Search Results (9,742)

Colorectal cancer is a leading cause of cancer death, yet its molecular heterogeneity remains poorly translated into individualized treatment. We present a reproducible artificial intelligence (AI) framework that integrates multi-omics benchmarking, sample-level drug prioritization, E3 ubiquitin ligase selection, and shape-anchored Proteolysis Targeting Chimera (PROTAC) design for KRASG12D in colon adenocarcinoma (COAD). A controlled synthetic benchmark comprising 425 tumor and 41 simulated normal profiles, parameterized to match The Cancer Genome Atlas (TCGA) distributions, was used for pipeline verification. Among sixteen methods, the Balanced Latent Integration with Stability Selection (BLISS) model achieved the highest silhouette width (0.86) and competitive agreement (Adjusted Rand Index, ARI, 0.90). The pipeline was validated on real data: a TCGA COAD cohort (186 tumors) with independent Consensus Molecular Subtype (CMS) labels and a CPTAC cohort (104 tumors). Integration modestly recovered CMS (ARI 0.28), and stage, not molecular cluster, drove survival (log-rank p = 0.005 versus 0.81). Sample-level prioritization differed from cluster-level ranking in 82.6% of profiles, below chance (p < 0.0001), without indicating efficacy. Candidate NOVEL00489 showed a good MM-GBSA estimate, matching the reference ASP3082. Compounds are computational candidates requiring experimental validation. This establishes a transparent benchmark for in silico degrader generation in precision oncology. Full article

Background/Objectives: OrganoHIPEC is a phase-II, two-stage, open-label clinical trial that investigates if cytoreductive surgery (CRS) and patient-tailored HIPEC, based on a preclinical platform using patient-derived organoids, can improve disease control in peritoneal metastases from colorectal cancer (CRC-PM). Methods: Adults with limited CRC-PM and no distant metastases were included. CRC-PM were sampled for organoid development during diagnostic laparoscopy. These organoids were used in an in vitro HIPEC model to test various drugs suitable for intraperitoneal administration. After 3–6 months of systemic chemotherapy, patients without progression underwent CRS/HIPEC with personalized regimens based on organoid drug response. To detect an increase in 12-month peritoneal disease-free survival from 40% to 60%, 24 patients are needed. According to the two-stage design, if <7 of 10 patients in Stage-1 remain PM-free at 12 months, the trial is terminated. Results: Forty-seven patients were enrolled. Among 31 patients with available organoid data, the most active drugs were mitomycin-C (n = 14), cisplatin/mitomycin-C (n = 12), and low-dose (120 min) oxaliplatin (n = 4). No patient was sensitive to high-dose oxaliplatin (30 min) and cisplatin/doxorubicin. Ten patients had a potential follow-up >12 months. Peritoneal relapse occurred at 8 months in two patients, and one died of liver metastases at 7 months. Seven patients remained PM-free for >12 months (median 16.4, range 12.6–28.4). Conclusions: A comprehensive precision approach using patient-derived organoids to guide personalized HIPEC is feasible and shows promising early results. High-dose oxaliplatin is poorly active. As 7/10 patients achieved the endpoint of 12-month PM-free survival, Stage-1 was successfully completed. The trial is proceeding to Stage-2. Full article

