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PubMed2026

Postoperative chemoradiotherapy in Wilms tumor with concurrent lung and lymph node metastasis.

BACKGROUND: An effective treatment strategy is essential for metastatic Wilms tumor (WT) management. To improve prognostic accuracy, this study examined metastatic patterns and key prognostic factors. METHODS: Children diagnosed with WT from 2010 to 2021 were identified from the SEER database. All patients underwent chemotherapy and surgical resection. Metastatic patterns, metastasis-related predictors, and prognostic factors were evaluated. RESULTS: Of the 1040 patients analyzed, 226 (21.7%) experienced lung metastasis, 31 (3.0%) liver metastasis, 6 (0.6%) bone metastasis, and 220 (21.2%) regional lymph node metastasis. Distant metastasis was associated with a higher incidence of lymph node metastasis (OR = 1.506, 95% CI 1.346-1.685, p < 0.001). Age 3-17 years (OR = 1.933, 95% CI 1.406-2.680, p < 0.001), left-sided (OR = 1.383, 95% CI 1.016-1.890, p = 0.040), bilateral (OR = 2.303, 95% CI 1.215-4.243, p = 0.009), and tumor size ≥135 mm (OR = 2.020, 95% CI 1.481-2.749, p < 0.001) were identified as predictors of metastasis. Both lymph node (p < 0.001) and lung metastasis (p < 0.001) were high-risk factors for WT. Radiotherapy provided long-term survival benefits for the metastatic population (p = 0.027), while postoperative chemotherapy showed better outcomes than preoperative or other strategies (p < 0.001). Further analysis demonstrated that the concurrent lung and lymph node metastasis group benefited more from postoperative chemoradiotherapy, with HRs of 0.226 (p = 0.028) for overall survival and 0.255 (p = 0.048) for cancer-specific survival. CONCLUSION: WT with concurrent lung and lymph node metastasis represents a distinct and aggressive metastatic phenotype associated with a significantly poor prognosis. Postoperative chemoradiotherapy may provide superior survival benefits for this high-risk population.

Humans↗

PubMed2025

Habitat radiomics predicts occult lymph node metastasis and uncovers immune microenvironment of head and neck cancer.

BACKGROUND: Occult lymph node metastasis (LNM) is a key prognostic factor for patients with head and neck squamous cell carcinoma (HNSCC). This study was to establish radiomics models derived from intratumoral, peritumoral, and habitat regions for identifying occult LNM in HNSCC. METHODS: Patients with pathologically confirmed HNSCC from three medical Centers (from March 2014 to April 2024) and The Cancer Genome Atlas (TCGA) were enrolled. Center 1 was split into training (n = 330) and internal test sets (n = 154), while Center 2 and Center 3 served as the external test set (n = 183). Genomic set (n = 50) from TCGA and single-cell RNA sequencing set (n = 6) from Center 1 were used for biological analysis. We used the intratumoral, peritumoral, and habitat volumes of interest (VOIs) to extract radiomics features, respectively. Based on Logistic Regression (LR), Support Vector Machine (SVM), and Random Forest (RF) classifiers, nine radiomics models were built to confirm the optimal predictive performance. The best-performing model, along with clinical-radiologic data, was combined to develop a hybrid model. The log-rank test was used to evaluate the model's prognostic performance. Additionally, bulk and single-cell RNA sequencing were applied for investigating the biological mechanisms underlying the optimal model. RESULTS: The RF-habitat radiomics model showed the best performance, achieving AUCs of 0.835-0.919 across all datasets. Survival analysis further confirmed the prognostic value of the RF-habitat radiomics model. The RF-habitat radiomics model and the hybrid model notably surpassed the clinical model in predictive performance. Moreover, the RF-habitat radiomics model was associated with the abundance level of exhaustion-associated CD8 + T cells, uncovering the immune microenvironment characteristics contributing to occult LNM in HNSCC. CONCLUSIONS: The RF-habitat radiomics model demonstrated excellent performance for predicting occult LNM in HNSCC across three cohorts, providing a non-invasive solution for occult LNM. Furthermore, radiogenomic analysis further revealed the biological associations of the model, primarily related to T cell dysfunction.

Humans↗

PubMed2026

Papillary Thyroid Carcinoma with Terminal Immune Exhaustion Phenotype Correlates with Increased Risk of Lymph Node Metastasis: An Exploratory Study Combining Flow Cytometry and TCGA.

