Colorectal Cancer Liver Metastases Patients Research Articles

Clinical significance of ribosomal protein S15 expression in patients with colorectal cancer liver metastases.

Liver metastasis is the most frequently observed distant metastasis of colorectal cancer, and the residual liver recurrence rate after hepatic resection is still high. To explore the mechanism of liver metastasis to discover potential new treatments, we assessed the relationship between the expression of differentially expressed genes (DEGs) and prognosis in patients with colorectal cancer liver metastasis (CRLM). The gene expression dataset was extracted from The Cancer Genome Atlas and the Gene Expression Omnibus. Significance analysis of DEGs between tumor and normal samples of colorectum, liver, and lung was conducted. A total of 80 CRLM patients were studied to assess the expression of RPS15, characteristics, and outcomes. We examined the relationships of RPS15 expression to cell viability and apoptosis invitro and vivo. Significance analysis identified 33 DEGs. In our cohorts, the overall survival rates were significantly lower in the high-RPS15-expression group, and high expression of RPS15 was an independent and unfavorable prognostic factor in recurrence-free survival and overall survival. Knockdown of RPS15 expression reduced the proliferative capacity of colorectal cancer cells and increased BAX-induced apoptotic cell death. RPS15 expression is an independent prognostic factor for CRLM patients and might be a novel therapeutic target for CRLM.

New insights into macrophage polarization and its prognostic role in patients with colorectal cancer liver metastasis

BackgroundAs liver metastasis is the most common cause of mortality in patients with colorectal cancer, studying colorectal cancer liver metastasis (CLM) microenvironment is essential for improved understanding of tumor biology and to identify novel therapeutic targets.MethodsWe used a multiplex immunofluorescence platform to study tumor associated macrophage (TAM) polarization and adaptive T cell subtypes in tumor samples from 105 CLM patients (49 without and 56 with preoperative chemotherapy).ResultsCLM exhibited M2 macrophage polarization, and helper T cells were the prevalent adaptive T cell subtype. The density of total, M2 and TGFβ-expressing macrophages, and regulatory T cells was lower in CLM treated with preoperative chemotherapy. CLM with right-sided primary demonstrated enrichment of TGFβ-expressing macrophages, and with left-sided primary had higher densities of helper and cytotoxic T cells. In multivariate analysis, high density of M2 macrophages correlated with longer recurrence-free survival (RFS) in the entire cohort [hazard ratio (HR) 0.425, 95% CI 0.219–0.825, p = 0.011) and in patients without preoperative chemotherapy (HR 0.45, 95% CI 0.221–0.932, p = 0.032). High pSMAD3-expressing macrophages were associated with shorter RFS in CLM after preoperative chemotherapy.ConclusionsOur results highlight the significance of a multi-marker approach to define the macrophage subtypes and identify M2 macrophages as a predictor of favorable prognosis in CLM.

Abstract 925: Continuing anti-EGFR treatment prolonged survival in mCRC patients receiving conversion liver resection

Abstract Introduction: Anti-EGFR monoclonal antibody plus doublet chemotherapy is the mainstay of first-line treatment of RAS/BRAF wild-type metastatic colorectal cancer (mCRC) patients. Some of these patients might undergo secondary resection. However, there is no standardized suggestion on whether colorectal cancer liver metastasis patients should keep target therapy after secondary resection. NCCN guidelines suggest chemotherapy only in patients receiving primary liver resection. Whether we could spare the use of target therapy after secondary resection is the main aim of our study. Methods: Using Taiwan's National Health Insurance Research Database, we established a cohort of KRAS wild-type mCRC patients treated with first-line anti-EGFR therapy plus doublet chemotherapy between 2013 and 2018. Secondary surgery was defined as either resection of liver metastases or radiofrequency ablation. Results: 5694 stage IV mCRC patients received anti-EGFR MAb plus doublet chemotherapy as a first-line treatment between 2013 and 2018. 174 patients were enrolled in the final analysis, with 153 continuing anti-EGFR MAb after secondary resection and 21 patients without anti-EGFR MAb. Compared with those who without anti-EGFR therapy after secondary resection, patients who continued anti-EGFR MAb exhibited significantly longer overall survival (OS; median, 43.8 vs. 31.9 months, p = 0.031) but not in time to treatment failure (TTF; median, 22.2 vs. 26.6 months, p = 0.841). The OS benefits of continuing anti-EGFR MAb remained regardless of left-sided or right-sided primary tumors (40.9 vs. 43.0 months, p = 0.980). The patient cohort from 2016 to 2018 showed more prolonged survival than from 2012 to 2015 (not reached vs. 40.450, p = 0.0305). TTF has no statistical difference when considering patient cohort or primary tumor location. In multivariate analyses, continuing first-line anti-EGFR MAb therapy after secondary resection remained an independent predictor of longer OS. Conclusion: For mCRC patients who received secondary resection after first-line anti-EGFR and doublet chemotherapy, continuing anti-EGFR MAb after resection was associated with significantly longer OS regardless of primary tumor sidedness. Citation Format: Yao-Yu Hsieh, Chin-Wen Tsai, T-CARE Group, Yi-Hsieh Liang. Continuing anti-EGFR treatment prolonged survival in mCRC patients receiving conversion liver resection [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 925.

