Search Results (1,196)

This review examines the clinical and practical implications of embedding molecular profiles directly into the 2023 FIGO staging system for endometrial carcinoma, in the context of the 2025 ESGO/ESTRO/ESP guidelines. The primary purpose is to navigate a central conflict in modern oncology: how to deliver increasingly personalized care while maintaining a globally accessible, equitable, and standardized cancer classification system. The 2023 FIGO update represents a paradigm shift from the traditional dualistic model (Type I versus Type II) by allowing molecular findings to redefine stage itself. While this integration offers clear benefits, it introduces significant challenges. First, the system depends on advanced molecular testing, creating a “rich-poor” divide where patients in resource-limited settings are systematically overtreated because testing is unavailable. Second, stage becomes unstable, changing with sequential histologic and molecular re-review, which causes confusion for patients and clinicians. Third, the system lumps prognostically distinct histotypes (Serous, Clear Cell, Carcinosarcoma, and Grade 3 Endometrioid) into a single aggressive stage, obscuring meaningful differences in survival. Fourth, it relies on subjective parameters such as “substantial” lymphovascular space invasion, for which no standardized definition exists, leading to high inter-observer variability. After analyzing these controversies, the review proposes a pragmatic solution: decouple anatomical staging from molecular risk stratification. Staging should remain a purely anatomical, universally applicable descriptor of tumor extent, while molecular and histologic data are used separately within a dynamic risk assessment model, as suggested by the European guidelines. This dual-track approach preserves global comparability, reduces inequity, and maintains diagnostic stability, while still enabling personalized treatment where advanced diagnostics are available. Full article

Background: Head and neck cutaneous squamous cell carcinoma (HNcSCC) presents intersecting oncologic, functional, and reconstructive challenges. Although numerous clinicopathologic factors have been associated with recurrence, metastasis, and survival, their relationship with reconstructive complexity and patient-centered outcomes remains insufficiently studied. This review aimed to examine how established oncologic risk factors might inform reconstructive planning while distinguishing measured reconstructive evidence from hypothesis-generating clinical inferences. Methods: A structured PubMed/MEDLINE search conducted through 15 July 2026 was used to identify the literature addressing clinicopathologic prognostic factors in HNcSCC. Twenty-nine prognostic publications were retained for structured charting. Additional reconstructive, functional, aesthetic, and patient-reported outcome sources were identified through reference-list screening and were used solely for narrative contextualization. Because no dedicated multi-database systematic search of reconstructive outcomes was performed, the article is presented as a structured narrative review and hypothesis-generating research framework rather than a systematic review of reconstructive evidence. Results: The prognostic literature reported associations between adverse oncologic outcomes and factors including tumor size and depth, perineural invasion, lymphovascular invasion, poor differentiation, immunosuppression, recurrent disease, positive margins, nodal involvement, and extranodal extension. However, most of these studies did not measure post-excision defect characteristics, reconstructive technique, wound complications, functional recovery, scar quality, aesthetic outcomes, or patient-reported outcomes. Direct reconstructive evidence was limited and predominantly derived from site-specific, mixed-histology, technical, or methodological publications. Consequently, clinicopathologic factors should be regarded as potential upstream variables for future investigation rather than validated predictors of reconstructive outcomes. Conclusions: Current evidence supports oncologic risk stratification more strongly than prediction of reconstructive difficulty or patient-centered outcomes in HNcSCC. Prospective studies should jointly measure patient, tumor, treatment-field, defect, reconstructive, functional, aesthetic, and patient-reported variables. The proposed framework is intended to guide such research and is not a validated clinical prediction model. Full article

