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 Effect of CacyBP/SIP on the Phosphorylation of ERK1/2 and p38 Kinases in Clear Cell Renal Cell Carcinoma.

The prognosis for patients with RCC is very poor because this cancer is diagnosed mainly in the metastatic stage and is resistant to radio- and chemotherapy. According to recent research, CacyBP/SIP exhibits phosphatase activity against MAPK and may be involved in many cellular processes. This function has not been studied in RCC so far, so we decided to test whether CacyBP/SIP has phosphatase function against ERK1/2 and p38 in high-grade clear cell RCC. The research material consisted of fragments of clear cell RCC, whereas the comparative material consisted of the adjacent normal tissues. Immunohistochemistry and qRT-PCR were used to identify the expression of CacyBP/SIP, ERK1/2, and p38. The studies showed an increase in immunoreactivity and gene expression of the parameters examined in clear cell RCC compared with normal tissues. Only in the case of ERK1/2 was it shown that the expression of the MAPK3 gene was downregulated and the MAPK1 gene was higher in clear cell RCC. These studies demonstrated that CacyBP/SIP lacked phosphatase function against ERK1/2 and p38 in high-grade clear cell RCC. Further research is needed because a better understanding of the role of CacyBP/SIP and MAPK offers hope for the treatment of urological cancer.

Glutathione Metabolism in Renal Cell Carcinoma Progression and Implications for Therapies.

A significantly increased level of the reactive oxygen species (ROS) scavenger glutathione (GSH) has been identified as a hallmark of renal cell carcinoma (RCC). The proposed mechanism for increased GSH levels is to counteract damaging ROS to sustain the viability and growth of the malignancy. Here, we review the current knowledge about the three main RCC subtypes, namely clear cell RCC (ccRCC), papillary RCC (pRCC), and chromophobe RCC (chRCC), at the genetic, transcript, protein, and metabolite level and highlight their mutual influence on GSH metabolism. A further discussion addresses the question of how the manipulation of GSH levels can be exploited as a potential treatment strategy for RCC.

Detecting circulating tumor DNA in renal cancer: An open challenge.

BACKGROUND: Detection of circulating tumor DNA (ctDNA) in blood of cancer patients is regarded as an important step towards personalized medicine and treatment monitoring. In the present study, we investigated the clinical applicability of ctDNA as liquid biopsy in renal cancer. METHODS: ctDNA in serum and plasma samples derived from ccRCC and colon cancer patients as well as ctDNA isolated from RCC xenografts with known VHL mutation status was investigated using next generation sequencing (NGS). Additionally, a Taqman mutation specific assay was used for specific VHL mutation detection in blood. RESULTS: In our study, we successfully identified KRAS mutation in colon cancer patients. We also confirmed the presence of specific VHL mutations in ctDNA derived from RCC xenografts indicating the capability of renal tumors to release DNA into the blood circulation. However, we could not detect any VHL mutation in plasma or serum samples derived from nine ccRCC patients. To increase the sensitivity, a VHL mutation specific Taqman assay was tested. With this approach, the pVHL mutation p.Val130Leu in exon 2 in one patient was successfully detected. CONCLUSION: These data suggest a reduced tumor DNA shedding and an increased clearance of the tumor DNA from the circulation in renal cancer patients independently of tumor size, metastases, and necrosis. This implies that highly sensitive detection methods for mutation calling and prior knowledge of the mutation are required for liquid biopsies in ccRCC.

Choosing the right cell line for renal cell cancer research.

Cell lines are still a tool of choice for many fields of biomedical research, including oncology. Although cancer is a very complex disease, many discoveries have been made using monocultures of established cell lines. Therefore, the proper use of in vitro models is crucial to enhance our understanding of cancer. Therapeutics against renal cell cancer (RCC) are also screened with the use of cell lines. Multiple RCC in vitro cultures are available, allowing in vivo heterogeneity in the laboratory, but at the same time, these can be a source of errors. In this review, we tried to sum up the data on the RCC cell lines used currently. An increasing amount of data on RCC shed new light on the molecular background of the disease; however, it revealed how much still needs to be done. As new types of RCC are being distinguished, novel cell lines and the re-exploration of old ones seems to be indispensable to create effective in vitro tools for drug screening and more.

