0.01) and a higher proportion of cT1 renal mass (87.6% vs. 93.0% vs. 93.6%, p < 0.01). No differences among the study groups were found regarding surgical approach (open vs. minimally-invasive) and type of surgery (PN vs. RN). We found that older patients experienced similar IOC (4.5% vs. 4.2% vs. 3.3%, p = 0.7) and AGC (23.1% vs. 20.0% vs. 21.5%, p = 0.4) compared to middle-aged and young patients, respectively. Similarly, there were no significant differences in HGC between the study cohorts (0.7% vs. 1.4% vs. 1.7%, p = 0.8). At multivariable analysis, open approach and PN significantly predicted the occurrence of AGCs, while only the open surgical approach was associated with the occurrence of HGCs., Conclusion: In kidney cancer tertiary referral centers, the risk of IOC and postoperative HGC after PN or RN for localized renal masses (LRM) is low, despite a non-negligible risk of AGC, especially in elderly patients. Further efforts should focus on identifying multidisciplinary strategies to select patients most likely to benefit from surgery among elderly candidates with LRMs and decrease the morbidity of surgery in this specific setting., Competing Interests: Declaration of competing interest None., (© 2023 Elsevier Ltd, BASO ∼ The Association for Cancer Surgery, and the European Society of Surgical Oncology. All rights reserved.)

Background: Lymph node (LN) metastases are associated with poor outcomes for patients with renal cell carcinoma (RCC). This study compared the survival outcomes of patients with stage III, node-positive disease (pT 123 N 1 M 0 ) and patients with stage III, node-negative disease (pT 3 N 0 M 0 )., Methods: A database of 4652 patients with RCC of any histological subtype treated with surgery at The University of Texas MD Anderson Cancer Center from 1993 to 2012 was retrospectively assessed. A total of 115 patients with pT 123 N 1 M 0 disease, 274 patients with pT 3 N 0 M 0 disease, and 523 patients with pT 123 N 0/x M 1 disease were included. Overall survival (OS) and cancer-specific survival (CSS) were estimated and compared between each cohort., Results: Median OS and CSS times were significantly better for pT 3 N 0 M 0 patients than pT 123 N 1 M 0 patients (OS, 10.2 vs 2.4 years, P < .0001; CSS, not reached vs 2.8 years, P < .0001). Similar median OS and CSS times were noted for pT 123 N 1 M 0 and pT 123 N 0/x M 1 patients (OS, 2.4 vs 2.4 years; P = .62; CSS, 2.8 vs 2.4 years; P = .10). In a multivariate analysis, tumor grade (hazard ratio [HR] for OS, 2.47; P < .0001; HR for CSS, 2.99; P < .0001) and pathologic LN involvement (HR for OS, 2.44; P < .0001; HR for CSS, 2.85; P < .0001) were associated with worse OS and CSS., Conclusions: Among RCC patients classified with stage III disease, those with pT 123 N 1 M 0 disease had significantly worse survival than those with pT 3 N 0 M 0 disease. OS and CSS were similar for patients with pT 123 N 1 M 0 disease and patients with pT 123 N 0/x M 1 disease (stage IV). If validated, these findings suggest that RCC patients with nodal disease should be reclassified as having stage IV disease., (© 2018 American Cancer Society.)

