Search Results (45,884)

Background: Vulvar cancer is a rare gynecologic malignancy comprising 1–3% of all cases. No established standard exists for advanced disease, and treatment is often extrapolated from cervical cancer. Although HER2 overexpression is well defined in breast cancer and recognized across multiple solid tumors, its prevalence and significance in vulvar cancer remain unclear. Recent activity of HER2-directed antibody–drug conjugate Trastuzumab deruxtecan in solid tumors with an objective response rate (ORR) of around 37% highlights the need to better characterize HER2 expression in vulvar cancer. Methods: We performed a systematic search of Medline, Embase, and the Cochrane Library up to May 2025. Eligible studies included ≥10 vulvar cancer cases, predominantly vulvar squamous cell carcinoma (VSCC), excluding vulvar Paget’s disease, with available HER2 assessment by immunohistochemistry and/or in situ hybridization. Two reviewers independently screened the studies. A random-effects model was used to estimate pooled HER2 positivity. Heterogeneity was assessed using Cochrane’s Q and Higgins’s I². Results: Of 506 records, nine retrospective studies including 769 patients with predominantly squamous cell carcinoma histology (98%, n = 752) met inclusion criteria. A total of 50 HER2-positive cases were observed. Median age at diagnosis of vulvar cancer was between 55 and 78, reported in three studies. Molecular profiling was limited. Among three studies with known TP53 status (n = 206), 59% of the tumors expressed TP53 (n = 122), and among two studies with known human papilloma virus (HPV) status (n = 128), 21% (n = 27) were HPV-positive. Six studies used American Society of Clinical Oncology/College of American Pathologists (ASCO/CAP) HER2 testing guidelines in breast cancer. Pooled HER2-positive expression across ASCO/CAP-based studies was 2% (95% CI: 1%, 3%) and for non-ASCO/CAP-based studies was 21% (95% CI: 2%, 52%). Exploratory pooled estimated proportion of HER2-positive expression was 5% (95% CI: 0.4%, 14%). There was substantial heterogeneity across studies, I² value of 91.1% [95% CI: 85.4%; 94.6%], and no significant publication bias was observed (Egger’s test p = 0.364). This study could not assess prognostic value of HER2 overexpression in VSCC. Conclusions: HER2 positivity in VSCC appears uncommon but it remains to be fully explored. Standardized assessment using contemporary ASCO/CAP breast, endometrial-specific and/or gastric criteria are needed to clarify the prevalence of HER2-positive versus HER2-low/ultralow disease to inform potential use of HER2-targeted therapy. Full article

Background: CDK4/6 inhibitors induce G1/S cell-cycle arrest in bladder cancer; however, adaptive resistance limits their therapeutic efficacy. The role of the m⁶A reader IGF2BP3 in regulating sensitivity to CDK4/6 inhibition remains largely unknown. Methods: Transcriptomic profiling was performed in palbociclib-treated bladder cancer cell lines (T24, RT112, and UMUC-3) to identify m⁶A regulators associated with drug response. The expression and clinical significance of IGF2BP3 were evaluated using The Cancer Genome Atlas (TCGA) data and an independent clinical cohort. Gain- and loss-of-function assays were conducted to investigate the effects of IGF2BP3 on cell proliferation and cell-cycle progression. Mechanistic studies, including RNA-binding, mRNA stability, ubiquitination, and in vivo tumorigenesis assays, were performed to elucidate the underlying regulatory network. Results: IGF2BP3 was identified as the only m⁶A regulator differentially expressed following palbociclib treatment. IGF2BP3 expression was significantly elevated in bladder cancer tissues compared with normal tissues and was associated with poor prognosis and Ki67 positivity. Functionally, IGF2BP3 overexpression (OE) promoted G1/S transition, increased MYC and downstream cell-cycle regulators, and partially rescued palbociclib-induced cell-cycle arrest, whereas IGF2BP3 knockdown (KD) suppressed cell proliferation in an MYC-dependent manner. Mechanistically, IGF2BP3 bound to MYC mRNA in an m⁶A-dependent manner and enhanced its stability. Furthermore, MKRN2 was identified as an E3 ubiquitin ligase that directly interacted with IGF2BP3, promoted its ubiquitination, and facilitated its proteasomal degradation. In vivo, MKRN2 co-overexpression attenuated IGF2BP3-driven tumor growth and synergized with palbociclib to maximally suppress tumor volume, reduce MYC and Ki67 expression, and induce apoptosis. Conclusions: These findings establish the MKRN2–IGF2BP3–MYC axis as a critical regulator of CDK4/6 inhibitor sensitivity in bladder cancer. Targeting IGF2BP3 or enhancing MKRN2 activity may represent a promising strategy to overcome adaptive resistance and improve the therapeutic efficacy of CDK4/6 inhibitors. Full article