Sequential pathogenesis of metastatic VHL mutant clear cell renal cell carcinoma: putting it together with a translational perspective.

Clear cell renal cell carcinoma (ccRCC) accounts for ∼80% of all RCC, and biallelic Von Hippel-Lindau (VHL) gene defects occur in ∼75% of sporadic ccRCC. The etiopathogenesis of VHL mutant metastatic RCC, based on our understanding to date of molecular mechanisms involved, is a sequence of events which can be grouped under the following: (i) loss of VHL activity (germline/somatic mutation + inactivation of the wild-type copy); (ii) constitutive activation of the hypoxia-inducible factor (HIF) pathway due to loss of VHL activity and transcription of genes involved in angiogenesis, epithelial-mesenchymal transition, invasion, metastasis, survival, anaerobic glycolysis and pentose phosphate pathway; (iii) interactions of the HIF pathway with other oncogenic pathways; (iv) genome-wide epigenetic changes (potentially driven by an overactive HIF pathway) and the influence of epigenetics on various oncogenic, apoptotic, cell cycle regulatory and mismatch repair pathways (inhibition of multiple tumor suppressor genes); (v) immune evasion, at least partially caused by changes in the epigenome. These mechanisms interact throughout the pathogenesis and progression of disease, and also confer chemoresistance and radioresistance, making it one of the most difficult metastatic cancers to treat. This article puts together the sequential pathogenesis of VHL mutant ccRCC by elaborating these mechanisms and the interplay of oncogenic pathways, epigenetics, metabolism and immune evasion, with a perspective on potential therapeutic strategies. We reflect on the huge gap between our understanding of the molecular biology and currently accepted standard of care in metastatic ccRCC, and present ideas for better translational research involving therapeutic strategies with combinatorial drug approach, targeting different aspects of the pathogenesis.

Germline genetic variations at 11q13 and 12p11 locus modulate age at onset for renal cell carcinoma.

PURPOSE: Few risk factors have been identified for renal cell carcinoma. We performed a validation study in a population with a European background to identify the most significant variants previously identified in association with renal cell carcinoma risk. MATERIALS AND METHODS: We performed a case-control validation study after recruiting 463 controls and 463 patients with a histologically confirmed diagnosis of clear cell renal cell carcinoma. For each patient and matched control we genotyped 8 single nucleotide polymorphisms selected from previous studies to evaluate the association between candidate single nucleotide polymorphisms and renal cell carcinoma susceptibility. RESULTS: After adjusting for patient age, gender, smoking status and body mass index the AG + AA genotypes from rs7105934 (11q13) were associated with a decreased risk of renal cell carcinoma (OR 0.50, 95% CI 0.33-0.75, p = 0.001) and the AC + CC genotypes from rs1049380 (ITPR2) were associated with an increased risk (OR 1.66, 95% CI 1.28-2.16, p <0.001). Kidney cancer developed at an older age in patients carrying the dominant risk allele A for rs7105934 (mean age at diagnosis 73.1 vs 68.9 years, p = 0.002) and at a younger age in those carrying the dominant allele C for rs1049380 (mean 68.1 vs 70.8 years, p = 0.005). CONCLUSIONS: In what is to our knowledge the first validation study of the main 8 single nucleotide polymorphism variants associated with renal cell carcinoma susceptibility we confirmed the association of 2 single nucleotide polymorphisms with the risk of renal cell carcinoma. Each variant influenced patient age at disease diagnosis.

Qualitative and quantitative characteristics of CEUS for renal cell carcinoma and angiomyolipoma: a narrative review.