Use of tryptic peptide MALDI mass spectrometry imaging to identify the spatial proteomic landscape of colorectal cancer liver metastases.

Colorectal cancer (CRC) is the second leading cause of cancer-related deaths worldwide. CRC liver metastases (CRLM) are often resistant to conventional treatments, with high rates of recurrence. Therefore, it is crucial to identify biomarkers for CRLM patients that predict cancer progression. This study utilised matrix-assisted laser desorption/ionisation mass spectrometry imaging (MALDI-MSI) in combination with liquid chromatography-tandem mass spectrometry (LC-MS/MS) to spatially map the CRLM tumour proteome. CRLM tissue microarrays (TMAs) of 84 patients were analysed using tryptic peptide MALDI-MSI to spatially monitor peptide abundances across CRLM tissues. Abundance of peptides was compared between tumour vs stroma, male vs female and across three groups of patients based on overall survival (0-3 years, 4-6 years, and 7+ years). Peptides were then characterised and matched using LC-MS/MS. A total of 471 potential peptides were identified by MALDI-MSI. Our results show that two unidentified m/z values (1589.876 and 1092.727) had significantly higher intensities in tumours compared to stroma. Ten m/z values were identified to have correlation with biological sex. Survival analysis identified three peptides (Histone H4, Haemoglobin subunit alpha, and Inosine-5’-monophosphate dehydrogenase 2) and two unidentified m/z values (1305.840 and 1661.060) that were significantly higher in patients with shorter survival (0-3 years relative to 4-6 years and 7+ years). This is the first study using MALDI-MSI, combined with LC-MS/MS, on a large cohort of CRLM patients to identify the spatial proteome in this malignancy. Further, we identify several protein candidates that may be suitable for drug targeting or for future prognostic biomarker development.

Non-alcoholic fatty liver disease promotes liver metastasis of colorectal cancer via fatty acid synthase dependent EGFR palmitoylation

Liver metastasis is the major reason for most of colorectal cancer (CRC) related deaths. Accumulating evidence indicates that CRC patients with non-alcoholic fatty liver disease (NAFLD) are at a greater risk of developing liver metastasis. With the growing prevalence of NAFLD, a better understanding of the molecular mechanism in NAFLD-driven CRC liver metastasis is needed. In this study, we demonstrated that NAFLD facilitated CRC liver metastasis as a metabolic disorder and promoted the stemness of metastatic CRC cells for their colonization and outgrowth in hepatic niches. Metabolically, the lipid-rich microenvironment in NAFLD activated de novo palmitate biosynthesis in metastatic CRC cells via upregulating fatty acid synthase (FASN). Moreover, increased intracellular palmitate bioavailability promoted EGFR palmitoylation to enhance its protein stability and plasma membrane localization. Furthermore, we demonstrated that the FDA-approved FASN inhibitor orlistat could reduce NAFLD-activated endogenous palmitate production, thus inhibiting palmitoylation of EGFR to suppress CRC cell stemness and restrict liver metastasis in synergy with conventional chemotherapy. These findings reveal that the NAFLD metabolic microenvironment boosts endogenous palmitate biosynthesis in metastatic CRC cells and promotes cell stemness via EGFR palmitoylation, and FASN inhibitor orlistat could be a candidate adjuvant drug to suppress liver metastasis in CRC patients with NAFLD.

