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Background/aim: To investigate the relationship between sex-related visceral obesity and WHO/ISUP nuclear grade in clear cell renal cell carcinoma (ccRCC). Materials and methods: Between January 2018 and June 2022, 95 patients (56 men and 39 women) with pathologically proven ccRCC who underwent abdominal computed tomography examination were retrospectively examined. The patients were classified into two groups: low- and high-WHO/ISUP nuclear grade ccRCC (n = 58 and n = 37), respectively. Patient height, weight, body mass index (BMI), sex, age, subcutaneous fat area (SFA), visceral fat area (VFA), total fat area (TFA), and percentage of visceral fat (VF%) were recorded for the two groups. Results: No significant differences were found in age, BMI, SFA, or TFA, but VFA and VF% were significantly higher in the high-grade patient group. In males, maximal tumor diameter (MTD) (67.8% sensitivity and 76.9% specificity) had the highest area under the curve (AUC), while in females, VF% (70.0% sensitivity and 73.7% specificity) had the highest AUC. VF% revealed an odds ratio (OR) of 1.09 in females with high-grade ccRCC, and in males, MTD was an independent predictor of ccRCC with an OR of 1.03. Conclusions: Sex-related body fat tissue, including VFA and VF%, could be used for estimating WHO/ISUP nuclear grade in patients with ccRCC, especially in females.

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Background: Many factors affect the prognosis of kidney renal clear cell carcinoma (KIRC). Early diagnosis can significantly improve the prognosis of KIRC patients. Therefore, a method needs to be developed to diagnose KIRC early, predict patient prognosis, and improve personalized treatments. The objective of this study is to utilize bioinformatics tools and public database resources to identify differentially expressed genes (DEGs) between renal cancer tissues and adjacent normal tissues, and to further screen for prognostic-related genes (PRGs) of KIRC. Methods: KIRC was studied using R language and FunRich software and several databases, including the Gene Expression Omnibus (GEO), The Cancer Genome Atlas (TCGA), the University of Alabama at Birmingham cancer data analysis Portal (UALCAN), and Tumor Immune Estimation Resource (TIMER) databases. Moreover, quantitative real-time polymerase chain reaction (qRT-PCR) was used to validate the expression of multiple genes in KIRC and adjacent normal tissues. Results: There were substantial differences in immune cell infiltration between the KIRC and adjacent normal tissues in the GSE40435 and GSE46699 datasets. In addition, we screened multiple PRGs of KIRC by combining the GEO and TCGA data. The UALCAN database verified that some representative PRGs were differently expressed depending on the lymph node metastasis status, grade, and stage of KIRC. The qRT-PCR results confirmed the expression of the PRGs in KIRC and adjacent normal tissues. Through the GO and KEGG analyses, interaction analysis, and TIMER database, we found that the prognosis of KIRC was closely related to immune microenvironment and vascular endothelial growth factor (VEGF)/VEGF receptor (VEGFR) signaling. Conclusions: Our findings could contribute to the prognosis prediction of KIRC, the selection of personalized treatments, and the early diagnosis of KIRC.