Schwann cells, the principal glial cells of the peripheral nervous system, play a central role in nerve repair following injury. Upon injury, mature Schwann cells dedifferentiate into repair Schwann cells. These processes are governed by complex gene regulatory networks, yet the quantitative dynamics of these processes remain unclear. Here, using a bottom-up systems biology approach, we constructed an endogenous regulatory network model based on experimentally validated interactions, without relying on high-throughput data as input. The model captures Schwann cell dedifferentiation dynamics and reveals a potential landscape composed of stable states and intermediate transition states. Simulations recapitulate post-injury trajectories and confirm the role of c-Jun upregulation in maintaining repair capacity. Furthermore, the model predicts multiple potential therapeutic targets, including tumor protein p53 (P53), c-Jun N-terminal kinase (JNK), and phosphatase and tensin homolog (PTEN), for sustaining repair competence. We also identify intrinsic heterogeneity within repair Schwann cells. Furthermore, we uncover key transition states that simultaneously connect repair-competent cells to both repair-deficient and apoptotic phenotypes. These intermediate states may represent critical regulatory bottlenecks and serve as key cellular targets for improving peripheral nerve regeneration. Overall, this work provides new insights into the precise regulation of Schwann cell fate and establishes a theoretical framework for regenerative medicine and clinical strategies in peripheral nerve repair. Full article

Hepatocellular carcinoma (HCC) is a heterogeneous primary liver malignancy characterized by limited treatment options and low overall survival rates. Recent studies have explored the role of programmed death ligand 1 (PD-L1), tumor-associated macrophages (TAMs), and epithelial-mesenchymal transition (EMT) in modulating tumor progression and the response to immunotherapy. This study aimed to investigate the association among PD-L1 expression, TAMs, and EMT in HCC, highlighting the recently proposed immunophenotypic variant—gastric-type HCCs. A retrospective cohort of 50 surgically resected HCC patients was analyzed. Immunohistochemical staining was performed for PD-L1 (clones 28-8 and 22C3), CD68 (TAMs), and EMT markers (VSIG-1, TTF-1, and vimentin). PD-L1 expression was detected in 52% of the patients and was significantly associated with high TAM counts (p < 0.001). Compared with PD-L1-negative patients, those with gastric-type HCCs, which are characterized by VSIG-1 and TTF-1 co-expression and vimentin negativity, demonstrated improved survival outcomes (p = 0.03). Integration of immune and EMT profiling of tumor cells in routine diagnostics may guide prognosis and immunotherapeutic strategies in HCC. Further molecular validation is required to confirm the biological significance of the proposed gastric-type HCC immunophenotype. Full article

Pituitary adenoma is a clinically important brain tumor whose progression and therapeutic outcomes are influenced by intricate interactions between tumor development and the host immune response. Globally, pituitary adenomas account for approximately 15% of all intracranial tumors. This study aims to investigate clinical MRI data obtained from a patient who recovered from a pituitary adenoma. The collected data provide measurements of tumor volume (mm) at several time points throughout the treatment period. The patient received vaccine-based therapy accompanied by regular clinical assessments, and achieved recovery after nearly twenty-two months. Motivated by the clinical observations and the underlying treatment mechanism, a mathematical model describing tumor–immune–vaccine interactions is developed. The proposed ordinary differential equation (ODE) framework incorporates tumor cells, immune cells, and vaccine components to characterize the temporal evolution of tumor volume during treatment. Fundamental dynamical properties of the model, including positivity, boundedness, existence of solutions, and equilibrium stability, are established through analytical techniques. In addition, numerical simulations are performed using the fourth-order Runge–Kutta (RK4) method and validated against the available clinical measurements. The numerical results exhibit close agreement between the observed and simulated data, yielding a minimal root mean square error (RMSE). Furthermore, sensitivity analysis highlights the significant role of immune- and vaccine-related parameters in regulating tumor suppression. The findings suggest that a relatively simple mechanistic framework can effectively capture the reduction in pituitary adenoma under vaccine-based therapy. Full article