Objective: To characterize the presence of bland (nontumor) thrombus in advanced renal cell carcinoma and assess the impact of this finding on cancer-specific survival., Methods: A multi-institutional database of patients treated with nephrectomy with caval thrombectomy for locally-advanced renal tumors was assembled from 5 tertiary care medical centers. Using clinicopathologic variables including patient age, body mass index, Eastern Cooperative Oncology Group performance status, tumor stage, grade, nodal status and histology, and nearest-neighbor and multiple-matching propensity score matched cohorts of bland thrombus vs nonbland thrombus patients were assessed. Multivariable analysis for predictors of cancer-specific survival was performed., Results: From an initial cohort of 579 patients, 446 met inclusion criteria (174 with bland thrombus, 272 without). At baseline, patients with bland thrombus had significantly worse performance status, higher tumor stage, higher prevalence of regional nodal metastases and higher nuclear grade (P < .01 for all). In both nearest-neighbor and multiple-matching propensity score matched cohorts, the presence of bland thrombus presence was associated with inferior median cancer-specific survival (28.1 months vs 156.8 months, and 28.1 months vs 76.7 months, P < .001 for both). The presence of bland thrombus remained independently associated with an increased risk of cancer-specific mortality on multivariable analysis (hazard ratio 4.33, 95% confidence interval 2.79-6.73, P < .001)., Conclusion: Presence of bland thrombus is associated with adverse survival outcomes in patients treated surgically for renal tumors with venous tumor thrombus. These findings may have important implications in patient counseling, selection for surgery and inclusion in clinical trials., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Objective: To examine the effect that neoadjuvant axitinib for the treatment of localized renal cell carcinoma has on body compartment composition., Materials and Methods: The study was based on a single-institution, single-arm clinical trial that enrolled 24 patients with locally advanced non-metastatic biopsy-proven clear cell renal cell carcinoma. Patients received axitinib orally for up to 12 weeks. Computed tomography scans were completed before the start of treatment, after 7 weeks of treatment and at the completion of 12 weeks of treatment. Patients underwent nephrectomy after axitinib treatment. The primary outcome of the current study was change in body compartment composition. Secondary outcomes included development of new-onset sarcopenia and changes in body weight., Results: A total of 23 patients had a complete set of imaging for evaluation, of which 19 (82.6%) lost weight. Median weight loss was 4.5 kg (P <.001). Seven patients (30.4%) had sarcopenia before treatment, with an additional 5 (21.7%) developing sarcopenia during treatment. Median decrease in skeletal muscle was 2.9 cm 2 /m 2 (P <.001), visceral adipose tissue was 4.9 cm 2 /m 2 (P = .132), and subcutaneous adipose tissue was 1.0 cm 2 /m 2 (P = .043). Ten of the 16 patients (62.5%) without baseline sarcopenia achieved a partial response, whereas only 1 of the 7 patients (14.3%) with baseline pretreatment sarcopenia achieved a partial response (P = .069)., Conclusion: Neoadjuvant axitinib resulted in a decrease in skeletal muscle and subcutaneous adipose tissue, as well as weight loss. Patients with baseline sarcopenia tended to have a lower response rate to neoadjuvant axitinib., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Purpose: Careful selection is critical to identify those with metastatic renal cell carcinoma who are most likely to benefit from cytoreductive nephrectomy. Surgery in patients who have metastatic renal cell carcinoma with tumor thrombus is complex and may not benefit some patients with poor overall survival. We evaluated whether preoperative variables or risk stratification systems could predict overall survival following cytoreductive nephrectomy., Materials and Methods: Prognostic factors for overall survival after surgery were evaluated in patients who had metastatic renal cell carcinoma with venous tumor thrombus at 5 institutions from 2000 to 2014. Prognostic variables, including metastatic renal cell carcinoma risk models, were evaluated for associations with overall survival. Multivariable analysis was used to determine independent associations of preoperative variables with overall survival., Results: A total of 427 patients with metastatic renal cell carcinoma were identified with tumor thrombus. Patients with inferior vena cava thrombus above the diaphragm had shorter median overall survival vs those with renal vein only thrombus (9.2 months, IQR 4.2-30.8, vs 21.7, IQR 7.7-42.8, p = 0.0165). Individual risk factors from prognostic models were evaluated among other preoperative characteristics for associations with overall survival in 122 patients (32%) who died within 270 days of surgery. Independent predictors of overall survival included lactate dehydrogenase greater than the upper limit of normal (p = 0.003), systemic symptoms (p = 0.003), inferior vena cava thrombus above the diaphragm (p = 0.02) and sarcomatoid features (p = 0.005)., Conclusions: Poor overall survival following cytoreductive nephrectomy in patients with metastatic renal cell carcinoma with tumor thrombus is associated with inferior vena cava thrombus above the diaphragm, poor risk group, systemic symptoms or sarcomatoid dedifferentiation. Patients with expected poor overall survival should be considered for preoperative systemic therapy clinical trials., (Copyright © 2017 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.)