Metastasis, chemoresistance, and tumour recurrence are facilitated by cancer stem cells (CSCs), a small subpopulation of cells capable of regenerating a primary tumour while maintaining the tumour’s genetic and phenotypic features. CSCs can be identified by the expression of specific markers; however, the CSC population in ovarian clear cell carcinoma (OCCC), a rare histotype of ovarian cancer, remains poorly defined. Given the well-established role that CSCs play in cancer progression and metastasis, it is critical to identify reliable markers of CSCs in OCCC. Here, we endeavoured to determine whether ALDH1 expression could be used to define OCCC stem cells in OCCC cell lines using a variety of methods including assessing ALDH1A1 expression in spheroids generated under distinct conditions. We also generated and used chemo-resistant cell lines to assess the enrichment of cancer stem cells. Human OCCC cell lines were enriched for CSCs using selective culture conditions and drug resistance methods. CSC-enriched spheroids demonstrated increased expression of stemness markers NANOG and SOX2, while ALDH1A1 expression was enriched only in drug-resistant cell lines, relative to parental cell lines. RNA-seq analyses of CSC-media-derived spheroids versus standard media spheroids provided novel data supporting CSC enrichment and identified transcription factors induced by CSC media. These findings highlight the ambiguous role of ALDH1A1 as a CSC marker in OCCC and demonstrates the utility of CSC enrichment methods for identifying CSC populations in OCCC cell lines. Full article

Background: Renal cell carcinomas (RCCs) represent neoplasms with variable biological behaviour, some of which remain difficult to classify within the current diagnostic framework. Clear cell papillary renal cell tumor (CCPRCT) is now recognised as an indolent entity, whereas RCC with fibromyomatous stroma (RCCFMS) remains a provisional subtype with partially overlapping morphological features. Methods: We analysed a multifocal RCC with clear cell morphology and prominent fibromyomatous stroma via whole-genome and RNA sequencing. The obtained molecular profile was compared with The Cancer Genome Atlas (TCGA) pan-cancer dataset, which includes 885 RCC cases, and histological re-evaluation of 10 identified similar cases was performed. Transcriptional data were mined for potential markers, which were validated in an independent cohort. Results: The 10 TCGA cases with similar transcriptomic features were characterised by diploid genomes, absence of recurrent chromosomal alterations, and lack of VHL mutations. Reduced VHL mRNA expression was observed, with increased methylation at selected CpG sites consistent with possible epigenetic down-regulation. Diagnostic variability was identified during histological re-evaluation of the 10 similar cases by three urological pathologists. Differential expression analysis highlighted cytokeratin 17 (CK17) and collagen 17A1 (COL17A1) as candidate markers. Immunohistochemical evaluation in a small (n = 6) independent CCPRCT cohort demonstrated expression of both markers, whereas tissue microarrays from 257 clear cell and 68 papillary RCC cases were found to be negative. Conclusions: These findings suggest that a subset of renal tumors with overlapping morphological features of CCPRCT and RCCFMS may share common molecular characteristics. CK17 and COL17A1 emerged as candidate markers for recognising these tumors, although their diagnostic sensitivity and specificity require validation across a broader spectrum of renal neoplasms. These observations are exploratory and hypothesis-generating, and further studies in large, well-characterised cohorts are required to clarify the biological and diagnostic significance of this subgroup. Full article

Background and Clinical Significance: This paper presents a case of Vogt–Koyanagi–Harada (VKH)-like disease following nivolumab and ipilimumab therapy for squamous cell carcinoma of the lung, complicated by transient type 1 macular neovascularisation (MNV). Case Presentation: A 67-year-old man presented with reduced visual acuity, more pronounced in the left eye, accompanied by headache and neurosensory hearing loss for 10 days. He had been receiving combination therapy with nivolumab and ipilimumab for approximately nine weeks. Slit-lamp examination and multimodal imaging revealed multiple serous retinal detachments, choroidal folds, and bacillary layer detachment. A bilateral VKH-like syndrome was considered the most likely diagnosis, consistent with an immune-related adverse event (irAE). High-dose systemic corticosteroids were initiated, resulting in marked anatomical improvement and recovery of visual acuity. Following multidisciplinary discussion with the patient’s oncologist, ipilimumab was permanently discontinued and nivolumab was rechallenged in combination with chemotherapy after resolution of the ocular adverse events, given the progression of the underlying malignancy. Notably, optical coherence tomography angiography (OCTA) additionally demonstrated a type 1 non-exudative MNV, which resolved spontaneously during follow-up. Conclusions: Nivolumab and ipilimumab, targeting PD-1 and CTLA-4, respectively, are effective anticancer therapies but may induce immune-related adverse events involving the eye. VKH-like disease is a rare but potentially vision-threatening complication. Early recognition and prompt treatment are essential for favourable visual outcomes. In summary, this is a rare case of VKH-like disease associated with nivolumab and ipilimumab therapy, complicated by transient inflammatory type 1 MNV. Clear guidelines are needed regarding management of ocular immune-related adverse events and decisions on continuation or discontinuation of life-prolonging immunotherapy. Full article

