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Simple Summary: Incidence of brain metastases from genito-urinary cancers has increased over the last years due to improved imaging techniques and better survival outcomes for patients even at an advanced metastatic stage thanks to therapeutic advances. However, no clear consensus exists on their management, and every case ought to be discussed in a multidisciplinary panel. We perform a single-centre retrospective study to report on incidence, patient demographics, clinicopathological characteristics, and treatment modalities. We also manage to identify predictive factors of outcome. Background: Incidence of brain metastases is precisely unknown and there is no clear consensus on their management. We aimed to determine the incidence of brain metastases among patients with genito-urinary primaries, present patients' characteristics and identify prognostic factors. Method: We identified 51 patients treated in Geneva University Hospitals between January 1992 and December 2019. We retrospectively correlated their overall survival with 23 variables. We repeated a multivariate analysis with significant variables. Results: Overall incidence of Brain Metastases (BMs) among Genito-Urinary (GU) patients is estimated to be 1.76% (range per primary GU tumour type: 0.00–6.65%). BMs originate from germ cell tumours in two cases (3.92%), from urothelial cell carcinoma in 15 cases (29.41%), from prostate cancer in 13 cases (25.49%), and from renal cell carcinoma in 21 cases (41.18%); there are no BMs from penile cancer in our cohort. The median age at BM diagnosis is 67 years old (range: 25–92). Most patients (54%) have a stage IV disease at initial diagnosis and 11 patients (22%) have BM at initial diagnosis. Only six patients (12%) are asymptomatic at BM diagnosis. The median Overall Survival (OS) from BM diagnosis is 3 months (range: 0–127). Five patients (10%) are long survivors (OS > 24 months). OS is significantly influenced by patient performance status and administration of systemic treatment. In the absence of meningeal carcinomatosis, OS is influenced by systemic treatment and stereotactic radiosurgery. We also apply the Graded Prognostic Assessment (GPA) score to our cohort and note significant differences between groups. Conclusion: Brain metastases from solid tumours is not a uniform disease, with a prognosis varying a lot among patients. The optimal management for patients with genito-urinary malignancies with brain metastases remain unclear and further research is needed. [ABSTRACT FROM AUTHOR]

Simple Summary: Stereotactic body radiotherapy (SBRT) is a treatment technique that delivers higher doses of conformal radiation precisely to specific targets. SBRT is utilized for the treatment of the more common cancers such as lung, liver and prostate malignancies, both in the early stage and the oligometastatic setting. The aim of this review is to highlight the current role of SBRT for renal cell carcinoma (RCC), a disease which was previously thought to be radioresistant, particularly to conventionally fractionated radiotherapy. There is now an increasing body of literature encompassing published phase II trials, reviews and meta-analyses demonstrating the effectiveness of SBRT in both early-stage RCC (as an alternative to patients who are not surgical candidates) and within the context of metastasis-directed therapy (MDT) for patients with oligometastatic and oligoprogressive RCC. Ongoing randomized trials are also exploring the role of SBRT as a cytoreductive treatment in metastatic RCC. Renal cell carcinoma (RCC) has been increasing in incidence by around 1.5% per year for several years. However, the mortality rate has been decreasing by 1.6% per year, and this can be attributed to stage migration and improvements in treatment. One treatment modality that has emerged in recent years is stereotactic body radiotherapy (SBRT), which is an advanced radiotherapy technique that allows the delivery of high-dose radiation to the tumor while minimizing doses to the organs at risk. SBRT has developed a role in the treatment of early-stage, oligometastatic and oligoprogressive RCC. In localized disease, phase II trials and meta-analyses have shown that SBRT provides a very high probability of long-term local control with a low risk of severe late toxicity. In oligometastatic (OMD) RCC, the same level of evidence has similarly shown good local control and minimal toxicity. SBRT could also delay the necessity to start or switch systemic treatments. Medical societies have started to incorporate SBRT in their guidelines in the treatment of localized disease and OMD. A possible future role of SBRT involves cytoreduction. It is theorized that SBRT can lower tumor burden and enhance immune-related response, but it cannot be recommended until the results of the phase II trials are published. [ABSTRACT FROM AUTHOR]

Simple Summary: ICI-based combinations have led to a significant change in mRCC medical treatment. However, data from real-world (RW) cohorts are rare. In this multicenter study, we evaluated the safety and effectiveness of cabozantinib plus nivolumab in real-world cohorts from centers in Germany, Switzerland, and Austria. The median PFS in the overall cohort was 18.6 months. We also analyzed subgroups in relation to the IMDC, histology, and with regard to the presence of bone metastasis. In summary, our real-word data support the promising efficacy data of the pivotal trials, particularly in patients with non-ccRCC and those without bone metastases at the start of the treatment. Introduction: Combinations of immune-checkpoint inhibitors (ICIs) are the standard of care (SOC) for treatment-naive metastatic renal cell carcinoma (mRCC) patients. In this multicenter study, we evaluated the RW safety and efficacy of cabozantinib plus nivolumab in mRCC patients. Methods: Data were retrospectively collected from twelve cancer centers in Germany, Switzerland, and Austria. Patients with advanced or mRCC were eligible. The investigator-based objective response rate (ORR) and progression free survival (PFS) were calculated from the start of the treatment to progression or death. Descriptive statistics and Kaplan–Meier (KM) plots were utilized where appropriate. Results: In total, 96 eligible patients (66.6% male) with a median age of 66.0 years were included. The most common histology was clear-cell RCC (ccRCC) in 63.4% (n = 61). A prior nephrectomy was performed in 60.4% (n = 58). ECOG 0-1 was 68.8% (n = 66). A partial response was documented in 43.8% of patients (n = 42), a stable disease in 32.3% (n = 31), and a progressive disease in 8.3% (n = 8) as the best overall response. Response data were not evaluable in 13.5% (n = 13). The median follow-up time was 12.7 months (95% CI, 10.0–15.3). The PFS rate at 6 months was 89.8% in the overall population (86.8% for ccRCC; 90.0% for non-ccRCC). Adverse events (AEs) were reported in 82.3% (n = 79) for all grades and 41.7% (n = 40) for grades 3–5. Elevated liver enzymes (34.4%), diarrhea (31.3%), and hand–foot syndrome (29.2%) were the three most frequent AEs of any grade and causality. Discussion/Conclusions: In this real-world cohort of mRCC patients, the application of cabozantinib plus nivolumab was shown to be safe and feasible. Our data support the use of cabozantinib plus nivolumab as a first-line standard therapy in mRCC patients. Major limitations were the retrospective data capture and short follow-up time of our study. [ABSTRACT FROM AUTHOR]

Simple Summary: In this work, we evaluated the need for frequent laboratory assessments in patients with metastatic renal cell carcinoma treated with nivolumab and nivolumab+ipilimumab during the TITAN-RCC clinical trial. We analysed how often reached criteria for dose delay or permanent discontinuation of therapy would have been missed if the frequency of laboratory testing had been reduced, in order to avoid over-sampling patients and to optimise clinical workflow and staffing. Our study showed that if the frequency of laboratory tests had been reduced, reached dose delay criteria would hardly have been missed. This would have affected up to 1% (2/207) of patients. An exception was dose delay due to the elevation of lipase blood levels which would have been missed in up to 7% (15/207) of patients. However, these patients presented with symptoms and would have been identified based thereupon. Discontinuation criteria would have only been overlooked for lipase (2% [4/207] of patients) and amylase (0.5% [1/207] of patients). Again, these patients would have been identified, since only symptomatic patients would have needed to discontinue treatment due to amylase or lipase laboratory values. In conclusion, in asymptomatic patients in our setting, laboratory analyses do not seem to be necessary before every treatment application. In clinical trials, laboratory values are assessed with high frequency. This can be stressful for patients, resource intensive, and difficult to implement, for example in office-based settings. In the prospective, multicentre phase 2 TITAN-RCC trial (NCT02917772), we investigated how many relevant changes in laboratory values would have been missed if laboratory values had been assessed less frequently. Patients with metastatic renal cell carcinoma (n = 207) received a response-based approach with nivolumab and nivolumab+ipilimumab boosts for non-response. We simulated that laboratory values were obtained before every second dose instead of every dose of the study drug(s). We assessed elevated leukocyte counts, alanine aminotransferase, aspartate aminotransferase, bilirubin, creatinine, amylase, lipase, and thyroid-stimulating hormone. Dose delay and discontinuation criteria were defined according to the study protocol. With the reduced frequency of laboratory analyses, dose delay criteria were rarely missed: in a maximum of <0.1% (3/4382) of assessments (1% [2/207] of patients) during nivolumab monotherapy and in a maximum of 0.2% (1/465) of assessments (1% [1/132] of patients) during nivolumab+ipilimumab boosts. An exception was lipase-related dose delay which would have been missed in 0.6% (25/4204) of assessments (7% [15/207] of patients) during nivolumab monotherapy and in 0.8% (4/480) of assessments (3% [4/134] of patients) during nivolumab+ipilimumab boosts, but would have required the presence of symptoms. Discontinuation criteria would have only been missed for amylase (<0.1% [1/3965] of assessments [0.5% (1/207) of patients] during nivolumab monotherapy, none during nivolumab+ipilimumab boosts) and lipase (0.1% [5/4204] of assessments [2% (4/207) of patients] during nivolumab monotherapy; 0.2% [1/480] of assessments [0.7% (1/134) of patients] during nivolumab+ipilimumab boosts). However, only symptomatic patients would have had to discontinue treatment due to amylase or lipase laboratory values. In conclusion, a reduced frequency of laboratory testing appears to be acceptable in asymptomatic patients with metastatic renal cell carcinoma treated with nivolumab or nivolumab+ipilimumab. [ABSTRACT FROM AUTHOR]