Incidental findings of renal masses are increasing. However, a substantial portion of surgically treated renal masses turn out to be benign on histopathological examination. Thus, there is a clear need for improved pre-surgical assessment to minimize unnecessary invasive procedures. The challenge intensifies when distinguishing between renal cell carcinoma (RCC) and angiomyolipoma (AML) in renal lesions smaller than 4 cm with minimal adipose tissue. In such cases, contrast-enhanced ultrasound (CEUS) has emerged as a valuable diagnostic tool, by utilizing both qualitative and quantitative parameters. Quantitative measures offer objectivity, reliability, and reproducibility compared to qualitative parameters, enabling the characterization of RCC subtypes and differentiation from AML. Qualitative features as enhancement pattern, degree, and peak were less helpful in distinguishing triphasic minimal fat AML (TAML) from epithelioid AML (EAML), with the pseudocapsule sign potentially being the only distinguishing qualitative feature. The pseudocapsule sign was more frequently observed in ccRCCs (38.0%) than in AMLs (15.6%). Moreover, it was detected in 40.0% of EAMLs and 34.5% of ccRCCs but not in TAMLs due to similar growth patterns between EAMLs and low-grade ccRCCs. Quantitative measures such as the time-to-peak (TTP) ratio can further enhance diagnostic accuracy and also TOC ratio should be considered, as it was higher in clear cell RCCs (ccRCCs) and in EAMLs compared to TAMLs, indicating behavior similar to ccRCCs. However, CEUS remains an operator-dependent exam.

Genetic study of the CDKN2A and CDKN2B genes in renal cell carcinoma patients.

Objectives: While recent studies have demonstrated several genetic alterations are associated with pathogenesis of RCC, the significance of cyclin-dependent kinase inhibitor 2A (CDKN2A) and cyclin-dependent kinase inhibitor 2B (CDKN2B) in tumorigenesis of RCC is less clear. We investigate the distribution of CDKN2A and CDKN2B mutations in patients with RCC and analyze the impact of CDKN2A and CDKN2B mutations on RCC. Methods: A pathological examination was conducted using thirty fresh renal tissue samples with renal masses that had undergone partial or radical nephrectomy. Multiplex ligation-dependent probe amplification (MLPA) was used to detect genetic aberrations of CDKN2A and CDKN2B in genomic DNA isolated from samples. Subsequently, CDKN2A and CDKN2B mutations were confirmed using chromosomal microarray technique. Results: Twenty-one patients were diagnosed with RCC, eight with benign diseases, including angiomyolipoma (AML) and oncocytoma, and one with mucinous adenocarcinoma of renal pelvis. Two of twenty-one patients (9.5 %) with clear-cell RCC were positive for CDKN2A and CDKN2B gene deletions. Interestingly, patients with CDKN2A and CDKN2B mutations were associated with sarcomatoid patterns of RCC (2 out of 4, 50 %). In contrast, no CDKN2A or CDKN2B deletions were detected in samples from benign renal tumors, papillary RCC, or other kidney cancers. Conclusions: This study demonstrated the potential use of CDKN2A and CDKN2B as biomarkers for the prognostic and molecular classification of renal cancer. CDKN2A and CDKN2B mutations may be associated with RCC development and sarcomatoid changes. Further research is needed to understand the underlying molecular mechanisms of CDKN2A and CDKN2B in the pathogenesis of RCC.

Emerging Role of Hippo-YAP (Yes-Associated Protein)/TAZ (Transcriptional Coactivator with PDZ-Binding Motif) Pathway Dysregulation in Renal Cell Carcinoma Progression.