Background: Mammalian arachidonic acid lipoxygenases (ALOXs) are non-heme iron-containing enzymes that oxygenate polyunsaturated fatty acids (PUFAs) with at least two isolated double bonds to hydroperoxy derivatives. The patho-physiological roles of these enzymes in inflammatory, hyperproliferative, and neurological diseases have made them promising targets for pharmacological interventions. Unfortunately, the expression levels of ALOX isoforms in mammalian cells are very low, which makes functional characterization of native enzymes and the development of isoform-specific inhibitors challenging. Methods: Here, we developed a unifying experimental protocol for fed-batch fermentation of mammalian ALOX isoforms in a bioreactor, followed by purification of the recombinant proteins and their functional characterization. Results: Our methodological protocol allowed the preparation of mg amounts of catalytically active human ALOX15, mouse Alox15 and human ALOX15B. The purified proteins are suitable for high-throughput inhibitor screening assays but can also be used as antigens for the preparation of isoform-specific antibodies and for direct structural analyses. Antibodies cross-reacting with human ALOX15 and ALOX15B have been detected in the blood of patients suffering from colorectal cancer. Conclusions: Our functional ALOX data stresses the catalytic differences between mouse and human ALOX15 orthologs, and these catalytic peculiarities need to be considered when the results of mechanistic studies obtained in mouse models of human diseases are transferred to the human situation. Full article

Colorectal cancer, especially the microsatellite-stable subtype, which accounts for 85% to 95% of cases, resists immune checkpoint inhibitors largely due to metabolic reprogramming in the tumor microenvironment. Lactate has evolved from a waste product into a central immunosuppressive regulator. Oncogenic KRAS and BRAF mutations drive aerobic glycolysis, causing glucose deprivation and massive lactate accumulation in the tumor microenvironment. Lactate suppresses immunity through three parallel mechanisms. It signals via GPR81 to recruit polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) and inhibit T-cell function. It contributes to histone H3K18 lactylation, which silences effector genes including IFN-γ and GZMB while upregulating PD-L1 expression. It also acidifies the microenvironment to pH 6.0–6.5, directly impairing NK and T-cell activity. Concurrent lipid abundance stabilizes the MCT4 lactate exporter, forming a bidirectional feed-forward loop that amplifies lactate effects. Spatial metabolic heterogeneity creates distinct immune battlefields, with a supportive ‘metabolic oasis’—a concept proposed in this review—at the invasive front and a deeply immunosuppressive core. Thus, lactate acts as an epigenetic and signaling hub that bridges oncogenic mutations, metabolic competition and immune evasion. Targeting lactate metabolism through LDHA or MCT4 inhibition, modulation of histone lactylation, or disruption of lactate-lipid crosstalk, when combined with classical immune checkpoint blockade and guided by spatial biomarkers, offers a promising strategy to overcome immunotherapy resistance in this challenging subtype. Full article

Colorectal cancer (CRC) progression is shaped by dynamic interactions between tumor-intrinsic metabolic adaptations and immune remodeling within the tumor microenvironment. In CRC, the expression of SMAD7, a classical inhibitor of TGF-β1 signaling, is increased and has been associated with tumor-associated inflammatory responses and malignant progression. In this study, we investigated the potential role of SMAD7 in regulating glycolytic metabolism and macrophage phenotype in CRC. Knockdown of SMAD7 in CRC cell lines resulted in reduced glycolytic activity, as demonstrated by decreased extracellular acidification rate, basal glycolysis, and glycolytic capacity. These metabolic changes were associated with reduced expression of the basal and IL-6- and IL-22-induced glycolytic enzyme hexokinase 2 (HK2), while glucose uptake was increased. Similar reductions in HK2 expression were observed in patient-derived CRC organoids following SMAD7 inhibition, supporting the relevance of this pathway in human tumor-derived models. Functionally, SMAD7 knockdown reduced lactate production by CRC cells and diminished the ability of tumor cell-derived conditioned medium to induce the expression of macrophage-associated immunoregulatory markers, including CD163, CD206, and ARG1. The addition of exogenous lactate restored these effects, indicating that tumor-derived lactate contributes to SMAD7-dependent control of the expression of macrophage-associated immunoregulatory markers. Analysis of human CRC transcriptomic datasets revealed positive associations between SMAD7 expression and macrophage-related signatures, including profiles associated with immunoregulatory tumor-associated macrophages. Together, these findings support a potential role for SMAD7 in controlling tumor metabolism and macrophage-associated immunoregulatory markers in CRC. Full article