BACKGROUND: Papillary thyroid carcinoma (PTC) is the most common thyroid malignancy, with lymph node metastasis (LNM) being a key predictor of recurrence and poor prognosis. Preoperative detection of LNM remains challenging due to the limitations of imaging modalities, leading to inadequate surgical resection in 20-30% of patients. While immune checkpoint molecules have been implicated in PTC progression, the heterogeneity of CD8+ T cell exhaustion subsets and their specific association with LNM remain poorly defined. In this study, we aimed to perform an exploratory characterization of the distinct immune landscape of PTC prone to LNM, with a focus on terminal immune exhaustion, in order to generate hypotheses for improved risk stratification and therapeutic strategies. METHODS: Fresh PTC tissues from 40 patients (22 LNM-positive and 18 LNM-negative) were analyzed via flow cytometry (FCM) to quantify immune cell subsets, inflammatory cytokines, and chemokines. Immunohistochemistry (IHC) validated CD45+ immune cell infiltration. Transcriptomic and clinical data from 448 PTC patients in The Cancer Genome Atlas (TCGA-PTC) cohort were used for bioinformatic analysis consistent with the observed phenotype, including Gene Set Variation Analysis (GSVA) of terminal exhaustion gene signatures. RESULTS: LNM-positive PTC exhibited a unique inflammatory milieu with significantly elevated IL-6, IL-1ra, CCL5, and IL-9 levels (all p < 0.05) in tumor interstitial fluid. FCM analysis revealed that LNM-positive PTC had increased infiltration of total CD45+ immune cells, CD3+ T cells, and CD3+CD8+ T cells (all p < 0.05). Critically, terminally exhausted PD-1hiTIM-3+ CD8+ T cells were significantly enriched in LNM-positive PTC (p = 0.022) and positively correlated with extrathyroidal extension (p = 0.044). Additionally, LNM risk was associated with increased CD4+ regulatory T (Treg) cell frequency (p = 0.023) and elevated CTLA-4 expression on CD4+ T cells (p = 0.047). In TCGA-PTC validation, the terminal exhaustion gene signature was predominantly enriched in LNM-positive (p < 0.0001) and advanced-stage PTC (p < 0.001) and strongly correlated with BRAF mutation (predominantly V600E) (p < 0.0001)-the most common oncogenic driver in aggressive PTC. CONCLUSIONS: Our findings suggest a terminal immune exhaustion phenotype (characterized by PD-1hiTIM-3+ CD8+ T cells and Treg enrichment) as a potential key feature associated with LNM-prone PTC. This phenotype shows consistency across clinical samples and TCGA datasets, linking BRAF mutation (predominantly V600E) to immune suppression and metastatic potential. These insights provide a novel exploratory immune-based biomarker for LNM risk stratification and support the potential of combining anti-PD-1/TIM-3 therapy with BRAF inhibitors for high-risk PTC, which should be confirmed in future studies.

lymph node metastasis↗

PubMed2026

Beyond Morphology: Reframing Lymph-Node Metastasis Prediction Through Clonal Ecology-Decades-Long Genomic Instability and Polyclonal-to-Monoclonal Transitions as the Missing Dimension in Cancer.

Recent whole-genome, lineage-tracing, single-cell, and spatial studies have reshaped our understanding of tumor evolution, revealing that cancers can arise from polyclonal populations, undergo decades-long genomic instability before clinical detection, and progress through dynamic changes in subclonal composition, cellular state, and ecological organization. These findings challenge the assumption underlying morphology-based prediction models that metastatic risk can be inferred from static histological features alone. Here, we revisit lymph-node metastasis prediction in colorectal cancer through clonal ecology, integrating computational pathology with evolutionary oncology. Drawing on the subclonal switchboard model proposed in 2012 and subsequent artificial intelligence (AI)-enabled approaches for tracking dominant and dormant subclones, we synthesize evidence that metastatic potential reflects clonal ancestry, evolutionary timing, spatial niche architecture, cellular plasticity, intercellular interactions, dormancy, and treatment-driven shifts in subclonal fitness. We define five complementary methodological pillars for operationalizing clonal ecology: single-cell transcriptomics for resolving rare subclones, evolutionary trajectories, and adaptive cell states; lineage tracing and phylogenetics for reconstructing clonal ancestry and divergence; spatial transcriptomics and genomics for mapping subclonal geography and tumor-stromal-immune interactions; longitudinal liquid biopsy surveillance for monitoring residual disease, clonal turnover, and emerging resistance; and AI-enabled multimodal integration for connecting histopathology, genomics, spatial biology, and longitudinal data into predictive ecological-state models. Multiple-instance learning and pathology foundation models provide scalable computational foundations for evolution-aware prediction. Translationally, dormant subclones represent actionable reservoirs of recurrence. A longitudinal clinical and experimental study of KMT2A-rearranged acute myeloid leukemia further supports central predictions of the subclonal switchboard framework by demonstrating treatment-associated shifts in subclonal dominance, persistence of cryptic adaptive programs, and ecological rewiring during resistance and relapse. We propose clonal ecology as a measurable dimension for extending morphology-driven prediction toward integrative models that anticipate evolutionary transitions, identify therapeutic windows, and proactively constrain adaptive tumor ecosystems before resistant or metastatic subclones achieve clinical dominance.

