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Background: Up to 15% of patients with locally advanced renal cell carcinoma (RCC) harbors tumor thrombus (TT). In those cases, radical nephrectomy (RN) and thrombectomy represents the standard of care. We assessed the impact of TT on long-term functional and oncological outcomes in a large contemporary cohort., Methods: Within a prospective maintained database, 1207 patients undergoing RN for non-metastatic RCC between 2000 and 2021 at a single tertiary centre were identified. Of these, 172 (14%) harbored TT. Multivariable logistic regression analyses evaluated the impact of TT on the risk of postoperative acute kidney injury (AKI). Multivariable Poisson regression analyses estimated the risk of long-term chronic kidney disease (CKD). Kaplan Meier plots estimated disease-free survival and cancer specific survival. Multivariable Cox regression models assessed the main predictors of clinical progression (CP) and cancer specific mortality (CSM)., Results: Patients with TT showed lower BMI (24 vs. 26 kg/m 2 ) and preoperative Hb (11 vs. 14 g/mL; all-p < 0.05). Clinical tumor size was higher in patients with TT (9.6 vs. 6.5 cm; p < 0.001). After adjusting for potential confounders, the presence of TT was significantly associated with a higher risk of postoperative AKI (OR 2.03, 95% CI 1.49-3.6; p < 0.001) and long-term CKD (OR: 1.32, 95% CI 1.10-1.58; p < 0.01). Notably, patients with TT showed worse long-term oncological outcomes and TT was a predictor for CP (2.02, CI 95% 1.49-2.73, p < 0.001) and CSM (HR 1.61, CI 95% 1.04-2.49, p < 0.03)., Conclusions: The presence of TT in RCC patients represents a key risk factor for worse perioperative, as well as long-term renal function. Specifically, patients with TT harbor a significant and early estimated glomerular filtration rate (eGFR) decrease. However, despite TT patients show a greater eGFR decline after surgery, they retain acceptable renal function, which remains stable over time., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Mucins are a family of high-molecular-weight glycoproteins. MUC1 is widely studied for its role in distinct types of cancers. In many human epithelial malignancies, MUC1 is frequently overexpressed, and its intracellular activities are crucial for cell biology. MUC1 overexpression can enhance cancer cell proliferation by modulating cell metabolism. When epithelial cells lose their tight connections, due to the loss of polarity, the mucins become dispersed on both sides of the epithelial membrane, leading to an abnormal mucin interactome with the membrane. Tumor-related MUC1 exhibits certain features, such as loss of apical localization and aberrant glycosylation that might cause the formation of tumor-related antigen epitopes. Renal cell carcinoma (RCC) accounts for approximately 3% of adult malignancies and it is the most common kidney cancer. The exact role of MUC1 in this tumor is unknown. Evidence suggests that it may play a role in several oncogenic pathways, including proliferation, metabolic reprogramming, chemoresistance, and angiogenesis. The purpose of this review is to explore the role of MUC1 and the meaning of its overexpression in epithelial tumors and in particular in RCC.

Context: The diagnostic accuracy of current imaging techniques in differentiating benign from malignant neoplasms in the case of indeterminate renal masses is still suboptimal., Objective: To evaluate the diagnostic accuracy of 99m Tc-sestamibi (SestaMIBI) single-photon emission tomography computed tomography (SPECT)/CT in characterizing indeterminate renal masses by differentiating renal oncocytoma and hybrid oncocytic/chromophobe tumor (HOCT) from (1) all other renal lesions and (2) all malignant renal lesions. Secondary outcomes were: (1) benign versus malignant; (2) renal oncocytoma and HOCT versus clear cell (ccRCC) and papillary (pRCC) renal cell carcinoma; and (3) renal oncocytoma and HOCT versus chromophobe renal cell carcinoma (chRCC)., Evidence Acquisition: A literature search was conducted up to November 2022 using the PubMed/MEDLINE, Embase, and Web of Science databases. Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines were followed to identify eligible studies. Studies included were prospective and retrospective cross-sectional studies in which SestaMIBI SPECT/CT findings were compared to histology after renal mass biopsy or surgery., Evidence Synthesis: Overall, eight studies involving 489 patients with 501 renal masses met our inclusion criteria. The sensitivity and specificity of SestaMIBI SPECT/CT for renal oncocytoma and HOCT versus all other renal lesions were 89% (95% confidence interval [CI] 70-97%) and 89% (95% CI 86-92%), respectively. Notably, for renal oncocytoma and HOCT versus ccRCC and pRCC, SestaMIBI SPECT/CT showed specificity of 98% (95% CI 91-100%) and similar sensitivity. Owing to the relatively high risk of bias and the presence of heterogeneity among the studies included, the level of evidence is still low., Conclusions: SestaMIBI