Background: Telomerase is a ribonucleic multimeric reverse transcriptase complex protecting the chromosomal ends from erosion and thereby from cellular senescence. The prognostic value of the components of this complex and their interrelationships with the immune system are not well understood. Objectives: We aimed to examine 15 telomerase-related genes across 7489 tumor samples from the TCGA database. Methods: The mRNA expression of these genes was analyzed using Kaplan–Meier statistics and hierarchical clustering analyses, alone or in combination with tumor infiltration counts for 11 immune cell types. As an additional analysis, univariable and multivariable Cox regression analyses have been performed. Results: Thirteen of 21 tumor types showed significant associations between gene expression in tumors and survival times of patients. Most gene correlations were found in hepatocellular carcinoma and renal clear cell carcinoma. In hepatocellular carcinoma, a high expression of DKC1, NHP2, GAR1, WRAP53, and ACD was associated with shorter survival. In renal clear cell carcinoma, TERT, DKC1, and PARN correlated with shorter survival, and NAF1, TERF2, POT1, and TINF2 with longer survival. DKC1 was the only gene significantly associated with poor prognosis in both tumor types. The telomerase-related genes correlated with patterns of immune cell infiltration, which influenced the survival of patients. The associations of mutation burden and neoantigen load with survival varied depending on the gene and patient groups. In renal clear cell carcinoma, TERT, DKC1, and PARN showed strong interactions with immune cell infiltration and neoantigen load. Conclusions: The combination of telomerase-related gene expression and immune-cell infiltration was associated with overall survival in hepatocellular carcinoma and renal clear cell carcinoma and warrants further evaluation as prognostic markers. Full article

Background/Objectives: Accurate prognostic stratification after nephrectomy for clear cell renal carcinoma (ccRCC) remains challenging. Traditional models often lack the intuitive clinical application or the ability to handle non-linear interactions between variables. We aimed to develop and internally validate a decision tree-based model to predict cancer-specific survival in patients with ccRCC following nephrectomy. Methods: We analyzed 79,526 patients with ccRCC who underwent nephrectomy from the SEER database (2012–2018). Patients were randomized into development (2/3) and validation (1/3) cohorts. A conditional inference tree was constructed to predict cancer-specific survival. Multiple imputation by chained equations was used to handle missing data. Discriminatory ability was assessed using the C-index. Net clinical benefit was evaluated with decision curve analysis. The model was evaluated using CHARMS and PROBAST. Results: A decision tree with 15 risk groups is presented, further classified into high-, intermediate-, and low-risk categories according to observed median survival. The final predictors were tumor localization, tumor grade, TNM stage, age, and sarcomatoid differentiation. The model demonstrated excellent discriminatory performance, with a C-index of 0.846 (95% CI: 0.834–0.847). PROBAST assessment showed low risk of bias and low concern regarding applicability. Conclusions: The use of decision trees provides an interpretable alternative to conventional regression-based models. Three main risk categories and 15 subgroups are proposed based on tumor localization, tumor grade, TNM stage, age, and sarcomatoid differentiation. Our model demonstrates good applicability and a low risk of bias according to PROBAST guidelines; however, external validation in independent cohorts is required prior to clinical implementation. Full article