Machine learning and statistical classification methods are widely applied to microbiome data for diagnostic, prognostic, and phenotypic insights. However, the complex, multivariate nature of microbiome communities makes it difficult to assess the relative performance of these methods. Most comparisons rely on a small number of published datasets, without considering their underlying ecological properties or how these properties may, in turn, influence classification performance. We introduced a coenocline-based simulation framework to generate synthetic microbiome datasets that incorporate realistic ecological variation arising from species’ responses to host-associated gradients such as disease severity. To evaluate the ecological fidelity of these simulations, we compared synthetic datasets to five widely used real-world microbiome datasets: Cirrhosis, Colorectal Cancer (CRC), Type 2 Diabetes (Chinese and Women cohorts), and the Human Microbiome Project (HMP). Comparisons across α-diversity (species richness), β-diversity (species composition and turnover), and abundance distributions demonstrated that coenocline simulations closely recapitulate the key ecological structures of empirical data. Synthetic datasets exhibited similar richness and abundance patterns to disease-associated microbiomes, with realistic distributions of few dominant and many rare taxa. Moreover, community composition analyses (Bray–Curtis index) revealed that the simulated datasets captured natural levels of compositional dissimilarity among samples, spanning the same variability range observed in real data. When compared against 100 independently simulated datasets, the coenocline model consistently reproduced empirical ranges of species diversity, relative abundance, and between-group compositional differences (ANOSIM-R values), confirming the model’s robustness and reproducibility. This coenocline-based simulation framework provides a novel, flexible, and ecologically grounded approach for generating synthetic microbiome data with controlled complexity. By reproducing realistic ecological gradients and community structures, the framework supplies the controlled test beds needed for systematic future benchmarking of machine learning and statistical classification methods across diverse and biologically meaningful scenarios. In doing so, it will help bridge the gap between ecological realism and computational modeling, thereby supporting more reliable and generalizable inference from microbiome data. Full article

Background/Objectives: Colorectal cancer (CRC) remains a leading cause of cancer-associated mortality worldwide. The current therapeutic interventions are heavily constrained by the development of resistance and severe systemic toxicity. To address these challenges, this study integrated a multi-disciplinary framework involving high-throughput in silico screening followed by in vitro experimental validation to identify novel genetic targets of CRC and evaluate the efficacy of FDA-approved drugs. The primary objective was to identify safe and selective therapeutic agents capable of modulating their effect. Methods: The methodology employed a systematic screening of recent large-scale Genome-Wide Association Studies (GWASs) to pinpoint novel targets, followed by in silico pathogenicity prediction, homology modelling and high-throughput virtual screening of over 1615 FDA-approved drugs. The prioritized candidates were validated in vitro using MTT cytotoxicity assays and differential gene expression analysis across CRC cell lines (HCT116 and HT29) and a non-tumorigenic control, Human embryonic kidney cell line HEK293. Results: In silico analysis identified CLUH, CLSTN3 and SLC11A2 as novel potential targets. Based on in silico predicted deleterious mutations and subsequent molecular docking-based virtual screening, Telmisartan, Dutasteride and Venetoclax were prioritized. This prioritization was supported by their high binding affinity and dose-dependent cytotoxicity in MTT assays; thus, suggesting their repurposing potential for CRC treatment. Telmisartan exhibited a superior therapeutic profile not only in terms of the statistically significant cytotoxicity (p < 0.01), but also its selective effect on HCT116 and HT29 when compared to high safety profile in HEK293. This was further validated when Telmisartan selectively downregulated CLUH and SLC11A2 in CRC cell lines, HCT116 and HT29 while maintaining expression levels in the non-cancerous HEK293 cell line remained significantly unaffected. Furthermore, a 100 ns molecular dynamics simulation confirmed the stable binding conformation and structural reliability of the SLC11A2 (Trp179Ser)–Telmisartan complex. Conclucions: Our findings conclude that Telmisartan is a promising candidate for drug repurposing for CRC treatment and capable of modulating selected novel biomarkers CLUH and SLC11A2. However, further multi-omics-based confirmatory studies and pre-clinical validation studies are needed in the future to confirm the long-term efficacy of this repositioning strategy. Full article

