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Over the past decade, the management of metastatic renal cell carcinoma (RCC) has undergone rapid evolution, culminating in a significant improvement in prognosis with frontline immunotherapy. RCC is a highly immunogenic and pro-angiogenic cancer, and mounting evidence has established the immunosuppressive effects of pro-angiogenic factors on the host's immune system. Anti-angiogenic agents such as tyrosine kinase inhibitors (TKIs) and bevacizumab, which obstruct the vascular endothelial growth factor pathway, have demonstrated the potential to enhance antitumor activity and improve the efficacy of immune checkpoint inhibitors (ICIs). Consequently, various combinations of TKIs and ICIs have been assessed and are currently considered the preferred regimens for all metastatic RCC patients, regardless of their prognostic risk score. Nevertheless, some inquiries have arisen within the medical community, as metastatic RCC patients with favorable risk scores who received ICIs and TKIs in combination showed no statistically significant advantage in overall survival compared to those treated with sunitinib alone. Considering these concerns, this review aims to elucidate the rationale behind TKI and ICI combination therapies, provide a summary of current first-line metastatic RCC combinations approved for use, with a focus on favorable-risk patients, and outline present challenges and future perspectives in this context., Competing Interests: Declaration of Competing Interest The authors declare that there are no conflicts of interest., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Renal cell carcinoma (RCC) is the third most common genitourinary cancer accounting for approximately 180,000 deaths worldwide in 2020. Although over two-thirds of patients initially present localized disease, up to 50% of them may progress to metastatic disease. Adjuvant therapy aims to reduce the recurrence risk and improve outcomes in several types of cancers but is currently an unmet need in RCC. The results achieved with tyrosine kinase inhibitors in metastatic RCC led to the evaluation of these target therapies in an early setting with conflicting results for disease-free survival and no overall survival (OS) benefit. Likewise, the results of immune checkpoint inhibitors (ICIs) in an adjuvant setting are conflicting. Available data did not show an improvement in OS with ICIs in the early phase, although a positive trend for pembrolizumab has been recorded, receiving the Food and Drug Administration's approval in this setting. However, the disappointing results of several ICIs and the heterogeneous pattern of RCC warrant biomarker identification and subgroup analyses to evaluate which patients could benefit from adjuvant therapy. In this review, we will discuss the rationale for adjuvant treatment in RCC, summarizing the results of the most important adjuvant therapy trials and current applications, to outline possible future directions., Competing Interests: The authors declare no conflict of interest with respect to the research, authorship, and/or publication of this article.