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OBJECTIVES: To systematically investigate the expression, prognostic value, genetic alterations, immune infiltration, and molecular function of Nck-associated protein 1 (NCKAP1) in a pan-cancer analysis, with a specific focus on its association with kidney renal cell carcinoma (KIRC). METHODS: We analyzed the role of NCKAP1 across various tumor types using data from The Cancer Genome Atlas (TCGA). The Gene Expression Profiling Interactive Analysis version 2 (GEPIA2) database was used to assess the correlation between NCKAP1 expression levels and overall survival (OS) and disease-free survival (DFS) across different cancers, as well as its association with cancer stage. Genetic alterations of NCKAP1 were explored using CBioPortal, and their prognostic implications were assessed. NCKAP1 was further analyzed through Gene Ontology and protein interaction network analyses. Immunohistochemistry (IHC) staining from the Human Protein Atlas (HPA) database evaluated NCKAP1 levels in KIRC tissues. Functional assays, including Cell Counting Kit-8 (CCK-8), colony formation, transwell, and wound healing assays, were conducted to determine the effects of NCKAP1 overexpression on cell growth rate and their ability to invade, proliferate, migrate in a KIRC (786-O) cell line. The relationship between NCKAP1 expression and immune infiltration in KIRC was systematically examined using the Tumor Immune Estimation Resource. RESULTS: NCKAP1 expression was significantly altered in most tumor types compared to corresponding non-tumor tissues. Survival analysis indicated that low NCKAP1 expression was associated with poor OS, DFS, and advanced cancer stage (P < 0.05) specifically in KIRC. Genetic alterations in NCKAP1 were linked to clinical outcome in cancer patients, and a positive correlation was observed between NCKAP1 expression and cancer-associated fibroblast infiltration (P < 0.05). Gene Ontology analysis revealed that NCKAP1 regulates the actin cytoskeleton and interacts with proteins such as CYFIP1, ABI2, WASF2, and BRK1. IHC staining showed significantly lower NCKAP1 levels in KIRC tissues compared to normal tissues. Overexpression of NCKAP1 in KIRC cell lines reduced cell proliferation, invasion, and migration (P < 0.05). NCKAP1 was also positively correlated with macrophage, neutrophil, and CD4+ T cell infiltration (P < 0.001). CONCLUSION: NCKAP1 may serve as a prognostic and immunological marker and may be a therapeutic target for KIRC.

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Background: Protein information is often replaced by RNA data in studies to understand cancer-related biological processes or molecular functions, and proteins of prognostic significance in Kidney clear cell carcinoma (KIRC) remain to be mined. Methods: The cancer genome atlas program (TCGA) data was utilized to screen for proteins that are prognostically significant in KIRC. Machine learning algorithms were employed to develop protein prognostic models. Additionally, immune infiltration abundance, somatic mutation differences, and immunotherapeutic responses were analyzed in various protein risk subgroups. Ultimately, the validation of protein-coding genes was confirmed by utilizing an online database and implementing quantitative real-time PCR (qRT-PCR). Results: The patients were divided into two risk categories based on prognostic proteins, and notable disparities in both overall survival (OS) and progression free interval (PFI) were observed between the two groups. The OS was more unfavorable in the high-risk group, and there was a noteworthy disparity in the level of immune infiltration observed between the two groups. In addition, the nomogram showed high accuracy in predicting survival in KIRC patients. Conclusion: In this research, we elucidated the core proteins associated with prognosis in terms of survival prediction, immunotherapeutic response, somatic mutation, and immune microenvironment. Additionally, we have developed a reliable prognostic model with excellent predictive capabilities.

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SWI/SNF (SWItch/Sucrose Non-Fermentable) is the most frequently mutated chromatin-remodelling complex in human malignancy, with over 20% of tumours having a mutation in a SWI/SNF complex member. Mutations in specific SWI/SNF complex members are characteristic of rare chemoresistant ovarian cancer histopathological subtypes. Somatic mutations in ARID1A, encoding one of the mutually exclusive DNA-binding subunits of SWI/SNF, occur in 42-67% of ovarian clear cell carcinomas (OCCC). The concomitant somatic or germline mutation and epigenetic silencing of the mutually exclusive ATPase subunits SMARCA4 and SMARCA2, respectively, occurs in Small cell carcinoma of the ovary, hypercalcaemic type (SCCOHT), with SMARCA4 mutation reported in 69-100% of SCCOHT cases and SMARCA2 silencing seen 86-100% of the time. Somatic ARID1A mutations also occur in endometrioid ovarian cancer (EnOC), as well as in the chronic benign condition endometriosis, possibly as precursors to the development of the endometriosis-associated cancers OCCC and EnOC. Mutation of the ARID1A paralogue ARID1B can also occur in both OCCC and SCCOHT. Mutations in other SWI/SNF complex members, including SMARCA2, SMARCB1 and SMARCC1, occur rarely in either OCCC or SCCOHT. Abrogated SWI/SNF raises opportunities for pharmacological inhibition, including the use of DNA damage repair inhibitors, kinase and epigenetic inhibitors, as well as immune checkpoint blockade.

