Clear Cell Research Articles

Causal role of ischemic heart disease in ovarian cancer subtypes

BackgroundIschemic heart disease (IHD) may share biological mechanisms with cancer, including ovarian cancer, through pathways such as chronic inflammation and oxidative stress. However, the relationship between IHD and ovarian cancer subtypes remains unclear. This study used Mendelian randomization (MR) to explore potential causal associations.MethodsA two-sample MR analysis was conducted using genetic instruments for IHD from large-scale genome-wide association studies (GWAS). The inverse-variance weighted (IVW) method was used as the primary analysis, supported by MR-Egger, weighted median, and MR-PRESSO for sensitivity analyses.ResultsNo significant association was found between IHD and overall ovarian cancer risk (OR = 0.97, 95% CI 0.92–1.03, P = 0.378). However, IHD was linked to a reduced risk of endometrioid ovarian cancer (OR = 0.86, 95% CI 0.76–0.98, P = 0.027). No associations were observed for serous, mucinous, or clear cell ovarian cancers. Sensitivity analyses confirmed robust findings.ConclusionsIHD may confer a protective effect against endometrioid ovarian cancer but does not influence overall ovarian cancer risk. These findings highlight the need for further research into subtype-specific mechanisms.

The application value of preoperative F-FDG PET/CT in preoperative localized clear cell renal cell carcinoma

Aim: In cancer tissues, glycolysis metabolism is often heightened, making 18F-fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT) useful for assessing glucose metabolism. However, the kidneys' high glucose metabolism makes it difficult to distinguish between normal renal tissue and renal cancer. This study aims to evaluate the maximum standardized uptake value (SUVmax) in renal cancer using PET/CT and determine its relationship to prognosis. Methods: We also aim to examine the correlation between SUVmax and clinical parameters and its potential link to prognosis. We enrolled 105 patients who underwent FDG-PET/CT between March 2012 and October 2017. These patients, diagnosed with localized renal cell carcinoma (RCC), underwent surgery and were pathologically confirmed to have clear cell RCC (ccRCC). We investigated the impact of SUVmax and other parameters on recurrence. Results: SUVmax and C-reactive protein (CRP) were associated with tumor progression, alongside stage, nuclear grade, microvascular invasion [v(+)], and tumor-infiltrating lymphocytes (TILs). Multivariate analysis with recurrence-free survival (RFS) as the endpoint indicated significant results (SUVmax ≥ 3.7: relative risk 8.98, P < 0.01; CRP ≥ 0.11 mg/dL: relative risk 6.03, P < 0.01, n = 89). In survival curve analysis with RFS, high SUVmax or elevated CRP predicted poor prognosis, with further worsening when v(+) was added. Conclusion: SUVmax is a strong prognostic factor for poor outcomes. CRP is also a prognostic factor, though it should be interpreted cautiously, as CRP reflects overall systemic conditions and may not exclusively represent renal cancer activity. Further research into pre-treatment RCC prognosis prediction is anticipated.

CT-based scoring system for diagnosing eosinophilic solid and cystic renal cell carcinoma versus clear cell renal cell carcinoma

Eosinophilic solid and cystic renal cell carcinoma (ESC-RCC) is rare and often misdiagnosed as clear cell renal cell carcinoma (ccRCC). Therefore, a CT-based scoring system was developed to improve differential diagnosis. Retrospectively, 25 ESC-RCC and 176 ccRCC cases, were collected. The two groups were matched on a 1:2 basis using the propensity-score-matching (PSM) method, with matching factors including sex and age. Finally, 25 ESC-RCC and 50 ccRCC cases were included and randomly divided into a training cohort (52 cases) and a validation cohort (23 cases). Logistic regression identified significant factors, constructed the primary model, and assigned weights for the scoring model. Diagnostic performance was compared using receiver operating characteristic curves, dividing points into three intervals. Multifactorial logistic regression identified three independent factors: intra-tumour necrosis (3 points), degree of corticomedullary phase (CMP) enhancement (3 points), and pseudocapsule (2 points). The primary model’s area under the curve (AUC) value was 0.954 (95% confidence interval [CI]: 0.857–0.993, P < 0.001), with 85.7% sensitivity and 94.1% specificity. The scoring model’s AUC value for the training cohort was 0.950 (95% CI: 0.852–0.991, P < 0.001), with 77.1% sensitivity and 100% specificity at a cut-off of 4 points. The validation cohort’s AUC was 0.942 (95% CI: 0.759–0.997, P < 0.001). The scoring system intervals were: ≥0 to < 2 points, ≥ 2 to ≤ 3 points, and > 3 to ≤ 8 points. Higher scores correlated with increased ccRCC incidence and decreased ESC-RCC incidence.The limitation of this study is the small sample size. A CT-based scoring system effectively differentiates ESC-RCC from ccRCC.