Background: Soil streptomycetes, particularly those isolated from extreme environments, are valuable sources of bioactive compounds. Their genomes encode a large number of biosynthetic gene clusters (BGCs), many of which can be simultaneously expressed. Methods: Molecular genetic methods were employed to identify Streptomyces anulatus 89 (Illumina NovaSeq 2 × 150 bp). Whole-genome phylogeny based on orthologous genes was employed using the Bacterial and Viral Bioinformatics Resource Centre services. Liquid chromatography–mass spectrometry analysis of biomass extract was carried out to identify antibiotics. Bioassays on cell lines were employed to evaluate the cytotoxicity and antitumor activity of the crude extract of the S. anulatus 89 strain. Results: Genome analysis identified 36 BGCs associated with secondary metabolites. The strain synthesized nactins, pladienolide, phenazinomycin, and 21-hydroxyoligomycin. The biomass extract demonstrated cytotoxicity against cancer cells and induced apoptosis. The A549 and A431 cell lines were the most sensitive. Changes in tumor cell morphology included rounding, shrinkage, increased granularity, and vacuolization. Conclusions: The ability of S. anulatus 89 to simultaneously synthesize different classes of anticancer antibiotics was reported. The investigated crude extract exhibited pronounced antitumor activity, making it a promising candidate for further studies. The underlying hypothesis suggested that strains with broad adaptive potential may serve as promising producers of natural products with antitumor properties. Full article

Background: Routine use of the chorioallantoic membrane (CAM) tumor model in nuclear imaging studies is hampered by small tumors, embryonic movements and laborious volume-restricted intravenous tracer/drug administration. We sought a workaround by using fast-growing tumors, high-resolution autoradiography and non-intravenous tracer administration. Methods: Dekalb White chicken eggs were grafted with C3H mammary carcinoma fragments or MOC2 oral squamous cell carcinoma fragments from donor mice. The tumor uptake of ¹⁸F-fluorodeoxyglucose (FDG) following in-yolk-sac injection, dripping after CAM scoring or allantoic cavity injection was evaluated using positron emission tomography (PET) and autoradiography. Using in-yolk-sac injection, eggs were administered different tracer mixtures, namely (1) pimonidazole (hypoxia-marker), FDG and ¹⁴C-2-deoxyglucose (¹⁴C-2DG), (2) pimonidazole, FDG and ¹⁴C-acetate or (3) pimonidazole, the hypoxia-selective tracer ¹⁸F-fluoroazomycin-arabinoside (FAZA) and ¹⁴C-2DG. For comparison, tumor-bearing mice were administered FDG/¹⁴C-acetate/pimonidazole. Gross tumor uptake was evaluated using PET. Tumor cryosections were analyzed using dual-tracer autoradiography. Complementary autoradiograms were co-registered, covered by a square grid (0.5 × 0.5 mm). Pearson correlation coefficients (PCC) were calculated from scatterplots. Results: C3H tumors reached a mean weight (with 95% confidence interval) of 0.32 g (0.28–0.37 g), while for MOC2, it was 0.19 g (0.09–0.29 g). In-yolk-sac tracer injection was simple and effective, producing high tracer uptake and contrast 3 h post-administration. Spatial tracer overlap (PCC) was: FDG vs. ¹⁴C-2DG, 0.95–0.97; FAZA vs. ¹⁴C-2DG, 0.71–0.79 and FDG vs. ¹⁴C-acetate, 0.26–0.84 (0.15–0.76 in mice). Pimonidazole revealed tumor hypoxia. Conclusions: Direct-grafting from donor mice generated larger tumors than previously reported. In-yolk-sac tracer administration was practical and allowed larger injected volumes. Autoradiography revealed that: (1) FDG and ¹⁴C-2DG can be used interchangeably, (2) ¹⁴C-2DG was elevated in FAZA-positive areas, suggesting that in some tumors FDG-PET may provide information on the intratumoral distribution of hypoxic areas, and (3) FDG and ¹⁴C-acetate showed variable overlap. We conclude that in-yolk-sac tracer injection and autoradiography simplify and optimize CAM-based nuclear imaging research. Full article

