Colorectal cancer liver metastasis (CRLM) is a leading cause of mortality, driven by poorly defined molecular interactions within the hepatic niche. Here, we identify a distinct population of pro-metastatic Early Growth Response 1 (Egr1)+ neutrophils that accumulate in the pre-metastatic liver. Mechanistically, we show that KIAA1199-high cancer cells secrete granulin-rich extracellular vesicles, which are internalized by hepatocytes. This uptake triggers a subset of functionally reprogrammed hepatocytes, characterized by a profound metabolic reprogramming and the suppression of peroxisome proliferator-activated receptor gamma (PPARγ) signaling, leading to increased secretion of Serum Amyloid A2 (SAA2). Hepatocyte-derived SAA2 subsequently activates Formyl Peptide Receptor 2 (FPR2) on neutrophils, stabilizing Egr1-driven transcriptional program via the PI3K-AKT pathway to enhance neutrophil survival and pro-angiogenic activity. These Egr1+ neutrophils co-localize with reprogrammed hepatocytes at the tumor-liver interface, where they promote vascular remodeling to facilitate metastatic colonization. Pharmacological restoration of PPARγ or FPR2 inhibition abrogate CRLM in preclinical models in female mice. Furthermore, a combined KIAA1199-SAA2 signature predicts liver metastasis risk in patients. Our findings delineate a KIAA1199-PPARγ/SAA2-Egr1 axis orchestrating the pre-metastatic niche and propose metabolic normalization as a preventative strategy for liver metastasis.

ASO Visual Abstract: The Effect of Pathological Response to Preoperative Therapy on Margin Status and Outcomes After Resection of Colorectal Liver Metastases.

Liver transplantation (LT) for unresectable colorectal liver metastases (CRLM) has regained interest after the TransMet trial, which reported 5-year survival exceeding 70%. However, estimates of transplant benefit (TB) are lacking. This study provides a first external validity assessment of the TransMet criteria and estimates the 5-year TB using a real-world international cohort. A retrospective multicenter study included 61 TransMet-eligible patients with unresectable CRLM who underwent LT between 2006 and 2020 across seven centers. Matching-adjusted indirect comparisons (MAICs) were used to improve comparability, with sensitivity analyses on effective sample size (ESS). Survival was analyzed using Kaplan-Meier curves and restricted mean survival time (RMST) up to 5 years. Weighted multivariable Cox regressions were employed to assess prognostic factors after transplantation. The 5-year RMST was identical in the weighted cohort (ESS=19) and the TransMet LT arm (51.0mo). Sensitivity analysis yielded 5-year RMST consistent with residual imbalance (48.2mo, ESS=35). KRAS mutation (HR 5.90, 95%CI:1.89-18.4), right-sided primary tumor (HR 4.17, 95%CI:1.40-12.4), and female sex (HR 5.73, 95%CI:1.04-31.6) were associated with poorer survival; CEA>=80ng/mL emerged as a potential prognostic factor (HR 6.3, 95%CI:1.73-22.6) across alternative specifications. The estimated 5-year TB of LT versus chemotherapy was 22.5 months (95% CI:15.5-29.6). The findings of this first real-world assessment of the TransMet trial criteria and 5-year TB estimation in unresectable CRLM point to reasonable prognostic candidates and support evaluating the inclusion of CRLM in LT allocation models. We advocate expanded multicenter data to reach sufficient prognostic stratification through well-calibrated, highly discriminative studies.

To assess the proportion of unresectable colorectal liver metastasis (CRLM) patients meeting liver transplant (LT) criteria and define their outcomes following hepatic artery infusion pump (HAIP) chemotherapy. The TransMet RCT demonstrates improved survival with combined LT and systemic versus systemic therapy alone; however, systemic therapy might not be the best control. This study assesses outcomes in similarly selected patients treated with HAIP. We identified unresectable CRLM patients treated with HAIP between 2006-2016. Modified TransMet/SECA-II selection criteria were applied, including pre-treatment with at least 1st line chemotherapy before HAIP placement. Overall survival (OS) and progression-free survival (PFS) were estimated using Kaplan-Meier methods from HAIP placement. Of 483 patients identified, 23 (4.8%) were LT-eligible. Median age was 52 years (range:37,73). Primary tumors were right-sided in 6 (23%) and rectal in 12 (52%). Eight (38%) patients were KRASmut. Median CRLM size and number were 28mm (range:9,92) and 11 (range:4,38). Median pre-HAIP chemotherapy cycles were 8 (range:3,20), and most patients were on 1st (15,65%) or 2nd (7,30%) line therapy. Conversion to resection occurred in 18 (78%) patients after a median of 5 (range:1,20) HAIP chemotherapy cycles. With a median follow-up time of 98 (95%CI:96,NR) months, median OS was 61 (95%CI:36,92) months, and 5-year OS was 53% (95%CI:36,79). Median PFS was 13 (95%CI:10,22) months. In this cohort, less than 5% of unresectable CRLM patients were LT-eligible. After treatment with HAIP chemotherapy, overall 5-year survival was 53%, similar to a recent LT randomized trial (5-year OS 57%).