SPECT/CT has good sensitivity and specificity in differentiating renal oncocytoma and HOCT from all other renal lesions, and in particular from those with more aggressive oncological behavior. Although these results are promising, further studies are needed to support the use of SestaMIBI SPECT/CT outside research trials., Patient Summary: A scan method called SestaMIBI SPECT/CT has promise for diagnosing whether kidney tumors are malignant or not. However, it should still be limited to research trials because the level of evidence from our review is low., (Copyright © 2023 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Introduction: A better definition of the prognostic significance of non-metastatic pT3a stage RCC subcategories is crucial to select the best candidate for adjuvant treatment. The aim of the study is to investigate the differential prognosis of extrarenal involvement in patients with non-metastatic pT3a RCC., Materialsand Methods: From a single institutional prospective database, 451 consecutive patients treated for pT3aN0/NxM0 RCC were selected and stratified according to pT3a subtypes (perirenal fat invasion, sinus fat invasion, segmental/renal vein thrombus, ≥ 2 features). Cancer specific survival (CSS), metastasis free survival (MFS) and relapse free survival (RFS) were primary endpoints of multivariable Cox regression models., Results: Overall, 67 (15%) patients presented with renal/segmental vein thrombus only, 185 (41%) with perirenal fat invasion, 101 (22%) with sinus fat invasion and 98 (22%) with ≥ 2 features. The presence of ≥ 2 pT3a features was associated with a higher risk of metastasis (HR=2.36; 95%CI 1.30-4.27; P value = .005), recurrence (HR=2.41; 95%CI 1.36-4.28; P value=.003) and cancer specific mortality (HR=3.54; 95%CI 1.45-8.63; P value = .005) compared to only 1 pT3a feature. Moreover, the presence of perirenal fat invasion was associated with lower CSS (HR=2.82; 95% CI 1.19-6.69; P value = .02) compared to sinus fat invasion or tumoral thrombus only., Conclusion: The concurrent presence of ≥ 2 pT3a features is associated to a higher risk of distant progression, relapse and cancer specific mortality, implying potential role for adjuvant therapy or a more stringent follow-up. Moreover, perirenal fat invasion is associated with worse CSS compared to other pT3a patterns taken alone., Competing Interests: Disclosure The authors have stated that they have no conflicts of interest., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: The role of lymph node dissection (LND) in patients with renal cell carcinoma (RCC) is still controversial. However, detecting lymph node invasion (LNI) is key due to prognostic implications and to identify patients who might benefit from adjuvant therapies such as adjuvant pembrolizumab., Materials and Methods: Out of 796 patients, 261 (33%) received eLND, of whom 62 (8%) for suspicious lymph node (LN) metastases at preoperative staging (cN1). eLND was divided in 3 anatomical areas: (1) hilar, (2) side-specific (pre-/para-aortic or pre-/para-caval) and (3) inter-aorto-caval nodes. Overall maximum LN diameter was measured by a dedicated radiologist for each patient. Multivariable logistic regression models (MVA) were tested for the effect of maximum LN diameter in predicting the presence of nodal metastases outside the anatomical area of cN1., Results: LNI was confirmed in 50% of cN1, whilst only 13 out of 199 cN0 patients were pN1 at final histology (6.5%; p < 0.001). In a per-patient analysis, of 62 cN1 patients, 24% vs. 18% vs. 8% harboured pN1 disease only inside vs. in-outside vs. only outside the suspicious anatomical field of cN1 at preoperative CT/MRI scan. At MVA, increasing diameter of suspicious LNs was independently associated with risk of finding positive LNs outside the suspicious anatomical field (OR 1.05, 95%CI 1.02-1.11; p = 0.02)., Conclusions: Roughly 50% of cN1 patients undergoing eLND will harbour LN metastases, also outside the suspicious radiological area, and maximum LNs diameter at preoperative imaging correlates with such risk. Thus, an eLND might be justified in patients with large suspicious LN metastases, to better stage this patient population and to improve postoperative treatment management., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Partial nephrectomy (PN) is a challenging procedure, which can be associated with severe complications. In consequence, the search for accurate and independent indicators of unfavorable surgical outcomes appears warranted. We aimed at evaluating the impact of frailty status on surgical, functional and oncologic outcomes in patients undergoing PN for renal cell carcinoma (RCC)., Methods: A retrospective, single-center study including 1,282 patients treated with PN for clinically localized cT 1 RCC was performed. The modified Frailty Index (mFI) was used to assess preoperative frailty. Multivariable logistic, Poisson and linear regression analyses(MVA) tested the effect of frailty on complications, acute kidney injury(AKI), renal function