Penile squamous cell carcinoma (PSCC) is a rare malignancy with limited therapeutic options in advanced and recurrent diseases. Advanced PSCC is typically managed with multimodal therapy, including neoadjuvant chemotherapy or chemoradiation followed by surgery; however, durable responses remain uncommon, and outcomes after recurrence are poor. Cancer vaccines represent a promising immunotherapeutic strategy, as these treatments induce tumor-specific immunity and heightened immune surveillance against penile cancer cells. While therapeutic cancer vaccines have not yet demonstrated consistent clinical efficacy as monotherapy in PSCC, their integration with complementary immune-modulating approaches, particularly immune checkpoint blockade, represents a rational strategy to enhance antitumor immunity. This review summarizes the rationale for vaccine development in PSCC, with emphasis on HPV-derived antigens, neoantigens, and emerging tumor-associated targets. We examine major vaccine platforms, including viral-vector, peptide-based, nucleic acid, and dendritic cell-based approaches. We also discuss how spatial transcriptomics, single-cell RNA sequencing, artificial intelligence-assisted antigen prediction, and nanotechnology-enhanced delivery systems may support future personalized vaccine development. Overall, therapeutic vaccines remain investigational in PSCC but may become relevant within biomarker-driven, combination-based immunotherapy strategies. Full article

Unc-51-like kinase 3 (ULK3) is a key member of the ULK serine/threonine kinase family. Aberrant ULK3 expression has been increasingly linked to tumorigenesis and malignant progression in multiple cancer types. However, the precise role of ULK3 in tumor initiation and progression remains incompletely understood. Leveraging integrated multi-omics data from The Cancer Genome Atlas (TCGA), the Genotype-Tissue Expression (GTEx) project, and the Clinical Proteomic Tumor Analysis Consortium (CPTAC), we systematically characterized the expression of ULK3 at both the transcript and protein levels across 33 cancer types. We also evaluated genomic alterations, prognostic significance, alternative splicing, pathway enrichment, tumor stemness, immune infiltration, and immunotherapy-related biomarkers. In parallel, we investigated the function of ULK3 in prostate cancer PC-3 cells using cellular localization analysis, wound-healing assays, and MTT assays. We further applied Connectivity Map (CMap) screening and molecular docking to identify candidate ULK3 activators. ULK3 was significantly upregulated in 13 cancer types, including Bladder Urothelial Carcinoma, Breast Invasive Carcinoma, and Lung Adenocarcinoma. In contrast, ULK3 was downregulated in Cholangiocarcinoma and Head and Neck Squamous Cell Carcinoma. High ULK3 expression was associated with poor overall survival in Adrenocortical Carcinoma, Kidney Renal Clear Cell Carcinoma, and Skin Cutaneous Melanoma. Copy number amplification contributed to ULK3 overexpression. A recurrent A206V missense mutation was detected in the protein kinase (Pkinase) domain. Genes co-expressed with ULK3 were enriched in RNA splicing, methylation, oxidative phosphorylation, and energy metabolism. ULK3 expression showed positive correlations with tumor stemness indices and m1A/m5C/m6A RNA modification regulators. From an immunological perspective, high ULK3 expression was associated with lower Immune Score, increased M2 macrophage infiltration, and co-expression of PD-L1, CTLA4, and LAG3 in most cancers. ULK3 expression was also correlated with Tumor Mutational Burden in Kidney Renal Clear Cell Carcinoma and Rectum Adenocarcinoma. In addition, ULK3 expression was associated with Microsatellite Instability in Brain Lower Grade Glioma, Lung Adenocarcinoma, and Uterine Corpus Endometrial Carcinoma. ULK3 overexpression promoted proliferation and migration in PC-3 cells. Cephaeline was screened as a putative ULK3 activator. Overall, ULK3 expression and amplification were associated with poor clinical outcomes, tumor stemness, immunosuppression, and RNA dysregulation. These findings highlight the potential value of ULK3 as a pan-cancer diagnostic and prognostic biomarker and as a predictor of immunotherapy response, particularly in prostate cancer. Full article

