Tertiary lymphoid structures generate and propagate anti-tumor antibody-producing plasma cells in renal cell cancer.

The presence of intratumoral tertiary lymphoid structures (TLS) is associated with positive clinical outcomes and responses to immunotherapy in cancer. Here, we used spatial transcriptomics to examine the nature of B cell responses within TLS in renal cell carcinoma (RCC). B cells were enriched in TLS, and therein, we could identify all B cell maturation stages toward plasma cell (PC) formation. B cell repertoire analysis revealed clonal diversification, selection, expansion in TLS, and the presence of fully mature clonotypes at distance. In TLS+ tumors, IgG- and IgA-producing PCs disseminated into the tumor beds along fibroblastic tracks. TLS+ tumors exhibited high frequencies of IgG-producing PCs and IgG-stained and apoptotic malignant cells, suggestive of anti-tumor effector activity. Therapeutic responses and progression-free survival correlated with IgG-stained tumor cells in RCC patients treated with immune checkpoint inhibitors. Thus, intratumoral TLS sustains B cell maturation and antibody production that is associated with response to immunotherapy, potentially via direct anti-tumor effects.

In vivo screens using a selective CRISPR antigen removal lentiviral vector system reveal immune dependencies in renal cell carcinoma.

CRISPR-Cas9 genome engineering has increased the pace of discovery for immunology and cancer biology, revealing potential therapeutic targets and providing insight into mechanisms underlying resistance to immunotherapy. However, endogenous immune recognition of Cas9 has limited the applicability of CRISPR technologies in vivo. Here, we characterized immune responses against Cas9 and other expressed CRISPR vector components that cause antigen-specific tumor rejection in several mouse cancer models. To avoid unwanted immune recognition, we designed a lentiviral vector system that allowed selective CRISPR antigen removal (SCAR) from tumor cells. The SCAR system reversed immune-mediated rejection of CRISPR-modified tumor cells in vivo and enabled high-throughput genetic screens in previously intractable models. A pooled in vivo screen using SCAR in a CRISPR-antigen-sensitive renal cell carcinoma revealed resistance pathways associated with autophagy and major histocompatibility complex class I (MHC class I) expression. Thus, SCAR presents a resource that enables CRISPR-based studies of tumor-immune interactions and prevents unwanted immune recognition of genetically engineered cells, with implications for clinical applications.

An interdisciplinary consensus on the management of brain metastases in patients with renal cell carcinoma.

Brain metastases are a challenging manifestation of renal cell carcinoma. We have a limited understanding of brain metastasis tumor and immune biology, drivers of resistance to systemic treatment, and their overall poor prognosis. Current data support a multimodal treatment strategy with radiation treatment and/or surgery. Nonetheless, the optimal approach for the management of brain metastases from renal cell carcinoma remains unclear. To improve patient care, the authors sought to standardize practical management strategies. They performed an unstructured literature review and elaborated on the current management strategies through an international group of experts from different disciplines assembled via the network of the International Kidney Cancer Coalition. Experts from different disciplines were administered a survey to answer questions related to current challenges and unmet patient needs. On the basis of the integrated approach of literature review and survey study results, the authors built algorithms for the management of single and multiple brain metastases in patients with renal cell carcinoma. The literature review, consensus statements, and algorithms presented in this report can serve as a framework guiding treatment decisions for patients. CA Cancer J Clin. 2022;72:454-489.

Crosstalk of disulfidptosis-related subtypes identifying a prognostic signature to improve prognosis and immunotherapy responses of clear cell renal cell carcinoma patients.