In this study, we aimed to determine the utility of cytoreductive nephrectomy (CN) in real-world clinical practice and investigate whether CN contributes to improved oncological outcomes in patients with metastatic renal cell carcinoma (mRCC). This retrospective multicenter cohort study enrolled patients with mRCC who received systemic therapy at six institutions between May 2005 and May 2023. The patients were divided into those who did not undergo CN (Group I) and those who underwent CN (Group II). The primary endpoints were oncological outcomes, including cancer-specific survival (CSS) and progression-free survival (PFS). Altogether, 137 patients with mRCC were included in this study. The median CSS was 14 months in Group I and 32 months in Group II (p < 0.001). Additionally, the median PFS in Groups I and II was 5 and 13 months, respectively (p = 0.006). A multivariate analysis showed that CN was an independent prognostic factor for CSS and PFS. Hence, CN is a potential treatment modality that can improve oncological outcomes in patients with mRCC. [ABSTRACT FROM AUTHOR]

The management of renal cell carcinoma (RCC) has been revolutionized over the past two decades with several practice-changing treatments. Treatment for RCC often requires a multimodal approach: Local treatment, such as surgery or ablation, is typically recommended for patients with localized tumors, while stage IV cancers often require both local and systemic therapy. The treatment of advanced RCC heavily relies on immunotherapy and targeted therapy, which are highly contingent upon histological subtypes. Despite years of research on biomarkers for RCC, the standard of care is to choose systemic therapy based on the risk profile according to the International Metastatic RCC Database Consortium and Memorial Sloan Kettering Cancer Centre models. However, many questions still need to be answered. Should we consider metastatic sites when deciding on treatment options for metastatic RCC? How do we choose between dual immunotherapy and combinations of immunotherapy and tyrosine kinase inhibitors? This review article aims to answer these unresolved questions surrounding the concept of personalized medicine. [ABSTRACT FROM AUTHOR]

Background/Aim: Numerous new treatment options have been approved for metastatic renal cell carcinoma (mRCC) in the last decade. Nevertheless, not all patients receive systemic therapy. Certain patients present with very advanced disease, poor Eastern Cooperative Oncology Group performance status (ECOG PS), or severe comorbidity, i.e. factors that lead oncologists to prefer best supportive care (BSC) instead of systemic therapy. The aim of this quality-of-care study was to identify baseline factors (disparities) associated with receipt of systemic therapy rather than BSC. Patients and Methods: This retrospective analysis included 140 consecutive patients managed in a rural region of Norway (2007-2022). Two differently managed groups were compared in univariate tests followed by multi-nominal regression. Results: The majority of patients (n=95, 68%) had received systemic therapy. Typical patients were males in their 60s or 70s, with clear cell histology, prior nephrectomy, and intermediate prognostic features. Patients who received systemic therapy lived significantly longer than those who did not (median 30.4 versus 5.0 months, p<0.001). Survival benefit of systemic treatment was observed even in patients with ECOG PS3 or age =80 years. In addition to younger age (p<0.001) and better ECOG PS (p<0.001), metachronous presentation was associated with higher rates of systemic therapy utilization (p=0.03). Conclusion: Assignment to systemic therapy for mRCC was individualized in the present patient population. In all age and ECOG PS subgroups, systemic therapy was associated with better survival (doubling at least). Optimum utilization rates are difficult to determine. However, in light of the survival outcomes, a rate of 12% in patients aged 80 years or older appears rather low. [ABSTRACT FROM AUTHOR]

Metastasis to the penis from renal cell carcinoma (RCC) or any other primary cancer site is unusual; when it does occur, it often involves multiple organs. A 75-year-old man presented with penile pain and swelling. Three months earlier, he had open radical nephrectomy with thrombectomy and was diagnosed with clear-cell RCC with tumor thrombosis in the inferior vena cava. The follow-up imaging indicated metastasis to the penis, prompting a total penectomy due to worsening pain. The excised mass displayed features consistent with metastatic RCC. This case underscores the need to consider rare metastatic sites, such as the metastasis of RCC to the penis, in RCC patients. [ABSTRACT FROM AUTHOR]

Simple Summary: Renal cell carcinoma (RCC) is common, affecting over 400,000 patients globally each year. In limited stage disease and where surgery is a feasible therapeutic option, event free survival rates are high. In contrast, locally advanced disease is associated with frequent relapse, and up to 30% of patients present with metastatic disease. Standard of care treatments for metastatic disease include tyrosine kinase inhibitors (TKI) and immune checkpoint inhibitors (ICI), but clinical responses are variable and generally not durable. Novel cell-based immunotherapy approaches such as Chimeric Antigen Receptor T-cells (CAR-T) and T-cell receptor engineered T-cells (TCR-T) have shown efficacy in some blood cancers and are currently under evaluation in solid tumours including RCC. Here, we review the landscape of cellular immunotherapy for RCC in the context of currently available therapies and outline how advanced engineering solutions may further enhance this therapeutic approach. Renal cell carcinoma (RCC) affects over 400,000 patients globally each year, and 30% of patients present with metastatic disease. Current standard of care therapy for metastatic RCC involve TKIs and ICIs, including combinatorial strategies, but this offers only modest clinical benefit. Novel treatment approaches are warranted, and cell-based immunotherapies for RCC hold significant promise. These are currently being tested in the pre-clinical setting and in early phase clinical trials. Here, we review the landscape of cellular immunotherapy for RCC in the context of currently available therapies, with a particular focus on defining the current best antigenic targets, the range of cell therapy products being explored in RCC, and how advanced engineering solutions may further enhance these therapies in the RCC space. [ABSTRACT FROM AUTHOR]

Simple Summary: This study investigated the efficacy of complete metastasectomy (CM) in metastatic renal cell carcinoma (mRCC) during the tyrosine kinase inhibitor (TKI) and immune checkpoint inhibitor (ICI) era. Analyzing data from a multi-institutional database with 367 mRCC patients, the CM group exhibited significantly longer overall survival than the non-CM group in unadjusted cohorts (p < 0.001, hazard ratio 0.49, 95% confidence interval 0.35–0.69). However, this superiority was not sustained in adjusted cohorts. The median disease-free survival (DFS) after CM was 24 months, with no significant differences noted based on the time of relapse. This study supports CM's potential in mRCC management during the TKI/ICI era, acknowledging limitations such as sample size and selection bias. Complete metastasectomy (CM) in metastatic renal cell carcinoma (mRCC) has demonstrated efficacy in the cytokine era, but its effectiveness in the era of tyrosine kinase inhibitors (TKIs) and immune checkpoint inhibitors (ICIs) remains unclear. A multi-institutional database included clinicopathological data of 367 patients with mRCC. Patients were divided into two groups: the CM group and the non-CM group. These two groups were compared before and after propensity score matching (PSM). Cox proportional hazard models were used to detect factors associated with disease-free survival (DFS) and overall survival (OS) from mRCC diagnosis. The CM group showed a significant association with longer overall survival compared to the non-CM group in the PSM-unadjusted cohorts (p < 0.001, hazard ratio 0.49, 95% confidence interval 0.35–0.69), but no superiority was noted in the adjusted cohorts. The median DFS after CM was 24 months, with no significant differences based on relapse timing. Notably, the international metastatic RCC database consortium risk categories and metastatic burden were associated with DFS. This study supports the potential of CM in mRCC management during the TKI/ICI era, although limitations including sample size and selection bias need to be considered. [ABSTRACT FROM AUTHOR]

Simple Summary: Belzutifan, a hypoxia-inducible factor-2 alpha (HIF-2α) inhibitor, has emerged as an exciting new treatment option not only for patients with Von Hippel-Lindau (VHL)-related renal cell carcinoma (RCC) but also for sporadic RCC. While initial clinical data are promising, potential resistance with HIF-2α inhibitors may occur with increased understanding of this class of therapy. Potential ways to further increase the antitumor activity of HIF-2α targeting include combination strategies with immune checkpoint inhibitors and other targeted agents as well as newer generation HIF-2α inhibitors that are currently under development. Germline inactivation of the Von Hippel-Lindau (VHL) tumor suppressor is the defining hallmark in hereditary VHL disease and VHL-associated renal cell carcinoma (RCC). However, somatic VHL mutations are also observed in patients with sporadic RCC. Loss of function VHL mutations result in constitutive activation of hypoxia-inducible factor-2 alpha (HIF-2α), which leads to increased expression of HIF target genes that promote angiogenesis and tumor growth. As of 2023, belzutifan is currently the only approved HIF-2α inhibitor for both VHL-associated and sporadic metastatic RCC (mRCC). However, there is potential for resistance with HIF-2α inhibitors which warrants novel HIF-2α-targeting strategies. In this review, we discuss the potential resistance mechanisms with belzutifan and current clinical trials evaluating novel combinations of belzutifan with other targeted therapies and immune checkpoint inhibitors which may enhance the efficacy of HIF-2α targeting. Lastly, we also discuss newer generation HIF-2α inhibitors that are currently under early investigation and outline future directions and challenges with HIF-2α inhibitors for mRCC. [ABSTRACT FROM AUTHOR]