Humans↗

PubMed2025

The association between rs2228226 and postoperative clinical outcomes in gastric adenocarcinoma: a retrospective study.

BACKGROUND: This study aims to investigate the differences in postoperative prognosis associated with the single nucleotide polymorphism (SNP) rs2228226 (G > C) in gastric adenocarcinoma (GAC) patients. METHODS: This study enrolled 661 patients with locally advanced (pT4a) GAC after surgery. DNA was extracted from their tissues and genotyped for rs2228226 using a MassARRAY Analyzer. Based on the patients' clinical and pathological information, a multifactorial Cox regression analysis was performed to assess the correlation between rs2228226 and the clinical prognosis of pT4a GAC patients. Survival differences among patients who received postoperative chemotherapy were also examined according to rs2228226. RESULTS: After excluding patients with distant metastasis, loss to follow-up, and those not meeting the inclusion criteria, a total of 463 patients with complete data were included. The rs2228226 genotype distribution was as follows: C/C = 57 (12.3%), G/C = 200 (43.2%), and G/G = 206 (44.5%). Patients with the C/C genotype had significantly shorter disease-free survival (DFS = 12 months) and overall survival (OS = 27 months) compared to those with the G/C or G/G genotype (DFS = 19 months, log-rank P = 0.003; OS = 35 months, log-rank P = 0.002). Further analysis of patients receiving chemotherapy identified the C/C genotype, advanced age, lymph node metastasis, degree of differentiation, and failure to achieve R0 resection as independent risk factors for tumor recurrence and metastasis (P < 0.05). The C/C genotype, lymph node metastasis, and tumor recurrence and metastasis were independent risk factors for mortality (P < 0.05). CONCLUSIONS: In pT4a GAC patients undergoing postoperative chemotherapy, the C/C genotype at rs2228226 is an independent risk factor for tumor recurrence, metastasis, and death. The rs2228226 (G > C) polymorphism may serve as a potential biomarker for predicting prognosis after chemotherapy in GAC.

Humans↗

PubMed2026

Prognostic Significance of Peri-Treatment Inflammatory Burden Index in Patients with Rectal Cancer Undergoing Preoperative Chemoradiotherapy.

Background/Objectives: Systemic inflammatory responses influence treatment response and oncological outcomes in patients with cancer. Growing evidence indicates that the inflammatory burden index (IBI) serves as a reliable prognostic indicator across various malignancies. However, the clinical significance of the peri-treatment inflammatory status in patients with rectal cancer (RC) undergoing preoperative chemoradiotherapy (CRT) remains unclear. Methods: We assessed the pre- and post-treatment IBI in 97 patients with RC who received preoperative CRT followed by total mesorectal excision at our institution. Results: Although no significant changes were observed in the pre- or post-CRT IBI and no associations were found with most clinicopathological factors, survival analysis revealed that a high pre-CRT IBI was significantly associated with shorter overall survival (OS) and disease-free survival (DFS). Multivariable analysis revealed that a high pre-CRT IBI and pathological lymph node metastasis remained independent prognostic factors for both outcomes. Subgroup analysis demonstrated that the prognostic value of the peri-treatment IBI differed according to the ypN status, with the pre-CRT IBI showing particularly strong prognostic performance in patients without pathological lymph node metastasis (ypN-). Conclusions: Pre-treatment assessment of the IBI may improve risk stratification in patients with RC undergoing preoperative CRT followed by curative resection.

chemoradiotherapy↗

PubMed2026

Prognostic value of genes associated with metastasis and propionate metabolism in rectal cancer.