Although Hippo-YAP/TAZ pathway involvement has been extensively studied in the development of certain cancers, the involvement of this cascade in kidney cancer progression is not well-established and, therefore, will be the focus of this review. Renal cell carcinoma (RCC), the most prevalent kidney tumor subtype, has a poor prognosis and a high mortality rate. Core Hippo signaling inactivation (e.g., LATS kinases) leads to the nuclear translocation of YAP/TAZ where they bind to co-transcriptional factors such as TEAD promoting transcription of genes which initiates various fibrotic and neoplastic diseases. Loss of expression of LATS1/2 kinase and activation of YAP/TAZ correlates with poor survival in RCC patients. Renal-specific ablation of LATS1 in mice leads to the spontaneous development of several subtypes of RCC in a YAP/TAZ-dependent manner. Genetic and pharmacological inactivation of YAP/TAZ reverses the oncogenic potential in LATS1-deficient mice, highlighting the therapeutic benefit of network targeting in RCC. Here, we explore the unique upstream controls and downstream consequences of the Hippo-YAP/TAZ pathway deregulation in renal cancer. This review critically evaluates the current literature on the role of the Hippo pathway in RCC progression and highlights the recent scientific evidence designating YAP/TAZ as novel therapeutic targets against kidney cancer.

Targeted therapies and the treatment of non-clear cell renal cell carcinoma.

BACKGROUND: Targeted therapies have shown profound effects on the outcome of patients with advanced renal cell carcinoma (RCC). However, the optimal treatment for RCC of non-clear cell histology (nccRCC)-typically excluded from trials of targeted agents-remains uncertain. MATERIALS AND METHODS: By carrying out extensive searches of PubMed and ASCO databases, we identified and summarised research into the biological characteristics, clinical behaviour and treatment of different histological subtypes of nccRCC, focusing on targeted therapy. RESULTS: The available data suggest that treatments currently approved for RCC are active in ncc subtypes, although the overall clinical benefit may be less than for clear cell RCC. Temsirolimus has proven benefit over interferon-alfa (IFN-α) in patients with nccRCC, based on phase III data, while everolimus, sunitinib and sorafenib have all demonstrated some degree of activity in nccRCC in expanded-access trials. No clear picture has emerged of whether individual histological subtypes are particularly responsive to any individual treatment. CONCLUSIONS: Further molecular studies into the pathogenesis of RCC histological subtypes will help direct the development of novel, appropriate targeted agents. Clinical trials specifically designed to evaluate the role of targeted agents in nccRCC are ongoing, and data from trials with sunitinib and everolimus will be reported soon.

Advanced Non-Clear Cell Renal Cell Carcinoma Treatments and Survival: A Real-World Single-Centre Experience.

BACKGROUND: Non-clear cell renal cell carcinoma (nccRCC) is a heterogeneous group of cancer. Treatment recommendations are extrapolated from ccRCC and lack solid evidence. Here, we review advanced nccRCC patients treated at our institute. PATIENTS AND METHODS: We collected retrospective data on all advanced nccRCC pts treated at the Istituto Oncologico Veneto from January 2008. We compared overall response rate (ORR), progression free survival (PFS) and overall survival (OS) according to histological subtypes and type of systemic treatments. Kaplan-Meier method, log-rank test and Cox regression were used to estimate and compare PFS and OS. RESULTS: Of 1370 RCC patients, 289 had a diagnosis of nccRCC and 121 were eligible for the analysis. Fifty-three pts showed papillary histology (pRCC), 15 chromophobe; 37 unclassified RCC (NOS-RCC), 16 other histologies. Pts with chromophobe and other hystologies showed poorer survival rates compared to pRCC and NOS-RCC (mOS 10.7 vs. 20.7 vs. 30.7, p = 0.34). Pts treated with combination regimens achieved a better OS (30.7 vs. 13.7, p = 0.10), PFS (12.7 vs. 6.4, p = 0.10) and ORR (42.4% vs. 13.9%, p = 0.002) than those treated with monotherapy. IMDC and Meet-URO score retained their prognostic value. CONCLUSION: Our retrospective real-life cohort of advanced nccRCC patients shows that immunotherapy-based combinations could improve ORR, PFS and OS compared to TKI monotherapy. Prospective trials for nccRCC patients utilizing novel therapies are ongoing and their results eagerly awaited.