The involvement of intestinal microbiota in the process of neutrophil-mediated colorectal cancer liver metastasis (CRCLM) is not yet fully understood. Here, we show that Escherichia coli (E. coli) is prevalent in CRC tissues with LM using 2bRAD-M-Seq and is linked to the release of neutrophil extracellular traps (NETs). Utilizing multi-omics and molecular techniques, we establish that E. coli recruits RIPK2, which promotes the binding of HNRNPK to the Atf3/Relb promoters in neutrophils, thereby enhancing their transcription. This process results in the upregulation of Ncf4, which triggers p-MLKL-mediated NET formation. NETs, in turn, increase the expression of TRPC1 and NFATC3 in CRC cells, promoting the calcium-dependent assembly of the STAT3/S100A8/9 heterotrimer. This trimer stabilizes STAT3-enhancer-promoter loops (EPLs), thereby reinforcing the Tns1 transcription and facilitating CRCLM. Our findings elucidate the mechanism by which E. coli-induced NETs promote CRCLM through epigenetic modifications, offering an insight into the role of EPLs in immune regulation and tumor progression.

KLF7 as a biomarker for the pre-metastatic state promotes colorectal cancer liver metastasis via TGFβ autocrine signaling.

Targeting colorectal cancer liver metastasis through repurposing metabolic and immune inhibitors: A theoretical study.

Hepatic Artery Infusion Pump Therapy in Unresectable and Resectable Liver Tumors.

Hepatic artery infusion (HAI) chemotherapy improves hepatic recurrence rates and survival for patients with colorectal liver metastases (CRLM) in the adjuvant setting. Dose reductions of HAI floxuridine (FUDR) are common due to hepatotoxicity. The impact of these dose adjustments on patient outcomes is unclear. This study retrospectively analyzed patients who underwent adjuvant HAI pump placement for CRLM between January 2000 and October 2017. The study enrolled only patients intended to receive six cycles of FUDR. Hepatic recurrence and overall survival (OS) were correlated with the number of FUDR cycles and dose density, defined as the actual FUDR dose received divided by the expected total during six cycles. The study identified 344 patients who met the inclusion criteria. Of these 344 patients, 173 received up to four cycles of FUDR and 171 received > 4 cycles. The median dose density was 0.42 (range, 0.17-1.13). Competing risk analysis of the two groups showed no difference in risk for liver recurrence (p = 0.357). Neither the cycles of FUDR received (hazard ratio [HR], 0.93; p = 0.237) nor the FUDR dose density (HR, 1.26; p = 0.631) was associated with hepatic recurrence in the univariable analysis. Dose density was not associated with improved OS (HR, 1.35; p = 0.486), although in the multivariable analysis, increased FUDR cycles were associated with improved OS (HR, 0.86; p = 0.005). In adjuvant HAI therapy for CRLM, neither the number of FUDR cycles nor the dose density of FUDR is associated with hepatic recurrence.

Ketogenic diet impairs NK cell cytotoxic function in colorectal cancer liver metastasis by inducing ferroptosis via suppression of the p62-Keap1-Nrf2 pathway.

EphA2-targeted NIR-I/II fluorescent probe for specific imaging of colorectal cancer.

ASO Visual Abstract: Worse Survival in Co-altered RAS-TP53 Patients with Resected Colorectal Liver Metastases.