A Potential Role of MicroRNA in the Renal Cancer and Its Tumor Microenvironment

Renal cell carcinoma (RCC) accounts for approximately 2.2% of all diagnosed cancers and 1.8% of cancer-related deaths. Clear cell renal cell carcinoma (ccRCC) is the most prevalent subtype of RCC, accounting for approximately 70–80% of all cases. Despite significant advancements in therapeutic strategies over recent decades, treatment outcomes for ccRCC patients remain suboptimal. Prognosis for individuals with advanced or metastatic ccRCC continues to be poor, with a 5-year survival rate below 10%. This is largely due to the intricate and heterogeneous nature of the tumor microenvironment (TME). Current biomarkers and screening techniques for RCC often lack sensitivity or are cost-prohibitive, highlighting the need for novel biomarkers that enable early detection, particularly in high-risk populations. MicroRNAs (miRNAs) exhibit unique properties that make them promising candidates for cancer biomarker development. Researchers have analyzed miRNA expression profiles in biological samples from RCC patients, identifying specific circulatory or urinary miRNAs as potential diagnostic or follow-up markers. Additionally, the expression patterns of certain miRNAs have been linked to patient responses to chemotherapy, immunotherapy, and targeted treatments such as sunitinib. This study reviews existing research on the role of miRNAs in RCC, including their potential as biomarkers, therapeutic targets, and regulators of treatment response in affected patients.

Bone marrow metastasis of ovarian cancer: A two‑center retrospective study and literature review.

Bone marrow metastasis (BMM) causes pancytopenia and disseminated intravascular coagulation (DIC), resulting in rapid mortality. The incidence of this disease is likely underestimated, with confirmed BMM occurring at approximately twice the rates expected clinically. The present study describes two detailed cases and includes a literature review of BMM caused by ovarian cancer. The existing medical records of patients admitted to Oita University Hospital (Yufu, Japan) and Saitama Medical University International Medical Center (Hidaka, Japan) were retrospectively analyzed and a literature review regarding BMM associated with ovarian cancer was conducted. The literature review of BMM of ovarian cancer, including the present cases, revealed that patient ages ranged between 37 and 71 years, with tumor histology described in 5 out of 8 cases. Notably, 3 previous cases involved rare histological types (small cell carcinoma, carcinosarcoma and mucinous carcinoid), whereas the present identified cases involved common types. The first case involved a patient who developed isolated BMM/carcinomatosis during maintenance therapy with olaparib for recurrent high-grade ovarian serous carcinoma. The patient initially presented with elevated cancer antigen 125 levels and decreased blood counts. Following the onset of BMM, the patient's lactate dehydrogenase level was elevated to 2,712 U/l. The second patient was diagnosed with BMM/carcinomatosis, concurrent with an initial diagnosis of ovarian clear cell carcinoma. Both patients subsequently developed pancytopenia and DIC, resulting in mortality. To the best of our knowledge, the present study is the first retrospective study of BMM of ovarian cancer. For early diagnosis, BMM should be considered in the differential diagnosis when a reduction in blood counts is accompanied by an elevation in serum tumor markers, regardless of histological type.

Overexpression of CHMP2B suppresses proliferation of renal clear cell carcinoma cells.