BACKGROUND: Research indicates that alterations in propionate metabolic pathways play a critical role in cancer development and invasion. Postoperative metastatic recurrence remains a major cause of mortality in patients with rectal cancer. However, propionate metabolism-related genes (PMRGs) in rectal cancer remain insufficiently characterized. Therefore, this study aimed to identify prognostic biomarkers associated with lymph node metastasis and propionate metabolism and construct a risk‑prediction model for rectal cancer via bioinformatic analyses. METHODS: The Cancer Genome Atlas-Rectum Adenocarcinoma (TCGA-READ) and GSE87211 datasets, together with a curated PMRGs gene set, were used in this study. Pearson correlation analysis was performed to assess associations between overlapping genes (differentially expressed genes between READ and normal tissues, as well as between N0 and N1-N2 stages) and PMRGs, leading to the identification of candidate genes. Functional enrichment analyses were subsequently conducted to characterize the biological roles of these candidates. Prognostic biomarkers were identified using univariate Cox regression combined with least absolute shrinkage and selection operator (LASSO) regression, and a prognostic model was constructed accordingly. Independent prognostic validation was then performed. In addition, immune checkpoint profiling and immunotherapy response analyses were conducted across risk subgroups. Single-gene Gene Set Enrichment Analysis (GSEA) was applied to elucidate the pathways associated with the identified biomarkers. Finally, drug sensitivity analyses were performed. RESULTS: A total of 157 candidate genes were identified through the analytical pipeline. Functional enrichment analysis indicated that these genes were primarily involved in inflammatory response regulation and tumor necrosis factor (TNF) signaling pathways. Five prognostic biomarkers were subsequently identified and incorporated into a predictive model. External validation using the GSE87211 cohort confirmed the robustness of the model. Risk score and disease status were identified as independent prognostic factors. Six immune checkpoint molecules exhibited differential expression between risk groups. Correlation analyses revealed that the risk score was positively associated with most immune checkpoint genes. Single-gene GSEA demonstrated that the biomarkers were mainly enriched in ribosomal biogenesis and cell adhesion molecule-related pathways. Furthermore, 51 therapeutic agents exhibited significantly different half-maximal inhibitory concentration (IC50) values between risk subgroups. CONCLUSIONS: This study identified five biomarkers (CCL24, IGFBP3, ODC1, PYGM, and VKORC1) associated with lymph node metastasis and propionate metabolism pathways, providing a potential foundation for prognostic prediction in patients with rectal cancer.

Rectal cancer↗

PubMed2025

Chromosomal instability by low-coverage whole-genome sequencing assay predicts prognosis in bladder cancer patients underwent radical cystectomy.

PURPOSE: To investigate chromosomal instability (CIN) in tumor tissue from radical bladder resection and to evaluate whether it can be used as a biomarker for the molecular typing of (BC). METHODS: DNA was extracted from formalin-fixed paraffin-embedded samples of 50 BC patients who were followed up to March 23 2023 using the Qiagen nucleic acid kits. We analyzed CIN in tumor of bladder by low-coverage whole genome sequencing (LC-WGS). Kaplan-Meier log-rank test was used to perform survival analysis. The association between variables and overall and progression-free survival was analyzed using the Cox proportional hazards model. RESULTS: There were 44 genome segments with statistically significant changes in copy number. CIN was significantly correlated with tumor stage, lymph node metastasis, relapse and survival status. Patients with high CIN were found to have a worse survival, with a median overall survival (OS) of 15 months. In addition, patients with high CIN were more likely to relapse, with a median progression-free survival (PFS) of 7 months. Patients with low CIN showed better OS and PFS. However, there was no significant difference in OS and PFS between T2 and T3-T4 patients. Multivariate cox regression analysis showed that high CIN was an independent predictor of OS, and high CIN and muscle invasion were independent predictors of PFS. Furthermore, patients with abnormal copy number of a single chromosome also had a poor prognosis, with a median survival of 14-30 months for OS and 5-10 months for PFS, while negative patients had a better prognosis. CONCLUSION: CIN was significantly correlated with tumor stage, lymph node metastasis, relapse and survival status of BC. Patients with high CIN or abnormal copy numbers of a single chromosome have a poor prognosis. CIN might be better than T stage in predicting the prognosis of patients with BC. Molecular typing of CIN can be used as an independent prognostic factor for BC.