Purpose: Management of metastatic renal cell carcinoma with sarcomatoid dedifferentiation remains a therapeutic challenge with no standard treatment strategies. We evaluated whether metastasectomy has any survival benefit in patients with metastatic sarcomatoid dedifferentiation treated with radical nephrectomy., Materials and Methods: From an institutional database of 273 patients with sarcomatoid dedifferentiation treated with nephrectomy we matched 80 with synchronous and asynchronous metastases for age, ECOG (Eastern Cooperative Oncology Group) performance status, histology and lymph node status. Matched pairs were then retained only if patients who did not undergo metastasectomy were alive at metastasectomy comparable to matched surgical patients to decrease the bias of survival outcomes. Overall survival from nephrectomy was studied using univariable and multivariable proportional hazards regression., Results: Median overall survival was 8.3 (95% CI 6.5-10.5) and 18.5 months (95% CI 11.5-42.9) in patients with synchronous and asynchronous metastases, respectively. Overall survival in patients who underwent metastasectomy for synchronous metastasis compared to nonsurgical patients was 8.4 and 8.0 months (p = 0.35), respectively. Similarly, overall survival in patients with asynchronous metastases treated with metastasectomy compared to the nonsurgical group was 36.2 and 13.7 months, respectively (p = 0.29). On multivariable analysis positive lymph nodes at nephrectomy were associated with an increased risk of death in the synchronous and asynchronous patient subgroups (HR 2.1, 95% CI 1.1-4.0, p = 0.03 and HR 3.3, 95% CI 1.2-9.2, p = 0.02, respectively)., Conclusions: In the current study there was no clear evidence of benefit in patients with sarcomatoid dedifferentiation who underwent metastasectomy after nephrectomy. Particularly, the group of patients with pathological lymph node positive disease at nephrectomy had considerably worse survival., Competing Interests: Jose A. Karam has served as a one-time consultant to Pfizer in 2013. Christopher G. Wood has received research funding from Pfizer and served as a consultant and on its advisory board. None of these are relevant to the current manuscript., (Copyright © 2016 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.)

Objective: To study the natural history, prognosticators, and outcomes in patients with renal cell carcinoma (RCC) with extension of tumor beyond Gerota׳s fascia or invading contiguously into the adrenal gland (pT4) or both., Patients and Methods: From 1992 to 2012, we identified 61 patients who underwent radical nephrectomy and were found to have pT4 disease. Clinicopathologic variables were queried using univariate analysis to identify relevant prognostic variables. Cox proportional hazards model was used for multivariate analysis of predictors of cancer-specific survival. Survival plots were estimated using Kaplan-Meier method and survival analysis using log-rank test., Results: Median age was 56 years (interquartile range: 49-64) and 49 (81.7%) patients had Eastern Cooperative Oncology Group Performance Status 0 or 1. At diagnosis, 22 (36.1%) patients showed nonmetastatic and 39 (63.9%) patients showed metastatic RCC. Overall, 49 (80.3%) patients had clear cell RCC, 24 (39.3%) patients had sarcomatoid features, and 39 (69.6%) patients had Fuhrman grade 3 to 4. There were 26 (42.6%) patients with pN0, 16 (26.2%) patients with pN1, and 19 (31.1%) patients with pNx. Median cancer-specific survival was 37 months for patients with nonmetastatic and 8 months for patients with metastatic RCC. On multivariate analysis, preoperative lactate dehydrogenase and alkaline phosphatase, M stage, pN stage, and sarcomatoid dedifferentiation were significantly associated with survival., Conclusions: Survival in patients with pT4 remains poor. The pT4 disease is associated with a locally and regionally invasive biology that requires specific attention and warrants careful study. Understanding the drivers of this unique phenotype would generate therapeutic interventions that can change the behavior of these uniquely aggressive tumors., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Background: Indeterminate pulmonary nodules (IPN) are of uncertain significance in patients with renal