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Pyrroline-5-carboxylate reductase (PYCR) is pivotal in converting pyrroline-5-carboxylate (P5C) to proline, the final step in proline synthesis. Three isoforms, PYCR1, PYCR2, and PYCR3, existed and played significant regulatory roles in tumor initiation and progression. In this study, we first assessed the molecular and immune characteristics of PYCRs by a pan-cancer analysis, especially focusing on their prognostic relevance. Then, a kidney renal clear cell carcinoma (KIRC)-specific prognostic model was established, incorporating pathomics features to enhance predictive capabilities. The biological functions and regulatory mechanisms of PYCR1 and PYCR2 were investigated by in vitro experiments in renal cancer cells. The PYCRs' expressions were elevated in diverse tumors, correlating with unfavorable clinical outcomes. PYCRs were enriched in cancer signaling pathways, significantly correlating with immune cell infiltration, tumor mutation burden (TMB), and microsatellite instability (MSI). In KIRC, a prognostic model based on PYCR1 and PYCR2 was independently validated statistically. Leveraging features from H&E-stained images, a pathomics feature model reliably predicted patient prognosis. In vitro experiments demonstrated that PYCR1 and PYCR2 enhanced the proliferation and migration of renal carcinoma cells by activating the mTOR pathway, at least in part. This study underscores PYCRs' pivotal role in various tumors, positioning them as potential prognostic biomarkers and therapeutic targets, particularly in malignancies like KIRC. The findings emphasize the need for a broader exploration of PYCRs' implications in pan-cancer contexts.

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Calcium ions (Ca2+) are crucial in tumorigenesis and progression, with their elevated levels indicating a negative prognosis in Kidney Renal Clear Cell Carcinoma (KIRC). The influence of genes regulating calcium ions on the survival outcomes of KIRC patients and their interaction with the tumor's immune microenvironment is yet to be fully understood. This study analyzed gene expression data from KIRC tumor and adjacent non-tumor tissues using the TCGA-KIRC dataset to pinpoint genes that are differentially expressed in KIRC. Intersection of these genes with those regulating calcium ions highlighted specific calcium ion-regulating genes that exhibit differential expression in KIRC. Subsequently, prognostic risk models were developed using univariate Cox and LASSO-Cox regression analyses to verify their diagnostic precision. Additionally, the study investigated the correlation between tumor immunity and KIRC patient outcomes, assessing the contribution of STAC3 genes to tumor immunity. Further exploration entailed SSGASE, single-cell analysis, pseudotime analysis and both in vivo and in vitro experiments to evaluate STAC3's role in tumor immunity and progression. Notably, STAC3 was significantly overexpressed in tumor specimens and positively correlated with the degree of malignancy of KIRC, affecting patients' prognosis. Elevated STAC3 expression correlated with enhanced immune infiltration in KIRC tumors. Furthermore, silencing STAC3 curtailed KIRC cell proliferation, migration, invasion, and stemness properties. Experimental models in mice confirmed that STAC3 knockdown led to a reduction in tumor growth. Elevated STAC3 expression is intricately linked with immune infiltration in KIRC tumors, as well as with the aggressive biological behaviors of tumor cells, including their proliferation, migration, and invasion. Targeting STAC3 presents a promising strategy to augment the efficacy of current therapeutic approaches and to better the survival outcomes of patients with KIRC.

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Ovarian clear cell carcinoma (OCCC) is a subtype of ovarian cancer and is highly malignant with high chemoresistance. CACNA1H is pivotal in tumor development. However, the role of CACNA1H in the acquisition process of chemotherapeutic resistance in OCCC cells is rarely reported. Therefore, this study aimed to explore the role of CACNA1H in chemotherapy resistance of OCCC cells and its related mechanism. Based on bioinformatics analysis, we found that CACNA1H was downregulated in chemoresistant OCCC patients compared to chemosensitive OCCC patients. Comparing DDP-resistant and sensitive OCCC cell lines, the resistant strain showed lower CACNA1H mRNA expression. CACNA1H expression was associated with calcium signaling pathways in chemoresistant OCCC patients. CACNA1H mRNA expression was significantly downregulated in OCCC cells compared to normal ovarian epithelial cells. When CACNA1H was overexpressed, intracellular Ca2+ concentration and protein levels of p-CaMKII and p-Akt were significantly upregulated, while protein levels of LC3-II/LC3-I and Beclin1 were downregulated, indicating a repression of autophagy. The rescue experiment revealed that CACNA1H overexpression in drug-resistant OCCC cells reduced autophagy-induced DDP resistance via CaMKII/Akt signaling. Overall, CACNA1H increased intracellular Ca2+ concentration and activated CaMKII/Akt signaling pathway in OCCC, thereby repressing autophagy to maintain the sensitivity of OCCC cells to DDP.