Humans↗

PubMed2025

Altered immune signatures in breast cancer lymph nodes with metastases revealed by spatial proteome analyses.

BACKGROUND: Metastasis to lymph nodes is strongly associated with reduced survival in breast cancer patients. To increase the understanding on how lymph node metastasis impairs the local immune response in affected lymph nodes, we here studied spatial proteomic changes of critical lymph node immune populations in uninvolved lymph nodes (UnLN) and paired lymph nodes with metastases (LNM) from five breast cancer patients. METHODS: The proteome was analyzed for cortical lymphocyte compartments, subcapsular sinus (SCS) and medullary sinus (MS) CD169+ macrophages, using the Digital Spatial Profiling (DSP) platform from NanoString. RESULTS: Our results identified a stable proteome of SCS CD169+ macrophages in LNM, with the exception for downregulation of the anti-apoptotic protein Bcl-xL and FAPα, but a clear reduction in numbers of SCS CD169+ macrophages in LNM. In contrast, the proteome of MS CD169+ macrophages, B-cell compartments and interfollicular T-cells showed altered immune signatures in LNM, indicating that the decline in SCS CD169+ macrophages coincide with a malfunction in the local, anti-tumor immune responses. CONCLUSIONS: The findings from our study support the notion that metastasis to lymph nodes in breast cancer patients modifies local immune responses. These changes may contribute to explain unsuccessful therapeutic responses, and thereby worsened prognosis, for breast cancer patients with LNM.

Breast Neoplasms↗

PubMed2026

Integrated bulk and single-cell RNA sequencing reveals a prognostic neuro-mimicry signature in papillary thyroid carcinoma.

BACKGROUND: Cancer cells can acquire neuron-like characteristics ("neural mimicry") to promote progression. However, the role of specific ion channel genes in Papillary Thyroid Carcinoma (PTC) and their clinical significance remains unclear. METHODS: We included transcriptomic data from 521 PTC patients in the TCGA cohort. A neuron-specific gene set was used to screen for potential targets. We constructed a prognostic model using LASSO logistic regression. To verify the cellular origin of the signature, we performed single-cell RNA sequencing (scRNA-seq) analysis on the GSE184362 dataset. RESULTS: We established an 8-gene signature involving KCNN4, KCNN1, KCNT2, SNAP25, KCNK16, GABRG1, GABRG2, and GABRB2. The model demonstrated good predictive performance for lymph node metastasis, with an AUC of 0.721 (95% CI 0.677-0.765). Single-cell analysis of seven integrated tumor samples (N = 65,744 cells) confirmed that GABRB2 was specifically enriched in malignant thyrocytes (EPCAM+/KRT18+) at 200-fold higher detection rates than immune cells (20.0% vs. 0.1%, P ≈ 0), supporting tumor-intrinsic neural mimicry. High-risk patients showed immunosuppressive features with altered immune cell infiltration patterns. CONCLUSION: This study identifies a malignant cell-intrinsic signature for predicting PTC prognosis. Validated by single-cell data, our findings suggest that targeting ion channels may represent a potential therapeutic strategy for modulating neuro-immune interactions in thyroid cancer, pending experimental validation.

GABRB2↗

PubMed2026

Paired genomic profiling of primary tumor and lymph-node metastases identifies candidate prognostic features in penile squamous cell carcinoma.

BACKGROUND: Penile squamous cell carcinoma (PSCC) is a rare malignancy with limited genomic data in Asian populations. Lymph node metastasis heavily dictates prognosis, yet molecular determinants of progression remain poorly understood. We aimed to characterize the genomic landscape and explore candidate prognostic genomic features using paired primary and metastatic PSCC tumors. PATIENTS AND METHODS: Targeted next-generation sequencing (437 cancer-related genes) was performed on primary tumors and matched lymph node metastases from 20 Chinese patients. Somatic alterations, intralesional heterogeneity, and tumor mutation burden (TMB) were analyzed and correlated with disease-free survival (DFS) and overall survival (OS). RESULTS: The most frequent primary tumor mutations included TP53 (45%) and TERT (40%). Notably, CCND1/FGF19 co-amplification (20% of cases) was associated with inferior DFS (P = .027) and showed a trend toward shorter OS (P = .050). Conversely, T-cell receptor (TCR) pathway alterations correlated with markedly improved survival. Comparing paired lesions revealed 59.8% shared alterations. Elevated TMB in metastases relative to matched primary tumors was significantly associated with poorer DFS (P = .008), while higher intralesional heterogeneity showed a trend toward worse OS. CONCLUSION: Paired profiling revealed broadly conserved genomic features together with lesion-specific divergence in PSCC. Recurrent CCND1/FGF19-containing 11q13 amplification, TCR pathway alterations, and elevated metastatic TMB warrant evaluation as potential prognostic features in larger, independently validated cohorts with integrated HPV and immune profiling.