BACKGROUND: Disulfidptosis is a novel form of programmed cell death induced by high SLC7A11 expression under glucose starvation conditions, unlike other known forms of cell death. However, the roles of disulfidptosis in cancers have yet to be comprehensively well-studied, particularly in ccRCC. METHODS: The expression profiles and somatic mutation of DGs from the TCGA database were investigated. Two DGs clusters were identified by unsupervised consensus clustering analysis, and a disulfidptosis-related prognostic signature (DR score) was constructed. Furthermore, the predictive capacity of the DR score in prognosis was validated by several clinical cohorts. We also developed a nomogram based on the DR score and clinical features. Then, we investigated the differences in the clinicopathological information, TMB, tumor immune landscapes, and biological characteristics between the high- and low-risk groups. We evaluated whether the DR score is a robust tool for predicting immunotherapy response by the TIDE algorithm, immune checkpoint genes, submap analysis, and CheckMate immunotherapy cohort. RESULTS: We identified two DGs clusters with significant differences in prognosis, tumor immune landscapes, and clinical features. The DR score has been demonstrated as an independent risk factor by several clinical cohorts. The high-risk group patients had a more complicated tumor immune microenvironment and suffered from more tumor immune evasion in immunotherapy. Moreover, patients in the low-risk group had better prognosis and response to immunotherapy, particularly in anti-PD1 and anti-CTLA-4 inhibitors, which were verified in the CheckMate immunotherapy cohort. CONCLUSION: The DR score can accurately predict the prognosis and immunotherapy response and assist clinicians in providing a personalized treatment regime for ccRCC patients.

Evolution of cell therapy for renal cell carcinoma.

Treatment for renal cell carcinoma (RCC) has improved dramatically over the last decade, shifting from high-dose cytokine therapy in combination with surgical resection of tumors to targeted therapy, immunotherapy, and combination therapies. However, curative treatment, particularly for advanced-stage disease, remains rare. Cell therapy as a "living drug" has achieved hematological malignancy cures with a high response rate, and significant research efforts have been made to facilitate its translation to solid tumors. Herein, we overview the cellular therapies for RCC focusing on allogeneic hematopoietic stem cell transplantation, T cell receptor gene-modified T cells, chimeric antigen receptor (CAR) T cells, CAR natural killer (NK) cells, lymphokine-activated killer (LAK) cells, γδ T cells, and dendritic cell vaccination. We have also included perspectives for using other recent approaches, such as CAR macrophages, dendritic cell-cytokine induced killer cells and regulatory CAR-T cells to shed light on preclinical development of cell therapy and advancing cell therapy into clinic to achieve cures for RCC.

Treatment and outcomes of clear cell sarcoma of the kidney: A report from the Children's Oncology Group studies AREN0321 and AREN03B2.

BACKGROUND: On the fifth National Wilms Tumor Study, treatment for clear cell sarcoma of the kidney (CCSK) included combined vincristine, doxorubicin, cyclophosphamide, and etoposide (regimen I) plus radiation therapy (RT), yielding 5-year event-free survival (EFS) rates of 100%, 88%, 73%, and 29% for patients who had with stage I, II, III, and IV disease, respectively. In the Children's Oncology Group study AREN0321 of risk-adapted therapy, RT was omitted for stage I disease if lymph nodes were sampled, and carboplatin was added for stage IV disease (regimen UH-1). Patients who had stage II/III disease received regimen I with RT. METHODS: Four-year EFS was analyzed for patients enrolled on AREN0321 and on those enrolled on AREN03B2 who received AREN0321 stage-appropriate chemotherapy. RESULTS: Eighty-two patients with CCSK enrolled on AREN0321, 50 enrolled on AREN03B2 only. The 4-year EFS rate was 82.7% (95% confidence interval [CI], 74.8%-91.4%) for AREN0321 and 89.6% (95% CI, 81.3%-98.7%) for AREN03B2 only (p = .28). When combining studies, the 4-year EFS rates for patients who had stage I (n = 10), II (n = 47), III (n = 65), and IV (n = 10) disease were 90% (95% CI, 73.2%-100.0%), 93.4% (95% CI, 86.4%-100.0%), 82.8% (95% CI, 74.1%-92.6%), and 58.3% (95% CI, 34%-100.0%), respectively. There were no local recurrences among seven patients with stage I disease who were treated without RT. One stage I recurrence occurred in the brain, which was the most common site of relapse overall. Among patients with local stage III tumors, neither initial procedure type, margin status, nor lymph node involvement were prognostic. CONCLUSIONS: Patients with stage I CCSK had excellent outcomes without local recurrences when treated without RT. Patients with stage IV disease appeared to benefit from a carboplatin-containing regimen, although their outcomes remained unsatisfactory. Further research is needed to improve outcomes for patients with advanced-stage disease (ClinicalTrials.gov identifiers NCT00335556 and NCT00898365).