decline after PN. Cumulative incidence and competing-risk analyses investigated survival outcomes., Results: Of 1,282 patients, 220 (17%) were frail. Overall, 982 (76%) vs. 123 (9.6%) vs. 171 (13%) patients underwent open vs. laparoscopic vs. robot-assisted PN. Median follow-up was 66 (IQR: 35-107) months. At MVA, frailty status predicted increased risk of complications [Odds ratio (OR): 1.46, 95%CI 1.17-1.84; P < 0.001]. Moreover, frail patients were at higher risk of postoperative AKI (OR: 1.95, 95%CI 1.13-3.35; P = 0.01). In frail patients, renal function permanently decreased over time (P = 0.01) without any renal function plateau or improvement during the follow-up, which were instead observed in the nonfrail cohort. At competing-risks analyses, frailty status predicted higher risk of other-cause mortality [Hazard ratio (HR): 1.67, 95%CI 1.05-2.66; P = 0.02], but not of cancer-specific mortality (P = 0.3)., Conclusions: Frailty status predicts higher risk of adverse surgical outcomes after PN. Moreover, greater renal function decline was observed in frail patients, compared with nonfrail patients. Finally, the risk of OCM significantly overcomes the risk of dying due to RCC in frail patients., Competing Interests: Conflict of interest statement All authors declare no conflict of interest., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Purpose: The KEYNOTE-564 trial showed improved disease-free survival (DFS) for patients with high-risk renal cell carcinoma (RCC) receiving adjuvant pembrolizumab as compared to placebo. However, if systematically administered to all high-risk patients, it might lead to the overtreatment in a non-negligible proportion of patient. Therefore, we aimed to determine the optimal candidate for adjuvant pembrolizumab., Methods: Within a prospectively maintained database we selected patients who fulfilled the inclusion criteria of the KEYNOTE-564. We compared baseline characteristics and oncologic outcomes in this cohort with those of the placebo arm of the KEYNOTE-564. Regression tree analyses was used to generate a risk stratification tool to predict 1-year DFS after surgery., Results: In the off-trial setting, patients had worse tumor characteristics then in the KEYNOTE-564 placebo arm, i.e. there were more pT4 (5.4 vs. 2.7%, p = 0.046) and pN1 (15 vs. 6.3%, p < 0.001) cases. Median DFS was 29 (95% CI 21-35) months as compared to value not reached in KEYNOTE-564 and 1-year DFS was 64.2% (95% CI 59.6-69.2) as compared to 76.2% (95% CI 72.2-79.7), respectively. Patients with pN1 were at the highest risk of 1-year recurrence (1-year DFS 28.6% [95% CI 20.2-40.3]); patients without LNI, but necrosis were at intermediate risk (1-year DFS 62.5% [95% CI 56.9-68.8]); those without LNI and necrosis were at the lowest risk (1-year DFS 83.8% [95% CI 79.1-88.9]). LVI substratification furtherly improved the accuracy in the prediction of early recurrence., Conclusions: Patients potentially eligible for adjuvant pembrolizumab have worse characteristics and DFS in the off-trial setting as compared to the placebo arm of the KEYNOTE-564. Patients with either LNI or necrosis were at the highest risk of early-recurrence, which make them the ideal candidate to adjuvant pembrolizumab., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Introduction: The impact of open versus minimally invasive surgery on recurrence pattern in the management of localized renal cell carcinoma (RCC) remains uncertain. We thus aimed to determine the impact of surgical approach on survival and recurrence pattern., Material and Methods: This is a multi-institutional, matched cohort study on patients with pT1-3aN0M0 RCC from the RECUR database. After propensity score matching between open and minimally invasive surgery, disease-free (DFS) survival and risk of first recurrence according to recurrence site, namely local recurrence, abdominal/retroperitoneal, thoracic/mediastinal or uncommon site metastases were investigated with Cox regression analysis. Overall (OS) and Cancer Specific Survival (CSS) were also assessed., Results: After matching, 1,019 patients who underwent open and 1,019 who underwent minimally invasive surgery were included (of which 70 robot-assisted). At 5.2 years of median follow-up, 130 patients in open and 125 in minimally invasive group experienced disease progression. A higher risk of local recurrence (HR 2.06; 95% CI 1.18-3.58, P-value = 0.01) and uncommon site metastases (HR 1.09; 95% CI 1.01-1.16; P-value = .04) was found for minimally invasive surgery relative to open surgery, while no difference was found in terms of DFS (HR 0.83; 95% CI 0.64-1.06; P-value = .14). No differences were found in terms of OS and CSS. Main limitation is the retrospective nature of the study., Conclusions: The risk for local recurrence and uncommon site metastases was higher for minimally invasive surgery compared to open surgery, although no differences were found for OS, CSS, and DFS., Competing Interests: Conflict of interest None, (Copyright © 2022 Elsevier Inc. All rights reserved.)