The role of adamalysins (ADAMs) has been widely described in many processes related to carcinogenesis, angiogenesis, inflammation, metastasis, and metabolic disorders. Despite numerous studies, their role in colorectal cancer (CRC) remains unclear. The aim of this study was to evaluate the expression of selected ADAM genes in colorectal cancer tissue and corresponding surgical margins. In addition, for a subgroup of patients, the expression of selected proteins from the ADAM family was assessed. The final study group consisted of 67 patients who underwent elective surgery for colorectal cancer. The relative expression of the ADAM10, 12, 17, and 28 genes was expressed as relative quantification (RQ) and determined by real-time quantitative PCR (RT-qPCR) in tumor tissue and surgical margins. In addition, for a subgroup of 45 patients, the expression of ADAM10, 12, and 17 proteins was assessed by ELISA. Associations between ADAM expression and clinicopathological parameters were analyzed statistically. ADAM12 gene expression was significantly higher in tumor than in margin tissue (median RQ: 0.995 vs. 0.251; p = 0.003), whereas ADAM28 RQ was significantly higher in the margin (median RQ: 0.400 vs. 0.204; p = 0.021). No significant differences were observed in the expression of the ADAM10, ADAM12, ADAM17, or ADAM28 genes based on tumor stage, sex, substance use, BMI, or age, except for nominally higher ADAM12 gene expression in patients over 65 years of age (p = 0.033). Among patients under 65 years of age with cardiovascular disease (CVD), ADAM28 RQ in tumor tissue was significantly higher than in those without CVD (p < 0.05). In obese patients with CVD, a markedly increased expression of ADAM28 in tumor tissue was observed, regardless of age (1.469 vs. 0.132; p < 0.005). Significant positive correlations were observed between the ADAM10 and ADAM17 RQ, and between the ADAM10 and ADAM28 RQ, in both tumor and marginal tissues (all adjusted p < 0.01). No significant correlations were found between gene expression and corresponding protein levels for ADAM10, ADAM12, or ADAM17. ADAM10, 12, 17, and 28 are poor biomarkers for colorectal cancer, but their significance may increase in patients with comorbid metabolic disorders. The lack of correlation between protein expression and gene expression suggests the contribution of post-transcriptional and post-translational regulatory mechanisms, which justifies further research. Full article

Background: The prognostic nutritional index (PNI) is an inexpensive marker derived from serum albumin and peripheral lymphocyte count. Although low PNI has been associated with adverse surgical outcomes, its incremental value beyond basic clinical variables and the stability of commonly used thresholds remain uncertain in heterogeneous colorectal surgical populations. We evaluated the association between preoperative PNI and postoperative complications and examined whether adding PNI improved a basic clinical model. Methods: This retrospective single-center cohort included 205 consecutive adults undergoing colorectal surgery between January 2024 and March 2026. PNI was calculated as albumin (g/L) + 5 × lymphocyte count (10⁹/L). PNI was modeled primarily as a continuous predictor; PNI < 45 was examined secondarily. ROC analysis, multivariable logistic regression, nested-model comparison, calibration assessment, bootstrap internal validation, complete-case sensitivity analysis, and exploratory subgroup analyses were performed. Results: Fifty-six patients (27.3%) had PNI < 45. Postoperative complications occurred in 67 patients (32.7%) overall and were more frequent with PNI < 45 (51.8% vs. 25.5%; RR 2.03, 95% CI 1.40–2.95; OR 3.14, 95% CI 1.65–5.95; Fisher p < 0.001). PNI alone showed modest discrimination (AUC 0.659); the Youden cutoff was 45.45 (sensitivity 50.7%, specificity 78.3%). In the complete-case multivariable model (n = 191), each 5-point decrease in PNI was associated with higher odds of complications (OR 1.52, 95% CI 1.22–1.90; p < 0.001). Adding continuous PNI to age, BMI, and operative approach increased AUC from 0.663 to 0.711 and improved model fit (likelihood-ratio χ² = 15.89, p < 0.001). Bootstrap resampling showed substantial cutoff variability (95% percentile interval 32.05–52.00). Conclusions: Lower preoperative PNI was associated with postoperative complications and added discriminatory information to a basic clinical model. However, its stand-alone discrimination was modest, the data-derived cutoff was unstable on bootstrap resampling, and residual confounding and clinical heterogeneity limit causal or treatment-directed interpretation. PNI should therefore be considered a risk marker rather than a stand-alone decision rule. Prospective interventional studies in well-defined patient groups are needed to determine whether PNI-guided nutritional optimization improves outcomes. Full article