Altered regulation of DPF3, a member of the SWI/SNF complexes, underlies the 14q24 renal cancer susceptibility locus.

Our study investigated the underlying mechanism for the 14q24 renal cell carcinoma (RCC) susceptibility risk locus identified by a genome-wide association study (GWAS). The sentinel single-nucleotide polymorphism (SNP), rs4903064, at 14q24 confers an allele-specific effect on expression of the double PHD fingers 3 (DPF3) of the BAF SWI/SNF complex as assessed by massively parallel reporter assay, confirmatory luciferase assays, and eQTL analyses. Overexpression of DPF3 in renal cell lines increases growth rates and alters chromatin accessibility and gene expression, leading to inhibition of apoptosis and activation of oncogenic pathways. siRNA interference of multiple DPF3-deregulated genes reduces growth. Our results indicate that germline variation in DPF3, a component of the BAF complex, part of the SWI/SNF complexes, can lead to reduced apoptosis and activation of the STAT3 pathway, both critical in RCC carcinogenesis. In addition, we show that altered DPF3 expression in the 14q24 RCC locus could influence the effectiveness of immunotherapy treatment for RCC by regulating tumor cytokine secretion and immune cell activation.

The 5th Kidney Cancer Research Summit: Research Accelerating Cures for Renal Cell Carcinoma in 2023.

The 5th Kidney Cancer Research Summit was a hybrid event hosted in Boston, MA in July 2023. As in previous editions, the conference attracted a wide representation of global thought leaders in kidney cancer spanning all stages of clinical and laboratory research. Sessions covered tumor metabolism, novel immune pathways, advances in clinical trials and immunotherapy, and progress toward biomarkers. The abstract presentations were published as a supplement in The Oncologist (https://academic.oup.com/oncolo/issue/28/Supplement_1). Aiming to be more concise than comprehensive, this commentary summarizes the most important emerging areas of kidney cancer research discussed and debated among the stakeholders at the conference, with relevant updates that have occurred since.

USP31 serves as a potential biomarker for predicting prognosis and immune responses for clear cell renal cell carcinoma via single-cell and bulk RNA-sequencing.

BACKGROUND: Currently, there is no research available on the prognosis, potential effect and therapeutic value of USP31 in clear cell renal cell carcinoma (ccRCC). To address this gap, the present study aimed to shed light on its potential roles and possible mechanisms in ccRCC. METHODS: R software was utilized to conduct bioinformatics analyses with the data derived from The Cancer Genome Atlas (i.e. KIRC) and Gene Expression Omnibus datasets. The expression of USP31 in ccRCC was validated by a PCR. The independent prognostic ability of USP31 was evaluated by Cox regression analysis. We conducted gene set enrichment analysis (GSEA) to explore the potential USP31-related pathways. We also discussed the relationships between USP31 and immunity, by predicting its possible upstream transcription factors (TFs) by ChEA3. RESULTS: In ccRCC, USP31 demonstrated a high level of expression and this increased expression was correlated with a poor prognosis (p < 0.05). Through univariate and multivariate Cox regression analysis, USP31 was identified as an independent prognostic factor for ccRCC (p < 0.05). Furthermore, eight USP31-related pathways were identified by GSEA (p < 0.05). Moreover, USP31 was found to be associated with microsatellite instability, tumor microenvironment, a variety of immune cells and immune checkpoints and immune infiltration (p < 0.05). Additionally, Patients with high USP31 expression in ccRCC were shown to have better curative effects after immunotherapy (p < 0.05). Finally, we found that AR, USF1, MXI1 and CLOCK could be the potential upstream TFs of USP31. CONCLUSIONS: USP31 could serve as a potential biomarker for predicting both prognosis and immune responses, revealing its potential mechanisms of TF-USP31 mRNA networks in ccRCC.

Dual-loss of PBRM1 and RAD51 identifies hyper-sensitive subset patients to immunotherapy in clear cell renal cell carcinoma.