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Clear cell sarcoma (CCS) is a rare melanocytic soft tissue sarcoma known for its propensity to metastasize to the lymph nodes and typically has an unfavorable prognosis. Currently, surgical resection is the primary treatment for localized CCS, while radiotherapy and chemotherapy are preferred for metastatic cases. The roles of adjuvant chemotherapy, radiotherapy, and lymph node dissection are controversial. Although immunotherapy has emerged as a promising avenue in CCS treatment research, there are no established clinical standards for postoperative follow-up. This editorial discusses a recent article by Liu et al, with a focus on current diagnostic modalities, treatment approaches, and the challenging prognosis associated with CCS. Our aim is to underscore the importance of long-term patient follow-up in CCS management.

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Schwannomas are usually benign tumors typically found in the head, neck, and extremities, with approximately 3% originating in the retroperitoneum. In this case, a young male presented with incidental masses in the left kidney and retroperitoneum. Abdominal pelvic enhanced computerized tomography (CT) revealed a tumor apparently originating from the left kidney, along with a retroperitoneal mass suspected to be a metastatic lymph node. Subsequently, a radical nephrectomy of the left kidney and retroperitoneal mass resection was performed. Pathological examination confirmed the left kidney mass as renal clear cell carcinoma and the retroperitoneal mass as schwannoma. The patient recovered uneventfully and was discharged from the hospital. A 6-month postoperative follow-up showed no evidence of recurrence. Preoperative diagnosis of schwannomas concurrent with other concurrent malignancies in rare sites, such as the retroperitoneum, is challenging due to their rare and non-specific radiological features. Although retroperitoneal schwannomas are rare, they should be considered in the differential diagnosis during CT examinations for renal cancer. Additionally, the advantages of a multidisciplinary team approach should be utilized in tumor management.

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Background: The prognosis for patients with kidney renal clear cell carcinoma (KIRC) remains unfavorable, and the understanding of SRY-box transcription factor 11 (SOX11) in KIRC is still limited. The purpose of this paper is to explore the role of SOX11 in the prognosis of KIRC. Methods: We analyzed SOX11 expression in KIRC and adjacent normal tissues using The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. Our study aims to establish a correlation between SOX11 expression and clinical pathological features. Differentially expressed genes (DEGs) were assessed using R software. Furthermore, we conducted Gene Ontology (GO)/Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses and gene set enrichment analysis (GSEA). Integration of data from the Tumor Immune Estimation Resource (TIMER) and TCGA databases allowed us to assess the association between SOX11 expression and immune infiltration in KIRC. Additionally, we analyzed the association between SOX11 gene expression and N6-methyladenosine (m6A) modification in KIRC using TCGA and GEO data. Results: Our findings revealed high SOX11 expression in KIRC, which showed a significant correlation with tumor staging and prognosis. GO/KEGG and GSEA analyses indicated that SOX11 was closely associated with sodium ion transport, synaptic vesicle circulation, and oxidative phosphorylation. Analysis of the TIMER and TCGA databases demonstrated correlations of SOX11 expression levels with the presence of CD8+ T lymphocytes, neutrophils, CD4+ T cells, as well as B cells. Moreover, both the TCGA and GEO datasets showed a substantial association between SOX11 and m6A modification-related genes, namely ZC3H13, FTO, METTL14, YTHDC1, IGF2BP1, and IGF2BP2. Conclusions: SOX11 exhibits a correlation with m6A modification and immune infiltration, suggesting its potential as a prognostic biomarker for KIRC.

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Sarcomatoid renal cell carcinoma typically signifies an exceptionally poor prognosis, with patients rarely surviving beyond one year. An 83-year-old male presented to our hospital with complaints of headache and left-sided limb weakness. Computed tomography (CT) scans of the head and lungs disclosed a mass within the right temporal lobe, accompanied by peritumoral edema in the right cerebral hemisphere. Brain magnetic resonance imaging (MRI) with contrast enhancement and diffusion-weighted imaging (DWI) delineated a mass in the right temporal lobe, measuring 3 × 3 × 3 cm. He underwent cytoreductive surgery successively in the neurosurgery and urology departments. Despite experiencing postoperative tumour recurrence, the patient has lived close to four years to date. This case report illustrates that cytoreductive surgery combined with systemic pharmacotherapy can still confer significant survival benefits for elderly patients.