To analyze the association of CHMP2B expression level of with clinicopathological characteristics and prognosis of clear cell renal cell carcinoma (CRCC) and the possible role of CHMP2B in tumorigenesis and progression of CRCC. RNAseq data of CRCC were downloaded from the TCGA database for analysis of CHMP2B expression levels in tumor and adjacent tissues and their correlation with clinicopathological characteristics of the patients. Survival outcomes of the patients with high and low CHMP2B expressions were analyzed using the Kaplan-Meier model, and the COX risk regression model was used for identifying the prognostic factors of the patients. The correlation between CHMP2B expression and immune infiltration, its co-expressed genes, and the effect of CHMP2B gene mutations on immunotherapy responses, and its immunohistochemical expression in CRCC and normal tissues were analyzed. Clinical samples of CRCC were collected to examine CHMP2B expressions using RT-PCR, and cell experiment was carried out to test the effect of CHMP2B overexpression on biological behaviors of CRCC cells. CHMP2B was significantly under-expressed in renal cancer tissues, and its overexpression obviously inhibited the proliferation of CRCC cells in vitro. CHMP2B expression level was significantly correlated with age, gender, lymph node metastasis, and tumor stage, and the patients with low CHMP2B expression had poor survival outcomes. Enrichment and co-expression gene analyses suggested that CHMP2B was mainly involved in viral outgrowth, necrotic apoptosis, endocytosis, and immune-regulatory processes in kidney cancer. CHMP2B is lowly expressed in renal cancer tissues to affect tumor progression and tumor immune processes, and may serve as a prognostic biomarker and therapeutic target for CRCC.

Immune-Based and Novel Therapies in Variant Histology Renal Cell Carcinomas.

Renal cell carcinoma (RCC) is a heterogeneous disease that represents the most common type of kidney cancer. The classification of RCC is primarily based on distinct morphological and molecular characteristics, with two broad categories: clear cell RCC (ccRCC) and non-clear cell RCC (nccRCC). Clear cell RCC is the predominant subtype, representing about 70-80% of all RCC cases, while non-clear cell subtypes collectively make up the remaining 20-30%. Non-clear cell RCC encompasses many histopathological variants, each with unique biological and clinical characteristics. Additionally, any RCC subtype can undergo sarcomatoid dedifferentiation, which is associated with poor prognosis and rapid disease progression. Recent advances in molecular profiling have also led to the identification of molecularly defined variants, further highlighting the complexity of this disease. While immunotherapy has shown efficacy in some RCC variants and subpopulations, significant gaps remain in the treatment of rare subtypes. This review explores the outcomes of immunotherapy across RCC subtypes, including rare variants, and highlights opportunities for improving care through novel therapies, biomarker-driven approaches, and inclusive clinical trial designs.

MYBL2 promotes proliferation of clear cell renal cell carcinoma by regulating TOP2A and activating AKT/mTOR signaling pathway.

Renal cell carcinoma (RCC) is one of the most common malignancies in the urinary system, and clear cell renal cell carcinoma (ccRCC) is the most common subtype. MYBL2 has been reported to be overexpressed in various tumors and associated with poor prognosis in patients, but its biological role in ccRCC remains unclear. In this study, we investigated the mRNA and protein expression levels of MYBL2 in ccRCC samples and evaluated the prognostic value of MYBL2 using TCGA dataset. Invitro functional assays were performed using CCK-8, EdU, colony formation, cell scratch, and transwell assays, as well as invivo tumorigenesis assays to investigate the biological functions of MYBL2 in ccRCC. Additionally, gene set enrichment analysis (GSEA) was used to explore the downstream pathways of MYBL2, which were further validated. Finally, we predicted the target genes of MYBL2 using bioinformatics and validated them using ChIP and dual-luciferase reporter gene assays. MYBL2 expression was significantly higher in ccRCC than in adjacent normal tissues and was associated with poor prognosis. MYBL2 expression was positively correlated with the pathological tumor grade and clinical TNM stage of ccRCC patients. Knockdown of MYBL2 significantly inhibited the proliferation of renal cancer cells invitro and invivo, and knockdown of MYBL2 could inhibit cell invasion and migration, while overexpression of MYBL2 had the opposite effect. GSEA revealed that MYBL2 was associated with the mTOR signaling pathway and cell cycle pathway, which was confirmed by our study. Finally, we found that TOP2A was a target gene of MYBL2, and MYBL2 could bind to the TOP2A promoter to regulate its transcriptional activity, promoting the proliferation of clear cell renal cell carcinoma cells. MYBL2 emerges as a highly expressed factor that significantly correlates with adverse patient prognosis in ccRCC. Mechanistically, MYBL2 transcriptionally upregulates TOP2A, thereby modulating the proliferation of ccRCC cells. Furthermore, MYBL2 activates the mTOR signaling pathway, a critical node in the progression of ccRCC. Collectively, these findings position MYBL2 as a promising candidate for both a biological marker and a therapeutic target in the management of ccRCC.

