Germline Susceptibility to Renal Cell Carcinoma and Implications for Genetic Screening.

PURPOSE: Genetic susceptibility to nonsyndromic renal cell carcinoma (RCC) remains poorly understood, especially for different histological subtypes, as does variations in genetic predisposition in different populations. The objectives of this study were to identify risk genes for RCC in the Canadian population, investigate their clinical significance, and evaluate variations in germline pathogenic variants (PVs) among patients with RCC across the globe. MATERIALS AND METHODS: We conducted targeted sequencing of 19 RCC-related and 27 cancer predisposition genes for 960 patients with RCC from Canada and identified genes enriched in rare germline PVs in RCC compared with cancer-free controls. We combined our results with those reported for patients from Japan, the United Kingdom, and the United States to investigate PV variations in different populations. Furthermore, we evaluated the performance of referral criteria for genetic screening for including patients with rare PVs. RESULTS: We identified 39 germline PVs in 56 patients (5.8%) from the Canadian cohort. Compared with cancer-free controls, PVs in CHEK2 (odds ratio [OR], 4.8 [95% CI, 2.7 to 7.9], P = 3.94 × 10-5) and ATM (OR, 4.5 [95% CI, 2.0 to 8.7], P = .016) were significantly enriched in patients with clear cell, whereas PVs in FH (OR, 215.1 [95% CI, 64.4 to 597.8], P = 6.14 × 10-9) were enriched in patients with non-clear cell RCCs. PVs in BRCA1, BRCA2, and ATM were associated with metastasis (P = .003). Comparative analyses showed an enrichment of TP53 PVs in patients from Japan, of CHEK2 and ATM in patients from Canada, the United States and the United Kingdom, and of FH and BAP1 in the United States. CONCLUSION: CHEK2, ATM, and FH are risk genes for RCC in the Canadian population, whereas PVs in BRCA1/2 and ATM are associated with risk of metastasis. Globally, clinical guidelines for genetic screening in RCC fail to include more than 70% of patients with rare germline PVs.

FOXC1 transcriptionally suppresses ABHD5 to inhibit the progression of renal cell carcinoma through AMPK/mTOR pathway.

BACKGROUND: Increased activity of the transcription factor FOXC1 leads to elevated transcription of target genes, ultimately facilitating the progression of various cancer types. However, there are currently no literature reports on the role of FOXC1 in renal cell carcinoma. METHODS: By using RT-qPCR, immunohistochemistry and Western blotting, FOXC1 mRNA and protein expression was evaluated. Gain of function experiments were utilized to assess the proliferation and metastasis ability of cells. A nude mouse model was created for transplanting tumors and establishing a lung metastasis model to observe cell proliferation and spread in a living organism. Various techniques including biological analysis, CHIP assay, luciferase assay, RT-qRCR and Western blotting experiments were utilized to investigate how FOXC1 contributes to the transcription of ABHD5 on a molecular level. FOXC1 was assessed by Western blot for its impact on AMPK/mTOR signaling pathway. RESULTS: FOXC1 is down-regulated in RCC, causing unfavorable prognosis of patients with RCC. Further experiments showed that forced FOXC1 expression significantly restrains RCC cell growth and cell metastasis. Mechanically, FOXC1 promotes the transcription of ABHD5 to activate AMPK signal pathway to inhibit mTOR signal pathway. Finally, knockdown of ABHD5 recovered the inhibitory role of FOXC1 overexpression induced cell growth and metastasis suppression. CONCLUSION: In general, our study demonstrates that FOXC1 exerts its tumor suppressor role by promoting ABHD5 transcription to regulating AMPK/mTOR signal pathway. FOXC1 could serve as both a diagnostic indicator and potential treatment focus for RCC.

Interaction between microglial cells and CD1C+ B dendritic cells leads to CD8+ T cells depletion during the early stages of renal clear cell carcinoma.