cell carcinoma., Objective: We sought to determine predictors of IPN progression to pulmonary metastasis and develop a tool for individualized risk stratification of patients who present with IPN on preoperative chest imaging in the setting of localized or locally advanced renal cell carcinoma., Design, Setting, and Participants: We reviewed all patients who had radical nephrectomy with no evidence of distant metastases at a single institution from 2005-2009 who had ≥1 IPN on chest computed tomography that measured <2 cm. All chest computed tomographies were rereviewed by a radiologist who was blinded to outcomes, to independently determine number, size, and location of nodules., Outcome Measurements and Statistical Analysis: The primary objective of the study was to develop a prognostic model to predict pulmonary metastases among radical nephrectomy patients who present with IPN based on readily available preoperative imaging and postoperative pathological criteria. Univariable and multivariable Cox regression models were used to assess the predictive factors for development of pulmonary metastasis. We developed a nomogram that predicted the 3-yr and 5-yr lung metastasis-free survival (LMFS), with assessment of discrimination and internal validation., Results and Limitations: Among 251 patients with IPN who underwent nephrectomy, 72 (29%) developed pulmonary metastases. Median follow-up for the cohort was 36.6 mo. Three-yr and 5-yr probability of LMFS for the overall cohort was 71% (95% confidence interval 65-77%) and 65% (95% confidence interval 57-72%), respectively. The nomogram developed included number and size of IPN along with postoperative pathological variables, and showed calibration with a concordance index (c-index) of 0.81 and a bootstrap corrected c-index of 0.78. Limitations include retrospective study with no external validation., Conclusions: We developed a nomogram to predict the individualized risk LMFS for patients who underwent nephrectomy for localized or locally advanced renal cell carcinoma., Patient Summary: We reviewed outcomes among kidney cancer patients who presented with small lung nodules and developed a clinical tool to predict risk of developing lung metastases., (Copyright © 2015 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Among patients with renal cell carcinoma (RCC), 25-30% present with metastatic disease at the time of initial diagnosis. Despite the ever-increasing array of treatment options available for these patients, surgery remains one of the cornerstones of therapy. Proper patient selection for cytoreductive surgery is paramount to its effective use in the management of patients with metastatic RCC despite the decrease in reported morbidity rates. We explore the evolving role cytoreductive surgery in metastatic RCC spanning the immunotherapy era to the targeted therapy era. Despite significant advances in the management of patients with metastatic RCC, further evidence on the definitive role of cytoreductive surgery in the targeted therapy era is awaited through large randomized trials., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Objective: Renal cell carcinoma with sarcomatoid dedifferentiation (sRCC) is associated with higher stage of presentation and worse survival. The objective of this study was to examine the clinicopathologic characteristics associated with overall survival (OS), specifically examining the percentage of sarcomatoid component (PSC)., Methods: We reviewed clinicopathologic data for all nephrectomized patients with confirmed sRCC. Histologic slides were rereviewed by dedicated genitourinary pathologists to ascertain PSC. Patient characteristics were tabulated overall and by disease stage. Cutpoints in the PSC providing a meaningful difference in OS were identified by recursive partitioning analysis (RPA). Factors selected included age group, gender, race, clinical stage, tumor histology, presurgical systemic therapy, lymphovascular invasion, and tumor size. The Kaplan-Meier method and log-rank test were used to assess differences in OS., Results: Among 186 patients with sRCC, 64 (34%) had localized, and 122 (66%) had metastatic disease at presentation. Patients had primarily clear cell histology (73%). Median follow-up was 12.1 months (range: 0.1-242.2mo). Median OS