The liver is the most common site of metastases from colorectal cancer (CRC), affecting up to half of patients throughout their disease course. Although contrast-enhanced computed tomography (CECT) is routinely used for staging and treatment monitoring, RECIST criteria poorly reflect biological heterogeneity and antiangiogenic therapy effects. Integrating radiological and radiomic biomarkers may enhance response evaluation and personalized treatment. This study aimed to evaluate portal-phase ring enhancement as a potential imaging biomarker of disease progression and prognosis in patients with colorectal liver metastases (CRLM) treated with bevacizumab-based chemotherapy and to explore its correlation with CT-derived radiomic features. Eighty consecutive patients with histologically confirmed CRLM treated with standard chemotherapy plus bevacizumab were retrospectively analyzed. Baseline and 3-month CECT scans were evaluated for the presence and evolution of portal-phase ring enhancement. Radiomic features were extracted and correlated with morphologic patterns, while survival outcomes were assessed using Kaplan-Meier and logistic regression analyses. Baseline portal-phase ring enhancement was observed in 32.5% of patients and was significantly associated with inferior overall survival (p = 0.001), a finding confirmed on follow-up imaging (p = 0.016). Among radiomic features, sphericity showed the strongest correlation with ring enhancement (p = 0.003), yielding a modestly discriminative model. Portal-phase ring enhancement represents a reproducible imaging biomarker of poor prognosis in bevacizumab-treated CRLM. Its correlation with distinct radiomic signatures reinforces its biological plausibility as a marker of tumor aggressiveness. Integrating this feature with shape-based metrics into early imaging evaluation may refine risk stratification and personalized management.

Cancer-associated fibroblasts (CAFs) transdifferentiated from hepatic stellate cells (HSCs) are a critical determinant of liver metastasis of colorectal cancer (CRC). However, the mechanisms behind transforming growth factor β (TGF-β)-stimulated activation of HSCs into CAFs remain poorly understood. Immunoprecipitation coupled with mass spectrometry identified tuftelin 1 (TUFT1) as a novel TGF-β receptor II (TβRII) binding protein in primary human HSCs and immortalized LX2 cells. TUFT1 interacts with TβRII via its fragments (amino acids 1-86, 87-157), protecting TβRII from lysosomal degradation to facilitate TGF-β signaling and myofibroblastic activation of HSCs. Mechanistically, TUFT1 competes with caveolin-1 for TβRII binding, retrieving TβRII from the lipid rafts/caveolae-mediated degradation pathway and sorting it into the endosome-mediated trafficking and signaling pathway. Clinically, TUFT1 expression was confirmed in the CAFs of patient-derived colorectal cancer liver metastasis (CRCLM) tissues. Both protein and transcript analyses revealed higher TUFT1 expression in the CAFs of CRCLM than in HSCs. Furthermore, bulk RNA sequencing indicated that knocking down TUFT1 altered the TGF-β transcriptome of HSCs and suppressed HSC expression of tumor-promoting factors. In HSC/CRC co-implantation and portal vein tumor injection mouse models, targeting TUFT1 of HSCs inhibited HSC activation and restricted CRC growth in both subcutaneous and hepatic sites. Taken together, our findings uncover the novel function of TUFT1 in the hepatic tumor microenvironment, highlighting its role as a critical regulator of HSC activation and the pro-metastatic hepatic niche via promoting TβRII protein stability. Targeting TUFT1 in HSCs presents a promising therapeutic approach for combating CRCLM.

Introduction: Operative time is commonly used as a surrogate marker for operative difficulty in liver resection, but the contribution of other intraoperative factors is less understood. This study aimed to develop an objective, composite score to assess operative difficulty and evaluate its association with postoperative and oncological outcomes in liver surgery. Methods: A retrospective cohort study was conducted on patients who underwent liver resection for malignant disease between 1999 and 2023 at an Australian tertiary hospital, using a prospectively maintained database. Principal component analysis (PCA) was applied to operative time, estimated blood loss, total time of hepatic inflow occlusion and the number of packed red bloods transfused intraoperatively to derive a composite operative difficulty score. Patients were then stratified into low, moderate and high difficult groups using Gaussian mixture models (GMM). Comparison of textbook oncological outcomes (TOO) achievement and futile resection rates were assessed using Chi-squared analysis. Kaplan-Meier analysis was used to assess recurrence-free and overall survival in subgroup analysis. Results: Of 729 patients, 699 met the inclusion criteria. GMM identified three distinct operative difficulty groups: low (n = 540), moderate (n = 143), and high (n = 16). TOO and non-futile resection rates declined with increasing difficulty: 77% and 58% (low), 47% and 52% (moderate), and 6% and 19% (high), respectively (p < 0.001, p = 0.004 respectively). Among patients with cholangiocarcinoma, median overall survival was inversely correlated with operative difficulty (40 months low, 16 months moderate, 7 months high, p = 0.004). In patients with colorectal liver metastases, there was a trend towards worse overall survival and disease-free survival with increasing operative difficulty, however, this did not reach statistical significance. Conclusions: An objective intraoperative difficulty score was developed and demonstrated a significant inverse association with both quality and oncological outcomes. While external validation is required, these findings support the potential of operative difficulty assessment to enhance perioperative decision-making, inform patient counselling, and optimise postoperative care planning.