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BACKGROUND: Kidney renal clear cell carcinoma (KIRC) represents a significant proportion of renal cell carcinomas and is characterized by high aggressiveness and poor prognosis despite advancements in immunotherapy. Disulfidptosis, a novel cell death pathway, has emerged as a critical mechanism in various cellular processes, including cancer. This study leverages machine learning to identify disulfidptosis-related long noncoding RNAs (DRlncRNAs) as potential prognostic biomarkers in KIRC, offering new insights into tumor pathogenesis and treatment avenues. RESULTS: Our analysis of data from The Cancer Genome Atlas (TCGA) led to the identification of 431 DRlncRNAs correlated with disulfidptosis-related genes. Five key DRlncRNAs (SPINT1-AS1, AL161782.1, OVCH1-AS1, AC131009.3, and AC108673.3) were used to develop a prognostic model that effectively distinguished between low- and high-risk patients with significant differences in overall survival and progression-free survival. The low-risk group had a favorable prognosis associated with a protective immune microenvironment and a better response to targeted drugs. Conversely, the high-risk group displayed aggressive tumor features and poor immunotherapy outcomes. Validation through qRT‒PCR confirmed the differential expression of these DRlncRNAs in KIRC cells compared to normal kidney cells, underscoring their potential functional significance in tumor biology. CONCLUSIONS: This study established a robust link between disulfidptosis-related lncRNAs and patient prognosis in KIRC, underscoring their potential as prognostic biomarkers and therapeutic targets. The differential expression of these lncRNAs in tumor versus normal tissue further highlights their relevance in KIRC pathogenesis. The predictive model not only enhances our understanding of KIRC biology but also provides a novel stratification tool for precision medicine approaches, improving treatment personalization and outcomes in KIRC patients.

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BACKGROUND: This study was conducted to determine the optimal monitoring after initial treatment of ovarian clear cell carcinoma (OCCC) using data from patients enrolled in the Japanese Gynecologic Oncology Group (JGOG) 3017 study. The JGOG study evaluated the efficacy of an irinotecan and cisplatin combination regimen compared with that of a paclitaxel and carboplatin regimen for OCCC patients who underwent primary surgery. METHODS: Yielding 619 total patients in this study, to analyze progression-free and overall survival, the hazards over time were estimated using kernel smoothing curves to identify the peak of event occurrence. The number of progression events was summed by progression site, and the cumulative incidence proportion was estimated for the major progression sites, considering competing risks. RESULTS: The peak hazard for progression or death was observed at 12 months post-treatment, and most events were observed by 24 months. The hazard for death peaked at 18 months post-treatment, with most events being observed by 48 months. The hazard for lung, liver, and spleen metastases remained constant for 18 months post-treatment, with a decreasing trend thereafter; most events were observed by 18 months. The hazard for peritoneal dissemination was constant for 12 months, with a decreasing trend thereafter, with most exacerbations observed by 24 months. The risk of pelvic recurrence peaked at 6 months, with most exacerbations observed by 24 months. DISCUSSION: The incidence of progression events for OCCC peaked at 12 months and most progression events occurred within 24 months. Close follow-up for the initial 24 months post-treatment and fewer visits thereafter may be acceptable. However, closely monitoring symptoms and examining patients based on differences in progression rates at different sites may be important.