Background/Objectives: Liver metastasis develops in approximately 50% of patients with colorectal cancer. Invasion of the biliary tract from colorectal liver metastasis (CRLM) is rarely reported. Preoperative diagnosis remains elusive, prohibiting optimal surgical management. The objective of this systematic review was to summarize the clinical, radiological, pathological, and treatment characteristics of ibCRLM and describe the reported outcomes. Methods: A systematic literature search of the Medline, Embase, Web of Science, CENTRAL, and CINAHL databases was undertaken for studies reporting clinical outcomes of patients with ibCRLM, up to May 2026. An individual patient data analysis approach was utilized. Results: Thirty-eight case reports and 10 case-series, incorporating 228 patients with biliary involvement from CRLM, were identified. Mean age was 62.4 ± 10.9 years, with a male-to-female ratio of 3.2:1. The majority of metastatic lesions were metachronous in 71.1% and solitary in 59.1% of patients. Surgical treatment was implemented in 89.2% of patients. Major hepatectomy was the most common procedure, being performed in 46.2% of patients, followed by minor hepatectomy in 38.7% and pancreatoduodenectomy in 4.3%. After a median follow-up of 52.5 months (range 2–164 months), the survival rate was 60.5%. Non-survivors were found to have significantly more synchronous CRLM (50% versus 0, p = 0.008), while a single patient did not receive any curative-intent treatment and died 20 days following CRLM presentation. Conclusions: IbCRLM is a distinct clinicopathological presentation of CRLM with characteristic radiological and pathological features. The available evidence suggests that selected patients may achieve favorable long-term outcomes following complete surgical resection, although these findings should be interpreted with caution given the limitations of the available literature. Full article