Simple Summary: The proven efficacy of mTOR inhibitor (mTORI), tyrosine kinase inhibitor (TKI) or immune checkpoint inhibitor (ICI) therapies in metastatic renal cell carcinoma (RCC) suggests that these agents should be investigated as adjuvant therapy with the aim of eliminating undetectable microscopic residual disease after curative resection. Our study aimed to compare the efficacy of these treatments using an innovative method that reconstructs individual patient data from Kaplan–Meier (KM) curves. Nine phase III trials describing different treatment options for adjuvant RCC were selected. Individual patient data were reconstructed from KM curves of disease-free survival (DFS) using the IPDfromKM method. DFS was then compared between the combination treatments and the control arm (placebo). The results were summarized as multi-treatment KM curves. Standard statistical tests were used, including the hazard ratio for superiority and the likelihood ratio test for heterogeneity. In the population of these nine trials, our study showed that two ICIs (nivolumab plus ipilimumab and pembrolizumab) and one TKI (sunitinib) were superior to the placebo, whereas the remaining TKIs and mTORIs were not. As we assessed DFS as the primary endpoint for the adjuvant comparison, the overall survival benefit remains unknown. This novel approach to studying survival has allowed us to make all of the indirect head-to-head comparisons between these agents in a context where no "real" comparative trials have been conducted. Background: The proven efficacy of mTOR inhibitors (mTORIs), tyrosine kinase inhibitors (TKIs) or immune checkpoint inhibitors (ICIs) in metastatic renal cell carcinoma (RCC) suggests that these agents should be investigated as adjuvant therapy with the aim of eliminating undetectable microscopic residual disease after curative resection. The aim of our study was to compare the efficacy of these treatments using an innovative method of reconstructing individual patient data. Methods: Nine phase III trials describing adjuvant RCC treatments were selected. The IPDfromKM method was used to reconstruct individual patient data from Kaplan–Meier (KM) curves. The combination treatments were compared with the control arm (placebo) for disease-free survival (DFS). Multi-treatment KM curves were used to summarize the results. Standard statistical tests were performed. These included hazard ratio and likelihood ratio tests for heterogeneity. Results: In the overall population, the study showed that two ICIs (nivolumab plus ipilimumab and pembrolizumab) and one TKI (sunitinib) were superior to the placebo, whereas both TKIs and mTORIs were inferior. As we assessed DFS as the primary endpoint for the adjuvant comparison, the overall survival benefit remains unknown. Conclusions: This novel approach to investigating survival has allowed us to conduct all indirect head-to-head comparisons between these agents in a context where no "real" comparative trials have been conducted. [ABSTRACT FROM AUTHOR]

Simple Summary: It is difficult to predict which patients with non-metastatic clear cell renal cell carcinoma (ccRCC) will develop metastatic disease after nephrectomy. Recent studies suggest that immune cell infiltration within ccRCC tumors may impact tumor progression. This study assessed the number and type of immune cells in non-metastatic ccRCC tumors that were surgically removed and their ability to predict which patients developed metastatic disease. We found that higher levels of a specific immune cell (CD8+ T cells) were linked to a lower risk of progressive disease. Patients who did progress had more exhausted CD8+ T cells in the tumor microenvironment. Additionally, our study design accounted for tumor heterogeneity by sampling tumors in multiple locations and showed differences in the spatial distribution of CD8+ T cells in tumors that progressed to metastatic disease. With further validation, this study shows that CD8+ T cell infiltration within ccRCC tumors could be used as a prognostic biomarker to predict progression to metastatic disease. Predicting which patients will progress to metastatic disease after surgery for non-metastatic clear cell renal cell carcinoma (ccRCC) is difficult; however, recent data suggest that tumor immune cell infiltration could be used as a biomarker. We evaluated the quantity and type of immune cells infiltrating ccRCC tumors for associations with metastatic progression following attempted curative surgery. We quantified immune cell densities in the tumor microenvironment and validated our findings in two independent patient cohorts with multi-region sampling to investigate the impact of heterogeneity on prognostic accuracy. For non-metastatic ccRCC, increased CD8+ T cell infiltration was associated with a reduced likelihood of progression to metastatic disease. Interestingly, patients who progressed to metastatic disease also had increased percentages of exhausted CD8+ T cells. Finally, we evaluated the spatial heterogeneity of the immune infiltration and demonstrated that patients without metastatic progression had CD8+ T cells in closer proximity to ccRCC cells. These data strengthen the evidence for CD8+ T cell infiltration as a prognostic biomarker in non-metastatic ccRCC and demonstrate that multi-region sampling may be necessary to fully characterize immune infiltration within heterogeneous tumors. Tumor CD8+ T cell infiltration should be investigated as a biomarker in adjuvant systemic therapy clinical trials for high-risk non-metastatic RCC. [ABSTRACT FROM AUTHOR]

The use of immune checkpoint inhibitors (ICIs) in combination with tyrosine kinase inhibitors or other ICIs has significantly improved the prognosis for patients with mccRCC. This marks a major milestone in the treatment of mccRCC. Nonetheless, most patients will discontinue first-line therapy. In this narrative review, we analyze the different patterns of treatment discontinuation in the four pivotal phase III trials that have shown an improvement in overall survival in mccRCC first-line therapy, starting from 1 January 2017 to 1 June 2023. We highlight the different discontinuation scenarios and their influences on subsequent treatment options, aiming to provide more data to clinicians to navigate a complex decision-making process through a narrative review approach. We have identified several causes for discontinuations for patients treated with ICI-based combinations, such as interruption for drug-related adverse events, ICI treatment completion, treatment discontinuation due to complete response or maximum clinical benefit, or due to progression (pseudoprogression, systemic progression, and oligoprogression); for each case, an extensive analysis of the trials and current medical review has been conducted. [ABSTRACT FROM AUTHOR]

Simple Summary: Oligo-recurrence and oligo-progression in oncology refer to scenarios in which five or fewer metastases develop after the primary lesions and other metastases have been treated using radical surgery or controlled using systemic therapy. Such scenarios are now considered favorable indications for metastasis-directed treatment (MDT), where a curative approach is possible. The primary strategy for recurrence and metastases in renal cell carcinoma (RCC) is systemic therapy, which includes immune checkpoint inhibitors (ICIs) and vascular endothelial growth factor receptor tyrosine kinase inhibitors. However, MDTs such as stereotactic body radiation therapy, which involves larger doses administered over fewer fractions than conventional radiation therapy, have shown the potential to improve outcomes for selected patients with RCC experiencing oligo-recurrence and oligo-progression. Combining MDT with ICIs may yield better results owing to their synergistic effects. In this review, we provide an overview of the current evidence related to the management of oligo-recurrent and -progressive RCC. One-third of renal cell carcinomas (RCCs) without metastases develop metastatic disease after extirpative surgery for the primary tumors. The majority of metastatic RCC cases, along with treated primary lesions, involve limited lesions termed "oligo-recurrent" disease. The role of metastasis-directed therapy (MDT), including stereotactic body radiation therapy (SBRT) and metastasectomy, in the treatment of oligo-recurrent RCC has evolved. Although the surgical resection of all lesions alone can have a curative intent, SBRT is a valuable treatment option, especially for patients concurrently receiving systemic therapy. Contemporary immune checkpoint inhibitor (ICI) combination therapies remain central to the management of metastatic RCC. However, one objective of MDT is to delay the initiation of systemic therapies, thereby sparing patients from potentially unnecessary burdens. Undertaking MDT for cases showing progression under systemic therapies, known as "oligo-progression", can be complex in considering the treatment approach. Its efficacy may be diminished compared to patients with stable disease. SBRT combined with ICI can be a promising treatment for these cases because radiation therapy has been shown to affect the tumor microenvironment and areas beyond the irradiated sites. This may enhance the efficacy of ICIs, although their efficacy has only been demonstrated in clinical trials. [ABSTRACT FROM AUTHOR]

Simple Summary: Localized renal cell carcinoma (RCC) has an excellent prognosis. However, once metastatic, patient prognosis declines significantly. There is a rare patient subgroup with localized RCC stage T1 with distant metastasis (M1) and no lymph node involvement (N0). In this study, the survival of patients diagnosed with clear cell RCC (ccRCC) stage T1N0M1 were evaluated in comparison to ccRCC patients stage T1 without metastases (N0M0). As expected, stage T1N0M1 ccRCC patients showed a significantly worse outcome than stage T1N0M0 patients. To further characterize tumor characteristics of stage T1N0M1 ccRCC patients, CD8+ tumor infiltrating lymphocytes (TILs) were analyzed, as it is known that a number of CD8+ TILs is associated with a worse prognosis. It could be shown that tumor specimens from stage T1N0M1 ccRCC patients harbor a substantially higher number of CD8+ TILs than specimens from stage T1N0M0 ccRCC patients, thus resembling advanced stage ccRCC. Nevertheless, long-term survival of stage T1N0M1 ccRCC patients is possible. Metastatic renal cell carcinoma (RCC) is among the most lethal urological malignancies. However, small, localized RCCs (≤7 cm, stage T1) have an excellent prognosis. There is a rare patient subgroup diagnosed with synchronous distant metastasis (T1N0M1), of which very little is known in terms of survival outcomes and underlying disease biology. Herein, we examined the long-term survival of 27 patients with clear cell RCC (ccRCC) stage T1N0M1 in comparison to 18 patients without metastases (T1N0M0). Tumor tissue was stained by immunohistochemistry for CD8+ tumor infiltrating lymphocytes (TILs). As expected, patients with stage T1N0M1 showed a significantly worse median cancer specific survival (CSS; 2.8 years) than patients with stage T1N0M0 (17.7 years; HR 0.077; 95% CI, 0.022–0.262). However, eight patients (29.6%) with ccRCC stage T1N0M1 survived over five years, and three of those patients (11.1%) survived over a decade. Some of these patients benefitted from an intensified, multimodal treatment including metastasis-directed therapy. The number of CD8+ TILs was substantially higher in stage T1N0M1 ccRCCs than in stage T1N0M0 ccRCCs, suggesting a more aggressive tumor biology. In conclusion, long-term survival is possible in patients with ccRCC stage T1N0M1, with some patients benefitting from an intensified, multimodal treatment approach. [ABSTRACT FROM AUTHOR]

Background: Epstein-Barr virus (EBV)-related nasopharyngeal cancer (NPC) is a common type of cancer in certain areas of the world such as southeast Asia, but is uncommon in Canada. There is currently no reliably effective standard treatment for incurable metastatic EBV-related NPC that progresses after first- line therapy with gemcitabine/cisplatin. Methods: With his consent, the health records of a patient with relapsed metastatic EBV-related NPC treated with pembrolizumab immunotherapy were retrospectively reviewed and reported. Case report: A male patient presented at age 15 with stage IVA EBV-related NPC. Despite response to initial chemoradiation and adjuvant chemotherapy, the patient experienced metastatic cancer relapse in lymph nodes and bone. There was initial response to gemcitabine/cisplatin chemotherapy, but the cancer progressed after 7 cycles. The patient was then switched to pembrolizumab and had a near complete clinical response after 14 cycles. Serum EBV titers have normalized and CT imaging shows only some healed bone metastasis. Retrospective assessment of tumor CPS PD-L1 was >20. Hypothyroidism developed, possibly due to radiation treatment, but otherwise he did not experience any other immune-mediated toxicities on or following treatment, which lasted in total 2 years with 41 cycles. To date, the patient has been observed off pembrolizumab for over one year and is highly functional without evidence of disease progression. Conclusion: This case illustrates the potential benefit of immunotherapy for improving survival and quality of life in selected patients with metastatic EBV- positive cisplatin-refractory NPC. [ABSTRACT FROM AUTHOR]