Background: Sunitinib remains an important VEGFR-targeted therapy for advanced clear cell renal cell carcinoma (ccRCC), but acquired resistance frequently limits its clinical benefit. The molecular mechanisms underlying sunitinib resistance remain insufficiently understood. Methods: Sunitinib-resistant ccRCC models were generated by serial in vivo selection using Caki-1 and 786-O xenografts. Transcriptomic profiling, integration with GSE76068, and siRNA-based screening were performed to identify candidate resistance drivers. DERL3 expression and function were validated using qRT-PCR, Western blot, immunohistochemistry, gain- and loss-of-function assays, xenograft models, and mechanistic analyses of endoplasmic reticulum stress, ROS, and apoptosis. Results: Serial in vivo selection established stable sunitinib-resistant Caki-1-SR and 786-O-SR cells with markedly increased IC50 values. Integrated transcriptomic analysis identified six consistently upregulated genes in resistant models and GSE76068, among which DERL3 knockdown most strongly restored sunitinib sensitivity. DERL3 was upregulated in resistant ccRCC cells and clinical resistant specimens. High intratumoral DERL3 expression was associated with poor response to neoadjuvant sunitinib and shorter progression-free and overall survival. Functionally, DERL3 overexpression increased sunitinib resistance in vitro and in vivo, whereas DERL3 silencing restored drug sensitivity. Mechanistically, DERL3 depletion activated pro-apoptotic endoplasmic reticulum stress, increased ROS accumulation, and enhanced caspase-dependent apoptosis. Suppression of endoplasmic reticulum stress reduced ROS generation and apoptosis induced by DERL3 knockdown. In resistant xenografts, DERL3-targeted inhibition enhanced the antitumor efficacy of sunitinib. Conclusions: DERL3 is a clinically relevant driver of acquired sunitinib resistance in ccRCC. Targeting DERL3 may restore sunitinib sensitivity by reactivating pro-apoptotic endoplasmic reticulum stress and ROS-dependent apoptosis. Full article

Introduction: The “obesity paradox” describes the observed association between improved cancer-specific (CSS) and overall (OS) survival observed among obese (BMI ≥ 30 kg/m²) patients with RCC. Prior studies have reported lower stage/grade tumors among obese patients to explain this. This study aimed to evaluate subcutaneous (SFA) and visceral fat area (VFA) associations with CSS, OS, tumor stage and grade among patients with non-metastatic clear cell RCC. Methods: Following IRB approval, patients undergoing nephrectomy for clear cell RCC between 2000 and 2023 were screened for inclusion. Eligible patients were those with non-metastatic disease and available preoperative imaging within 90 days of surgery. SFA and VFA were determined using mid-L3 imaging and standardized Hounsfield Unit thresholds. Multivariable Cox models evaluated factors associated with 5-year CSS and OS, and multivariable logistic regression models evaluated associations with pathologic stage (pT) 3–4 and Fuhrman grade 3–4 disease. Results: 400 patients were included. Higher SFA quartiles were independently associated with improved CSS (Q3 HR 0.21, p = 0.029; Q4 HR 0.24, p = 0.042) and OS (Q2-Q4 HR range 0.35–0.52, all p < 0.05) compared to Q1. VFA was not independently associated with OS and showed only an isolated association with CSS in the third quartile (HR 2.95, p = 0.041). Neither SFA nor VFA were independently associated with RCC stage or grade. Conclusions: Greater subcutaneous adiposity was associated with improved 5-year CSS/OS, whereas visceral adiposity did not demonstrate consistent associations with survival outcomes. These findings refine the obesity paradox and reflect the importance of fat distribution as a more specific risk factor than weight-based measures such as BMI alone. Full article

Background/Objectives: Loss of phosphatase and tensin homolog (PTEN) activity is a frequent feature of non-small-cell lung cancer (NSCLC), and epigenetic repression may contribute to its reduced expression. This study investigated the effects of 5-aza-2′-deoxycytidine (5-aza-dC) on PTEN, DNA methyltransferase 1 (DNMT1), PTEN promoter methylation-specific amplification patterns, and miR-148a-3p expression in NSCLC models. Methods: Publicly available cancer-genomics datasets were analyzed to compare PTEN and DNMT1 transcript abundance and to assess the association between PTEN methylation and transcript abundance in lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC). A549 and H460 cells were exposed to 2.5 or 5 µM 5-aza-dC for 72 h. Reverse-transcription quantitative PCR (RT-qPCR), Western blotting, methylation-specific PCR (MSP-PCR), and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assays were used to evaluate RNA expression, protein abundance, methylation-specific amplification, and metabolic activity, respectively. Results: Bioinformatic analyses showed lower PTEN and higher DNMT1 expression in both NSCLC subtypes, together with inverse associations between PTEN methylation and transcript abundance. In both cell lines, 5-aza-dC reduced MTT metabolic activity and DNMT1 expression. PTEN mRNA and protein abundance increased significantly at 5 µM, whereas no significant changes were detected at 2.5 µM. MSP-PCR revealed persistent heterogeneous PTEN methylation-specific amplification patterns without clear evidence of progressive promoter demethylation. miR-148a-3p exhibited a biphasic response in A549 cells but remained unchanged in H460 cells. Conclusions: These findings support an association between 5-aza-dC exposure, increased PTEN expression, and reduced DNMT1 expression in NSCLC cells. Quantitative methylation analysis and mechanistic validation are required to clarify the contribution of miR-148a-3p to this regulatory association. Full article