Renal clear cell carcinoma (RCC) is a type of malignant tumor, which, in addition to surgical resection, radiotherapy, and chemotherapy, has been widely treated through immunotherapy recently. However, the influence of the tumor microenvironment and the infiltrating immune cells within it on immunotherapy remains unclear. It is imperative to study the interactions between various immune cells of RCC. The scRNA-seq dataset from GEO's database was used to analyze the immune cells present in tumor tissue and peripheral blood samples. Through quality control, clustering, and identification, the types and proportions of infiltrating immune cells were determined. The cellular differences were determined, and gene expression levels of the differentially present cells were investigated. A protein-protein interaction network analysis was performed using string. KEGG and GO analyses were performed to investigate abnormal activities. The microglia marker CD68 and CD1C+ B dendritic cells marker CD11C were detected using multiplex immunofluorescence staining. Many depleted CD8+ T cells (exhausted CD8+ T cells) appeared in tumor tissues as well as microglia. CD1C+ B dendritic cells did not infiltrate tumor tissues. HSPA1A was correlated with DNAJB1 in microglia. Compared with Paracancer tissues, microglia increased while CD1C+ B dendritic cells decreased in pathological stages I and I-II in cancerous tissues. An altered tumor microenvironment caused by increases in microglia in RCC in the early stage resulted in an inability of CD1C+ B dendritic cells to infiltrate, resulting in CD8+ T cells being unable to receive the antigens presented by them, and in turn being depleted in large quantities.

Validation and Comparison of Prognostic Models in Renal Carcinoma in a Tertiary Hospital.

BACKGROUND: Renal cell carcinoma (RCC) is the third most frequent urological neoplasia. Proper risk stratification is essential for adequate management. Various calculators are available. This project aims to evaluate the accuracy of the calculators applied to our patients. METHODS: We performed a retrospective study of the nephrectomies due to RCC performed from January 2008 to December 2013. We applied the most widely used predictive models (University of California, Los Angeles Integrated Staging System (UISS), Stage, Size, Grade and Necrosis (SSIGN), Memorial Sloan Kettering Cancer Center (MSKCC) and International Metastatic RCC Database Consortium (IMDC)) to stratify patients in different risk groups. We evaluated progression-free survival (PFS) or death caused by RCC (cancer-specific survival (CSS)) or other causes (overall survival (OS)). RESULTS: We analysed 238 patients. The 5-year OS, CSS and PFS were 76%, 85% and 83%, whereas the 10-year OS, CSS and PFS were 47%, 75% and 77%, respectively. The 5-year survival analysis by risk groups according to the prognostic models showed that the PFS was 0% and 20.4% in high- and intermediate-risk metastatic RCC (mRCC). Moreover, the PFS was 90%, 95.2% and 98.9% in localised high-, intermediate- and low-risk RCC according to the UISS (area under the receiver operating characteristics curve (AUC): 0.93). The SSIGN model showed a CSS of 99% for the group with the lowest score and 5.3% for the group with the worst prognosis (AUC: 0.91). The OS of mRCC showed medians of 13.25 and 87 months according to MSKCC (AUC: 0.75) and 16, 23 and 85 months according to IMDC (AUC: 0.71) (high risk, intermediate and low). CONCLUSIONS: The validation of the predictive models carried out with our patients showed consistency in many of the results. Risk stratification should be implemented.

Perioperative, functional and oncologic outcomes of percutaneous ablation versus minimally invasive partial nephrectomy for clinical T1 renal tumors: outcomes from a pooled analysis.