Role of stromal PD-L1 expression in colorectal liver metastasis

Background and AimThe outcomes of immune checkpoint blockade for colorectal cancer (CRC) treatment are unsatisfactory. Furthermore, the efficacy of immune checkpoint blockade for liver metastasis of various cancer is poor. Here, we investigated the relationship between stromal programmed death-ligand 1 (PD-L1) expression and the prognosis of patients with colorectal cancer liver metastasis (CRLM).MethodsThe present study enrolled 84 CRLM patients who underwent surgery (R0) for CRC. Immunohistochemistry was performed to analyze stromal PD-L1 expression in CRLM.ResultsStromal PD-L1 was expressed in 52.3% of CRLM samples, which was associated with fewer not optimally resectable metastases (p = 0.04). Stromal PD-L1 also tended to associate with a lower tumor grade (p = 0.08). Stromal PD-L1-positive patients had longer overall survival (p = 0.003). Multivariate analysis identified stromal PD-L1 expression (p = 0.008) and poorer differentiation (p < 0.001) as independent prognostic indicators. Furthermore, stromal PD-L1 expression was correlated to a high number of tumor-infiltrating lymphocytes (TILs). Stromal PD-L1– and low TIL groups had shorter OS than stromal PD-L1 + and high TIL groups (46.6% vs. 81.8%, p = 0.05) Stromal PD-L1-positive patients had longer disease-free survival (DFS) (p = 0.03) and time to surgical failure (p = 0.001). Interestingly, stromal PD-L1 expression was positively related to the desmoplastic subtype (p = 0.0002) and inversely related to the replacement subtype of the histological growth pattern (p = 0.008).ConclusionsStromal PD-L1 expression may be a significant prognostic marker for CRLM.

Concomitant NAFLD Facilitates Liver Metastases and PD-1-Refractory by Recruiting MDSCs via CXCL5/CXCR2 in Colorectal Cancer

Background and AimsBoth Non-alcoholic fatty liver disease (NAFLD) and colorectal cancer (CRC) are prevalent worldwide. The effect of concomitant NAFLD on the risk of colorectal liver metastasis (CRLM) and its mechanisms have not been definitively elucidated. MethodsWe observed the effect of concomitant NAFLD on CRLM in the mouse model, and explored the underlying mechanisms of specific myeloid-derived suppressor cells (MDSCs) recruitment, then tested the therapeutic application based on the mechanisms; finally we validated our findings in the clinical samples. ResultsHere we prove that in different mouse models, NAFLD induces F4/80+ Kupffer cells to secret chemokine CXCL5, then recruits CXCR2+ myeloid-derived suppressor cells (MDSCs) to promote the growth of CRLM. CRLM with NAFLD background are refractory to the anti-PD-1 monoclonal antibody treatment, but when combined with Reparixin, an inhibitor of CXCR1/2, dual-therapy cures the established CRLM in mice with NAFLD. Our clinical studies also indicate that fatty liver diseases increase the infiltration of CXCR2+ MDSCs, as well as the hazard of liver metastases in CRC patients. ConclusionsCollectively, our findings highlight the significance of a selective CXCR2+/CD11b+/Gr-1+ subset myeloid cells in favoring the development of CRLM with NAFLD background, and identify a pharmaceutic medicine which is already available for the clinical trials and potential treatment.

Prognostic role of serum carcinoembryonic antigen in patients receiving liver resection for colorectal cancer liver metastasis: A meta-analysis.