A risk signature constructed by Tregs-related genes predict the clinical outcomes and immune therapeutic response in kidney cancer

Regulatory T cells (Tregs) have been found to be related to immune therapeutic resistance in kidney cancer. However, the potential Tregs-related genes still need to be explored. Our study found that patients with high Tregs activity show poor prognosis. Through co-expression and differential expression analysis, we screened several Tregs-related genes (KTRGs) in kidney renal clear cell carcinoma. We further conducted the univariate Cox regression analysis and determined the prognosis-related KTRGs. Through the machine learning algorithm—Boruta, the potentially important KTRGs were screened further and submitted to construct a risk model. The risk model could predict the prognosis of RCC patients well, high risk patients show a poorer outcomes than low risk patients. Multivariate Cox regression analysis reveals that risk score is an independent prognostic factor. Then, the nomogram model based on KTRG risk score and other clinical variables was further established, which shows a high predicted accuracy and clinical benefit based on model validation methods. In addition, we found EMT, JAK/STAT3, and immune-related pathways highly enriched in high risk groups, while metabolism-related pathways show a low enrichment. Through analyzing two other external immune therapeutic datasets, we found that the risk score could predict the patient's immune therapeutic response. High-risk groups represent a worse therapeutic response than low-risk groups. In summary, we identified several Tregs-related genes and constructed a risk model to predict prognosis and immune therapeutic response. We hope these organized data can provide a theoretical basis for exploring potential Tregs' targets to synergize the immune therapy for RCC patients.

CD11c-Expressing Microglia Are Transient, Driven by Interactions With Apoptotic Cells.

Microglia, the parenchymal macrophage of the central nervous system, serve crucial remodeling functions throughout development. Microglia are transcriptionally heterogenous, suggesting that distinct microglial states confer discrete roles. Currently, little is known about how dynamic these states are, the cues that promote them, or how they impact microglial function. In the developing retina, we previously found a significant proportion of microglia express CD11c (Integrin αX, Itgax, subunit of complement receptor 4) which has also been reported in other developmental and disease contexts. Here, we sought to understand the regulation and function of CD11c+ microglia. We found that CD11c+ microglia track with prominent waves of neuronal apoptosis in postnatal retina. Using genetic fate mapping, we provide evidence that microglia transition out of the CD11c state to return to homeostasis. We show that CD11c+ microglia have elevated lysosomal content and contribute to the clearance of apoptotic neurons, and found that acquisition of CD11c expression is partially dependent upon the TAM receptor AXL. Using selective ablation, we found CD11c+ microglia are not uniquely critical for phagocytic clearance of apoptotic cells. Together, our data suggest that CD11c+ microglia are a transient state induced by developmental apoptosis rather than a specialized subset mediating phagocytic elimination.

Establishment of a 3D-Printed Tissue-on-a-Chip Model for Live Imaging of Bacterial Infections.

Despite advances in healthcare, bacterial pathogens remain a severe global health threat, exacerbated by rising antibiotic resistance. Lower respiratory tract infections, with their high death toll, are of particular concern. Accurately replicating host-pathogen interactions in laboratory models is crucial for understanding these diseases and evaluating new therapies. In this communication, we briefly present existing in vivo models for cystic fibrosis and their limitations in replicating human respiratory infections. We then present a novel, 3D-printed, cytocompatible microfluidic lung-on-a-chip device, designed to simulate the human lung environment, and with possible use in recapitulating general infectious diseases.Our device enables the colonisation of fully differentiated lung epithelia at an air-liquid interface with Pseudomonas aeruginosa, a key pathogen in many severe infections. By incorporating dynamic flow, we replicate the clearance of bacterial toxins and planktonic cells, simulating both acute and chronic infections. This platform supports real-time monitoring of therapeutic interventions, mimics repeated drug administrations as in clinical settings, and facilitates the analysis of colony-forming units and cytokine secretion over time. Our findings indicate that this lung-on-a-chip device has significant potential for advancing infectious disease research, in optimizing treatment strategies against infections and in developing novel treatments.