BACKGROUND: Homologous recombination deficiency (HRD), though largely uncharacterized in clear cell renal cell carcinoma (ccRCC), was found associated with RAD51 loss of expression. PBRM1 is the second most common mutated genes in ccRCC. Here, we introduce a HRD function-based PBRM1-RAD51 ccRCC classification endowed with diverse immune checkpoint blockade (ICB) responses. METHODS: Totally 1542 patients from four independent cohorts were enrolled, including our localized Zhongshan hospital (ZSHS) cohort and Zhongshan hospital metastatic RCC (ZSHS-mRCC) cohort, The Cancer Genome Atlas (TCGA) cohort and CheckMate cohort. The genomic profile and immune microenvironment were depicted by genomic, transcriptome data and immunohistochemistry. RESULTS: We observed that PBRM1-loss ccRCC harbored enriched HRD-associated mutational signature 3 and loss of RAD51. Dual-loss of PBRM1 and RAD51 identified patients hyper-sensitive to immunotherapy. This dual-loss subtype was featured by M1 macrophage infiltration. Dual-loss was, albeit homologous recombination defective, with high chromosomal stability. CONCLUSIONS: PBRM1 and RAD51 dual-loss ccRCC indicates superior responses to immunotherapy. Dual-loss ccRCC harbors an immune-desert microenvironment but enriched with M1 macrophages. Dual-loss ccRCC is susceptible to defective homologous recombination but possesses high chromosomal stability.

The development of chimeric antigen receptor T-cells against CD70 for renal cell carcinoma treatment.

In this study, we investigated CD70 as a promising target for renal cell carcinoma (RCC) therapy and developed a potent chimeric antigen receptor T (CAR-T) cells for potential clinical testing. CD70, found to be highly expressed in RCC tumors, was associated with decreased survival. We generated CAR-T cells expressing VHH sequence of various novel nanobodies from immunized alpaca and a single-chain variable fragment (scFv) derived from human antibody (41D12). In our in vitro experiments, anti-CD70 CAR-T cells effectively eliminated CD70-positive tumor cells while sparing CD70-negative cells. The nanobody-based CAR-T cells demonstrated significantly higher production of cytokines such as IL-2, IFN-γ and TNF-ɑ during co-culture, indicating their potential for enhanced functionality. In xenograft mouse model, these CAR-T cells exhibited remarkable anti-tumor activity, leading to the eradication of RCC tumor cells. Importantly, human T cell expansion after infusion was significantly higher in the VHH groups compared to the scFv CAR-T group. Upon re-challenging mice with RCC tumor cells, the VHH CAR-T treated group remained tumor-free, suggesting a robust and long-lasting anti-tumor response. These findings provide strong support for the potential of nanobody-based CD70 CAR-T cells as a promising therapeutic option for RCC. This warrants further development and consideration for future clinical trials and applications.

Swine pseudorabies virus attenuated vaccine reprograms the kidney cancer tumor microenvironment and synergizes with PD-1 blockade.

The global incidence rate of kidney cancer (KC) has been steadily increasing over the past 30 years. With the aging global population, kidney cancer has become an escalating concern that necessitates vigilant surveillance. Nowadays, surgical intervention remains the optimal therapeutic approach for kidney cancer, while the availability of efficacious treatments for advanced tumors remains limited. Oncolytic viruses, an emerging form of immunotherapy, have demonstrated encouraging anti-neoplastic properties and are progressively garnering public acceptance. However, research on oncolytic viruses in kidney cancer is relatively limited. Furthermore, given the high complexity and heterogeneity of kidney cancer, it is crucial to identify an optimal oncolytic virus agent that is better suited for its treatment. The present study investigates the oncolytic activity of the Pseudorabies virus live attenuated vaccine (PRV-LAV) against KC. The findings clearly demonstrate that PRV-LAV exhibits robust oncolytic activity targeting KC cell lines. Furthermore, the therapeutic efficacy of PRV-LAV was confirmed in both a subcutaneous tumor-bearing nude mouse model and a syngeneic mouse model of KC. Combined RNA-seq analysis and flow cytometry revealed that PRV-LAV treatment substantially enhances the infiltration of a diverse range of lymphocytes, including T cells, B cells, macrophages, and NK cells. Additionally, PRV-LAV treatment enhances T cell activation and exerts antitumor effects. Importantly, the combination of PRV-LAV with anti-PD-1 antibodies, an approved drug for KC treatment, synergistically enhances the efficacy against KC. Overall, the discovery of PRV-LAV as an effective oncolytic virus holds significant importance for improving the treatment efficacy and survival rates of KC patients.