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OBJECTIVE: To investigate pantothenate kinases 1 (PANK1) expression in kidney renal clear cell carcinoma (KIRC) tissues, analyze its correlation with clinicopathological features and prognosis, and explore its impact on invasion, migration, and apoptosis in KIRC cells. METHODS: GEPIA (gene expression profiling interactive analysis), UALCAN and LinkedOmics, were employed to analyze PANK1 expression in KIRC tissues and its correlation with clinical characteristics. Comparative analyses were performed between KIRC (Caki-1 and 786-O) and noncancerous renal cells (HK-2 and RPTEC). Transfection with PANK1 activation particles was conducted, followed by Wound healing, Transwell assay, Annexin V-fluorescein isothiocyanate/propidium iodide (Annexin V-FITC/PI) staining, quantitative reverse-transcription polymerase chain reaction (qRT-PCR), and Western blotting. RESULTS: PANK1 was down-regulated in KIRC tissues and cells compared to normal tissues and noncancerous cells. Correlation analyses linked PANK1 expression with clinicopathological features in KIRC, with high PANK1 expression associated with a favorable outcome. High PANK1 expression correlated positively with E-cadherin (CDH1), tight junction protein 1 (TJP1), Fas cell surface death receptor (FAS), caspase-8 (CASP8), and CASP9, while showing a negative correlation with vimentin (VIM), snail family transcriptional repressor 1 (SNAIL1), twist family BHLH transcription factor 1 (TWIST1), and TWIST2. PANK1 overexpression increased CDH1, TJP1, FAS, CASP8, and CASP9 while downregulating SNAIL1, VIM, TWIST1, and TWIST2, inhibiting invasion and migration, and promoting apoptosis in KIRC cells. CONCLUSION: PANK1 down-regulation in KIRC tissues correlated with clinicopathological features and prognosis. Its overexpression modulated epithelial-mesenchymal transition (EMT)-related gene, inhibited invasion, promoted apoptosis in KIRC cells, highlighting its role in disease progression and therapeutic potential.

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Epithelial ovarian cancer (EOC) is widely recognized as the most lethal gynecological malignancy; however, its early-stage detection remains a considerable clinical challenge. To address this, we have introduced a new method, named Comprehensive Serum Glycopeptide Spectral Analysis (CSGSA), which detects early-stage cancer by combining glycan alterations in serum glycoproteins with tumor markers. We detected 1712 glycopeptides using liquid chromatography-mass spectrometry from the sera obtained from 564 patients with EOC and 1149 controls across 13 institutions. Furthermore, we used a convolutional neural network to analyze the expression patterns of the glycopeptides and tumor markers. Using this approach, we successfully differentiated early-stage EOC (Stage I) from non-EOC, with an area under the curve (AUC) of 0.924 in receiver operating characteristic (ROC) analysis. This method markedly outperforms conventional tumor markers, including cancer antigen 125 (CA125, 0.842) and human epididymis protein 4 (HE4, 0.717). Notably, our method exhibited remarkable efficacy in differentiating early-stage ovarian clear cell carcinoma from endometrioma, achieving a ROC-AUC of 0.808, outperforming CA125 (0.538) and HE4 (0.557). Our study presents a promising breakthrough in the early detection of EOC through the innovative CSGSA method. The integration of glycan alterations with cancer-related tumor markers has demonstrated exceptional diagnostic potential.

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BACKGROUND: The identification of reliable prognostic markers is crucial for optimizing patient management and improving clinical outcomes in clear cell renal cell carcinoma (ccRCC). METHODS: We used the GSE89563 dataset from the GEO database and the Kidney Clear Cell Carcinoma (KIRC) dataset from the TCGA database to develop a prognostic model based on weighted gene co-expression network analysis (WGCNA) and non-negative matrix factorization (NMF) to predict disease progression and prognosis in ccRCC. RESULT: We utilized WGCNA to identify risk genes and applied NMF to stratify high-risk populations in ccRCC. We characterized the immune gene features of these high-risk groups and ultimately developed a risk prediction model for ccRCC patients using a Lasso regression approach. The risk score was calculated as follows: Risk score = SUM (-0.136394797 ANK3 + 0.004238138 BIVM_ERCC5 - 0.046248451 C4orf19 - 0.036013206 F2RL3 - 0.125531316 GNG7 - 0.012698109 METTL7A + 0.078462369 MSTO1 - 0.050450656 PINK1 - 0.059446590 SLC16A12 - 0.039883686 SLC2A9 + 0.083310722 TLCD1 - 0.059801739 WDR72 + 0.071430088 ZNF117). CONCLUSION: We develop a prognostic model for clear cell renal cell carcinoma and analyzed immune response in subgroups and confirmed protein-level expression concordance.