BackgroundPrevious studies of minimally invasive liver surgery described results and experiences in high-volume centres and early adopters, but data on national levels are lacking. This study evaluated the implementation and outcomes of minimally invasive liver surgery in Sweden over a 15-year period, with a focus on colorectal liver metastases.MethodsData from patients undergoing liver surgery between 2009 and 2023 were obtained from the Swedish National Quality Registry for Liver, Gallbladder and Bile Duct Cancer, and evaluated in time intervals. Propensity score matching analysis was used to compare outcomes between open and minimally invasive liver surgery for colorectal liver metastases.ResultsA total of 9977 procedures were included in the study, of which 1490 (14.9%) were minimally invasive. Minimally invasive liver surgery was used increasingly over time, and had better short-term outcomes than open liver operations, including less blood loss (median 200 (interquartile range 50–400) versus 500 (250–1000) ml; P < 0.001), fewer major complications (127 (9.3%) versus 1697 (21.9%); P < 0.001), and a lower 30-day mortality rate (6 patients (0.4%) versus 107 (1.3%); P = 0.004). Use of robotically assisted liver surgery increased over time and it constituted 311 minimally invasive liver procedures (38.4%) in the late time period. Propensity score matching analysis for patients with colorectal liver metastases showed reduced blood loss with minimally invasive liver surgery (P < 0.001), a similar rate of radical resections, and similar overall survival.ConclusionThe study demonstrated safe nationwide implementation of minimally invasive liver surgery. Use of the minimally invasive approach increased over time, including a rapid rise for robotically assisted procedures in the later period. Minimally invasive liver surgery maintained or improved favourable short-term outcomes without adverse effects on morbidity, mortality or long-term survival after surgery for colorectal liver metastases.

BackgroundThe incidence of colorectal cancer is increasing, and the liver remains the predominant site for metastases. Whereas liver resection is the standard treatment for colorectal liver metastases (CRLMs), liver transplantation (LT) has re-emerged as a viable option for selected patients. The aim of this study was to investigate whether tumour volume and changes in tumour volume during chemotherapy before transplantation predict overall survival.MethodsPatients who underwent LT for CRLMs between November 2006 and August 2020 were included. Tumour volumes were measured via manual segmentation on computerized tomography scans at baseline, at maximum tumour volume, and immediately before LT. Response to chemotherapy was assessed using Response Evaluation Criteria in Solid Tumours (RECIST) criteria, and the heterogeneous response was noted to investigate whether this subgroup performs differently. Receiver operating characteristic analysis was conducted to determine a tumour volume cut-off value for predicting overall survival. Overall survival between groups was compared using Kaplan–Meier curves and log rank test.ResultsFifty-nine patients who underwent LT for CRLMs were analysed retrospectively. Receiver operating characteristic analysis revealed that final tumour volume at time of LT was a strong predictor of 5-year overall survival (area under the curve= 0.789), with a 35 mL cut-off providing optimal clinical discrimination. Patients achieving a final tumour volume below 35 mL, either consistently or via downstaging, demonstrated significantly improved survival compared with those with persistently high tumour volumes (4.54 years versus 2.17 years; P < 0.001). Heterogeneous responses to chemotherapy were associated with poorer prognosis with no patients surviving beyond 2.16 years (P < 0.001).ConclusionDynamic tumour assessment, particularly measuring tumour volume to below 35 mL, is an important prognostic marker in LT for CRLMs.