Identification of PANoptosis-related signature reveals immune infiltration characteristics and immunotherapy responses for renal cell carcinoma.

PANoptosis is a specific type of inflammatory programmed cell death (PCD) modality that can be involved in three key modes of cellular programmed cell death-pyroptosis, apoptosis and necroptosis. We analyzed PANoptosis activity in three common renal cell carcinoma subtypes (Clear cell renal cell carcinoma, Papillary renal cell carcinoma, and Chromophobe renal cell carcinoma) separately and constructed a new PANoptosis immunity index (PANII). In three renal cell carcinomas, we found that PANII was an effective predictor of immunotherapy efficacy in KIRC, KIRP and KICH, and the high PANII group was characterized by high immune infiltration and sensitivity to immunotherapy, while the low PANII group was prone to immune escape and immunotherapy resistance. We performed molecular docking prediction of each core protein comprising PANII and identified natural small molecule compounds with the highest affinity to target proteins. In addition, we found that down-regulation of PYCARD inhibited the proliferation and migration of renal clear cell carcinoma cells by in vitro functional assays, suggesting that PYCARD could be a novel target for renal clear cell carcinoma therapy. Our findings that the PANoptosis characterization-based index (PANII) helps to elucidate the tumor microenvironmental features of three common renal cell carcinoma subtypes and identify patient populations that will benefit from immunotherapy, providing a new tool for the clinical diagnosis and treatment of patients with intermediate- and advanced-stage renal cell carcinoma.

The vasculogenic mimicry related signature predicts the prognosis and immunotherapy response in renal clear cell carcinoma.

BACKGROUND: Clear cell carcinoma of the kidney is a common urological malignancy characterized by poor patient prognosis and treatment outcomes. Modulation of vasculogenic mimicry in tumor cells alters the tumor microenvironment and the influx of tumor-infiltrating lymphocytes, and the combination of its inducers and immune checkpoint inhibitors plays a synergistic role in enhancing antitumor effects. METHODS: We downloaded the data from renal clear cell carcinoma samples and vasculogenic mimicry-related genes to establish a new vasculogenic mimicry-related index (VMRI) using a machine learning approach. Based on VMRI, patients with renal clear cell carcinoma were divided into high VMRI and low VMRI groups, and patients' prognosis, clinical features, tumor immune microenvironment, chemotherapeutic response, and immunotherapeutic response were systematically analyzed. Finally, the function of CDH5 was explored in renal clear cell carcinoma cells. RESULTS: VMRI can be used for prognostic and immunotherapy efficacy prediction in a variety of cancers, which consists of four vasculogenic mimicry-related genes (CDH5, MMP9, MAPK1, and MMP13), is a reliable predictor of survival and grade in patients with clear cell carcinoma of the kidney and has been validated in multiple external datasets. We found that the high VMRI group presented higher levels of immune cell infiltration, which was validated by pathological sections. We performed molecular docking prediction of vasculogenic mimicry core target proteins and identified natural small molecule drugs with the highest affinity for the target protein. Knockdown of CDH5 inhibited the proliferation and migration of renal clear cell carcinoma. CONCLUSIONS: The VMRI identified in this study allows for accurate prognosis assessment of patients with renal clear cell carcinoma and identification of patient populations that will benefit from immunotherapy, providing valuable insights for future precision treatment of patients with renal clear cell carcinoma.

NCCN Guidelines® Insights: Kidney Cancer, Version 2.2024.

The NCCN Guidelines for Kidney Cancer provide multidisciplinary recommendations for diagnostic workup, staging, and treatment of patients with renal cell carcinoma (RCC). These NCCN Guidelines Insights focus on the systemic therapy options for patients with advanced RCC and summarize the new clinical data evaluated by the NCCN panel for the recommended therapies in Version 2.2024 of the NCCN Guidelines for Kidney Cancer.

Clear cell and non-clear cell renal cell carcinoma in young adults: clinicopathological features, survival outcomes and prognostic factors.