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PURPOSE: Immune checkpoint inhibitor (ICI)-based combination therapy is a standard systemic treatment for metastatic renal cell carcinoma (mRCC). Although differential pharmacologic action between ICI+ICI and ICI+tyrosine kinase inhibitor (TKI) combinations may affect outcomes, comparative studies using real-world data are few. METHODS: We retrospectively analyzed the records of 447 mRCC patients treated with 1st-line ICI-based combinations at multiple institutions between January 2018 and August 2023, and selected 320 patients diagnosed with clear cell RCC (ccRCC) for further study. Cohorts were matched using one-to-one propensity scores based on IMDC risk classification. Overall survival (OS), progression-free survival (PFS), objective response rates (ORRs), and treatment-related adverse events (TrAE) were compared. RESULTS: The matching process yielded 228 metastatic ccRCC patients treated with ICI+ICI (n = 114) or ICI+TKI (n = 114). Median OS was 53 months (95%CI: 33-NA) in patients treated with ICI+ICI and was not reached (95%CI: 43-NA) with ICI+TKI (P = 0.24). Median PFS was significantly shorter for ICI+ICI (13 months, 95%CI: 7-25) than for ICI+TKI (25 months, 95%CI: 13-NA) (P = 0.047). There were no differences in second-line PFS for sequential therapy after 1st-line combinations of ICI+ICI or ICI+TKI (6 vs. 8 months, P = 0.6). There were no differences in ORR between the 2 groups (ICI+ICI: 51% vs. ICI+TKI: 55%, P = 0.8); the progressive disease (PD) rate was significantly higher in patients treated with the ICI+ICI combination (24% vs. 11%, P = 0.029). The rate of any grade TrAE was significantly higher in patients treated with ICI+TKI (71% vs. 85%, P = 0.016), but we found no differences in severe TrAE between the 2 groups (39% vs. 36%, P = 0.8). CONCLUSIONS: In a matched cohort of real-world data, we confirmed comparable OS benefits between ICI+ICI and ICI+TKI combinations. However, differential clinical behaviors in terms of PFS, PD rates, and TrAE between ICI-based combinations may enrich clinical decision-making.

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Background: The clinical role of claudin 8 (CLDN8) in kidney renal clear cell carcinoma (KIRC) remains unclarified. Herein, the expression level and potential molecular mechanisms of CLDN8 underlying KIRC were determined. Methods: High-throughput datasets of KIRC were collected from GEO, ArrayExpress, SRA, and TCGA databases to determine the mRNA expression level of the CLDN8. In-house tissue microarrays and immunochemistry were performed to examine CLDN8 protein expression. A summary receiver operating characteristic curve (SROC) and standardized mean difference (SMD) forest plot were generated using Stata v16.0. Single-cell analysis was conducted to further prove the expression level of CLDN8. A clustered regularly interspaced short palindromic repeats knockout screen analysis was executed to assess the growth impact of CLDN8. Functional enrichment analysis was conducted using the Metascape database. Additionally, single-sample gene set enrichment analysis was implied to explore immune cell infiltration in KIRC. Results: A total of 17 mRNA datasets comprising 1,060 KIRC samples and 452 non-cancerous control samples were included in this study. Additionally, 105 KIRC and 16 non-KIRC tissues were analyzed using in-house immunohistochemistry. The combined SMD was -5.25 (95% confidence interval (CI): -6.13 to -4.37), and CLDN8 downregulation yielded an SROC area under the curve (AUC) close to 1.00 (95% CI: 0.99 - 1.00). CLDN8 downregulation was also confirmed at the single-cell level. Knocking out CLDN8 stimulated KIRC cell proliferation. Lower CLDN8 expression was correlated with worse overall survival of KIRC patients (hazard ratio of CLDN8 downregulation = 1.69, 95% CI: 1.2 - 2.4). Functional pathways associated with CLDN8 co-expressed genes were centered on carbon metabolism obstruction, with key hub genes ACADM, ACO2, NDUFS1, PDHB, SDHD, SUCLA2, SUCLG1, and SUCLG2. Conclusions: CLDN8 is downregulated in KIRC and is considered a potential tumor suppressor. CLDN8 deficiency may promote the initiation and progression of KIRC, potentially in conjunction with metabolic dysfunction.