Objectives: The treatment landscape for metastatic renal cell carcinoma changed a lot in the last few years. This study aimed to assess the treatment sequences and outcomes for metastatic renal cell carcinoma in a real-world setting. Materials and methods: We enrolled patients with metastatic renal cell carcinomawho received first-line systemic treatment with tyrosin kinase inhibitors monotherapy, ipilimumab plus nivolumab, or pembrolizumab plus axitinibbetween January2009 and May 2023 on the database of TriNetX network. Overall survival, time on treatment and time to next treatment were evaluated using Kaplan-Meiermethod. Results: Totally, 4183 received tyrosine kinase inhibitor monotherapy, 1555 received ipilimumab plus nivolumab, and 559 received axitinib plus pembrolizumab. Median time on treatment was 2.5 months for the tyrosine kinase inhibitor monotherapy cohort, 5.4 months for the ipilimumab plus nivolumab cohort, and 8.3 months for the pembrolizumab plus axitinib cohort. Median time to next treatment was 16.6 months for both the tyrosine kinase inhibitor monotherapy and ipilimumab plus nivolumab cohorts, and 22.1 months for the pembrolizumab plus axitinib cohort. Median overall survival was 42.2 months for the tyrosine kinase inhibitor monotherapy cohort, 39.7monthsfor the ipilimumab plus nivolumab cohort, and not reached for the pembrolizumab plus axitinib cohort. In comparison with the tyrosine kinase inhibitor monotherapy cohort, patients in the pembrolizumab plus axitinib cohort showed survival benefit (log-rank p = 0.0168) in overall survival, but not the case in the ipilimumab plus nivolumab cohort. Conclusion: There was a trend toward using first-line immuno-oncology based therapy for patients with metastatic renal cell carcinoma in a real-world practice. Axitinib plus pembrolizumuab cohort had survival benefits over tyrosine kinase inhibitor and ipilimumab plus nivolumab cohorts, while patients in the ipilimumab plus nivolumab cohort had more distant metastases and comorbidities. [ABSTRACT FROM AUTHOR]

Cancer stem-like cells (CSCs), a subpopulation of cancer cells, possess remarkable capability in proliferation, self-renewal, and differentiation. Their presence is recognized as a crucial factor contributing to tumor progression and metastasis. CSCs have garnered significant attention as a therapeutic focus and an etiologic root of treatment-resistant cells. Increasing evidence indicated that specific biomarkers, aberrant activated pathways, immunosuppressive tumor microenvironment (TME), and immunoevasion are considered the culprits in the occurrence of CSCs and the maintenance of CSCs properties including multi-directional differentiation. Targeting CSC biomarkers, stemness-associated pathways, TME, immunoevasion and inducing CSCs differentiation improve CSCs eradication and, therefore, cancer treatment. This review comprehensively summarized these targeted therapies, along with their current status in clinical trials. By exploring and implementing strategies aimed at eradicating CSCs, researchers aim to improve cancer treatment outcomes and overcome the challenges posed by CSC-mediated therapy resistance. [ABSTRACT FROM AUTHOR]

Objectives: Although biomarkers predicting therapy response in first‐line metastatic renal carcinoma (mRCC) therapy remain to be defined, C‐reactive protein (CRP) kinetics have recently been associated with immunotherapy (IO) response. Here, we aimed to assess the predictive and prognostic power of two contemporary CRP kinetics definitions in a large, real‐world first‐line mRCC cohort. Methods: Metastatic renal carcinoma patients treated with IO‐based first‐line therapy within 5 years were retrospectively included in this multicentre study. According to Fukuda et al., patients were defined as 'CRP flare‐responder', 'CRP responder' and 'non‐CRP responder'; according to Ishihara et al., patients were defined as 'normal', 'normalised' and 'non‐normalised' based on their early CRP kinetics. Patient and tumor characteristics were compared, and treatment outcome was measured by overall (OS) and progression‐free survival (PFS), including multivariable Cox regression analyses. Results: Out of 316 mRCC patients, 227 (72%) were assigned to CRP groups according to Fukuda. Both CRP flare‐ (HR [Hazard ratio]: 0.59) and CRP responders (HR: 0.52) had a longer PFS, but not OS, than non‐CRP responders. According to Ishihara, 276 (87%) patients were assigned to the respective groups, and both normal and normalised patients had a significantly longer PFS and OS, compared with non‐normalised group. Conclusion: Different early CRP kinetics may predict therapy response in first‐line mRCC therapy in a large real‐world cohort. However, further research regarding the optimal timing and frequency of measurement is needed. [ABSTRACT FROM AUTHOR]

Simple Summary: In recent years, several therapeutic advances have been made in clear cell renal cell carcinoma (ccRCC) resulting in novel treatment regimens of increased effectiveness. These advances are largely due to breakthroughs in technologies, particularly in transcriptomics, such as single-cell RNA sequencing (scRNA-seq). Using this technology, we have gained a deeper understanding of the biology of ccRCC and revealed various cell populations and their interactions in disease progression. While localized ccRCC patients have shown promising responses to treatment, however, patients with advanced or metastatic disease remain a therapeutic challenge. To address this gap, recent studies have utilized scRNA-seq to investigate both primary and metastatic ccRCC in search of promising therapeutic targets. This review aims to summarize the current state of knowledge in the field, highlight available treatment options and underscore the critical steps needed to improve survival rates, especially for metastatic ccRCC patients. Over the past two decades, significant progress has been made in the treatment of clear cell renal cell carcinoma (ccRCC), with a shift towards adopting new treatment approaches ranging from monotherapy to triple-combination therapy. This progress has been spearheaded by fundamental technological advancements that have allowed a deeper understanding of the various biological components of this cancer. In particular, the rapid commercialization of transcriptomics technologies, such as single-cell RNA-sequencing (scRNA-seq) methodologies, has played a crucial role in accelerating this understanding. Through precise measurements facilitated by these technologies, the research community has successfully identified and characterized diverse tumor, immune, and stromal cell populations, uncovering their interactions and pathways involved in disease progression. In localized ccRCC, patients have shown impressive response rates to treatment. However, despite the emerging findings and new knowledge provided in the field, there are still patients that do not respond to treatment, especially in advanced disease stages. One of the key challenges lies in the limited study of ccRCC metastases compared to localized cases. This knowledge gap may contribute to the relatively low survival rates and response rates observed in patients with metastatic ccRCC. To bridge this gap, we here delve into recent research utilizing scRNA-seq technologies in both primary and metastatic ccRCC. The goal of this review is to shed light on the current state of knowledge in the field, present existing treatment options, and emphasize the crucial steps needed to improve survival rates, particularly in cases of metastatic ccRCC. [ABSTRACT FROM AUTHOR]

Although five immune‐oncologic‐drug‐based combination therapies, such as ipilimumab plus nivolumab, avelumab plus axitinib, pembrolizumab plus axitinib, nivolumab plus cabozantinib, and pembrolizumab plus lenvatinib, have been approved for advanced renal cell carcinoma (RCC) in Japan, the optimal therapy for advanced RCC has not been determined. Without head‐to‐head comparison, several network meta‐analyses using phase 3 clinical trials presented the highest likelihood of maximal overall survival, progression‐free survival, and objective response rate according to several categories such as the International Metastatic Renal Cell Carcinoma Database Consortium risk group, programmed cell death 1‐ligand 1 expression, sarcomatoid features, or the safety profile of treatment‐related adverse events; however, they did not include the results of additional long‐term follow‐up data in each clinical trial. In the real world, advanced RCC treatment depends on several factors, such as age, comorbidity, tumor burden, or the presence of symptoms that affect daily life. To relieve tumor‐related symptoms, tumor burden reduction is required, which may lead to the use of therapies with high response rates and low risk of disease progression. Moreover, patients with comorbidities, such as uncontrolled diabetes, are required to avoid steroid therapy for adverse events, which may necessitate the use of therapies with a low incidence of adverse events that are needed for high‐dose steroids or permanent steroid replacement therapy. Moreover, novel drugs, such as the hypoxia‐inducible factor 2a inhibitor (belzutifan) or immunostimulatory interleukin‐2 cytokine prodrug (bempegaldesleukin) have been developed, and phase 3 clinical trials of combination therapy using these drugs for treatment‐naïve advanced RCC are ongoing. Further development of systemic therapies for advanced RCC is required. [ABSTRACT FROM AUTHOR]

Our understanding of angiogenesis has significantly expanded over the past five decades. More recently, research has focused on this process at a more molecular level, looking at it through the signaling pathways that activate it and its non-direct downstream effects. This review discusses current findings in molecular angiogenesis, focusing on its impact on the immune system. Moreover, the impairment of this process in cancer progression and metastasis is highlighted, and current anti-angiogenic treatments and their effects on tumor growth are discussed. [ABSTRACT FROM AUTHOR]