Humans↗

PubMed2026

TRIM49 Deficiency Stabilizes a Galectin-3/EGR1 Transcriptional Complex That Drives Invasiveness of Gastric Adenocarcinoma.

UNLABELLED: Tissue invasion is an initiating step of the cancer metastatic cascade. Unraveling the mechanisms underlying intracellular signaling pathway rewiring that activates downstream transcriptional machinery to drive invasiveness could help identify improved strategies to prevent and treat metastasis. Through an unbiased genome-wide CRISPR screen in a mouse model of gastric adenocarcinoma (GAC), an E3 ubiquitin ligase, tripartite motif-containing protein 49 (TRIM49), was identified as a potent suppressor of cancer invasiveness. In two thirds of GAC, TRIM49 expression was downregulated in invading cancer cells, in which TRIM49 deficiency correlated with deeper tumor infiltration and lymph node metastasis and was indicative of shorter overall patient survival. In multiple orthotopic GAC mouse models, TRIM49-deficient cancer cells were highly infiltrative, leading to multiorgan metastasis. Mechanistically, galectin-3, a putative regulator of cancer invasion, was stabilized in TRIM49-deficient cancer, largely because of the failure to undergo TRIM49-mediated polyubiquitination and proteasomal degradation. Consequently, galectin-3 assembled a complex with EGR1, thereby regulating transcriptional activities of a proinvasive gene module. As the galectin-3/EGR1 complex acted as a key node relaying proinvasive signaling, its disruption using GB1107, an oral galectin-3 inhibitor, suppressed tissue infiltration and metastasis of patient-derived xenografts. Taken together, a proinvasive galectin-3/EGR1 transcriptional complex was exploited by TRIM49-deficient GAC to fuel tissue invasion, representing an Achilles' heel that is potentially targetable to prevent metastasis. SIGNIFICANCE: A proinvasion galectin-3/EGR1 transcriptional complex is a therapeutic vulnerability in the highly invasive TRIM49-deficient gastric adenocarcinoma, which can be disrupted by the oral galectin-3 inhibitor GB1107 to prevent cancer spreading.

Stomach Neoplasms↗

PubMed2026

Real-world outcomes of ipilimumab plus nivolumab in esophageal squamous cell carcinoma: a multi-institutional large cohort study.

BACKGROUND: Combination immune checkpoint inhibition with ipilimumab plus nivolumab (NIVO + IPI) has shown promising efficacy in advanced esophageal squamous cell carcinoma (ESCC) in the CheckMate648 trial. However, real-world evidence regarding its safety, efficacy as first-line therapy, and host-related biomarkers relevant to immunotherapy remains limited. METHODS: This multicenter retrospective study evaluated a large cohort of 111 patients with unresectable advanced or recurrent ESCC who received first-line NIVO + IPI therapy. Treatment response, treatment-related adverse events, and prognostic factors were analyzed. RESULTS: The objective response and disease control rates in cases with target lesions were 44.0% and 70.7%, respectively. Treatment-related adverse events ≥ Grade 2 occurred in 58 (52.3%) patients, including one Grade 4 event (type 1 diabetes) and two Grade 5 events (biliary infection and myocarditis). The median overall survival (OS) and progression-free survival were 22 months (95% confidence interval [CI]: 13-not reached) and 5 months (95% CI 3-8), respectively. OS was significantly affected by lymph node metastasis in unresectable advanced disease and by liver metastasis in recurrent disease. Multivariate analysis of OS identified the C-reactive protein-to-albumin ratio (CAR), a marker of host immune-inflammatory status, as the only independent prognostic parameter (hazard ratio = 2.99, 95% CI 1.35-6.63, P = 0.0071). CONCLUSIONS: In this large real-world cohort, first-line NIVO + IPI therapy demonstrated meaningful clinical activity and an acceptable safety profile in advanced ESCC. Treatment outcomes varied according to metastatic patterns, suggesting an influence of organ-specific immune microenvironments, and CAR emerged as a simple and robust prognostic biomarker. These findings support the real-world applicability of dual immune checkpoint blockade and highlight the importance of host immune context in patient selection.