Purpose: Metastatic ccRCC has peculiar tropism in the pancreas. We describe the characteristics and pathways of progression of patients with PM in a large multi-institutional consortium and compare them to patients with metastases from ccRCC at other sites., Methods: Detailed clinical and histopathological data were collected. To account for differences in baseline characteristics between the two groups, IPTW was used to compare the two groups in terms of PFS and OS., Results: Of the 182 patients, 33 (18%) had pancreatic, 94 (52%) pulmonary, 30 (16%) bone, 13 (7%) hepatic, and 12 (7%) brain metastases. Patients with PM had less aggressive ccRCC at baseline compared to those with progression at other sites in terms of tumour stage and grade. Median time from ccRCC surgery to PM was 8 (95%CI 5-10) vs. 1 year (95%CI 1-2) for progression to other sites (p < 0.001). Median IPTW-weighted time to second progression was 4.3 years (95%CI 2.4-not reached) for patients with PM vs 1.1 year (95%CI 0.8-2.3) for those with progression in other sites (p < 0.001). The most frequent second progression sites were pancreas (24%) and liver (15%) in patients with PM, while progression to the pancreas was rare (4%) in those with a different first progression site. Surgery alone (55%) or in combination with medical therapy (30%) was more frequent in the PM group than in other sites (p < 0.001). Median IPTW-OS time was longer for patients with PM [8.8 years (95%CI 6.5-not reached)] compared to those with first progression in other sites [2.8 years (95%CI 1.9-4.3), p < 0.001]., Conclusion: Pancreatic tropism is typical of ccRCC tumours with more indolent behaviour than those progressing to other sites. A long follow-up period is necessary to distinguish PM from ccRCC., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

The recent introduction of immunotherapy in the first line setting of advanced renal cell carcinoma (aRCC) has dramatically improved patients' prognosis. The aim of the current meta-analysis was to provide level 1a evidence supporting the use of pembrolizumab plus tyrosine kinase inhibitors (TKI) as first-line treatment for advanced RCC. All published randomized prospective trials including patients with advanced RCC treated with pembrolizumab in combination with TKIs vs Sunitinib were included in this meta-analysis. An algorithm was used to reconstruct survival data from the published Kaplan-Meier curves of overall survival (OS), progression free survival (PFS) and duration of response (DoR) from the included trials. Restricted mean survival time (RMST) with 95% confidence interval (CI) for comparison among the different regimens was calculated. Main outcomes were differences in RMST for OS, PFS and DoR for pembrolizumab plus TKIs vs sunitinib arm. Reconstructed survival data from 1,573 patients were retrieved from 2 trials (KEYNOTE-581 and KEYNOTE-426) comparing pembrolizumab plus TKI (lenvatinib or axitinib, respectively) to sunitinib. Patients who received pembrolizumab-lenvatinib or pembrolizumab-axinitinib had better OS (24-month ΔRMST of 1.79 months [95% CI: 0.12-2.50; P < 0.001]), PFS (24-month ΔRMST of 3.83 months [95% CI: 2.93-4.74; P < 0.001]) and DoR (24-month ΔRMST of 2.32 months [95% CI: 0.97-3.67; P < 0.001]) relative to sunitinib. Pembrolizumab-lenvatinib combination gave a marginal benefit in terms of OS, PFS and DoR relative to pembrolizumab-axitinib group. By relying on individual survival data, we provided a level-1a evidence supporting the use of pembrolizumab plus TKI for first-line aRCC treatment., (Copyright © 2022. Published by Elsevier Inc.)