Purpose: Immune-based (IO)-combinations are the backbone in the systemic therapy of metastatic renal cell carcinoma (mRCC). Despite phase III clinical trial data, real world data are of special importance to reflect clinical practice. Methods: This retrospective study included 201 mRCC patients receiving first-line systemic therapy from January 2006. Clinicopathological and treatment-related data were recorded. Progression-free (PFS) and overall survival (OS) were analyzed using descriptive statistics and Kaplan–Meier analysis. Results: Over the years, IO-based therapies have increased significantly. The collective comprises 76 patients with first-line IO-based therapy (IO-IO:55, TKI-IO:21) and 125 patients with TKI-monotherapy. PFS was significantly improved with TKI-IO combinations if compared to both TKI-monotherapy (23.9 vs. 10.3 months, HR 0.48, p = 0.034) and IO-IO combination (23.9 vs. 6.1 months, HR 0.37, p = 0.012). OS for TKI-IO treated patients was longer compared to TKI-monotherapy (HR 0.37, p = 0.050) at median follow-up of 24.1 versus 29.9 months. In a subanalysis of nivolumab treated patients, starting from second-line (n = 40), PFS was 5.5 months. The addition of nivolumab either in second-or later lines improved OS compared to repeated TKI- or mTOR-therapies alone (6.13 vs. 2.61 years, HR 0.46, p = 0.003). Conclusion: Both first-line IO-based combinations and nivolumab after first-line TKI-monotherapy prolong OS in a real-world setting. [ABSTRACT FROM AUTHOR]

Simple Summary: Over the last 10 years, there has been a vast increase in the use of targeted and immunotherapy drugs in the management of advanced kidney cancer. As patients are living longer with cancer that has spread, the natural history has altered, with problems of poor tumour control in one or a few areas only. Local surgical removal of the tumour(s) frequently cannot be applied due to technical challenges or patient factors. Thermal ablation or stereotactic body radiotherapy (SBRT) may be utilised. Thermal ablation is a minimally invasive treatment where heat is generated and passed via a probe into the tumour to cause cancer cell death. SBRT is a non-invasive treatment where high radiobiological doses of radiation are precisely delivered in one, or a few, treatments to kill cancer cells. This systematic review aims to evaluate the existing evidence for these treatments to help improve personalised care for individual patients. Intensified systemic therapy in metastatic renal cell carcinoma (mRCC) has led to improved patient outcomes. Patients commonly require local control of one or a few metastases. The aim was to evaluate metastasis-directed ablative therapies in extracranial mRCC. Two databases and one registry were searched, using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) approach, for all prospective and matched-pair case–control mRCC studies of radiofrequency ablation (RFA), cryotherapy, microwave ablation (MWA), and stereotactic body radiotherapy (SBRT). Eighteen studies were identified. Fourteen investigated SBRT in 424 patients. Four thermal ablation studies were identified: two cryotherapy (56 patients) and two RFA studies (90 patients). The median participant number was 30 (range 12–69). The combined median follow-up was 17.3 months (range 8–52). Four SBRT studies reported local control (LC) at 12 months, median 84.4% (range 82.5–93). Seven studies (six SBRT and one cryotherapy) reported an LC rate of median 87% (79–100%). Median overall survival (OS) was reported in eight studies (five SBRT, two cryotherapy, and one RFA) with a median of 22.7 months (range 6.7–not reached). Median progression-free survival was reported in seven studies (five SBRT, one cryotherapy, and one RFA); the median was 9.3 months (range 3.0–22.7 months). Grade ≥ 3 toxicity ranged from 1.7% to 10%. SBRT has excellent local control outcomes and acceptable toxicity. Only four eligible thermal ablative studies were identified and could not be compared with SBRT. Translationally rich definitive studies are warranted. [ABSTRACT FROM AUTHOR]

Clear cell renal cell carcinoma (ccRCC) is the most common and aggressive histological type of cancer in this location. Distant metastases are present in approximately 30% of patients at the time of first examination. Therefore, the ability to predict the occurrence of metastases in patients at early stages of the disease is an urgent task aimed at personalized treatment. Samples of tumor and paired histologically normal kidney tissue from patients with metastatic and non-metastatic ccRCC were studied. Gene expression was analyzed using real-time PCR. The level of gene methylation was evaluated using bisulfite conversion followed by quantitative methylation-specific PCR. Two groups of genes were analyzed in this study. The first group includes genes whose expression is significantly reduced during metastasis: CA9, NDUFA4L2, EGLN3, and BHLHE41 (p < 0.001, ROC analysis). The second group includes microRNA genes: MIR125B-1, MIR137, MIR375, MIR193A, and MIR34B/C, whose increased methylation levels are associated with the development of distant metastases (p = 0.002 to <0.001, ROC analysis). Based on the data obtained, a combined panel of genes was formed to identify patients whose tumors have a high metastatic potential. The panel can estimate the probability of metastasis with an accuracy of up to 92%. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background: Clear cell renal cell cancer (ccRCC), the 8th leading cause of cancer-related death in the US, is challenging to treat due to high level intratumoral heterogeneity (ITH) and the paucity of druggable driver mutations. CcRCC is unusual for its high frequency of epigenetic regulator mutations, such as the SETD2 histone H3 lysine 36 trimethylase (H3K36me3), and low frequency of traditional cancer driver mutations. In this work, we examined epigenetic level ITH and defined its relationships with pathologic features, aspects of tumor biology, and SETD2 mutations. Results: A multi-region sampling approach coupled with EPIC DNA methylation arrays was conducted on a cohort of normal kidney and ccRCC. ITH was assessed using DNA methylation (5mC) and CNV-based entropy and Euclidian distances. We found elevated 5mC heterogeneity and entropy in ccRCC relative to normal kidney. Variable CpGs are highly enriched in enhancer regions. Using intra-class correlation coefficient analysis, we identified CpGs that segregate tumor regions according to clinical phenotypes related to tumor aggressiveness. SETD2 wild-type tumors overall possess greater 5mC and copy number ITH than SETD2 mutant tumor regions, suggesting SETD2 loss contributes to a distinct epigenome. Finally, coupling our regional data with TCGA, we identified a 5mC signature that links regions within a primary tumor with metastatic potential. Conclusion: Taken together, our results reveal marked levels of epigenetic ITH in ccRCC that are linked to clinically relevant tumor phenotypes and could translate into novel epigenetic biomarkers. [ABSTRACT FROM AUTHOR]

Simple Summary: Immune checkpoint inhibitors (ICIs) are being increasingly used after primary treatment of early-stage tumors to treat any residual disease and prevent recurrence. Herein, we provide a comprehensive review of pivotal clinical studies demonstrating efficacy and safety outcomes when ICIs are utilized after surgery in patients with melanoma, urothelial cancer, renal cell carcinoma, lung cancer, gastroesophageal cancer, and hepatobiliary malignancies. In addition, we highlight the potential role of these agents within the emerging field of transplant oncology. To guide the selection of eligible patients for ICIs, we outline approved and emerging biomarkers that may predict benefit from use of these agents and help monitor response, especially in the absence of visible disease on imaging. Furthermore, we provide real-world considerations with regards to tolerability and cost-effectiveness of these agents and necessary future directions that should be explored to increase the survival outcomes associated with the use of ICIs after surgery. The rationale for administering immune checkpoint inhibitors (ICIs) in the adjuvant setting is to eradicate micro-metastases and, ultimately, prolong survival. Thus far, clinical trials have demonstrated that 1-year adjuvant courses of ICIs reduce the risk of recurrence in melanoma, urothelial cancer, renal cell carcinoma, non-small cell lung cancer, and esophageal and gastroesophageal junction cancers. Overall survival benefit has been shown in melanoma while survival data are still not mature in other malignancies. Emerging data also show the feasibility of utilizing ICIs in the peri-transplant setting for hepatobiliary malignancies. While ICIs are generally well-tolerated, the development of chronic immune-related adverse events, typically endocrinopathies or neurotoxicities, as well as delayed immune-related adverse events, warrants further scrutiny regarding the optimal duration of adjuvant therapy and requires a thorough risk–benefit determination. The advent of blood-based, dynamic biomarkers such as circulating tumor DNA (ctDNA) can help detect minimal residual disease and identify the subset of patients who would likely benefit from adjuvant treatment. In addition, the characterization of tumor-infiltrating lymphocytes, neutrophil-to-lymphocyte ratio, and ctDNA-adjusted blood tumor mutation burden (bTMB) has also shown promise in predicting response to immunotherapy. Until additional, prospective studies delineate the magnitude of overall survival benefit and validate the use of predictive biomarkers, a tailored, patient-centered approach to adjuvant ICIs that includes extensive patient counseling on potentially irreversible adverse effects should be routinely incorporated into clinical practice. [ABSTRACT FROM AUTHOR]

Simple Summary: Clear cell renal cell carcinoma (ccRCC) progression, which is the most common form of kidney cancer, is associated with the loss of the Von Hippel-Lindau (VHL) gene in renal epithelium. VHL promotes proteasomal degradation of Hypoxia Inducible Factor alpha (HIF-α) thereby inhibiting the transcription of genes that are required for cell growth and proliferation during hypoxia (lack of oxygen). Accumulation of HIF-α consequent to VHL loss results in the activation of HIF target genes irrespective of oxygen availability which initiates tumorigenesis in the kidney. In this review, we discuss which signaling networks and genes are upregulated in response to HIF-α activation and how they drive ccRCC progression. We also highlight the potential therapies available to treat ccRCC patients as well as several medical and scientific challenges that impede the scientific investigation in this field. The clear cell variant of renal cell carcinoma (ccRCC) is the most common renal epithelial malignancy and responsible for most of the deaths from kidney cancer. Patients carrying inactivating mutations in the Von Hippel-Lindau (VHL) gene have an increased proclivity to develop several types of tumors including ccRCC. Normally, the Hypoxia Inducible Factor alpha (HIF-α) subunits of the HIF heterodimeric transcription factor complex are regulated by oxygen-dependent prolyl-hydroxylation, VHL-mediated ubiquitination and proteasomal degradation. Loss of pVHL function results in elevated levels of HIF-α due to increased stability, leading to RCC progression. While HIF-1α acts as a tumor suppressor, HIF-2α promotes oncogenic potential by driving tumor progression and metastasis through activation of hypoxia-sensitive signaling pathways and overexpression of HIF-2α target genes. One strategy to suppress ccRCC aggressiveness is directed at inhibition of HIF-2α and the associated molecular pathways leading to cell proliferation, angiogenesis, and metastasis. Indeed, clinical and pre-clinical data demonstrated the effectiveness of HIF-2α targeted therapy in attenuating ccRCC progression. This review focuses on the signaling pathways and the involved genes (cyclin D, c-Myc, VEGF-a, EGFR, TGF-α, GLUT-1) that confer oncogenic potential downstream of the VHL-HIF-2α signaling axis in ccRCC. Discussed as well are current treatment options (including receptor tyrosine kinase inhibitors such as sunitinib), the medical challenges (high prevalence of metastasis at the time of diagnosis, refractory nature of advanced disease to current treatment options), scientific challenges and future directions. [ABSTRACT FROM AUTHOR]