The objective of this study was to perform a comprehensive pooled analysis aimed at comparing the efficacy and safety of percutaneous ablation (PCA) versus minimally invasive partial nephrectomy (MIPN), including robotic and laparoscopic approaches, in patients diagnosed with cT1 renal tumors. We conducted a comprehensive search across four major electronic databases: PubMed, Embase, Web of Science, and the Cochrane Library, targeting studies published in English up to April 2024. The primary outcomes evaluated in this analysis included perioperative outcomes, functional outcomes, and oncological outcomes. A total of 2449 patients across 17 studies were included in the analysis. PCA demonstrated superior outcomes compared to MIPN in terms of shorter hospital stays (WMD: - 2.13 days; 95% Confidence Interval [CI]: - 3.29, - 0.97; p = 0.0003), reduced operative times (WMD: - 109.99 min; 95% CI: - 141.40, - 78.59; p < 0.00001), and lower overall complication rates (OR: 0.54; 95% CI: 0.40, 0.74; p = 0.0001). However, PCA was associated with a higher rate of local recurrence when compared to MIPN (OR: 3.81; 95% CI: 2.45, 5.92; p < 0.00001). Additionally, no significant differences were observed in major complications, estimated glomerular filtration rate decline, creatinine variation, overall survival, recurrence-free survival, and disease-free survival between the two treatment modalities. PCA presents a notable disadvantage regarding local recurrence rates in comparison to MIPN. However, PCA offers several advantages over MIPN, including shorter durations of hospital stay, reduced operative times, and lower complication rates, while achieving similar outcomes in other oncologic metrics.

Targeted therapies in children with renal cell carcinoma (RCC): An International Society of Pediatric Oncology-Renal Tumor Study Group (SIOP-RTSG)-related retrospective descriptive study.

INTRODUCTION: Introduction: Renal cell carcinoma (RCC) is a very rare pediatric renal tumor. Robust evidence to guide treatment is lacking and knowledge on targeted therapies and immunotherapy is mainly based on adult studies. Currently, the International Society of Pediatric Oncology-Renal Tumor Study Group (SIOP-RTSG) 2016 UMBRELLA protocol recommends sunitinib for metastatic or unresectable RCC. METHODS: This retrospective study describes the effects of tyrosine kinase inhibitors (TKI), anti-programmed cell death 1 (PD-(L)1) monoclonal antibodies, and immunotherapeutic regimens in advanced-stage and relapsed pediatric RCC. RESULTS: Of the 31 identified patients (0-18 years) with histologically proven RCC, 3/31 presented with TNM stage I/II, 8/31 with TNM stage III, and 20/31 with TNM stage IV at diagnosis. The majority were diagnosed with translocation type RCC (MiT-RCC) (21/31) and the remaining patients mainly presented with papillary or clear-cell RCC. Treatment in a neoadjuvant or adjuvant setting, or upon relapse or progression, included mono- or combination therapy with a large variety of drugs, illustrating center specific choices in most patients. Sunitinib was often administered as first choice and predominantly resulted in stable disease (53%). Other frequently used drugs included axitinib, cabozantinib, sorafenib, and nivolumab; however, no treatment seemed more promising than sunitinib. Overall, 15/31 patients died of disease, 12/31 are alive with active disease, and only four patients had a complete response. The sample size and heterogeneity of this cohort only allowed descriptive statistical analysis. CONCLUSION: This study provides an overview of a unique series of clinical and treatment characteristics of pediatric patients with RCC treated with targeted therapies.

[Clinicopathological features of BAP1 mutated clear cell renal cell carcinoma].

Objective: To investigate the clinicopathological characteristics, immunophenotypes, molecular features, and differential diagnosis of BAP1 mutated clear cell renal cell carcinoma (CCRCC) for better understanding this entity. Methods: Clinical data, histological morphology, immunophenotypes and molecular characteristics of 18 BAP1 mutated CCRCC cases diagnosed at the Department of Pathology, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China from January 2020 to December 2022 were analyzed. The patients were followed up. Results: There were 17 males and 1 female patients, aged from 39 to 72 years, with an average age of 56.3 years. Sixteen patients with primary CCRCC were followed up for an average of 24 months, 7 patients had metastases occurred from 4 to 22 months postoperatively. Thirteen of the 16 patients were alive at the time of the last follow-up while 3 patients died 12, 15, and 20 months after the surgery, respectively. One patient underwent retroperitoneal mass resection, but had lung metastasis 32 months after surgery. One case received cervical tumor resection and died at 22 months after the surgery. Characteristic CCRCC regions were identified in 11 of the 18 cases. The tumor cells were arranged in papillary, alveolar, and large nest patterns. Abundant lymphoid tissue, necrosis, and psammoma bodies were seen. Tumor cells showed abundant eosinophilic cytoplasm, and sometimes exhibited rhabdoid differentiation. Round eosinophilic globules were located in the cytoplasm and extracellular matrix. There were 9 cases with WHO/International Society of Urological Pathology grade 3, and 9 cases with grade 4. PAX8 (18/18), carbonic anhydrase 9 (CA9, 16/18), CD10 (18/18), and vimentin (18/18) were positive in the vast majority of tumors.TFE3 was expressed in 5 cases, with strong expression in only 1 case. Eighteen cases were all positive for P504s. Twelve cases harbored a BAP1 mutation combined with von Hippel-Lindau (VHL) mutation, and 2 cases had mutations in BAP1, VHL and PBRM1 simultaneously. SETD2 mutation was not found in any of the cases. Conclusions: BAP1 mutated CCRCC contained papillary, alveolar, and large nest patterns, eosinophilic cytoplasm, high-grade nucleoli, and collagen globules, with P504s positivity. In practical work, when encountering CCRCC containing these features, pathologists should consider the possibility of BAP1 mutations and conduct related molecular tests.