Humans↗

PubMed2026

Decreased expression of Krüppel-like factor 4 is associated with colorectal cancer progression.

Krüppel-like factor 4 (KLF4), a key transcription factor,plays an important role in cell proliferation, differentiation, and apoptosis. Here, we explored the prognostic value of KLF4 and its role in colorectal cancer (CRC) progression. We analyzed transcriptomic data and clinical information related to CRC from The Cancer Genome Atlas (TCGA) and the Gene Expression Omnibus (GEO) database. database. Immunohistochemistry was performed to evaluate KLF4 expression in CRC tissue samples. Additionally, we examined the relationship between clinicopathological factors and patient prognosis using Cox proportional hazards model analysis. Lentiviral transfection was used to create KLF4 knockdown HCT-116 cells. Analysis of the TCGA database and two GEO datasets (GSE21510 and GSE117606) revealed that KLF4 was expressed at low levels in CRC. Furthermore, reduced KLF4 levels correlated with lymph node metastasis, distant metastasis, and advanced TNM staging. ROC curve analysis indicated that KLF4 can effectively differentiate cancerous tissue from normal tissue. Functional enrichment analysis identified KLF4 as significantly linked to the glycoprotein metabolic pathway. Our detection of KLF4 expression in CRC tissue samples confirmed its decreased levels and their association with poorer patient survival. However, KLF4 was not identified as an independent prognostic factor. In vitro, KLF4 knockdown promoted HCT-116 cell migration and invasion and downregulated the mRNA expression of glycoprotein synthesis- and glycosylation-related genes. Conversely, KLF4 re-expression markedly reversed these effects. Our findings suggested that low KLF4 expression served as a predictor factor for disease progression in CRC patients. Furthermore, reduced KLF4 levels enhance the migration and invasion of CRC cells, which may be related to impaired glycoprotein metabolism.

Colorectal cancer↗

PubMed2026

CD44 gene rs9666607 polymorphism is associated with papillary thyroid carcinoma and interacts with CREB3L1.

BACKGROUND: The incidence of papillary thyroid carcinoma (PTC) has been rising. CD44 is involved in cell adhesion and migration, but the role of its genetic variation in PTC remains unclear. METHODS: This study aimed to investigate the association of CD44 gene polymorphisms with PTC and to examine the interaction between CD44 and CREB3L1. This study enrolled 354 patients with PTC, and the genotype distribution of the CD44 polymorphism (rs9666607) was analyzed. Key PTC genes were screened using the Gene Expression Omnibus (GEO) database (GSE33630). Gene Ontology (GO) functional enrichment and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses were performed on these key genes. CD44 expression was validated using TCGA database, ELISA, qRTPCR, Western blot, and IHC in patient tissues, PTC mouse model, and human cell lines. The direct interactive molecules were screened through a bioinformatics method. RESULTS: The GSE33630 dataset identified a total of 124 upregulated and 85 downregulated differentially expressed genes. Enrichment analysis revealed 12 key PTC genes, including CD44. TCGA database validation revealed that CD44 was significantly overexpressed in PTC patients. The rs9666607‑A allele was associated with an increased risk of PTC and lymph node metastasis under a dominant model. CD44 mRNA and protein levels were significantly higher in PTC tissues versus adjacent tissue and further elevated in metastatic cases. Bioinformatic analysis predicted CD44 interaction with the transcription factor CREB3L1, and this was confirmed by molecular docking. CREB3L1 expression was synchronously upregulated with CD44 in PTC. CONCLUSION: CD44 polymorphisms, particularly the rs9666607-A allele, are significantly associated with PTC risk and metastasis in the studied population. CD44 is overexpressed in PTC, and its interaction with CREB3L1 suggests a potential novel interaction in PTC pathogenesis.

Hyaluronan Receptors↗

PubMed2026

Hyperlactate-Associated Lysine Lactylome Remodeling in Laryngeal Squamous Cell Carcinoma.