Simple Summary: We evaluated the efficacy and safety of immune checkpoint inhibitors (ICIs) and tyrosine kinase inhibitors (TKI) (ICI+TKI) in 51 patients with advanced or metastatic renal cell carcinoma (mRCC). In this study, 7.0 months was the median follow-up period. The overall survival rates at 6, 12, and 18 months were 93.1%, 82.5%, and 68.8%, respectively. The median progression-free survival (PFS) was 19.0 months. The objective response and disease control rates were 68.6% and 88.2%, respectively. Patients aged ≥70 years and those with poor-risk mRCC had significantly poorer PFS than their counterparts. ICI+TKI-related adverse events occurred in 43 patients (84.3%) with any grade and in 22 patients (43.1%) with grade ≥3. Treatment selection with poor prognostic factors may be prudent, even though ICI+TKI is an efficacious and safe first-line treatment in patients with mRCC. We evaluated the efficacy and safety of combination therapy with immune checkpoint inhibitors (ICIs) and tyrosine kinase inhibitors (TKI) as first-line therapy for patients diagnosed as having advanced or metastatic renal cell carcinoma (mRCC). We enrolled 51 patients to receive ICI+TKI therapy for mRCC at 9 Japanese institutions. The overall survival (OS) of the patients treated with ICI+TKI was the primary endpoint., and the secondary endpoints were progression-free survival (PFS), objective response rate (ORR), and disease control rate (DCR). Furthermore, we analyzed the clinical prognostic and predictive factors in patients with mRCC treated with ICI+TKI therapy. Seven months was the median follow-up period. The OS rates at 6, 12, and 18 months were 93.1, 82.5, and 68.8%, respectively. The median PFS for patients who received ICI+TKI was 19.0 months, ORR was 68.6%, and DCR was 88.2%. ICI+TKI-related adverse events occurred in 43 patients (84.3%) with any grade and in 22 patients (43.1%) with grade ≥3. Treatment selection with poor prognostic factors may be prudent, even though ICI+TKI is an efficacious and safe first-line treatment in patients with mRCC. [ABSTRACT FROM AUTHOR]

The role of cytoreductive nephrectomy has become unclear since the introduction of immunotherapy which is now the backbone of the treatment for metastatic renal cell carcinoma. Different combinations are used based on the prognosis. Achieving a complete response would be ideal and includes radiographic disappearance of lesions. However, there have been a few reported cases of pathological complete response with persistent radiographic evidence of cancer. The authors report a case of pathological complete response despite persistent radiographic evidence of residual disease in a patient with metastatic renal cell carcinoma treated with pembrolizumab and axitinib. The patient subsequently underwent cytoreductive nephrectomy after the 13th dose of pembrolizumab. The resected mass consisted of scar tissue with no viable tumor cells seen on pathology but only scar tissue. This case reveals that persistent radiographic evidence of the tumor may be explained by scar tissue, challenging the role of cytoreductive nephrectomy in the era of immunotherapy. [ABSTRACT FROM AUTHOR]

Simple Summary: Epigenetic modifications, such as DNA methylation and histone modification, have been found to alter in various cancer types. These modifications lead to uncontrolled cellular proliferation, evasion from apoptosis, and metastasis. Deregulation in epigenetic pathways often results in the suppression of tumor-suppression genes or activation of oncogenes in cancers. Inhibitors targeting deregulated enzymes can restore balance by reactivating altered pathways. Several inhibitors that target DNA methylation and histone modifications are currently being used in clinics and have shown promising results in cancer therapeutics. The three-dimensional architecture of genomes is complex. It is organized as fibers, loops, and domains that form high-order structures. By using different chromosome conformation techniques, the complex relationship between transcription and genome organization in the three-dimensional organization of genomes has been deciphered. Epigenetic changes, such as DNA methylation and histone modification, are the hallmark of cancers. Tumor initiation, progression, and metastasis are linked to these epigenetic modifications. Epigenetic inhibitors can reverse these altered modifications. A number of epigenetic inhibitors have been approved by FDA that target DNA methylation and histone modification. This review discusses the techniques involved in studying the three-dimensional organization of genomes, DNA methylation and histone modification, epigenetic deregulation in cancer, and epigenetic therapies targeting the tumor. [ABSTRACT FROM AUTHOR]

Simple Summary: Glycosaminoglycans (GAGs) are a class of carbohydrates that has been closely associated with cancer progression. GAGs have been implicated in cancer cell growth and are known to be involved in cell signaling. As GAGs are present in the extracellular matrix that surround tumor cells (tumor environment), they are intricately involved in the processes of cell migration and invasion, which are crucial for metastasis (spread to distant organs) to take place. Hence, the significance of this review is to explore the potential use of GAGs as biomarkers and therapeutic targets for metastatic renal cancer, which has poor rates of survival and faced with major challenges, that include lack of precise monitoring of disease treatment and effective treatment strategies with minimal toxicity. Renal cell carcinoma (RCC) makes up the majority of kidney cancers, with a poor prognosis for metastatic RCC (mRCC). Challenges faced in the management of mRCC, include a lack of reliable prognostic markers and biomarkers for precise monitoring of disease treatment, together with the potential risk of toxicity associated with more recent therapeutic options. Glycosaminoglycans (GAGs) are a class of carbohydrates that can be categorized into four main subclasses, viz., chondroitin sulfate, hyaluronic acid, heparan sulfate and keratan sulfate. GAGs are known to be closely associated with cancer progression and modulation of metastasis by modification of the tumor microenvironment. Alterations of expression, composition and spatiotemporal distribution of GAGs in the extracellular matrix (ECM), dysregulate ECM functions and drive cancer invasion. In this review, we focus on the clinical utility of GAGs as biomarkers for mRCC (which is important for risk stratification and strategizing effective treatment protocols), as well as potential therapeutic targets that could benefit patients afflicted with advanced RCC. Besides GAG-targeted therapies that holds promise in mRCC, other potential strategies include utilizing GAGs as drug carriers and their mimetics to counter cancer progression, and enhance immunotherapy through binding and transducing signals for immune mediators. [ABSTRACT FROM AUTHOR]

Simple Summary: To summarize the main discoveries made over the past few years to treat metastatic clear cell renal cell carcinoma, including different generations of anti-VEGF TKIs and immune checkpoint inhibitors (ICI), and provide an overview of the future developments to come in this field. We discuss new therapeutic approaches, such as escalation/de-escalation str. Clear cell renal cell carcinoma (RCC) oncogenesis is mainly driven by VHL gene inactivation, leading to overexpression of vascular endothelial growth factor (VEGF). The use of tyrosine-kinase inhibitors (TKIs) directed against VEGF and its receptor (VEGFR) revolutionised the management of metastatic renal cancer in the 2000s. The more recent development of next-generation TKIs such as cabozantinib or lenvatinib has made it possible to bypass some of the mechanisms of resistance to first-generation anti-VEGFR TKIs. During the decade 2010–2020, the development of immune checkpoint blockade (ICB) therapies revolutionised the management of many solid cancers, including RCC, in first- and subsequent-line settings. Dual ICB or ICB plus anti-VEGFR TKI combinations are now the standard of care for patients with advanced clear cell RCC. To optimise these combination therapies while preserving patient quality of life, escalation and de-escalation strategies are being evaluated in prospective randomised trials, based on patient selection according to their prognosis risk. Finally, new therapeutic approaches, such as targeting hypoxia-inducible factor (HIF) and the development of innovative treatments using antibody-drug conjugates (ADCs), CAR-T cells, or radiopharmaceuticals, are all potential candidates to improve further patient survival. [ABSTRACT FROM AUTHOR]

Simple Summary: Elevated serum C-reactive protein (CRP) level is one of the most established markers of systemic inflammation, potentially affecting tumor immune-microenvironmental status. Thus, we assessed the predictive value of serum CRP level for metastatic renal cell carcinoma (mRCC) treated with first-line ipilimumab and nivolumab using our real-world clinical dataset including non-clear cell RCC (nccRCC). Treatment record of 74 patients treated with ipilimumab and nivolumab for intermediate or poor-risk RCC defined by IMCD (international metastatic RCC database consortium). The one-year overall survival (OS) rate and objective response rate were 65% and 41% for all 74 mRCC patients, respectively. The receiver operating characteristic curve identified 1.0 mg/dL of serum CRP level as an ideal cut-off for predicting overall survival (OS). OS for patients with CRP > 1 mg/dL was significantly shorter than those with CRP < 1 mg/dL in both ccRCC (58 patient: p = 0.009) and nccRCC (16 patients: p = 0.008). The present study suggested that serum CRP level is a prognostic indicator for OS. Serum C-reactive protein (CRP) is known to be a biomarker for systemic inflammatory reactions. In the present study, we sought to measure the predictive value of serum CRP level for metastatic renal cell carcinoma (mRCC) treated with first-line ipilimumab and nivolumab using our real-world clinical dataset including non-clear cell RCC (nccRCC). The clinical record of patients who underwent the first-line ipilimumab plus nivolumab treatment for mRCC including ccRCC and nccRCC from 2018 to 2021 was retrospectively analyzed. All patients were diagnosed with either intermediate or poor-risk group defined by IMCD (international metastatic RCC database consortium). In total, 74 patients were involved. The median age was 68 years and 24 (32.4%) patients deceased during the follow-up. Forty-five (61%) and 29 (39%) patients were classified into intermediate and poor-risk groups. The one-year overall survival (OS) rate and objective response rate were 65% and 41% for all 74 mRCC patients, respectively. The receiver operating characteristic curve identified 1.0 mg/dL of serum CRP level as an ideal cut-off for predicting overall survival (OS). Serum CRP > 1.0 mg/dL and nccRCC were the independent predictors for OS in 74 mRCC patients. OS for patients with CRP > 1 mg/dL was significantly shorter than those with CRP < 1 mg/dL in both ccRCC (58 patient: p = 0.009) and nccRCC (16 patients: p = 0.008). The present study indicated that serum CRP level is a prognostic indicator for OS in both ccRCC and nccRCC patients treated with the first-line ipilimumab plus nivolumab treatment. [ABSTRACT FROM AUTHOR]