No difference in oncological outcomes and perioperative complications between patients with ESRD with unilateral and bilateral UTUC receiving radical nephroureterectomy.

Patients with end stage renal disease (ESRD) are at high risk of developing upper tract urothelial carcinoma (UTUC). Due to high recurrence rate of UTUC in contralateral kidney and ureter, and high risk of complications related to surgery and anesthesia, whether it's necessary to remove both kineys and ureters at one time remains in debate. We utilized Taiwanese UTUC Registry Database to valuate the difference of oncological outcomes and perioperative complications between patients with ESRD with unilateral and bilateral UTUC receiving surgical resection. Patients with ESRD and UTUC were divided into three groups, unilateral UTUC, previous history of unilateral UTUC with metachronous contralateral UTUC, and concurrent bilatetral UTUC. Oncological outcomes, perioperative complications, and length of hospital stays were investiaged. We found that there is no diffence of oncological outcomes including overall survival, cancer specific survival, disease free survival and bladder recurrence free survival between these three groups. Complication rate and length of hospital stay are similar. Adverse oncological features such as advanced tumor stage, lymph node involvement, lymphovascular invasion, and positive surgical margin would negatively affect oncological outcomes.

Resection of extensive segments of inferior vena cava without reconstruction in the treatment of renal carcinoma with inferior vena cava tumor thrombus: A case report.

We present a 55-year-old male patient with right renal carcinoma with long inferior vena cava (IVC) tumor thrombus who underwent robot-assisted laparoscopic radical nephrectomy with extensive IVC resection and left renal vein ligation. The patient had a history of hematuria only prior to admission. Our case involved resection of the entire abdominal segment of the IVC and left renal vein without reconstruction. Unfortunately, the patient passed away over a year after the surgery due to brain metastasis.

Survival characteristics of Wilms Tumor, a reference developed from a longitudinal cohort study.