Background: In recent decades, the incidence of colorectal cancer (CRC) has been rising worldwide. CRC ranks second in cancer-related mortality. The identification of reliable biomarkers for early diagnosis and prognosis prediction, along with a deeper understanding of the underlying molecular events, holds substantial promise for improving patient outcomes. The tissue inhibitor of the metalloproteinase 1 (TIMP1) gene is overexpressed in various gastrointestinal malignancies and contributes to tumor progression. However, its role in regulating the CRC tumor immune microenvironment (TIME) and its potential as a clinically actionable prognostic biomarker remain unclear. Methods: To probe how TIMP1 acts as a prognosis-related candidate biomarker in colorectal carcinoma, TCGA-derived datasets were adopted to conduct Kaplan–Meier survival assessment. We also investigated the connection between the expression abundance of TIMP1 and the infiltration of immune populations and intratumoral lymphocytes; furthermore, immune checkpoint-related genes were systematically assessed across multiple tumor types via the TISIDB and TIMER2.0 platforms, with particular emphasis on CRC. We adopted the ESTIMATE scoring system to figure out how TIMP1 gene expression correlates with the phenotypic properties of the colorectal-cancer TIME. We relied on the limma toolkit for the screening of differential transcripts from high-TIMP1 and low-TIMP1 cohorts. Enrichment assessments covering Gene Ontology terms and Kyoto Encyclopedia of Genes and Genomes entries were then carried out to predict the potential biological pathways associated with TIMP1. We constructed the protein–protein interaction map for TIMP1-interacting partners via the STRING repository. To further explore TIMP1-correlated genes, we performed Venn diagram intersection analysis combined with Spearman’s correlation test. Finally, quantitative reverse-transcription PCR was then implemented to detect TIMP1 messenger-RNA abundance inside the RKO colorectal carcinoma cell line as well as normal colonic epithelial CCD-18Co cells, which offered in vitro experimental verification for our bioinformatic outcomes. Results: According to outcome data, TIMP1 transcripts were markedly up-regulated in CRC specimens and cell lines relative to normal samples. Elevated TIMP1 expression served as a poor-prognosis indicator for overall survival (hazard ratio [HR] = 0.43, 95% confidence interval [CI] = 0.29–0.64, p < 0.001) and disease-specific survival (HR = 0.39, 95% CI = 0.22–0.68, p = 0.001) among colorectal-carcinoma patients. TIMP1-high and TIMP1-low groups exhibited notable differences in immune cell infiltration (CD8⁺ T, macrophage, mast, neutrophil, B, monocyte, dendritic, and CD4⁺ T cells). TIMP1 expression was also significantly correlated with tumor-infiltrating lymphocytes, key immune checkpoint genes (e.g., CD274 [PD-L1] and CTLA4), and immunomodulatory chemokines (e.g., CCL3 and CCL5). Twelve TIMP1-interacting DEGs were selected: COL5A1, FN1, PRG4, and a cluster of nine MMPs (MMP1/2/3/7/8/9/11/13/14), all of which showed significant positive correlations with TIMP1 (r = 0.31–0.63, all p < 0.001). Conclusions: TIMP1 expression correlates with features of the tumor immune microenvironment and extracellular matrix remodeling in CRC, suggesting that TIMP1 shows potential as a candidate biomarker. However, its potential as a therapeutic target warrants further experimental investigation. Full article

Cancer metastasis, characterized by the dissemination of malignant cells from the primary tumor to distant organs, remains the leading cause of cancer-related mortality in solid tumors. In colorectal cancer (CRC), increasing attention has been directed toward therapeutic strategies aimed at suppressing cancer cell migration and invasion rather than solely reducing tumor mass, giving rise to the concept of migrastatic therapies. In the present study, green-synthesized silver nanoparticles (AgNPs), previously obtained using aqueous extracts of Filipendula ulmaria (L.) Maxim. and Salvia verticillata L., were evaluated for their antimigratory and anti-inflammatory potential in human colorectal carcinoma HCT-116 cells. Treatment with AgNPs induced considerable perturbations in cellular redox homeostasis, as evidenced by increased intracellular reactive oxygen species (ROS), lipid peroxidation (LPO), glutathione (GSH), and nitric oxide (NO) levels. These redox alterations were accompanied by a significant inhibition of cancer cell migration, together with reduced expression of matrix metalloproteinases MMP-2 and MMP-9, key mediators of extracellular matrix remodeling associated with tumor progression. AgNP exposure was associated with activation of the cytoprotective transcription factor Nrf-2 and suppression of the pro-inflammatory NF-κB/COX-2 signaling axis, indicating coordinated modulation of redox-sensitive pathways linked to tumor cell motility and inflammatory responses. Collectively, these findings demonstrate that green-synthesized AgNPs derived from F. ulmaria and S. verticillata exert multi-level regulatory effects on redox balance, inflammatory signaling, and migration-associated molecular markers in colorectal cancer cells. This study supports their potential as promising migrastatic nanocarriers for further investigation in colorectal cancer research. Full article