IntroductionColorectal cancer frequently leads to liver metastases (CRLM), posing a major challenge to long-term survival. Prognosis remains heterogeneous, and traditional clinical risk scores often lack biological depth and spatial information. Advances in radiomics and machine learning (ML) offer the potential for improved, explainable outcome prediction; however, robust and interpretable prognostic models for CRLM remain an unmet need. This study aimed to develop and validate explainable ML models based on radiomic features extracted from both metastatic lesions and background liver tissue, enhancing the prediction of recurrence and overall survival (OS) status in patients with CRLM.Materials and methodsPatient data and contrast-enhanced CT images from two independent cohorts were analysed: a publicly available TCIA-CRLM series, employed as the discovery set, and a real-life clinical cohort, used as an external validation set. Segmentation focused on the largest liver metastasis (L-MAX) and surrounding healthy liver tissue (L-BKG), extracting radiomic features from both areas and their ratios (L-MAX/L-BKG). An end-to-end pipeline for data preprocessing and classification was designed. Multiple ML and Deep Learning (DL) classifiers were trained and validated. Model interpretability was assessed using SHapley Additive exPlanations (SHAP) analysis to identify key predictive radiomic determinants. Performances were compared to recognized clinical models.ResultsFor recurrence prediction, the best-performing classifier was a soft-voting ensemble of a multilayer perceptron (MLP) optimized via a Genetic Algorithm (GA); for OS status classification, the best performance was obtained by a hard-voting ensemble of a GA-optimized MLP. Both classifiers demonstrated robust discrimination capabilities in external validation, with AUCs of 0.78 and 0.68, respectively. The explainability analysis performed with SHAP revealed the most relevant radiomic determinants in the classification. These features retained prognostic significance in the independent cohort, supporting their use for clinical risk stratification.DiscussionExplainable ML models leveraging both lesion-centric and contextual liver radiomics offer clinically transparent prediction of recurrence and survival in CRLM. SHAP highlighted clinically plausible, reproducible imaging determinants, enabling risk stratification. The validation of specific radiomic determinants suggests the potential practical utility of this approach, laying out the groundwork for integrating with DL and multi-omic data in future oncology strategies.

Major hepatectomy (MH) has traditionally been associated with higher R0 rates in colorectal liver metastases (CRLM), but at the cost of increased morbidity. Parenchymal-sparing hepatectomy (PSH) has emerged as an alternative approach aimed at reducing perioperative complications while preserving functional liver parenchyma without compromising oncological outcomes. We retrospectively analyzed 248 consecutive patients undergoing liver resection for CRLM between 2016 and 2025, classified as PSH (n = 215, 86.7%) or MH (n = 33, 13.3%). MH was performed more frequently in patients with greater tumor burden, including larger lesions, more numerous metastases, and bilobar disease (all p < 0.001). PSH was associated with shorter hospital stay, fewer postoperative complications, and lower 30-day readmission rate. In multivariable Cox analyses, surgical strategy was not associated with recurrence-free survival or overall survival, which were primarily driven by tumor burden. Among patients who developed liver recurrence, repeat hepatectomy was more often feasible after PSH than MH (p = 0.026), emphasizing the long-term value of preserving functional parenchyma. Overall, PSH was associated with lower postoperative morbidity, enabling earlier recovery, while facilitating future liver resections when needed in this chronically evolving disease.

Background: Preoperative chemotherapy is increasingly used for colorectal liver metastases (CRLM), but simple risk stratification tools for routine practice remain limited. We developed a simple risk model to predict outcomes after curative-intent CRLM resection, including in patients receiving preoperative chemotherapy. Methods: We retrospectively analyzed 115 patients who underwent initial curative-intent liver resection for CRLM at two centers. Factors associated with recurrence-free survival (RFS) and overall survival (OS) were evaluated using Cox proportional hazards models and log-rank tests. Model performance was benchmarked against the Beppu nomogram and Fong's clinical risk score using the area under the curve (AUC). Outcomes were also assessed based on response to preoperative chemotherapy. Results: Having ≥3 CRLMs was the only independent predictor common to both OS and RFS. Among patients with 1-2 CRLMs, the largest tumor diameter being ≥5 cm independently predicted RFS. A composite high-risk definition (≥3 CRLMs, or 1-2 CRLMs with a diameter ≥ 5 cm) independently predicted recurrence (HR 2.05, p = 0.007) and overall mortality (HR 2.24, p = 0.017). The AUCs were similar to the Beppu nomogram for recurrence (0.68 vs. 0.70 (p = 0.683) at 36 months, 0.66 vs. 0.68 (p = 0.766) at 60 months) and to Fong's score for survival (0.59 vs. 0.64 (p = 0.430) at 36 months, 0.65 vs. 0.74 (p = 0.074) at 60 months). Among patients receiving preoperative chemotherapy (n = 72), high-risk status was associated with poorer RFS (HR 3.11, p < 0.001) and OS (HR 2.80, p = 0.010). Within this subgroup, progressive disease (PD) was associated with worse outcomes than disease control (CR/PR/SD). Conclusions: This two-variable, rule-based model provides an easy-to-use tool for postoperative risk stratification after CRLM resection, and incorporating chemotherapy response may further refine prognostication.