Laryngeal squamous cell carcinoma (LSCC) lacks reliable biomarkers, and the roles of lactate metabolism and lysine lactylation (Kla) remain largely unknown. We profiled the lysine lactylome of LSCC, paired it with adjacent normal tissues, and integrated the data with quantitative proteomic and transcriptomic analyses. LSCC exhibited a hyperlactate-associated phenotype characterized by dysregulated lactate-related genes (LRGs), altered protein abundance, increased tissue lactate, and globally increased Kla levels. Data-independent acquisition mass spectrometry (DIA-MS) identified 1616 Kla sites on 1468 peptides from 688 proteins, with most differential sites being upregulated in tumors. Differentially lactylated proteins were enriched in cell-matrix adhesion, cell migration, chromatin remodeling, and gene-regulatory processes and were clustered into cytoskeletal and nuclear regulatory modules. Multiple Kla sites were also detected on the core histones. Immunoblotting and tissue microarray analyses confirmed increased pan-Kla expression in the LSCC. Pan-Kla levels were independent of sex and age but positively correlated with the tumor stage and lymph-node metastasis. These findings provide a systematic resource for hyperlactate-associated lactylome remodeling in LSCCs and identify candidate Kla-related molecular features associated with clinicopathological progression for future functional and clinical evaluation.

Humans↗

PubMed2026

Splenic hilum nodal involvement in resected left-sided pancreatic cancer: meta-analysis.

BACKGROUND: Splenectomy is standard of care during left pancreatectomy for pancreatic ductal adenocarcinoma (PDAC) to obtain adequate lymphadenectomy. However, evidence supporting this approach is lacking. Splenic preservation would reduce short-term morbidity and is essential for emerging oncological adjunctive therapies, including immunotherapy and personalized cancer vaccines. This study reviewed the incidence of splenic hilum nodal involvement (SHNI) in left-sided PDAC. METHODS: A systematic review of the PubMed, Embase, and Cochrane databases was performed, identifying studies published from inception to July 2026. Outcomes of interest were the rate of SHNI (station 10), overall survival, and the rate of splenic artery nodal involvement (SANI; station 11). Meta-analyses were conducted using random-effects models. Subgroup analyses for SHNI were performed per tumour localization (pancreatic neck, body, tail). RESULTS: Among 2776 screened studies, 22 with 2260 patients undergoing left pancreatectomy for PDAC were included. The pooled prevalence of SHNI was 3.7% (95% confidence interval (c.i.) 2.2% to 6.2%); 1.1% for pancreatic body PDAC (95% c.i. 0.3% to 4.3%) and 9.7% for pancreatic tail PDAC (95% c.i. 3.5% to 24.0%). SHNI was not significantly associated with survival (pooled hazard ratio 2.05; 95% c.i. 0.89% to 4.72; P = 0.072). The pooled prevalence of SANI was 39.1% (95% c.i. 25.1% to 55.1%). CONCLUSION: In patients undergoing left pancreatectomy for PDAC, the presence of SHNI is rare, particularly in pancreatic body cancer (1.1%). These findings suggest that the relevance of routine splenectomy remains unclear, especially for pancreatic body PDAC. However, because the quality of current evidence is low, further investigation in prospective studies is required.

Humans↗

PubMed2026

An integrated single-cell and spatial transcriptomic atlas of thyroid cancer progression identifies prognostic fibroblast subpopulations.

Although well-differentiated thyroid carcinoma (WDTC) is characterized by a robust treatment response, aggressive subtypes, such as anaplastic thyroid carcinoma (ATC), remain highly lethal. To understand thyroid cancer evolution in both children and adults, we analyzed single-cell transcriptomes of 423,733 cells from 81 samples and spatially resolved key tumor and microenvironment populations across 28 tumors with spatial transcriptomics, including rare and unique composite WDTC/ATC tumors and pediatric diffuse sclerosing thyroid carcinomas. Additionally, we identified gene signatures of stromal cell populations in 5 large thyroid cancer bulk RNA-sequencing cohorts. Through this multi-institutional effort, we defined a population of POSTN+ myofibroblast cancer-associated fibroblasts (myCAFs) that are intimately associated with invasive tumor cells and correlate with poor prognosis, lymph node metastasis, and disease progression in thyroid carcinoma. We also revealed a population of inflammatory CAFs that are distant to tumor cells and are found in the inflammatory stromal microenvironment of autoimmune thyroiditis. Together, our study provides spatial profiling of thyroid cancer evolution in samples with mixed WDTC/ATC histopathology and identifies a prognostic myCAF subtype with potential clinical utility in predicting aggressive disease in both children and adults.

Humans↗