OBJECTIVES: Renal cell carcinoma (RCC) is infrequent among young adults. Few studies reported the outcome of RCC in young adults by pathological subtypes. The purpose of this study was to explore the clinicopathological features, survival outcomes and prognostic factors of young adult patients with clear cell (CCRCC) and non-clear cell renal cell carcinoma (NCCRCC). METHODS: This study included young adult patients aged 18-40 years who were diagnosed as renal cell carcinoma (RCC) between 2012 and 2022 at Peking University Third Hospital. All patients underwent either partial nephrectomy or radical nephrectomy, and some received adjuvant therapy. A comparative analysis was performed to investigate the differences in clinicopathological characteristics between the cohort of CCRCC and NCCRCC. Kaplan-Meier survival analysis was utilized to plot survival curves for young adults with RCC. The univariate and multifactorial prognostic analyses were conducted using the log-rank test and COX proportional hazards model. RESULTS: A total of 300 RCC patients aged 18-40 years were performed, of which 201 were diagnosed with CCRCC (67%) and 99 were diagnosed with NCCRCC(33%). The NCCRCC included 29 cases (9.7%) of chromophobe RCC, 28 cases (9.3%) of MiT family translocation RCC, 22 cases (7.3%) of papillary RCC, 11 cases (3.7%) of low malignant potential multifocal cystic RCC, and 6 cases of unclassified RCC (2.0%), 2 cases of mucinous tubule and spindle cell carcinoma (0.7%), and 1 case of FH-deficient RCC (0.3%).The mean age was 33.4 ± 6.1 years old. The overall and progression free 5-year survival rate was 99.1 and 95.3%, respectively. The NCCRCC cohort demonstrated a statistically significant decrease in progression-free survival (PFS) rate when compared to the CCRCC cohort (p < 0.001). There was no statistically significant difference observed in overall survival (OS) (p = 0.069). Pathological stage was a significant independent predictor for OS (p = 0.045). Pathological stage and nuclear grade were both independent predictors for PFS (p = 0.020; p = 0.005). CONCLUSIONS: The clinical and pathological features of young adults diagnosed with CCRCC exhibit notable distinctions from those of NCCRCC patients. The survival outcome was significantly influenced by the pathological stage, while both the nuclear grade and pathological stage had a significant impact on tumor progression. This study offered significant contributions to the understanding of the clinicopathological characteristics and prognostic determinants of renal cell carcinoma (RCC) in young adults.

The impact of the COVID-19 pandemic on renal cancer care.

PURPOSE: To evaluate the impact of the COVID-19 pandemic on renal cell carcinoma (RCC) care in the Netherlands. METHODS: Newly diagnosed RCCs between 2018 and 2021 were selected from the Netherlands Cancer Registry; 2020-2021 was defined as COVID period and 2018-2019 as reference period. Numbers of RCCs were evaluated using 3-week-moving averages, overall and by disease stage and age. Changes in treatment were evaluated with logistic regression analyses. To evaluate possible delays in care, time to start of treatment was assessed. The cumulative number of metastatic RCC (mRCC) over time was assessed to evaluate stage shift. RESULTS: During the 1st COVID wave (weeks 9-22, 2020), the number of new RCC diagnoses decreased with 15%. Numbers restored partially in 2020, but remained 10% lower compared to 2018/2019. The decline was mostly due to a drop in T1a/T1b RCCs and in age > 70 years. 2021 showed similar numbers of new RCC diagnoses compared to 2018/2019 without an increase due to previously missed RCCs. Treatment-related changes during the 1st COVID wave were limited and temporarily; less surgery in T1a RCCs in favor of more active surveillance, and in mRCC targeted therapy was preferred over immunotherapy. Time to start of firstline treatment was not prolonged during the 1st COVID wave. No increase in mRCC was found until the end of 2021. CONCLUSIONS: The COVID-19 pandemic resulted in fewer RCC diagnoses, especially T1a/T1b tumors. Treatment-related changes appeared to be limited, temporarily and in accordance with the adapted guidelines. The diagnostic delay could lead to more advanced RCCs in later years but there are no indications for this yet.