Background/Objectives: Metastatic colorectal cancer (mCRC) remains difficult to treat, largely due to chemotherapy resistance. Mutations in TP53 impair apoptosis and are associated with poor response to irinotecan. This study aimed to determine whether targeting Survivin, a key inhibitor of apoptosis, and using the disulfiram-derived compound CuET could restore apoptotic signaling and improve irinotecan efficacy. Methods: Human CRC cell lines with varying TP53 status and murine tumor models were treated with irinotecan (or its active metabolite SN-38), the Survivin inhibitor YM-155, and CuET, alone or in combination. Cell viability, clonogenic survival, and apoptotic signaling were assessed using cytotoxicity assays, flow cytometry, confocal microscopy, and Western blotting. In vivo efficacy was evaluated in xenograft and syngeneic mouse models through tumor growth measurements and histological analyses. Results: Inhibition of Survivin with YM-155 enhanced irinotecan-induced cytotoxicity and promoted caspase-dependent apoptosis in CRC cells. Irinotecan treatment induced Survivin expression, suggesting an adaptive resistance mechanism that was reversed by YM-155. CuET demonstrated potent cytotoxic activity independent of TP53 status and partially suppressed Survivin expression. Importantly, CuET restored sensitivity to irinotecan in TP53-deficient models and significantly enhanced antitumor efficacy in vivo, leading to reduced tumor growth, decreased proliferation, and increased apoptosis. Conclusions: These findings identify Survivin-mediated apoptotic resistance as a key determinant of irinotecan response in CRC. Targeting this pathway, either directly through Survivin inhibition or through CuET-induced stress responses, restores apoptotic sensitivity and enhances chemotherapy efficacy. This study supports the development of combination strategies incorporating CuET to overcome resistance in TP53-mutant CRC. Full article

The present study investigated the anticancer effects of irinotecan (IR) combined with the acid ceramidase inhibitor Ceranib-2 in HT-29 human colorectal cancer cells. Cell viability was assessed using the MTT assay, apoptosis was evaluated by Annexin V flow cytometry, and morphological alterations were examined by fluorescence microscopy. Both irinotecan and Ceranib-2 significantly reduced cell viability in a dose-dependent manner. Notably, the combination treatment produced greater growth inhibition than either agent alone (p < 0.01). Morphological analysis revealed pronounced apoptotic features, including nuclear condensation, membrane blebbing, and cytoskeletal disruption, particularly in the combination-treated cells. Annexin V analysis further demonstrated that combined treatment markedly increased apoptotic cell populations compared with single-agent treatments (p < 0.01). These findings suggest that Ceranib-2 enhances the anticancer activity of irinotecan and that this combination may represent a promising therapeutic strategy for colorectal cancer. Full article

Background: Risk stratification after colorectal cancer surgery remains challenging. We evaluated whether a perioperative ratio combining immediate postoperative lactate with preoperative albumin is associated with in-hospital mortality after elective colorectal resection. Methods: In this single-center retrospective cohort, 282 patients underwent open elective colorectal resection. The perioperative lactate-to-albumin ratio (LAR) was calculated as arterial lactate (mmol/L) divided by serum albumin (g/dL), and discrimination was assessed by receiver operating characteristic (ROC) analysis with age-adjusted association by Firth’s penalized logistic regression and fixed-model bootstrap validation. Results: Seventeen patients (6.0%) died in hospital, and mortality rose across LAR tertiles (2.1%, 5.3%, and 10.6%; p = 0.014). LAR showed moderate discrimination (AUC 0.73; 95% CI 0.58–0.87; optimism-corrected AUC 0.78), with no evidence of better discrimination than lactate or albumin alone. At the Youden threshold of 0.555, sensitivity was 76.5% and specificity 61.1%. The age-adjusted Firth odds ratio was 1.19 per 0.1-unit increase (95% CI 1.09–1.29). Conclusions: The perioperative lactate-to-albumin ratio was associated with in-hospital mortality after age adjustment in this single-center cohort. Given the small number of deaths and absence of external validation, LAR should be regarded as a candidate marker requiring prospective multicenter validation before clinical application. Full article