was 12.6 months (95% CI: 10.7-14.9mo). Univariate RPA identified a PSC cutpoint of 10% as prognostically significant. Patients with PSC>10% were at higher risk of death when compared with patients with PSC≤10% (45% vs. 61% 1-y OS; P = 0.04). Multivariate RPA revealed that tumor size, presence of metastatic disease, and PSC were significantly associated with OS. Among 4 identified groups, patients with localized disease and tumor size≤10cm were most likely to be alive at 1 year (89%), and patients with metastatic disease and PSC>40% were least likely to be alive at 1 year (28%; P<0.001)., Conclusion: PSC appears to be a prognostic factor in patients with sRCC, with larger percentage of involvement portending a worse survival, especially in patients with metastatic disease., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Purpose of Review: Management of patients with metastatic renal cell carcinoma is challenging and continues to be delivered in a multidisciplinary context. Even with the advent of systemic targeted therapy, complete remission with these new agents is rare using systemic therapy alone. Surgical resection of the primary tumor and metastatic deposits continues to play an important role in managing patients with metastatic renal cell carcinoma when aiming for complete remissions. To date, despite the lack of level 1 evidence, metastasectomy appears to prolong survival and achieve long-term cure in carefully selected patients. This review examines current evidence for the role of metastasectomy in renal cell carcinoma., Recent Findings: Studies continue to consistently support a benefit of complete metastasectomy for overall and cancer-specific survival at most sites for resection, with the exception of brain and bone, which tend to perform for symptomatic relief and palliation. Metastasectomy has not yet been examined in a randomized setting. The debate of survival benefit because of selection bias of patients or differences in tumor biology is relevant and has yet to be resolved in the literature. Clearly, careful patient selection remains paramount in optimizing survival benefit from metastasectomy., Summary: Patients with isolated surgically resectable metastatic disease, with long disease-free intervals, and with good performance status are likely to benefit the most from metastasectomy.

Purpose: Isolated local retroperitoneal recurrence after radical nephrectomy for renal cell carcinoma poses a therapeutic challenge. We investigated outcomes in patients with localized retroperitoneal recurrence treated with surgical resection., Materials and Methods: This was a retrospective, single institutional study of 102 patients with retroperitoneal recurrence treated with surgery from 1990 to 2014. Demographics, clinical and pathological features, location of retroperitoneal recurrence and perioperative complications are reported using descriptive statistics. We studied recurrence-free and cancer specific survival using univariate and multivariate analyses., Results: Median age at retroperitoneal recurrence diagnosis was 55 years (IQR 49-64). Cancer was pT3-4 in 62 patients (60.8%) and pN1 in 20 (19.6%). No patients had distant metastatic disease at retroperitoneal recurrence surgery. Median time from nephrectomy to retroperitoneal recurrence diagnosis was 19 months (IQR 5-38.8). The median size of the resected retroperitoneal recurrence was 4.5 cm (IQR 2.7-7). Median followup after recurrence surgery was 32 months (IQR 16-57). Metastatic progression was observed in 60 patients (58.8%) postoperatively. Neoadjuvant and salvage systemic therapy was administered in 46 (45.1%) and 48 patients (47.1%), respectively. On multivariate analysis pathological nodal stage at original nephrectomy and maximum diameter of retroperitoneal recurrence were identified as independent risk factors for cancer specific death., Conclusions: Clinicopathological factors at nephrectomy as well as retroperitoneal recurrence surgery are important prognosticators. Aggressive surgical resection offers potential cure in a substantial number of patients with retroperitoneal recurrence with acceptable complications and still has a dominant role in the management of isolated locally recurrent RCC., (Copyright © 2015 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.)