Simple Summary: The association between the tumor immune microenvironment (TIME) of primary lesions and time to metastasis remains unknown. The aim of our retrospective study was to investigate the differences in the TIME of primary lesions based on time intervals to metastasis, mainly between the synchronous group (SG; metastasis within 3 months) and metachronous group (MG; metastasis after 3 months), and its association with clinicopathological parameters in patients with metastatic renal cell carcinoma (mRCC). SG showed more immunogenic feature of TIME (PD-L1 positivity, CD8+ TIL infiltration) and poor prognostic pathological features (WHO/ISUP grade 4, necrosis, lymphovascular invasion, infiltrative growth pattern, and sarcomatoid differentiation). In addition, we observed that the time to metastasis differed by TIME characteristics (PD-L1 status, immunophenotype), which were associated with the WHO/ISUP grade. The TIME of primary lesions could affect the time to metastasis. Biological or immunological differences in primary lesions between synchronous and metachronous metastatic renal cell carcinoma (mRCC) have been reported. However, the association between the tumor immune microenvironment (TIME) of primary lesions and time to metastasis remains unknown. We investigated the differences in the TIME of primary lesions based on time intervals to metastasis, mainly between the synchronous group (SG; metastasis within 3 months) and metachronous group (MG; metastasis after 3 months), and its association with clinicopathological parameters in patients with mRCC. Overall, 568 patients treated first-line with vascular endothelial growth factor receptor inhibitors comprised the analysis population (SG: N = 307 [54.0%]; MG: N = 261 [46.0%]). SG had a higher proportion of patients with poor prognostic pathological feature tumors: WHO/ISUP grade 4, necrosis, lymphovascular invasion, infiltrative growth pattern, and sarcomatoid differentiation. Regarding the TIME, more immunogenic features were seen in SG than MG, with a higher PD-L1 positivity and a lower proportion of the desert phenotype. This is the first study to examine the differences in the TIME of primary lesions in patients with mRCC based on the time intervals to metastasis. The TIME of primary lesions could affect the time to metastasis. [ABSTRACT FROM AUTHOR]

Simple Summary: Despite the many ongoing advances in cancer prevention, diagnosis and clinical management, global mortality from human cancers remains at high levels. Notably, more effective treatment of many cancers is advancing due to introduction of novel biologic therapies targeted to tumor signaling and immunologic pathways. Tumor growth is dependent on a sustained blood supply of nutrients and oxygen, and this process termed tumor-associated angiogenesis (TAA) has prognostic and therapeutic importance in several human malignancies. This review addresses use of squalamines to stop tumor growth. This naturally occurring compound can inhibit angiogenesis in tumors thereby reducing malignant progression in preclinical studies and in early clinical trials. Mechanisms of action of squalamine in human vascular endothelial cells indicate that this compound attaches to cell membranes, potentially interacting with calmodulin, Na+/H+ exchanger isoform NHE3 and other signaling pathways involved in the angiogenic process. Thus, squalamine elicits blockade of VEGF-induced endothelial tube-like formation in vitro. Further, squalamine reduces growth of several preclinical models of human cancers in vivo and acts to stop metastatic tumor spread, actions due largely to blockade of angiogenesis induced by the tumor and tumor microenvironment. Squalamine in Phase I/II trials, alone or combined with standard care, shows promising antitumor activity with limited side-effects in patients with advanced solid cancers. Increased attention on squalamine regulation of signaling pathways with or without combination treatments in solid malignancies deserves further study. [ABSTRACT FROM AUTHOR]

Approximately 21% of patients with renal cell cancer (RCC) present with synchronous metastatic disease at the time of diagnosis, and metachronous metastatic disease occurs in 20–50% of cases within 5 years. Recent advances in adjuvant treatment of aggressive RCC following surgery suggest that biomarker-based prediction of risk for distant metastasis could improve patient selection. Biometrical analysis of TCGA-KIRC data identified candidate loci in the NK6 homeobox 2 gene (NKX6-2) that are hypermethylated in primary metastatic RCC. Analyses of NKX6-2 DNA methylation in three gene regions including a total of 16 CpG sites in 154 tumor-adjacent normal tissue, 189 RCC, and 194 metastatic tissue samples from 95 metastasized RCC patients revealed highly significant tumor-specific, primary metastatic-specific, and metastatic tissue-specific hypermethylation of NKX6-2. Combined CpG site methylation data for NKX6-2 and metastasis-associated genes (INA, NHLH2, and THBS4) demonstrated similarity between metastatic tissues and metastatic primary RCC tissues. The random forest method and evaluation of an unknown test cohort of tissues using receiver operator characteristic curve analysis revealed that metastatic tissues can be differentiated by a median area under the curve of 0.86 (p = 1.7 × 10−8–7.5 × 10−3) in 1000 random runs. Analysis of variable importance demonstrated an above median contribution for decision-making of at least one CpG site in each of the genes, suggesting superior informativity for sites annotated to NHLH2 and NKX6-2. Thus, DNA methylation of NKX6-2 is associated with the metastatic state of RCC tissues and contributes to a four-gene-based statistical predictor of tumoral and metastatic renal tissues. [ABSTRACT FROM AUTHOR]

The advent of immune checkpoint inhibitors in combination with multitarget tyrosine kinase inhibitors has become a standard first-line treatment for metastatic renal cell cancer. Along with survival improvement, new toxicities have emerged. Such adverse events are still complex to be managed and some of them are rare and could be insidious or even fatal. Medical oncologists dispose of guidelines about the management of toxicities from immune checkpoint inhibitors but not for combinations. Therefore, it is still difficult to properly attribute and manage additive or overlapping adverse events. We report two clinical cases regarding rare treatment-related endocrine toxicities—hypophysitis and thyroiditis—with particular focus on their management. To this purpose, immune checkpoint-related toxicities guidelines represent the starting point. However, their implementation with additional measures is needed, considering the increasing complexity of current clinical scenarios. The goal is to correctly recognize adverse events and address side effects, so as not to discontinue effective treatments. We, therefore, aim at discussing the points of proper management of toxicities and individuating potential areas of improvement. [ABSTRACT FROM AUTHOR]

Background: Stereotactic ablative body radiotherapy (SABR) is one of the treatment options for oligometastatic renal cell carcinoma (RCC) but is limited by a lack of data to evaluate high-dose SABR to all/multiple sites. Objective: This study retrospectively investigated the efficacy and prognostic factors of high-dose SABR for oligometastatic RCC patients. Design, setting, and participants: Patients with oligometastatic RCC on systemic therapy were retrospectively collected. Intervention(s): All patients were treated with SABR (40–50 Gy/5 fractions) for small tumors or partial-SABR (tumor center boosted with 6–8 Gy/3–5 fractions with 50–60 Gy/20–25 fractions to the whole tumor volume) for bulky tumors or tumors adjacent to critical organs. Outcome measurements and statistical analysis: Progression-free survival (PFS) and overall survival (OS) were calculated. Results and limitations: In total, 35 patients were enrolled, of which 88.5% had intermediate- or high-risk disease, with 60% on second- to fourth-line systemic therapy. The median follow-up time was 17 months. The median PFS and OS times were 11.3 and 29.7 months, respectively. Univariate analysis showed that an OS benefit was found in patients who received radiation before tyrosine kinase inhibitor (TKI) failure (p = 0.006) and where there was a short time interval (

Simple Summary: Kidney cancer occurs more commonly within the general population and has historically been associated with morbidity and early death. The most common form of kidney cancer is clear cell renal cell carcinoma. Thankfully, there now have multiple new therapies available for patients with metastatic disease that are improving the lives of patients. However, the number of new drugs and treatment types has created a degree of complexity in treatment planning. We review the most recent data in the metastatic disease space surrounding treatment for patients with newly diagnosed metastatic clear cell renal cell carcinoma. These treatments include surgery, radiation, and systemic therapies. Current systemic therapies include drugs that activate the immune system to target cancer cells and small-molecule drugs that target a cancer cell's ability to grow and survive. The therapeutic landscape for metastatic renal cell carcinoma has rapidly evolved over the years, and we are now in an era of combination therapy strategies employing immune checkpoint blockade and anti-angiogenesis targeted therapy. Since 2018, we have gained regulatory approval for four distinct combination therapies, all with survival benefits, and with guideline recommendation for use in the front-line setting. As such, treatment selection has become increasingly complex with a myriad of treatment choices but little high-level head-to-head data to guide treatment selection. Heterogeneity in tumor biology further complicates treatment selection as tumors vary in behavior and treatment responsiveness. Ongoing development of biomarkers will certainly assist in this setting, and validation of predictive markers represents an unmet need. In their absence, we highlight features of disease and nuances to datasets from landmark prospective clinical trials to help inform treatment selection. There is growing evidence to support deferring upfront systemic therapy in some patients, with opportunities for active surveillance or metastasis-directed therapy. In others, upfront systemic therapy is warranted and necessitates thoughtful consideration of multiple clinicopathologic parameters to inform optimal patient-centered decision making. [ABSTRACT FROM AUTHOR]