Background: To date, multidisciplinary team (MDT) evaluation, enrollment in trials evaluating the role of perioperative therapies and deferred active treatments represent accepted strategies for patients with Renal Cell Carcinoma (RCC), which are under investigation to maximize cancer control and implement health care policies and value-based care. Here, we aimed to identify subgroups of patients with RCC who may benefit from early referral for MDT evaluation at diagnosis in light of an increased risk of recurrence relative to the risk of dying of other causes., Methods: We relied on a prospective dataset including patients diagnosed with RCC from 1998 to 2019 and treated by means of surgery alone at a tertiary referral center. The risk of other cause mortality (OCM) was evaluated against the risk of distant metastasis over time by means of the Weibull regression. Patients were stratified based on clinical stage (cT1a; cT1b; cT2; cT3-4), age (<60; 60-70; >70) and comorbidities [Charlson comorbidity index (CCI) 0 vs. ≥1]. For each combination of cT stage, age, and CCI, the potential need for an MDT referral was defined when the risk of recurrence exceeded the risk of OCM within the lower limit of the 95% CI of the meantime to recurrence., Main Findings: Overall, 1,162 (51%) patients had no comorbidities. Median follow-up was 7 years. Patients who would benefit most from an MDT evaluation are those diagnosed with A) cT3-4 disease (any age or comorbidity) or B) cT2 cancers if healthy and younger than 70 years or younger than 60 years with at least 1 comorbidity or C) cT1b if younger than 60 years and without comorbidities., Conclusions: Our findings can help selecting the optimal candidates for multidisciplinary evaluations and to consider RCC patients for clinical trials, deferred treatment, and treatment policy improvement. Also, our findings can be useful in the case of major healthcare disruptions, such as pandemics., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: Despite papillary renal cell carcinoma (pRCC) subtype represents the second most common histological renal tumor, controversial findings have been shown regarding its prognosis. Thus, we investigated the natural history of patients harbouring pRCC, focusing on its clinicopathological characteristics and long-term oncologic outcomes among pRCC subtypes., Materials and Methods: We identified 447 patients treated with either partial (PN) or radical nephrectomy (RN) for pRCC at a single tertiary centre, between 1994 and 2019. First, we explored differences in baseline and clinicopathological characteristics. Second, Kaplan-Meier plots investigated progression-free survival (PFS) and cancer-specific survival (CSS) differences among pRCC subtypes. Third, multivariable Cox-regression analyses (MVA) were used to assess predictors of clinical progression (CP) and cancer-specific mortality (CSM)., Results: Overall, 120 (27%) patients had symptoms at time of diagnosis. 263 (58.8%) vs. 184 (41.2%) patients underwent PN vs. RN. At histopathological evaluation, 243 (54.4%) harboured pRCC type I vs. 204 (45.6%) type II. pRCC type II more frequently showed higher tumor grade, tumor necrosis or lymphovascular invasion (all P<0.001). After a median follow-up of 51 months, 2.5% and 11% of patients had local relapse and CP, respectively. Kaplan-Meier plots revealed 93 vs. 83% 5-year PFS (P<0.001) and 96 vs. 89% 5-year CSS (P=0.01) for non-metastatic pRCC type I vs. II, respectively. At MVA, pRCC type II predicted higher risk of CP (Hazard ratio [HR]: 3.03, 95%CI 1.42-6.44; P=0.01), as well as of CSM (HR: 2.60, 95%CI 1.05-6.29; P=0.02), relative to pRCC type I., Conclusions: PRCC type II harbour more unfavorable tumor characteristics, such as higher tumor grade, more frequent tumor necrosis or lymphvascular invasion, which translates into worse long-term oncologic outcomes, compared with pRCC type I. Thus, patients harbouring pRCC type II may benefit from stricter follow-up, as well as earlier risk-based adjuvant therapies, based on potential worse oncologic outcomes in this patient population., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Objectives: European Urology Association guidelines suggest the use of integrated prognostic systems to assess oncologic outcomes after surgery in patients with localized renal cell carcinoma (RCC). We performed a head-to-head comparison among all the EAU guidelines recommended prognostic models in RCC., Methods: The study included 2,014 patients treated with surgery for clinically localized RCC. Patients