Exploring Renal Malignancies in Saudi Arabia: Insights from a Tertiary Care Center Study.

This retrospective study aims to describe the characteristics of renal cell carcinoma (RCC) in Saudi Arabia, in terms of epidemiology, clinical presentation, tumor subtype, Fuhrman grade, tumor size and stage, and overall survival. A total of 431 adult patients with a histopathological diagnosis of RCC between 2015 and 2023 were included in the analysis. Most patients (72.4%) had clear cell tumors, followed by chromophobe (15.1%) and papillary (12.5%) subtypes. In males, papillary RCC (85.2%) was more common compared to clear cell (59.8%) and chromophobe (67.7%) subtypes. Significant differences were observed in median body mass index (BMI) across tumor subtypes, and papillary tumor patients exhibited the highest incidence of hematuria (33.3%) compared to other subtypes. The Fuhrman grade also varied significantly among RCC types. Survival times were found to be lower for patients with papillary tumors. No significant difference was observed based on patients' nationality. This study can inform clinical decision-making on patient prognosis and management as well as public health efforts aimed at reducing the alarming rise of RCC incidence.

Real World Data of Diagnosis, Survival, and Treatment Outcomes in Patients With Metastatic Non Clear Cell Renal Cell Carcinoma.

INTRODUCTION: Metastatic non clear cell renal cell carcinoma (nccRCC) is an heterogenous group, usually excluded from phase 3 trials. We report real life data of prognosis and systemic management of those patients. METHODS: We retrospectively included 102 metastatic nccRCC patients (unspecified papillary, n = 10; type 1 and 2 papillary n = 10 and n = 32; translocation RCC, n = 9; chromophobe, n = 14; collecting duct, n = 14) treated between 2006 and 2020. Objective response rate (ORR), progression-free survival (PFS) and overall survival (OS) were evaluated. RESULTS: Among patients who underwent pathological review, 40.8% presented a complete histological discordance. First line treatments were mainly tyrosine kinase inhibitor (60.8%), combination including immunotherapy (7.8%) or combination of chemotherapy (13.7%). Median ORR ranged from 0% in unspecified papillary RCC to 42.9% in type 1 papillary RCC. Median PFS ranged from 2.9 months in collecting duct carcinoma to 10.9 months in type 1 papillary RCC. Median OS ranged from 6.8 months in collecting duct carcinoma to 29.1 months in MiT family translocation RCC. Thirty (29.4%) patients were included in a treatment trial during their treatment course. CONCLUSION: Metastatic nccRCC patients have variable prognosis due to heterogeneity of histological subtypes. Their diagnosis and access to therapeutic innovation remain suboptimal. Dedicated prospective trials are needed.

CT radiomics for differentiating oncocytoma from renal cell carcinomas: Systematic review and meta-analysis.

BACKGROUND: Radiomics is a type of quantitative analysis that provides a more objective approach to detecting tumor subtypes using medical imaging. The goal of this paper is to conduct a comprehensive assessment of the literature on computed tomography (CT) radiomics for distinguishing renal cell carcinomas (RCCs) from oncocytoma. METHODS: From February 15th 2012 to 2022, we conducted a broad search of the current literature using the PubMed/MEDLINE, Google scholar, Cochrane Library, Embase, and Web of Science. A meta-analysis of radiomics studies concentrating on discriminating between oncocytoma and RCCs was performed, and the risk of bias was assessed using the Quality Assessment of Diagnostic Accuracy Studies method. The pooled sensitivity, specificity, and diagnostic odds ratio were evaluated via a random-effects model, which was applied for the meta-analysis. This study is registered with PROSPERO (CRD42022311575). RESULTS: After screening the search results, we identified 6 studies that utilized radiomics to distinguish oncocytoma from other renal tumors; there were a total of 1064 lesions in 1049 patients (288 oncocytoma lesions vs 776 RCCs lesions). The meta-analysis found substantial heterogeneity among the included studies, with pooled sensitivity and specificity of 0.818 [0.619-0.926] and 0.808 [0.537-0.938], for detecting different subtypes of RCCs (clear cell RCC, chromophobe RCC, and papillary RCC) from oncocytoma. Also, a pooled sensitivity and specificity of 0.83 [0.498-0.960] and 0.92 [0.825-0.965], respectively, was found in detecting oncocytoma from chromophobe RCC specifically. CONCLUSIONS: According to this study, CT radiomics has a high degree of accuracy in distinguishing RCCs from RO, including chromophobe RCCs from RO. Radiomics algorithms have the potential to improve diagnosis in scenarios that have traditionally been ambiguous. However, in order for this modality to be implemented in the clinical setting, standardization of image acquisition and segmentation protocols as well as inter-institutional sharing of software is warranted.