Efficacy and safety of neoadjuvant therapy with tislelizumab plus axitinib for nonmetastatic renal cell carcinoma with inferior vena cava tumor thrombus: a retrospective study

In renal cell carcinoma (RCC) patients with inferior vena cava (IVC) tumor thrombus, neoadjuvant therapy could alleviate the burden of tumor thrombus, enhance the safety and feasibility of surgical resection, and improve patient prognosis. The combination of tislelizumab and axitinib has demonstrated efficacy in the treatment of advanced RCC. Our study aimed to evaluate the efficacy and safety in the neoadjuvant therapy setting of tislelizumab and axitinib in RCC patients with IVC tumor thrombus. In this retrospective study, seven patients of nonmetastatic RCC with IVC tumor thrombus who received 3 cycles of neoadjuvant therapy with tislelizumab plus axitinib at the First Affiliated Hospital of Xiamen University from May 2020 to December 2023 were included. The main outcomes included objective response rate (ORR), reduction of tumor thrombus size and level, surgical outcomes, and adverse events (AEs). The median age was 66 (range, 50–72) years, and five (71.4%) patients were male. Five (71.4%) patients were diagnosed with clear cell carcinoma, and two (28.6%) patients were papillary type I carcinoma. Four (57.1%) patients had level II tumor thrombus and three (42.9%) patients had level III. The ORR of patients was 57.1%. The mean decrease in thrombus diameter and length was 5.8 (1.8–17.2) mm and 18.5 (4.4–41.5) mm, respectively. All patients showed a decrease in IVC tumor thrombus. The mean time from the end of neoadjuvant therapy to radical nephrectomy and thrombectomy was 31.7(range, 22–45) days. No intraoperative complications or postoperative Clavien-Dindo grade>3 complications occurred. The most common AEs were all grade 1–2, and only one patient had grade 4 hepatic impairment. No AEs delayed the surgery schedule. This study of RCC patients receiving neoadjuvant combination with tislelizumab and axitinib effectively reduced primary tumor and IVC tumor thrombus with the absence of serious AEs, demonstrating a promising neoadjuvant therapy.

Evidence of DNA methylation heterogeneity and epipolymorphism in kidney cancer tissue samples.

Clear cell renal cell carcinoma (ccRCC) is characterised by significant genetic heterogeneity, which has diagnostic and prognostic implications. Very limited evidence is available regarding DNA methylation heterogeneity. We therefore generate sequence level DNA methylation data on 136 multi-region tumour and normal kidney tissue from 18 ccRCC patients, along with matched whole exome sequencing (85 samples) and gene expression (47 samples) data on a subset of samples. We perform a comprehensive systematic analysis of heterogeneity between patients, within a patient and within a sample. We demonstrate that bulk methylation data may be deconvoluted into cell-type-specific latent methylation components (LMCs), and that LMC1, which is likely to represent T cells, is associated with prognostic parameters. Differential epipolymorphism was noted between ccRCC and normal tissue in the promoter region of genes which are known to be associated with kidney cancer. This was externally validated in an independent cohort of 71 ccRCC and normal kidney tissues. Differential epipolymorphism in the gene promoter was a predictor of gene expression, after adjusting for average methylation. This represents the first evaluation of epipolymorphism in ccRCC and suggests that gains and losses in methylation disorder may have a functional relevance, gleaning important information on tumourigenesis.

Ovarian clear cell carcinoma: open questions on the management and treatment algorithm.

Ovarian clear cell carcinoma (OCCC) accounts for ~10% of all epithelial ovarian cancers and is considered a different entity from the more common high-grade serous ovarian carcinoma (HGSC), with distinct clinical presentations, different risk, and prognostic factors, and specific molecular features. Most OCCCs are diagnosed at an early stage and show favorable outcomes, in contrast to those diagnosed at advanced stages, which exhibit intrinsic resistance to platinum-based chemotherapy regimens and a very poor prognosis. The standard treatment of advanced OCCC is currently based on primary debulking surgery followed by platinum-based chemotherapy according to recent international guidelines. However, these recommendations are extrapolated from several trials mainly featuring a large cohort of HGSC, with only a small minority of OCCC. Because of its rarity, many questions remain unanswered regarding the surgical and medical treatment. Lymph node staging, fertility-sparing treatment, the use of targeted therapies and radiotherapy as well as the adjuvant treatment for early-stage disease and second or further lines of chemotherapy are still under debate. This review aims to address these unresolved issues, by providing a comprehensive overview of the current data on this disease, and to suggest possible directions for future research.