Background: To investigate the perioperative and morbidity outcomes after partial nephrectomy (PN) in patients with short life expectancy (SLE) (≥95% 10-year expected mortality (10y-EM)), to assess the main predictors of outcomes in this population and to compare these results with those of a group at the opposite upper range with long LE (LLE, ≤5% 10y-EM) relying on a multicenter Italian prospective registry of kidney surgery (the RECORD 2 project)., Methods: Clinical data of 4,325 patients undergone kidney surgery were collected at 26 urological Italian Centers from 2013 to 2016. SLE was defined as a ≥95% 10y-EM (assessed using the age-adjusted Charlson comorbidity index [CCI]). A multivariable logistic regression for overall postoperative complications, acute kidney injury (AKI), positive surgical margins (SM) and ∆ estimated glomerular filtration rate (eGFR) ≥25% at 2 years from surgery was performed in patients with SLE including clinically relevant variables. Adjusted outcomes reported as mean (SD) of the 2 groups were generated using separate multivariable logistic regression models and compared., Results: Overall, 559 patients with SLE were selected. Patients had an ASA score ≥3 in 58.4% of cases. A clinical T1a, T1b, and T2 stage was found in 412 (74.5%), 124 (22.4%), and 17 (3.1%) patients. The median PADUA score was 7 (6-8). Surgical and medical postoperative complication rates were registered in 14.8% and 6% cases. Postoperative AKI was reported in 27.3% cases, positive surgical margins (PSM) in 9.3% cases. In this subgroup of patients, ASA score, cerebrovascular disease, surgery in low volume centers, and open surgery were independent predictors of overall complications. ASA and PADUA scores, renal clamping, resection technique and lower eGFR at baseline were independent predictors of AKI. PADUA score, open approach and resection technique were independent predictors of PSM. Cardiovascular disease, hilar clamping, and resection technique were independent predictors of eGFR decrease >25% at 2 years from surgery. Patients with SLE were compared with those with LLE (n = 302). All analyzed parameters at baseline were significantly different among the groups with the exception of cancer laterality. After adjusting for several clinical variables, the SLE group had a significantly higher risk rate of adjusted overall postoperative complication rate compared to the LLE group (20.6% ± 0.36 vs. 9.9% ± 0.65, P < 0.0001), while the overall intraoperative complications (4.1% ±0.13 vs. 2.3% ± 0.23), overall postoperative major complications (3.8% ± 0.09 vs. 1.9% ± 0.14) adjusted AKI (24.2% ± 0.37 vs. 22.6% ± 0.92), positive surgical margins (8% ± 0.22 vs. 6.4% ± 0.49), and 2-year RF loss (13.4% ± 0.17 vs. 12.4% ± 0.74)., Conclusion: In selected patients with SLE, PN is feasible with an acceptable safety profile that is overall comparable to patients with no LE limitations. While a robotic approach and surgery performed in high volume centers could reduce the risk of complications, an off-clamp approach and a SE surgical technique may decrease the risk of postoperative AKI and of longer term eGFR decrease., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Purpose: to evaluate clinical predictors of positive surgical margins (PSMs) in a large multicenter prospective observational study and to develop a clinic nomogram to predict the likelihood of PSMs after partial nephrectomy (PN)., Materials and Methods: We prospectively evaluated 4308 patients who had surgical treatment for renal tumors between January 2013 and December 2016 at 26 urological Italian Centers (RECORd 2 project). Two multivariable logistic models were evaluated to predict the likelihood of PSMs. Center caseload was dichotomized using a visual assessment adjusted for several predictors of PSMs. A nomogram predicting PSMs was developed., Results: Overall, 2076 patients treated with PN were evaluated. pT1a, pT1b, pT2 and pT3a were recorded in 68.7%, 22.6%, 2.1% and 6.6% of the patients, respectively. PSMs were recorded in 342 (16.5%) patients. From a null multivariable model against number of PN/year, 60 PN/year were identified as the best cut-off to define a high-volume centre. At multivariable analysis, clinical stage (cT1a vs. cT2 [OR 1.94]; p = 0.03), volume centre (≤60 PN/year) (OR 2.22; p < 0.0001), imperative vs elective indication (OR 2.10; p = 0.04), surgical technique (laparoscopic vs. open [OR 1.62; p = 0.002), lymphovascular invasion (OR 2.27; p = 0.01) and upstaging to pT3a (OR 2.81; p < 0.0001) were independent predictors of PSMs. The final nomogram included age, ASA score, Charlson score, clinical tumor stage, surgical indication, surgical approach, surgical technique, PADUA score, clamp procedure and volume centre., Conclusions: PSMs after PN were significantly more likely in patients with lower clinical stage, higher PADUA score, in individuals referred to laparoscopic PN and in those treated at lower volume centers. We used these data to develop a nomogram to predict such risk., (Copyright © 2020 Elsevier Ltd, BASO ~ The Association for Cancer Surgery, and the European Society of Surgical Oncology. All rights reserved.)

Patients diagnosed with non-clear renal cell carcinoma have often been excluded from clinical trials due to the shortage of treatments available, the low incidence of tumours with non-clear histology, and the corresponding diversity of intrinsic molecular features. This approach led to a knowledge gap in finding the optimal treatment for patients diagnosed with non-clear cell renal carcinoma. Cabozantinib, a potent multiple tyrosine kinase receptor inhibitor, has been recently investigated in patients with non-clear cell histologies of renal cell cancer. In this review, we have summarized available data on the use of cabozantinib in non-clear renal cell carcinoma., Competing Interests: Declaration of Competing Interest Authors declare no conflict of interest., (Crown Copyright © 2020. Published by Elsevier B.V. All rights reserved.)

The etiology and progression of renal carcinomas (RCC) is still poorly understood. RCC have been classified into several pathological entities. The most frequent type, clear cell carcinoma, accounts for about 80% of sporadic RCC and shows several chromosome abnormalities documented both by conventional cytogenetics, loss of eterozygosity (LOH) and replication error (RER) studies. In 10 clear cell type sporadic RCC we evaluated LOH and RER using a set of 10 microsatellite markers covering the chromosome 3p region, which has been suggested for interstitial deletions. Electrophoresis was performed by automated sequencer ABI Prism 377 and data were analyzed with Genescan and Genotyper 2.5 softwares. We revealed allelic loss in 48,7% of informative microsatellites and a single case of RER. We found the highest LOH frequency in 3p25-26 region where maps Von Hippel-Lindau (VHL) oncosuppressor gene. In addition, DNA hypermethylation, an alternative mechanism of VHL gene silencing, was evaluated by methylation-specific PCR. However hypermethylation status was not detected in any of our tumor samples.