Carcinoembryonic antigen (CEA) is a broad-spectrum tumor marker for differential diagnosis, monitoring, and response assessment of a variety of malignancies. To evaluate whether serum CEA could predict the prognosis in patients with colorectal cancer liver metastasis (CRCLM) before and after liver resection (LR). PubMed, Embase, Cochrane, and Web of Science were systematically searched to retrieve literature, with a search cut-off date of February 27, 2023. Articles were strictly screened for inclusion according to pre-specified inclusion and exclusion criteria. Data were pooled and analyzed using Stata 16.0. This meta-analysis included 36 studies involving a total of 11143 CRCLM patients. The results showed that a high pre-LR serum CEA level was correlated with poor overall survival (OS) [hazard ratio (HR) = 1.61, 95% confidence interval (CI): 1.49-1.75, P < 0.001] and recurrence-free survival (HR = 1.27, 95%CI: 1.11-1.45, P < 0.001) in CRCLM patients. A high post-LR serum CEA level predicted poor OS (HR = 2.66, 95%CI: 2.10-3.38, P < 0.001). A comparison by treatment modality, analysis modality, patient source, and cutoff-value showed that overall, high preoperative and postoperative serum CEA levels remained correlated with a poor prognosis. This study concluded that high pre-LR and post-LR serum CEA levels were significantly correlated with a poor prognosis in CRCLM patients.

Multilevel Heterogeneity of Colorectal Cancer Liver Metastasis.

Colorectal cancer liver metastasis (CRLM) is a highly heterogeneous disease. Therapies that target both primary foci and liver metastasis are severely lacking. Therefore, understanding the features of metastatic tumor cells in the liver is valuable for the overall control of CRLM patients. In this review, we summarize the heterogeneity exhibited in CRLM from five aspects (gene, transcriptome, protein, metabolism, and immunity). In addition to genetic heterogeneity, the other four aspects exhibit significant heterogeneity. Compared to primary CRC, the dysregulation of epithelial-mesenchymal transition (EMT)-related proteins, the enhanced metabolic activity, and the increased infiltration of immunosuppressive cells are detected in CRLM. Preclinical evidence shows that targeting the EMT process or enhancing cellular metabolism may represent a novel approach to increasing the therapeutic efficacy of CRLM.

Survival Evidence of Local Control for Colorectal Cancer Liver Metastases by Hepatectomy and/or Radiofrequency Ablation.

Hepatectomy and/or local ablation therapy have been recommended for colorectal cancer liver metastases (CRLM). However, they still lack strong evidence for their survival benefits, in addition to systemic therapy. This study aims to evaluate the survival evidence of hepatectomy and/or radiofrequency ablation (RFA) therapy in CRLM patients from a large multi-institutional database. A total of 20,251 patients with colorectal cancer, 4521 of whom were with CRLM, were screened for eligibility. Finally, 2612 patients (637 hepatectomy, 93 RFA, 92 combined hepatectomy and RFA, and 1790 non-aggressive treatment) were enrolled. Frequency matching analysis was used to adjust for baseline differences. The 5-year overall survival (OS) was as follows: hepatectomy alone was 47.8%, combined hepatectomy plus RFA was 35.9%, RFA alone was 29.2%, and the non-aggressive treatment group was 7.4%. Kaplan-Meier curves showed that hepatectomy, RFA, and combination were significantly associated with a better OS compared to those without aggressive local therapy (p < 0.001). Multivariate Cox regression analysis showed that male gender (hazard ratio (HR) 0.89; 95% confidence interval (CI), 0.81-0.97; p = 0.011), old age (≥60 years) (HR 1.20; 95% CI, 1.09-1.32; p < 0.001), high CEA level (>5 ng/mL) (HR 2.14; 95% CI, 1.89-2.42; p < 0.001), primary right-sided cancer (HR 1.35; 95% CI, 1.22-1.51; p < 0.001), extrahepatic metastasis (HR 1.46; 95% CI, 1.33-1.60; p < 0.001), systemic therapy (HR 0.7; 95% CI, 0.62-0.79; p < 0.001), and aggressive local therapy (hepatectomy vs. non-local therapy HR 0.22; 95% CI, 0.20-0.26; p < 0.001; RFA vs. non-local therapy HR 0.29; 95% CI, 0.29-0.41; p < 0.001) were independent factors associated with OS. In the frequency matching analysis, patients receiving hepatectomy and/or RFA resulted in a better OS than those without (p < 0.001). In conclusion, aggressive local treatment provides survival advantages over systemic therapy alone among CRLM patients.

Plasma Methylated SEPT9 as a Novel Biomarker for Predicting Liver Metastasis in Colorectal Cancer.