A Novel Case of Pulmonary Sclerosing Diffuse PEComatosis With Neuroendocrine Cell Hyperplasia.

Proliferations of neoplastic perivascular epithelioid cells (PECs) may occur within the lung and extrathoracic sites. The term "PEComatosis" is applied to multiple or diffuse microscopic proliferations of neoplastic PECs. Pulmonary diffuse PEComatosis is extremely rare, with only one case documented in the literature to date. We herein report a novel sclerosing variant of diffuse PEComatosis in a 68-year-old woman with clinical tuberous sclerosis complex (TSC), who underwent lung resection for evaluation of persistent, bilateral ground glass opacities. The patient had no respiratory complaints or ventilatory defects in pulmonary function tests. The morphologic features resembled the previous description of pulmonary diffuse PEComatosis, showing interstitial nodular and diffuse proliferation of predominantly clear epithelioid cells with PEC differentiation by immunohistochemistry. The PEComatous proliferation was accompanied by a pattern of sclerosis that overlapped with the sclerosing variant of PEComa. There was no evidence of lymphangioleiomyomatosis. The changes were complicated by neuroendocrine cell hyperplasia, which has not previously been reported in the lungs of patients with TSC.

Correlation between cathepsins and the likelihood of renal cancer: a Mendelian randomization study.

Previous studies have established a relationship between cathepsins and renal cancer. Nonetheless, the specific causal connection between the two factors continues to be ambiguous. The aim of this study is to evaluate the causal relationship between cathepsins and renal cancer via employing Mendelian randomization (MR). The summary data of genome-wide association study were used for univariable MR (UVMR), reverse MR, and multivariable MR (MVMR) analyses. The primary MR method used in this study was Inverse variance weighting. UVMR analysis showed that cathepsin Z increased the overall risk of renal cancer and cathepsin F were observed increased the risk of clear cell renal cell carcinoma. Furthermore, the concentration of cathepsin S had a significant positive correlation with the risk of papillary renal cell carcinoma (pRCC), whereas that of cathepsin G was negatively correlated with the risk of pRCC. Reverse MR analysis showed that renal cancer reduced the concentration of cathepsin H. MVMR analysis showed that the concentration of cathepsin B had a significant positive correlation with overall risk of renal cancer and pRCC. In addition, a higher concentration of cathepsin S was significantly associated with an increased risk of pRCC. This study confirmed a direct link between cathepsins and the risk of renal cancer. Specifically, cathepsin S has a significant positive correlation with the risk of pRCC. The findings of our research could provide significant contributions to both fundamental and clinical investigations pertaining to renal cancer. Key message What is already known on this topic? - Previous studies have suggested the role of some cathepsins in renal cancer occurrence and progression. However, the causal link between different cathepsins and renal cancer is unknown. What this study adds? - Our Mendelian randomization (MR) study revealed that the effects of different cathepsins on the risk of renal cancer. Remarkably, both univariable MR and multivariable MR demonstrated that the levels of cathepsin S increases the risk of papillary renal cell carcinoma. How this study might affect research, practice or policy? - The findings offer novel insights into the relationship between cathepsins and renal cancer, which may have implications for the prevention and management of renal cancer.

Histomorphologically defined renal cell carcinomas 2025 : Current WHO classification and emerging future subtypes

The latest edition of the WHO classification of urinary and male genital tumours was published in 2022. The revision was based on the newest scientific literature. This article summarizes the updated recommendations regarding the classification of histomorphologically defined tumours. The current edition of the WHO classification made some adjustments on the classification of histomorphologically defined tumour types. Papillary renal cell carcinoma is no longer categorized into two subtypes. Also, the new classification recognized the benign nature of clear cell papillary tumours, which are no longer regarded as carcinomas. Finally, several emerging renal tumours were introduced.

First-line pembrolizumab-axitinib versus sunitinib in metastatic RCC: subgroup analysis of patients enrolled in the phase 3 KEYNOTE-426 in Eastern Asia.