Chronic inflammation is a hallmark of the breast cancer tumor microenvironment and is also known to be associated with disease progression and therapeutic response. Interleukin-1 (IL-1) signaling has been widely studied in breast cancer biology; however, the long-term effect of sustained IL-1 exposure on hormone receptor-positive breast cancer cells remain poorly understood. In this study, we investigated how chronic IL-1 exposure influences inflammatory response, hormone dependency, and therapeutic sensitivity in ERα+/PR+ breast cancer models, MCF7 and T47D. Chronic IL-1 exposure attenuated response to subsequent acute IL-1 treatment, but the chronically exposed cells remained sensitive to serum deprivation, retained dependence on estrogen or progesterone receptor signaling, and responded robustly to endocrine and chemotherapeutic treatments. Extensive changes in basal gene expression and histone modification revealed that chronic IL-1 exposure alters transcriptional reprogramming and chromatin remodeling. Together, these findings demonstrate that chronic IL-1 signaling drives selective inflammatory response in hormone receptor-positive MCF7 and T47D breast cancer cells. This work underscores the continued therapeutic relevance of hormone receptor-targeted strategies in chronically inflamed tumors and provides insight into how sustained inflammatory stress shapes tumor behavior and gene regulation predicted to promote tumor progression. Full article

Background: Head and neck squamous cell carcinoma (HNSCC) remains a highly aggressive malignancy with poor clinical outcomes. Although poly(ADP-ribose) polymerase (PARP) inhibitors have shown promising activity in tumors with homologous recombination deficiency, their efficacy in BRCA wild-type HNSCC remains limited. Reactive oxygen species (ROS)-induced DNA damage may increase cellular dependence on DNA repair pathways and thereby enhance sensitivity to PARP inhibition. This study investigated whether ROS-mediated DNA damage could sensitize BRCA wild-type HNSCC cells to the PARP inhibitor olaparib. Methods: BRCA wild-type HSC-3 and SCC-25 HNSCC cell lines were exposed to H₂O₂ to induce oxidative stress. Intracellular ROS levels were quantified using DCFDA assays, DNA double-strand breaks were evaluated by γ-H2AX ELISA, PARP activity was assessed by ELISA, and cell viability was determined using MTT assays. Expression levels of DNA repair genes (PARP1, PARP2, BRCA1, BRCA2, RAD51, and MLH1), checkpoint kinases (ATM, ATR, and CHK1), the homologous recombination regulator FANCD2, and redox defense genes (NQO1, GPX4, and SLC7A11) were analyzed by qRT-PCR. Therapeutic selectivity was assessed using HGF-1 normal human gingival fibroblasts as a normal cell control. Apoptosis was measured through caspase-3/7 activity assays, and drug interactions were evaluated using the Chou–Talalay method. Results: H₂O₂ treatment increased intracellular ROS levels in both cell lines, accompanied by significant induction of DNA damage as demonstrated by elevated γ-H2AX levels. ROS induction markedly enhanced olaparib sensitivity, significantly reducing IC₅₀ values in both HSC-3 and SCC-25 cells. Combined H₂O₂ and olaparib treatment produced strong synergistic cytotoxicity, suppressed DNA repair, checkpoint kinase, and redox defense gene expression, and increased caspase-3/7 activity compared with control cells. Importantly, the combination demonstrated selective cytotoxicity toward cancer cells, with normal HGF-1 cells retaining significantly higher viability. Conclusions: ROS-induced DNA damage significantly enhances the anti-tumor activity of olaparib in BRCA wild-type HNSCC cells through a functional synthetic lethal-like interaction involving the simultaneous collapse of DNA repair capacity, checkpoint activation, and oxidative stress buffering, culminating in apoptosis induction. These findings support the rationale for combining ROS-generating therapies with PARP inhibitors in HNSCC treatment. Full article