Background/Objectives: Evaluation of renal tumour masses relies on conventional imaging, which cannot reliably characterise the histopathological type, and no validated blood-based diagnostic marker is available for renal cell carcinoma. The cfDNA integrity index, the ratio of long to short circulating cell-free DNA (cfDNA) fragments, may reflect the necrotic origin of tumour-derived DNA and is a candidate qualitative marker of malignancy. This exploratory, single-centre case–control study assessed the preoperative plasma cfDNA integrity index in patients with clear cell renal cell carcinoma (ccRCC). Methods: Plasma concentrations of 90 bp and 222 bp cfDNA fragments were measured by quantitative real-time PCR (qPCR) in 46 patients with histopathologically confirmed ccRCC (before surgery) and 17 healthy volunteers; the two groups were a convenience sample, were not matched, and differed in age and body-mass index. The cfDNA integrity index was defined as the ratio of the 222 bp to the 90 bp fragment concentration. Results: The cfDNA integrity index was higher in patients with ccRCC than in controls (median 0.28 vs. 0.15; p < 0.001, Mann–Whitney test) and rose progressively across healthy, non-metastatic (M0) and metastatic (M1) groups (p < 0.001, Kruskal–Wallis test; M0 vs. M1 p = 0.004). In unadjusted ROC analysis, both the integrity index (AUC 0.83, 95% CI 0.72–0.94) and its long 222 bp fragment component (AUC 0.93) discriminated patients with ccRCC from healthy volunteers, and the index separated metastatic from non-metastatic disease with an AUC of 0.79 (95% CI 0.64–0.88). The index was higher in high-grade (Fuhrman G3 + G4) tumours (p = 0.04) and in tumours with lymphovascular invasion (p < 0.001), and correlated with primary-tumour diameter. Conclusions: In this exploratory cohort, the preoperative plasma cfDNA integrity index was higher in patients with ccRCC than in healthy volunteers and was associated with several adverse pathological features; these findings require confirmation in larger, matched studies that include benign renal masses before any diagnostic role can be claimed. Full article

Liver sinusoidal endothelial cells are highly specialized endothelial cells that contribute to liver homeostasis through their remarkable scavenger function. Through a broad repertoire of scavenger receptors, including mannose receptor, scavenger receptor H, fragment crystallizable gamma receptor IIb, LSECs efficiently clear waste and toxins, altering drug distribution and metabolism. However, this scavenger function can be disrupted by aging, toxins, and transcription factors, thereby promoting the accumulation of harmful substances within the hepatic microenvironment. Impaired LSEC scavenger function contributes to the initiation and progression of multiple liver diseases, such as metabolic dysfunction associated steatotic liver disease, alcoholic liver disease, liver fibrosis, hepatocellular carcinoma, and antibody-based drug-related liver injury. Emerging pharmacological evidence suggests that antioxidant agents, anti-angiogenic strategies and anti-inflammatory interventions may partially restore the expression or function of LSEC scavenger receptors to alleviate liver diseases. In summary, the scavenger function of LSECs serves as a key gatekeeper in liver homeostasis, and targeted modulation of this function holds great potential for the treatment of liver diseases. Full article