Simple Summary: We evaluated the efficacy and safety of molecular-targeted therapies (MTTs) in 29 patients who discontinued the combination therapy of nivolumab plus ipilimumab (NIVO+IPI) for advanced or metastatic renal cell carcinoma as real-world outcomes. Patients receiving MTTs had a median follow-up of 8 months. The objective response rate was 44.8%, and the disease control rate was 72.4%. After NIVO+IPI, the median overall survival was 18 months, and progression-free survival (PFS) was 8 months. Patients with bone metastases had a significantly shorter median PFS when treated with MTTs after NIVO+IPI than those without bone metastases (4 vs. 12 months, p = 0.012). MTTs may be a useful secondary treatment option after the discontinuation of NIVO+IPI. This study aimed to evaluate the effectiveness and safety of molecular-targeted therapies (MTTs) after the discontinuation of nivolumab and ipilimumab (NIVO+IPI) combination therapy in patients who had been diagnosed with advanced/metastatic renal cell carcinoma as real-world outcomes. We enrolled patients treated with MTTs following initial therapy with NIVO+IPI at nine institutions in Japan. We evaluated the objective response rate (ORR) as the primary endpoint and disease control rate (DCR), best overall response, and oncological outcomes (overall survival (OS) and progression-free survival (PFS)) as the secondary endpoints. We also evaluated factors predictive of disease progression after the administration of MTTs. Patients were followed up for a median of 8 months. The ORR was 44.8%, and the DCR was 72.4%. The median OS and PFS of MTTs after NIVO+IPI were 18 months and 8 months, respectively. A total of 31% of patients experienced grade 3/4 MTT-related adverse events. The median PFS in patients with bone metastases was significantly shorter than that in those without bone metastases (4 vs. 12 months, p = 0.012). MTTs may be a useful secondary treatment option after the discontinuation of NIVO+IPI. [ABSTRACT FROM AUTHOR]

Background. Sex, age, and International Metastatic Renal-Cell Carcinoma Database Consortium (IMDC) prognostic risk may influence the immune response. Nonetheless, the correlation between these factors and the survival benefits of immune-based combination therapies in patients with metastatic renal cell carcinoma (mRCC) is controversial and undefined. As a result, the purpose of this research is to evaluate the potential differences of immune-based combination therapies on survival benefits from mRCC subgroups. Methods. PubMed, Cochrane Library, Embase, and http://www.clinicaltrials.gov were searched from inception to March 17, 2022. Randomized clinical trials (RCTs) comparing overall survival (OS) or progression-free survival (PFS) in patients with mRCC treated by immune-based combinations vs. contemporary first-line therapies were included. Results. Five RCTs with a total of 4206 subjects were included. An OS and PFS benefit of immune-based combinations were found for patients of different sex, age, and IMDC intermediate/poor risk. No obvious difference in relative PFS benefit from immune-based combinations over the control group was found in patients of different genders (P = 0.71 , I2 = 0%), ages (P = 0.55 , I2 = 0%), or IMDC prognostic risks (P = 0.38 , I2 = 0%). However, the difference in OS benefit was significant regarding age (P = 0.009 , I2 = 85.5%) and IMDC prognostic risk (P = 0.004 , I2 = 82.2%). Conclusions. This meta-analysis found that immune-based combination therapies should not be restricted to certain patients with mRCC in gender categories. However, age and IMDC prognostic risk of mRCC patients are associated with different outcomes of OS and thus help identify those patients most probably to benefit from immune-based combination therapies. [ABSTRACT FROM AUTHOR]

While surgical resection has remained the mainstay of treatment in early-stage renal cell carcinoma (RCC), therapeutic options in the advanced setting have remarkably expanded over the last 20 years. Tyrosine kinase inhibitors targeting the vascular endothelial growth factor receptor (VEGF-TKIs) and anti-programmed cell death 1 (PD-1)/anti-programmed death-ligand 1 (PD-L1)-based immune checkpoint inhibitors (ICIs) have become globally accepted options in the upfront metastatic setting, with different ICI-based combination strategies improving overall survival compared to single-agent Sunitinib. Although some patients benefit from long-term responses, most eventually develop disease progression. Ongoing efforts to better understand the biology of RCC and the different mechanisms of acquired resistance have led to the identification of promising therapeutic targets. Belzutifan, a novel agent targeting the angiogenic pathway involving hypoxia-inducible factors (HIFs), has already been approved for the treatment of early-stage tumors associated with VHL disease and represents a very promising therapy in advanced RCC. Other putative targets include epigenetic regulation enzymes, as well as several metabolites such as adenosine, glutaminase and tryptophan, which are critical players in cancer cell metabolism and in the tumor microenvironment. Different methods of immune regulation are also being investigated, including CAR-T cell therapy and modulation of the gut microbiome, in addition to novel agents targeting the interleukin-2 (IL-2) pathway. This review aims to highlight the emergent novel therapies for RCC and their respective completed and ongoing clinical trials. [ABSTRACT FROM AUTHOR]

Simple Summary: Renal cell carcinoma (RCC) is the sixth most frequently diagnosed cancer in men and the tenth in women with a rising incidence. The treatment of metastasized RCC has dramatically changed in the last decade, improving the overall survival of patients significantly. In this context, cornerstones of the treatment have been tyrosine kinase inhibitors (TKI), with Sunitinib being the preferred first-line treatment for most cases. With the introduction of immunotherapy and combination therapy, this changed recently. The current article summarizes the available literature on TKI treatment of metastasized RCC and shows the current part of TKIs in the treatment algorithm as well as its potential future role. Background: To review and discuss the literature on applying tyrosine kinase inhibitors (TKIs) in the treatment of metastasised renal cell carcinoma (mRCC). Materials and Methods: Medline, PubMed, the Cochrane database, and Embase were screened for randomised controlled trials, clinical trials, and reviews on treating renal cell carcinoma, and the role of TKI. Each substance's results were summarised descriptively. Results: While TKI monotherapy is not currently recommended as a first-line treatment for metastasized renal cell carcinoma, TKIs are regularly applied to treat treatment-naïve patients in combination with immunotherapy. TKIs depict the first-choice alternative therapy if immunotherapy is not tolerated or inapplicable. Currently, seven different TKIs are available to treat mRCC. Conclusions: The importance of TKIs in a monotherapeutic approach has declined in the past few years. The current trend toward combination therapy for mRCC, however, includes TKIs as one significant component of treatment regimens. We found that to remain applicable to ongoing studies, both when including new substances and when testing novel combinations of established drugs. TKIs are of major importance for the treatment of renal cancer now, as well as for the foreseeable future. [ABSTRACT FROM AUTHOR]

Simple Summary: Renal cell carcinoma (RCC) in metastatic form is a lethal pathology difficult to treat; therefore, the research of new therapeutic options for the treatment of metastatic patients is crucial to improve quality of life and overall survival. Recently, new signaling pathways and biological processes involved in cancer development and progression by scientific research community have been identified. These components including factors affecting angiogenesis, cell migration and invasion, autophagy and ferroptosis that are dysregulated in kidney cancer represent novel possible target molecules. In this work, we discuss current and new therapies for kidney cancer treatment; in particular, agents targeting new molecules involved in renal carcinogenesis that in future might become more powerful drugs for the cure of metastatic RCC. Patients suffering from metastatic renal cell carcinoma (mRCC) show an overall survival rate of lower than 10% after 5 years from diagnosis. Currently, the first-line treatment for mRCC patients is based on antiangiogenic drugs that are able to inhibit tyrosine kinase receptors (TKI) in combination with immuno-oncology (IO) therapy or IO-IO treatments. Second-line therapy involves the use of other TKIs, immunotherapeutic drugs, and mTOR inhibitors. Nevertheless, many patients treated with mTOR and TK inhibitors acquire drug resistance, making the therapy ineffective. Therefore, the research of new therapeutic targets is crucial for improving the overall survival and quality of life of mRCC patients. The investigation of the molecular basis of RCC, especially in clear cell renal cell carcinoma (ccRCC), has led to the identification of different signaling pathways that are involved in renal carcinogenesis. Most of ccRCCs are associated with mutation in VHL gene, which mediates the degradation of hypoxia-inducible factors (HIFs), that, in turn, regulate the pathways related to tumorigenesis, including angiogenesis and invasion. Renal tumorigenesis is also associated with the activation of tyrosine kinases that modulate the PI3K-Akt-mTOR pathway, promoting cell proliferation and survival. In ccRCC, the abnormal activity of mTOR activates the MDM2 protein, which leads to the degradation of tumor suppressor p53 via proteasome machinery. In addition, p53 may be degraded by autophagy in a mechanism involving the enzyme transglutaminase 2 (TG2). Suppression of wild-type p53 promotes cell growth, invasion, and drug resistance. Finally, the activation of ferroptosis appears to inhibit cancer progression in RCC. In conclusion, these pathways might represent new therapeutic targets for mRCC. [ABSTRACT FROM AUTHOR]

Simple Summary: Nowadays, most metastatic renal cell carcinoma (mRCC) patients are candidates for immunotherapy. Risk stratification is based on the IMDC model that was developed in an earlier era of vascular endothelial growth factor receptor inhibitors (VEGFRi). An updated, more accurate model is needed. This paper suggests an updated risk-stratification model based on five factors that are strongly correlated with overall survival in a real-world cohort of patients with mRCC treated with checkpoint inhibitors in any line of treatment during the course of their disease. Compared with the commonly used IMDC criteria, in this cohort, our model was better able to predict survival. Immunotherapy has transformed the landscape of treatment in metastatic renal cell carcinoma (mRCC) in the last decade. Currently, prognostic risk stratification is based on the model developed in the era of vascular endothelial growth factor receptor inhibitors (VEGFRi) by Heng in 2009. Our study aims to find the most relevant risk criteria for mRCC patients treated with checkpoint inhibitors (CPI). In a retrospective cohort study, laboratory, pathology, demographic, and clinical data were retrieved from electronic medical records of consecutive mRCC patients treated with CPI in a tertiary center between 2015 and 2020. An unbiased multivariate analysis was performed to define predictive variables with a bootstrap validation step. We analyzed data on 127 patients with a median follow-up of 60 months. The median overall survival (OS) since the diagnosis of metastatic disease was 57 months. The response rate for CPI was 39%. Five risk factors were correlated with worse OS: intact primary kidney tumor (HR 2.33, p = 0.012), liver metastasis (HR 3.33, p = 0.001),