Background/Objectives: Curcumin shows broad anticancer activity but limited clinical success as a standalone agent because of poor bioavailability and inconsistent tumor exposure. This review introduces the concept of curcumin as a molecular synergy amplifier and proposes that successful combinations depend on three interdependent determinants: mechanistic complementarity, suppression of adaptive resistance networks, and pharmacokinetic synchronization. Methods: Evidence on combinations with chemotherapeutics, natural bioactives, and nanotechnology-enabled delivery systems was critically evaluated, with emphasis on mechanism, resistance reversal, drug ratio, administration sequence, and tumor exposure. Results: Curcumin enhances therapeutic efficacy by sensitizing cancer cells, suppressing adaptive resistance pathways, targeting cancer stemness, and promoting multiple forms of programmed cell death. Importantly, analysis of current evidence indicates that therapeutic success depends not only on molecular synergy but also on pharmacokinetic synchronization between curcumin and partner agents. Many combinations demonstrating strong in vitro synergy fail to translate in vivo because optimal drug ratios, timing, and tumor exposure cannot be maintained. Nanotechnology-based co-delivery systems partially overcome these limitations through synchronized delivery and controlled release. Conclusions: Curcumin should be viewed as a molecular synergy amplifier whose clinical utility depends on mechanistic complementarity and pharmacokinetic synchronization with co-administered therapies. This framework provides a rationale for the design of next-generation curcumin-based combination therapies and identifies key priorities for clinical translation. Full article

Background: Chronic atrophic gastritis (CAG) is a prevalent precancerous gastric disorder characterized by persistent inflammation, glandular atrophy, and progressive mucosal damage, for which effective multi-target therapeutic strategies remain insufficient. The Lian-Huo-Hua-Zhuo formula (LHHZ), a traditional Chinese herbal prescription, has demonstrated potential anti-inflammatory and gastrointestinal protective effects in clinical practice; however, its active constituents and mechanisms of action against CAG remain undefined. This study aimed to clarify the absorbed bioactive components of LHHZ and explore its therapeutic mechanism for CAG. Methods: Ultra-high-performance liquid chromatography coupled with quadrupole Orbitrap high-resolution mass spectrometry was employed to identify the absorbed components of LHHZ in the gastric and intestinal tissues of mice. The therapeutic effects of LHHZ on CAG were assessed through histopathological staining, ultrastructural observation, and evaluation of serum and gastric functional indicators. Network pharmacology, molecular docking, and molecular dynamics simulations were integrated to predict the core targets and key signaling pathways, while the regulatory effects on the interleukin-17 (IL-17) signaling pathway were further validated by immunofluorescence staining, real-time quantitative polymerase chain reaction, and Western blotting. Additionally, 16S ribosomal RNA gene sequencing and targeted metabolomics were applied to investigate the effects of LHHZ on gut microbiota composition and short-chain fatty acid (SCFA) metabolism. Results: The results revealed that 55 and 48 absorbed components were identified in the gastric and intestinal tissues, respectively, predominantly derived from Coptis chinensis Franch. and Pogostemon cablin (Blanco) Benth. LHHZ significantly alleviated gastric mucosal lesions, reduced intestinal metaplasia, restored the ultrastructure of gastric mucosal cells, improved gastric functional indicators including pepsinogen I (PG I), pepsinogen II (PG II), and gastrin-17 (GAS-17), and decreased the levels of pro-inflammatory cytokines. Network pharmacology combined with in vitro and in vivo experiments demonstrated that the core bioactive components of LHHZ can target and regulate interleukin-1 beta (IL-1β) and tumor necrosis factor-alpha (TNF-α), attenuate activation of the IL-17 signaling pathway, and suppress the secretion of downstream pro-inflammatory factors. Furthermore, LHHZ enhanced the alpha diversity of gut microbiota, reduced the Firmicutes to Bacteroidetes (F/B) ratio, restored the abundance of SCFA-producing bacteria such as Bacteroidales and Oscillospirales, and normalized the aberrant levels of eight SCFAs. Significant correlations were also observed between gut microbiota composition and SCFA metabolism. Conclusions: These findings suggest that LHHZ alleviates CAG by inhibiting inflammation via the IL-17 signaling pathway and by modulating the gut microbiota–SCFA axis, thereby providing preclinical evidence supporting its further investigation and development for multi-target therapeutic strategies against CAG. Full article