Background: Endometriosis-associated ovarian cancers (EAOCs), encompassing clear cell (CC) and endometrioid carcinomas (EC), constitute distinct biological entities yet lack robust biomarkers for precise classification, prognostication, and therapeutic decision-making in women. Therefore, we aimed to describe novel biomarkers. Methods: In this study, we conducted an integrated transcriptomic analysis, powered by machine learning, to discover novel consensus biomarkers and delineate cancer hallmark signatures specific to EC and CC. Drawing on gene expression profiles from EAOC specimens, we merged differential expression analysis with LASSO regression and Random Forest classification to generate a reliable biomarker panel that effectively distinguishes EC from CC. Kaplan–Meier survival analyses and mutation analyses have been performed for selected biomarker genes. Results: Novel biomarkers, among others, the genes RPS28, EPAS1, ALKBH2, and DCLRE1A, uncover extensive transcriptional alterations tied to hypoxia signaling, oxidative stress, DNA repair, and metabolic reprogramming. Gene Ontology and pathway enrichment analyses revealed synchronized upregulation of epithelial–mesenchymal transition, TNF-α/NF-κB signaling, oxidative stress, hypoxia, and KRAS signaling pathways. Conclusions: Our work establishes novel exploratory transcriptomic candidates for innovative consensus biomarkers, yielding novel diagnostic and prognostic insights into EAOC and supporting further study of subtype-associated expression programs. The current study was designed primarily as an integrative computational investigation aimed at identifying candidate genes and molecular pathways distinguishing CC from EC. Full article

Background: Clear cell renal cell carcinoma (ccRCC) is characterized by marked molecular heterogeneity, aggressive clinical behavior, and prominent angiogenesis, highlighting the need to better understand the functional regulators underlying tumor progression and vascular remodeling. OTOF has previously been reported as a prognostically relevant gene in ccRCC; however, its biological function and potential involvement in tumor angiogenesis remain unclear. Methods: In the present study, we investigated the biological and pro-angiogenic roles of OTOF and explored the signaling pathways potentially involved. Results: Analysis of the TCGA-KIRC cohort confirmed that elevated OTOF expression was associated with unfavorable clinical outcomes. Functional experiments demonstrated that OTOF knockdown suppressed ccRCC cell proliferation, migration, and invasion and inhibited xenograft tumor growth. OTOF depletion also reduced intratumoral vascularization and impaired the ability of ccRCC cell-conditioned medium to promote HUVEC tube formation. Mechanistically, OTOF knockdown decreased VEGFA levels and was accompanied by reduced AKT phosphorylation and suppression of downstream HIF/VEGFA signaling. Pharmacological modulation of AKT signaling and VEGFA add-back experiments further supported the functional involvement of the AKT/HIF/VEGFA pathway in OTOF-associated angiogenesis. Conclusions: These findings extend previous observations regarding the prognostic relevance of OTOF by providing functional and mechanistic evidence that OTOF contributes to ccRCC progression and angiogenesis, at least in part, through AKT-dependent HIF/VEGFA signaling. Full article

Here, we report the identification of a previously unrecognized population of tumor-induced podoplanin-positive (PDPN⁺) cells in clear-cell renal cell carcinoma (ccRCC) that exhibit features of under-differentiated lymphatic endothelial cells (LECs). These PDPN⁺ cells lack a complete repertoire of canonical LEC markers, including VE-cadherin, LYVE1, and VEGFR3, and fail to form functional lymphatic vessels, indicating a dysplastic phenotype. We termed these cells dysLECs and found that these cells are induced by BMP10 produced specifically by tumor cells. In turn, dysLECs secrete CXCL13, which promotes tumor cell proliferation and metastasis. Ligand-receptor analyses revealed a highly tumor-specific reciprocal signaling circuit: kidney tubule cells deficient in the von Hippel-Lindau (VHL) tumor suppressor gene uniquely express BMP10, a TGF-β family cytokine, whereas its receptor ALK1 is restricted to dysLECs; conversely, dysLECs produce CXCL13, while VHL mutant kidney tubule cells uniquely express its receptor, CXCR5. Pharmacological inhibition of ALK1 reduced CXCL13 production and suppressed the hyperplastic phenotype of VHL mutant tumor cells in vivo, whereas BMP10 neutralization inhibited tumor growth and metastasis in an orthotopic ccRCC xenograft model. Collectively, these findings identify a dysplastic population of PDPN⁺ lymphatic-like endothelial cells and define a tumor-specific BMP10-CXCL13 signaling axis that drives ccRCC progression, uncovering a previously unrecognized therapeutic vulnerability in this disease. Full article