Survival benefit of nephroureterectomy in systemic therapy exposed metastatic upper tract urinary urothelial carcinoma patients.

BACKGROUND: It is unknown whether the stage of the primary may influence the survival (OS) of metastatic upper tract urothelial carcinoma (mUTUC) patients treated with nephroureterectomy (NU) and systemic therapy (ST). We tested this hypothesis within a large-scale North American cohort. METHODS: Within Surveillance Epidemiology and End Results database 2000-2020, all mUTUC patients treated with ST+NU or with ST alone were identified. Kaplan-Maier plots depicted OS. Multivariable Cox regression (MCR) models tested for differences between ST+NU and ST alone predicting overall mortality (OM). All analyses were performed in localized (T1-T2) and then repeated in locally advanced (T3-T4) patients. RESULTS: Of all 728 mUTUC patients, 187 (26%) harbored T1-T2 vs 541 (74%) harbored T3-T4. In T1-T2 patients, the median OS was 20 months in ST+NU vs 10 months in ST alone. Moreover, in MCR analyses that also relied on 3 months' landmark analyses, the combination of ST+NU independently predicted lower OM (HR 0.37, p < 0.001). Conversely, in T3-T4 patients, the median OS was 12 in ST+NU vs 10 months in ST alone. Moreover, in MCR analyses that also relied on 3 months' landmark analyses, the combination of ST+NU was not independently associated with lower OM (HR 0.85, p = 0.1). CONCLUSIONS: In mUTUC patients, treated with ST, NU drastically improved survival in T1-T2 patients, even after strict methodological adjustments (multivariable and landmark analyses). However, this survival benefit did not apply to patients with locally more advanced disease (T3-T4).

Definitions and unmet needs in the management of oligomestatic renal cell carcinoma in the modern era.

PURPOSE OF REVIEW: Oligometastatic renal cell carcinoma (RCC) is a complex entity, potentially leading to a specific clinical management of these patients. Recent and ongoing trials have raised several unresolved questions that could impact clinical routine practice, advocating for the integration of novel treatment options (systemic treatment, cytoreductive surgery, or stereotactic body radiotherapy - SBRT) with varied modalities and objectives. RECENT FINDINGS: Immunotherapy represents a breakthrough in the systemic treatment of mRCC. However, many questions are still unsolved regarding the perfect timing for starting systemic and whether the systemic treatment could improve the activity of metastases-directed strategies. Moreover, the widespread use of adjuvant immunotherapy will challenge the treatment paradigm in the oligorecurrent scenario. Radical surgery of metastases and more recently SBRT - both eventually associated with systemic treatment - actually represent two important approaches to be considered in oligometastatic patients. SUMMARY: Oligometastatic RCC represents a status including a wide spectrum of clinical conditions that requires a tailored treatment approach. The correct management integrates local approaches (either metastasectomy or SRBT) and systemic (immune)-therapy. Several unmet needs have to be investigated, mainly regarding the lack of prospective randomized trials that directly compare modern therapies and different integration strategies.

Defining oligometastatic state in uro-oncological cancers.

PURPOSE OF REVIEW: Oligometastatic tumors illustrate a distinct state between localized and systematic disease and might harbor unique biologic features. Moreover, these tumors represent a different clinical entity, with a potential of long-term disease control or even cure, therefore they receive growing attention in the field of urologic oncology. RECENT FINDINGS: Currently, there is no consensus on the definition of oligometastatic prostate cancer, most experts limit it to a maximum of three to five lesions and involvement of no more than two organs, excluding visceral metastases. Quality data on oligometastatic bladder cancer is scarce, however, a consensus of experts defined it as a maximum of three metastatic lesions, either resectable or suitable for stereotactic therapy, without restrictions to the number of organs involved. As for kidney cancer, a maximum number of five metastases, without limitations to the location are defined as oligometastatic, with an important implication of timing of developing metastases since diagnosis of the primary tumor. SUMMARY: Defining oligometastatic state among urological tumors reflecting their distinct biological and clinical behavior is crucial to establish a sound framework for future clinical trials, and to facilitate guideline and policy formulation for improved patient care. Advancements in molecular imaging are expected to transform the field of oligometastatic urologic tumors in the future.