were classified into prognostic risk groups, based on each of the five EAU guidelines recommended prognostic model definition, namely UISS, Leibovich 2003, VENUSS, GRANT, and Leibovich 2018 score. Prognostic accuracy of each prognostic model to predict clinical progression or cancer-specific mortality (CSM) was assessed, and ROC curves were calculated, according to histological subtype, namely clear-cell, papillary, and chromophobe RCC., Results: Of 2,014 patients, 1,575 (78%) harboured clear-cell, 312 (16%) papillary, and 127 (6%) chromophobe RCC. Median follow-up was 66 months [Interquartile range (IQR): 29-120]. In clear-cell RCC, low-risk patients rates ranged from 21% to 64%, according prognostic model. The same phenomenon was observed for papillary and chromophobe RCC. In clear-cell RCC, Leibovich 2018 resulted the most accurate model in predicting clinical progression (88.1%) and CSM (86.8%). Conversely, VENUSS or UISS prognostic models predicting oncologic outcomes represented the most accurate in papillary (88.7% and 84.8%) or chromophobe (87.8% and 89.1%) RCC, respectively., Conclusions: A non-negligible difference in terms of performance accuracy exists among the EAU guidelines recommended prognostic models. Thus, their adoption in RCC should be histology-specific and follow-up strategies based on prognostic risk class appear justified only if the appropriate model is used to stratify patients into prognostic risk groups., Competing Interests: Declaration of Competing interest All authors declare no conflict of interest., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Purpose of Review: While the molecular and genetic bases of Von Hippel-Lindau (VHL) disease have been extensively investigated, limited evidence is available to guide diagnosis, local or systemic therapy, and follow-up. The aim of the current review is to summarize the ongoing trials both in preclinical and clinical setting regarding VHL disease management., Recent Findings: Although genotype/phenotype correlations have been described, there is considerable inter and intra-familiar heterogeneity in VHL disease. Genetic anticipation has been reported in VHL disease. From a clinical point of view, expert-opinion-based protocols suggest testing those patients with any blood relative of an individual diagnosed with VHL disease, those with at least 1 or more suggestive neoplasms or patients presenting with clear cell renal cell carcinoma (ccRCC) diagnosed at a less than 40 years old, and/or multiple ccRCC. Clinical research is focused on safety and efficacy of systemic agents for patients with VHL-related ccRCC, with the aim to possibly preserve kidney function and improve patient survival., Summary: To date, preclinical and clinical research on the topic is scarce and clinical guidelines are not supported by strong validation studies., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

The indications for adjuvant vascular endothelial growth factor-tyrosine kinase inhibitor (VEGF-TKI) agents after curative intent nephrectomy for renal cell carcinoma are still a matter of debate. The ASSURE, PROTECT and ATLAS trials have failed to meet their primary end-points. Conversely, S-TRAC has shown a disease free survival (DFS) benefit. To date, meta-analyses have repeatedly proved the absence of a clinical benefit, in term of DFS and overall survival (OS). Nevertheless, the results of the SORCE trial have been recently released and might add valuable information. We pooled the results of all five reported trials testing for any potential DFS and OS benefits associated with VEGF-TKI use. Interestingly, for pooled DFS we found a marginal positive hazard ratio (HR) of 0.92 (95% confidence interval [CI] 0.85-1.00; P-value = 0.049) in favor of adjuvant VEGF-TKI agents. This benefit was more pronounced for DFS in the sub-groups of only high-risk patients (HR: 0.89, 95% CI 0.80-0.99; P-value = 0.026), but less pronounced in clear-cell only subgroup (HR 0.92, 95% CI: 0.85-1.00; P-value = 0.044). Overall survival benefit was instead not reached. However, pooled relative risk for high-grade (grade ≥3 according to CTCAE classification) adverse events was irremediably high, 2.56 (95% CI: 2.15-3.04; P-value < 0.001). Given the marginal benefit in terms of DFS and the drawback of high-grade adverse events, even after the SORCE trial publication, adjuvant VEGF-TKIs therapy cannot be considered in the whole group of patients with non-metastatic high-risk renal cell carcinoma after surgery., (Copyright © 2021. Published by Elsevier Inc.)