Surgical and oncological management of renal medullary carcinoma in a young patient: a case report.

Renal medullary carcinoma (RMC) is a rare form of renal cell carcinoma that has a poor prognosis. It is known to be associated with sickle cell trait or disease, although the exact underlying mechanisms are still unclear. The diagnosis is made through immunochemical staining for SMARCB1 (INI1). In this report, we present a case of a 31-year-old male patient with sickle cell trait who was diagnosed with stage III right RMC. Despite the poor prognosis, the patient survived for a remarkable duration of 37 months. Radiological assessment and follow-up were primarily performed using 18F-FDG PET/MRI. The patient underwent upfront cisplatin-based cytotoxic chemotherapy before surgical removal of the right kidney and retroperitoneal lymph node dissection. Identical adjuvant chemotherapy was administered post-surgery. Disease relapses were detected in the retroperitoneal lymph nodes; these were managed with chemotherapy and surgical rechallenges. We also discuss the oncological and surgical management of RMC, which currently relies on perioperative cytotoxic chemotherapy strategies, as there are no known alternative therapies that have been shown to be superior to date.

Novel Targeted Therapies for Renal Cell Carcinoma: Building on the Successes of Vascular Endothelial Growth Factor and mTOR Inhibition.

Targeted therapies have revolutionized the treatment of renal cell carcinoma (RCC). The VHL/HIF pathway is responsible for the regulation of oxygen homeostasis and is frequently altered in RCC. Targeting this pathway as well as the mTOR pathway have yielded remarkable advances in the treatment of RCC. Here, we review the most promising novel targeted therapies for the treatment of RCC, including HIF2α, MET, metabolic targeting, and epigenomic reprogramming.

Very low risk T1a renal cell carcinoma presenting with pathological fracture caused by a solitary metastases to the contralateral arm.

BACKGROUND: Renal Cell Carcinomas are notorious for asynchronous metastases, atypical metastatic sites and late relapses even decades after nephrectomy. It is quite rare though for RCCs to present as metastatic, solitary and symptomatic bone lesions. Even more uncommon is a solitary bone metastasis much larger that the primary tumour caused by a low risk primary T1a RCC which would have otherwise been eligible for active surveillance. CASE PRESENTATION: An otherwise healthy 68-year-old female was seen by the orthopaedics for right shoulder and upper arm worsening pain. Imaging showed a pathological fracture caused by a 5.5 cm lytic lesion involving the coracoid process and proximal humerus. She underwent proximal humeral replacement and histology of the lesion showed metastatic RCC. Whole body CT scan revealed a primary tumour of the left kidney less than 4cm in diameter. The patient underwent laparoscopic radical nephrectomy and diagnosis of a T1a, clear cell RCC without adverse pathological features was confirmed. She has been on systematic therapy with oral TKIs since and is free from recurrence at 12-months follow up. CONCLUSIONS: Even T1a RCCs without adverse pathological features can give rise to distant metastases following unpredictable patterns of spread thereby questioning the safety of active surveillance in healthy and fit patients.

Outcomes of patients with advanced non-clear cell renal cell carcinoma treated with first-line immune checkpoint inhibitor therapy.