The phase 3 open-label KEYNOTE-426 study demonstrated that first-line pembrolizumab plus axitinib improved overall survival (OS) and progression-free survival (PFS) versus sunitinib for metastatic renal cell carcinoma (mRCC) in a global population. This subgroup analysis investigated the efficacy and safety of pembrolizumab-axitinib versus sunitinib in patients enrolled in KEYNOTE-426 in East Asia (Japan, South Korea, and Taiwan). Adults with clear cell mRCC were randomly assigned 1:1 to receive intravenous pembrolizumab 200mg every 3weeks with oral axitinib 5mg twice daily or oral sunitinib 50mg once daily (4weeks on/2weeks off). Dual primary endpoints were OS and PFS, assessed by blinded independent central review. Secondary endpoints were objective response rate (ORR) and safety. The East Asian subgroup comprised 130 patients (pembrolizumab-axitinib, n=62; sunitinib, n=68; 15.1% of the global intention-to-treat population). Compared with sunitinib, pembrolizumab-axitinib OS hazard ratio (HR) was 0.85 [95% confidence interval (CI) 0.50-1.44; 36-month rates, 62.9% and 58.8%, respectively] and PFS HR was 0.59 (95% CI 0.38-0.92) in favor of pembrolizumab-axitinib. ORR favored pembrolizumab-axitinib (64.5% vs 44.1% for sunitinib). The results were generally consistent with the intention-to-treat population. Grade≥3 treatment-related adverse events (TRAEs) occurred in 69.4% of patients on pembrolizumab-axitinib and 74.6% on sunitinib; 16 (25.8%) patients on pembrolizumab-axitinib and 17 (25.4%) patients on sunitinib discontinued due to adverse events. No deaths from TRAEs occurred. Pembrolizumab-axitinib improved efficacy for East Asian patients with untreated clear cell mRCC, consistent with results from the global population. Safety was manageable. ClinicalTrials.gov identifier: NCT02853331.

Pancreatic Serous Neoplasm and Metastatic Clear Cell Renal Cell Carcinoma

Pancreatic Serous Neoplasm and Metastatic Clear Cell Renal Cell Carcinoma

Clinical significance and pro-oncogenic function of DBF4 in clear cell renal cell carcinoma

BackgroundClear cell renal cell carcinoma (ccRCC) is the most common malignant urological tumor, and regrettably, and is insensitive to chemotherapy and radiotherapy, resulting in poor patient outcomes. DBF4 plays a critical role in DNA replication and participates in various biological functions, making it an attractive target for cancer treatment. However, its significance in ccRCC has not yet been explored.MethodsWe utilized external datasets and bioinformatics analyses to investigate the significance of DBF4 in ccRCC. We analysed its expression patterns, prognostic and diagnostic value, and potential mechanisms. We subsequently validated our findings through an immunohistochemistry (IHC) assay of ccRCC clinical samples. We further investigated the impact of DBF4 on the progression of ccRCC cells. Various assays, including assessments of cell proliferation, apoptosis, the cell cycle, cell migration and invasion, and colony formation, and xenograft tumor models were subsequently performed following to the knockdown of DBF4 expression via shRNA.ResultsBioinformatics analyses revealed that DBF4 is significantly overexpressed in ccRCC tissues compared with adjacent normal tissues. This overexpression was confirmed by IHC analysis of 75 pairs of clinical ccRCC tumor and adjacent tissues. Kaplan-Meier analysis revealed that high DBF4 expression was associated with a significantly lower five-year overall survival rate. Moreover, DBF4 expression was identified as an independent risk factor in multivariate Cox regression analysis. GO and KEGG pathway enrichment analyses revealed a substantial enrichment of terms associated with cell division, whereas gene set enrichment analysis (GSEA) revealed correlations between increased DBF4 expression and the activation of cell cycle-related pathways. Subsequent in vitro and in vivo experiments demonstrated that DBF4 knockdown in ccRCC cells not only suppressed proliferation and migration in vitro but also significantly inhibited tumor growth in xenograft mice by arresting the cell cycle at the G1/G0 phase, which was mediated by the inhibition of MCM2 phosphorylation and cyclin D1 and CDK4 expression.ConclusionThe current study revealed that DBF4 overexpression is a significant factor associated with malignant features and poor prognosis in patients with ccRCC. Therefore, it was proposed that DBF4 could serve as a novel potential prognostic biomarker and molecular target for ccRCC.Clinical trial numberNot applicable.