Purpose: The role of non-tumour renal biopsy in predicting renal function after surgery for renal cell carcinoma (RCC) is poorly investigated. The aim of the study was to assess the impact of renal parenchymal histology on renal function after radical nephrectomy in a cohort of patients with RCC., Methods: This cohort study included 171 patients with RCC submitted to radical nephrectomy between 2006 and 2018. Two biopsy samples from normal parenchyma were collected at nephrectomy and renal parenchyma damage (RPD) was scored on histologic samples according to validated methodology. The outcomes were eGFR after surgery and its reduction > 25% relative to baseline at maximum 12 months' follow-up. Linear and logistic multivariable regression were used, adjusting for age at surgery, presence of hypertension, diabetes, clinical tumour size, time from surgery and basal eGFR., Results: 171 patients were enrolled and RPD was demonstrated in 64 (37%). Patients with RPD had more comorbidities (CCI > 2 in 25 vs. 9%, p < 0.001), in particular hypertension (70 vs. 53%; p = 0.03), diabetes with (5% vs. 0%, p = 0.007) or without (31 vs. 18%; p = 0.007) organ damage, cerebrovascular disease (19 vs. 5%; p = 0.006) and nephropathy (20 vs. 3%; p = 0.0004). At multivariable analyses, RPD was associated with lower eGFR (Est. - 5.48; 95% CI - 9.27: - 1.7; p = 0.005) and with clinically significant reduction of eGFR after surgery (OR 3.06; 95% CI 1.17: 8.49; p = 0.026)., Conclusions: Presence of RPD in non-tumour renal tissue is an independent predictor of functional impairment in patients with RCC. Such preliminary finding supports the use of parenchyma biopsy during clinical decision making., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH, DE part of Springer Nature.)

Objective: The treatment landscape for renal cell carcinoma (RCC) is rapidly evolving. The aim of this review is to summarize the randomized-controlled trials evaluating the role of immunotherapy in neoadjuvant or adjuvant setting., Materials and Methods: We searched PubMed, Cochrane Central Register of Controlled Trials, and ClinicalTrials.gov for studies including neoadjuvant or adjuvant immunotherapy, and provided a brief overview of the pharmacodynamics of immunotherapy for RCC., Results: Several drugs are currently under investigation. In the neoadjuvant setting, four studies are evaluating the role of single-agent immunotherapy, one of dual-agent immunotherapy, and four studies the role of immunotherapy in combination with tyrosine kinase inhibitors or anti-interleukin-1 beta. In the adjuvant setting, two studies are evaluating the role of single-agent immunotherapy and two of dual-agent immunotherapy., Conclusions: The approval of immune checkpoint inhibition as a front-line therapeutic strategy for advanced RCC has also ultimately led to the investigation of these agents first in the adjuvant and then in the neoadjuvant setting. Currently, there are nine studies aimed to evaluate the role of immunotherapy in the neoadjuvant setting and four studies in the adjuvant setting.

The role of cytoreductive nephrectomy (CN) patients with metastatic renal cell carcinoma (mRCC) is unclear. To define the proportion of symptomatic mRCC, to investigate the impact of CN on symptomatic improvement and perioperative morbidity, and to elucidate the trade-off between such benefit and harm, an observational study of 317 mRCC patients treated with CN was performed. Symptomatic mRCC was defined as the presence of any sign or symptom causally related to the disease. Sign or symptom resolution and improvement were defined as the absence of all the signs and symptoms recorded at baseline, and the absence of at least one sign or symptom recorded at baseline, respectively. Perioperative morbidity was assessed using the Clavien-Dindo classification. Response to CN was classified as beneficial, mixed, or harmful according to the trade-off between symptomatic improvement and perioperative morbidity. The proportions of local, metastasis-specific, and general signs or symptoms were 37%, 23%, and 27%, respectively. The proportions of any sign or symptom resolution and improvement after CN were 43% and 71%, respectively. The proportions of local sign or symptom resolution and improvement after CN were 91% and 95%, respectively. The risks of any complication and major complication were 37% and 10%, respectively. At regression analysis, symptomatic status was not associated with perioperative morbidity. The proportion of beneficial response was invariably higher than the proportion of harmful response. At mRCC diagnosis, two out of three patients suffer from any sign or symptom, and one out of three suffers from local signs or symptoms. CN has a positive impact on symptomatic status. PATIENT SUMMARY: Most metastatic renal cell carcinoma patients are symptomatic, and they should be aware that cytoreductive nephrectomy has a positive impact on symptomatic status., (Copyright © 2020. Published by Elsevier B.V.)