BACKGROUND: Immune checkpoint inhibitors (ICI) have demonstrated impressive activity in metastatic clear-cell renal cell carcinoma (ccRCC) and have become standard treatment options for patients with advanced disease. Data supporting the effectiveness of ICI-based therapy in advanced non-clear cell RCC (nccRCC) is more limited. METHODS: We performed a retrospective analysis using the International Metastatic RCC Database Consortium (IMDC) to evaluate the outcomes of patients with advanced nccRCC. Patients were classified into three groups based on first-line therapy: ICI-based therapy (monotherapy or combination), vascular endothelial growth factor (VEGF) inhibitor monotherapy, or mammalian target of rapamycin (mTOR) inhibitor monotherapy. The primary outcome was overall survival (OS). Secondary outcomes were time to treatment failure (TTF) and objective response rate (ORR). We used the Kaplan-Meier method to compare OS and TTF between treatment groups and Cox proportional hazards models to adjust for prognostic covariates. RESULTS: We identified a total of 1145 patients with metastatic nccRCC. The most common subtype was papillary RCC (54.9%). For first-line therapy, 74.3% received VEGF monotherapy, 15% received mTOR monotherapy, and 10.7% received ICI-based therapy. Median OS in the ICI group was 28.6 months, versus 16.4 months in the VEGF group and 12.2 months in the mTOR group. Median TTF in the ICI group was 6.9 months, versus 5.0 months in the VEGF group and 3.9 months in the mTOR group. ORR was 27.2% in the ICI group, 14.5% in the VEGF group, and 9% in the mTOR group. After adjusting for the IMDC risk group, histological subtype, and age, the hazard ratio for OS was 0.57 (95% CI 0.42-0.78, p < 0.0001) for ICI versus VEGF and 0.50 (95% CI 0.36-0.71, p < 0.0001) for ICI versus mTOR. CONCLUSIONS: In advanced nccRCC, first-line ICI-based treatment appears to be associated with improved OS compared to VEGF and mTOR targeted therapy. These results should be confirmed in prospective randomised trials.

A Molecularly Characterized Preclinical Platform of Subcutaneous Renal Cell Carcinoma (RCC) Patient-Derived Xenograft Models to Evaluate Novel Treatment Strategies.

Renal cell carcinoma (RCC) is a kidney cancer with an onset mainly during the sixth or seventh decade of the patient's life. Patients with advanced, metastasized RCC have a poor prognosis. The majority of patients develop treatment resistance towards Standard of Care (SoC) drugs within months. Tyrosine kinase inhibitors (TKIs) are the backbone of first-line therapy and have been partnered with an immune checkpoint inhibitor (ICI) recently. Despite the most recent progress, the development of novel therapies targeting acquired TKI resistance mechanisms in advanced and metastatic RCC remains a high medical need. Preclinical models with high translational relevance can significantly support the development of novel personalized therapies. It has been demonstrated that patient-derived xenograft (PDX) models represent an essential tool for the preclinical evaluation of novel targeted therapies and their combinations. In the present project, we established and molecularly characterized a comprehensive panel of subcutaneous RCC PDX models with well-conserved molecular and pathological features over multiple passages. Drug screening towards four SoC drugs targeting the vascular endothelial growth factor (VEGF) and PI3K/mTOR pathway revealed individual and heterogeneous response profiles in those models, very similar to observations in patients. As unique features, our cohort includes PDX models from metastatic disease and multi-tumor regions from one patient, allowing extended studies on intra-tumor heterogeneity (ITH). The PDX models are further used as basis for developing corresponding in vitro cell culture models enabling advanced high-throughput drug screening in a personalized context. PDX models were subjected to next-generation sequencing (NGS). Characterization of cancer-relevant features including driver mutations or cellular processes was performed using mutational and gene expression data in order to identify potential biomarker or treatment targets in RCC. In summary, we report a newly established and molecularly characterized panel of RCC PDX models with high relevance for translational preclinical research.