BACKGROUND: Wilms tumor (WT) survival has been affected by the evolution in clinical and biological prognostic factors. Significant differences in survival rates indicate the need for further efforts to reduce these disparities. This study aims to evaluate the clinicopathological data impact on survival among patients after Wilm's diagnosis. METHODS: The study utilized the SEERStat Database to identify Wilms tumor patients, applying SEERStat software version 8.3.9.2 for data extraction. Selection criteria involved specific codes based on the International Classification of Diseases for Oncology (ICDO-3), excluding cases with unknown SEER stage, incomplete survival data, unknown size, or lymph node status. Statistical analyses, including Kaplan-Meier estimates and Cox regression models, were conducted using R software version 3.5. Standardized mortality ratios (SMR) were computed with SEER*Stat software, and relative and conditional survival analyses were performed to evaluate long-term survival outcomes. RESULTS: Of 2273 patients diagnosed with Wilms tumor, (1219 patients, 53.6% were females with an average age group of 3-8 years (50.2%). The overall mean survival after five years of diagnosis was 93.6% (2.6-94.7), and the overall mean survival rate was 92.5% (91.3-93.8) after ten years of diagnosis. Renal cancers were identified as the leading cause of death (77.3%), followed by nonrenal cancers (11%) and noncancer causes (11%). Additionally, robust relative survival rates of 98.10%, 92.80%, and 91.3% at one, five, and ten years, respectively, were observed, with corresponding five-year conditional survival rates indicating an increasing likelihood of survival with each additional year post-diagnosis. Univariate Cox regression identified significant prognostic factors: superior CSS for patients below 3 years (cHR 0.48) and poorer CSS for those older than 15 years (cHR 2.72), distant spread (cHR 10.24), regional spread (cHR 3.09), and unknown stage (cHR 4.97). In the multivariate model, age was not a significant predictor, but distant spread (aHR 9.22), regional spread (aHR 2.84), and unknown stage (aHR 4.98) were associated with worse CSS compared to localized tumors. CONCLUSION: This study delving into WT survival dynamics reveals a multifaceted landscape influenced by clinicopathological variables. This comprehensive understanding emphasizes the imperative for ongoing research and personalized interventions to refine survival rates and address nuanced challenges across age, stage, and tumor spread in WT patients.

Enhancing the Efficacy of Radiomics-Based Prediction of Fuhrman Pathological Grading in Renal Clear Cell Carcinoma Using Multilayer Spiral CT Imaging.

BACKGROUND: Clear cell renal cell carcinoma (ccRCC) is the most prevalent subtype of renal cell carcinoma (RCC). Conventional pathological methods of Fuhrman pathological grading system have limitations. This study aims to investigate the efficacy of radiomics-based multilayer spiral computed tomography (CT) imaging of Fuhrman pathological grading in ccRCC. METHODS: A retrospective analysis was conducted on the clinical data of ccRCC patients admitted in our hospital from March 2023 to March 2024. The patients were classified as low-grade (Fuhrman pathological grades I and II) or high-grade (Fuhrman pathological grades III and IV). Statistical methods, including correlation analysis, receiver operating characteristic (ROC) curves and construction of a joint predictive model, were utilised to assess the predictive value of these imaging omics indicators for Fuhrman pathological grading in ccRCC. The primary outcome assessment parameter in this study was the predictive value of these imaging omics indicators for Fuhrman pathological grading in ccRCC. RESULTS: The clinical data from 101 ccRCC patients were examined, with 56 cases classified as low-grade and 45 cases as high-grade. The grey-level co-occurrence matrix (GLCM) features between low and high Fuhrman grading groups, including contrast (0.24 ± 0.08 vs. 0.33 ± 0.09), energy (0.73 ± 0.05 vs. 0.67 ± 0.06) and homogeneity (0.63 ± 0.05 vs. 0.57 ± 0.05), showed notable distinctions (p < 0.001). The CT imaging characteristics between low and high Fuhrman grading groups, including enhancement homogeneity (0.34 ± 0.08 vs. 0.26 ± 0.08) and washout half-time (28.57 ± 4.35 vs. 34.72 ± 5.62) demonstrated a substantial variation between the groups (p < 0.001). The enhancement homogeneity (r = 0.476), washout half-time (r = -0.519), contrast (r = 0.454), energy (r = -0.453) and homogeneity (r = -0.541) showed significant correlations with Fuhrman pathological grading. The predictive value of these features was evident, with a combined imaging genomics model exhibiting an area under the curve of 0.929. CONCLUSIONS: This study demonstrated the potential of radiomics-based prediction using multilayer spiral CT imaging for accurately predicting Fuhrman pathological grading in ccRCC.

TIGIT expression in renal cell carcinoma infiltrating T cells is variable and inversely correlated with PD-1 and LAG3.