Cartilage oligomeric matrix protein (COMP) influences extracellular matrix remodeling. We investigated its clinical, prognostic, and immunomodulatory significance in colorectal cancer (CRC). COMP was quantified via ELISA in 107 paired CRC and normal tissues. Expression was correlated with clinicopathological features, mutational profiles, microsatellite instability (MSI), tumor-infiltrating lymphocytes (TILs), immune checkpoints, and multiplex cytokine networks. For transcriptomic validation, the FieldEffectCrc dataset was used for Gene Set Enrichment Analysis (GSEA), and The Cancer Genome Atlas (TCGA) CRC cohort for survival analysis. COMP was significantly upregulated in CRC tissues (p < 0.001) and correlated with advanced T, N, and overall pathological stages (all p < 0.05, tau = 0.18, 0.21, and 0.23, respectively). High COMP expression was linked to restricted immune infiltration (reduced stromal TILs, p < 0.05, tau = −0.23), elevated levels in microsatellite stable (MSS) compared to MSI tumors (p < 0.01), and correlated positively with immune exhaustion markers (T-cell immunoglobulin and mucin-domain containing-3 (TIM-3), galectin-9 (GAL9), sialic acid-binding Ig-like lectin 9 (SIGLEC9)). Transcriptomic data linked high COMP to worse disease-specific and progression-free survival, and enrichment in pro-tumorigenic pathways (epithelial-to-mesenchymal transition, angiogenesis, IL-6 signaling). COMP upregulation defines an immunosuppressive microenvironment in CRC, particularly in MSS tumors. It represents an important prognostic biomarker and potential therapeutic target for overcoming immunotherapy resistance. Full article

Background: Mutations in the KRAS oncogene occur in approximately 40% of colorectal cancers, predominantly within exon 2. Non-exon 2 mutations are less common and remain poorly characterized in terms of their clinical and biological significance. Systemic inflammatory markers are well-established prognostic indicators in colorectal cancer, yet whether their prognostic value differs across KRAS mutation subtypes has yet to be defined. We aimed to characterize and compare the clinicopathological and inflammatory profiles of patients with exon 2 versus non-exon 2 KRAS-mutated colorectal cancer and evaluate their prognostic implications. Methods: This retrospective cohort study analyzed 272 patients with microsatellite stable metastatic colorectal cancer with KRAS mutations, comprising 236 exon 2 and 36 non-exon 2 cases. Clinical, molecular, and laboratory data, including baseline systemic inflammatory markers, were extracted from electronic medical records. Survival outcomes and the prognostic impact of these variables were evaluated with Kaplan-Meier curves and univariable and multivariable Cox proportional hazards regression analyses. Results: Non-exon 2 mutations were significantly more frequent in female patients (64% vs. 45%, p = 0.048) and in left-sided primary tumors (83% vs. 64%, p = 0.035). Median overall survival was 45.7 months for the non-exon 2 group compared to 32.4 months for the exon 2 cohort; KRAS mutation subtype was not significantly associated with overall survival on univariable or multivariable analysis (univariable HR 1.36, 95% CI 0.85–2.16, p = 0.2; multivariable HR 1.376, 95% CI 0.794–2.383, p = 0.255). Systemic inflammation demonstrated distinct prognostic value, with elevated white blood cells, absolute neutrophil count, platelets, neutrophil-to-lymphocyte ratio, platelet-to-lymphocyte ratio, and low albumin levels demonstrating association with worse overall survival in the exon 2 cohort. Conversely, only an elevated neutrophil-to-lymphocyte ratio predicted worse survival in the non-exon 2 group. Conclusions: KRAS exon 2 and non-exon 2 mutated metastatic colorectal cancers exhibit distinct clinical and inflammatory characteristics. Systemic inflammation exerts a significantly greater prognostic impact in exon 2 disease. As the therapeutic landscape for KRAS-mutated CRC continues to evolve, these findings hold promise for informing KRAS mutation-specific approaches to patient stratification and treatment planning. Full article