PURPOSE: Immune checkpoint inhibitors have revolutionized the treatment of renal cell carcinoma (RCC), but many patients do not respond to therapy and the majority develop resistant disease over time. Thus, there is increasing need for alternative immunomodulating agents. The co-inhibitory molecule T-cell immunoglobulin and ITIM domain (TIGIT) may play a role in resistance to approved immune checkpoint inhibitors and is being investigated as a potential therapeutic target. The purpose of this study was to quantify TIGIT positivity in tumor-infiltrating T cells in RCC. METHODS: We employed tissue microarrays containing specimens from primary RCC tumors, adjacent normal renal tissue, and RCC metastases to quantify TIGIT within tumor-infiltrating CD3+ T cells using quantitative immunofluorescent analysis. We also compared these results to TIGIT+ CD3+ levels in four other tumor types (melanoma, non-small cell lung, cervical, and head and neck cancers). RESULTS: We did not observe significant differences in TIGIT positivity between primary RCC tumors and patient-matched metastatic samples. We found that the degree of TIGIT positivity in RCC is comparable to that in lung cancer but lower than that in melanoma, cervical, and head and neck cancers. Correlation analysis comparing TIGIT positivity to previously published, patient-matched spatial proteomic data by our group revealed a negative association between TIGIT and the checkpoint proteins PD-1 and LAG3. CONCLUSION: Our findings support careful evaluation of TIGIT expression on T cells in primary or metastatic RCC specimens for patients who may be treated with TIGIT-targeting antibodies, as increased TIGIT positivity might be associated with a greater likelihood of response to therapy.

Adjuvant Everolimus in Non-Clear Cell Renal Cell Carcinoma: A Secondary Analysis of a Randomized Clinical Trial.

Importance: Clinical trial data on adjuvant therapy in patients with non-clear cell renal cell carcinoma (RCC) are scant. Objective: To evaluate the effect of adjuvant everolimus after nephrectomy on recurrence-free survival (RFS) and overall survival (OS) in patients with localized papillary and chromophobe RCC. Design, Setting, and Participants: This prespecified subgroup analysis of a phase 3 randomized clinical trial, EVEREST, included patients enrolled between April 1, 2011, and September 15, 2016. Eligible patients had fully resected RCC at intermediate-high risk (pT1 grade 3-4, N0 to pT3a grade 1-2, N0) or very-high risk (pT3a grade 3-4 to pT4 any grade or N+) for recurrence who had received radical or partial nephrectomy. Final analyses was completed in March 2022. Intervention: The intervention group received 54 weeks of everolimus (10 mg orally daily); the control group received a matching placebo. Main Outcomes and Measures: The main outcomes were RFS, OS, and rates of adverse events. For testing the hazard ratio (HR) for treatment effect, a Cox regression model was used for both OS and RFS. Results: Of 1545 adult patients with treatment-naive, nonmetastatic, fully resected RCC in EVEREST, 109 had papillary RCC (median [range] age, 60 [19-81] years; 82 [75%] male; 50 patients [46%] with very high-risk disease) and 99 had chromophobe RCC (median [range] age 51 [18-71] years; 53 [54%] male; 34 patients [34%] with very high-risk disease). Among 57 patients with papillary RCC in the intervention group, 26 (46%) completed 54 weeks of treatment, and among 53 patients with chromophobe RCC in the intervention group, 26 (49%) completed 54 weeks of treatment. With a median (IQR) follow-up of 76 (61-96) months, adjuvant everolimus did not improve RFS compared with placebo in either papillary RCC (5-year RFS: 62% vs 70%; HR, 1.19; 95% CI, 0.61-2.33; P = .61) or chromophobe RCC (5-year RFS: 79% vs 77%; HR, 0.89; 95% CI, 0.37-2.13; P = .79). In the combined non-clear RCC cohort, grade 3 or higher adverse events occurred in 48% of patients who received everolimus and 9% of patients who received placebo. Conclusions and Relevance: In this clinical trial assessing the use of adjuvant everolimus, postoperative everolimus did not show evidence of improved RFS among patients with papillary or chromophobe RCC, and results from the study do not support adjuvant everolimus for this cohort. However, since the lower bounds of the 95% CIs were 0.61 and 0.89, respectively, potential treatment benefit in these subgroups cannot be ruled out. Trial Registration: ClinicalTrials.gov Identifier: NCT01120249.