This study aimed to explore the role of plasma methylated SEPT9 (mSEPT9) in predicting liver metastasis (LM) in colorectal cancer (CRC) patients. The clinicopathological information of 115 consecutive CRC patients were collected. The differences of clinical characteristics and several biomarkers between CRC patients with LM and those with non-liver metastasis (NM) were analyzed. Multivariate logistic regression analysis was used to identify the risk factors for predicting LM in CRC patients. Receiver operating characteristic curve (ROC) analysis was applied to investigate the sensitivity and specificity of potential biomarkers in indicating the presence of LM in CRC. Compared with the CRC without LM, the levels of plasma mSEPT9 and carcinoembryonic antigen (CEA) were significantly increased in CRC with LM. Multivariate logistic regression analysis showed that plasma mSEPT9 was an independent risk factor for predicting LM in CRC. ROC curves showed that mSEPT9 and CEA could efficiently distinguish LM from NM in CRC. The area under the curve (AUC) of mSEPT9 was 0.850, which was slightly higher than that of CEA (0.842). The optimal cut-off value of mSEPT9 was 35.09 with a sensitivity of 81.82% and a specificity of 73.33%, both similar with that of CEA (sensitivity 87.27% and specificity 75.00%). In addition, the combination of mSEPT9 and CEA had a higher specificity than CEA alone (81.70% Vs 75.00%). Our findings suggest, for the first time, that plasma mSEPT9 might serve as a potential biomarker to predict LM in CRC, which deserves further in-depth study.

The Short-term Efficacy of Contrast-enhanced Ultrasound (CEUS) and Gd-EOB-DTPA-enhanced Magnetic Resonance Imaging (MRI) Fusion Imaging-guided Radiofrequency Ablation (RFA) for Colorectal Liver Metastasis (CRLM).

This study is to explore the efficacy of contrast-enhanced ultrasound (CEUS) / Gd-EOB-DTPA-enhanced magnetic resonance imaging (MRI) fusion imaging-guided（fusion group）radiofrequency ablation (RFA) versus conventional ultrasound imaging-guided (conventional group) RFA for colorectal cancer liver metastases (CRLM) in a short-term. From December 2020 to December 2021, patients who underwent imaging-guided RFA of CRLM at our hospital with available CT/MRI images were enrolled consecutively. 22 patients with 46 lesions had undergone conventional group RFA whereas 29 patients with 63 lesions had undergone fusion group RFA. The lesion detection rate, technical success, local tumor progression (LTP) and complications were calculated. In this retrospective study, 51 patients with 130 lesions were diagnosed with CRLM. However, there were 12 lesions and 9 lesions invisible in the conventional group and fusion group, respectively. The lesion detection rate on the fusion imaging was significantly higher than on the US or CEUS in the fusion group (P＜0.05). There were no significant differences of the detection rate between the conventional group and the fusion group (P=0.207). In both groups, the technical success rate was 100%. For local tumor progression (LTP), there were no significant differences between the two groups (P＞0.05). The complications after ablation had no significant differences between the two groups (P=0.97). CEUS/ Gd-EOB-DTPA-enhanced MRI fusion imaging is a safe and effective method for RFA in the management of CRLM patients, and it may improve the therapeutic effect by detecting small lesions early.

Adjuvant systemic chemotherapy with or without hepatic arterial infusion of floxuridine in patients following colorectal cancer liver metastases resection (HARVEST): A prospective, randomized controlled trial.

3516 Background: Several retrospective studies have previously demonstrated that a combination of adjuvant systemic chemotherapy and hepatic arterial infusion (HAI) could benefit patients following colorectal cancer liver metastases (CRLM) resection. This prospective clinical study aimed to determine whether adding HAI to adjuvant systemic chemotherapy could reduce the risk of recurrence following CRLM resection. Methods: The HARVEST study is an investigator-initiated, prospective, randomized controlled trial investigating the efficacy and safety of adjuvant intravenous chemotherapy with or without HAI floxuridine (FUDR) in CRLM patients that underwent liver metastasectomy. Patients in the systemic chemotherapy plus HAIC arm (HAI group) received systemic FOLFOX (q2w) plus HAI (FUDR, d1-14, q4w) for up to 6 months, while the systemic chemotherapy group without HAI (non-HAI group) received intravenous FOLFOX only. The primary study endpoint is the relapse-free survival in the modified intention-to-treat (mITT) population. Blood samples at different time points were also collected and circulating tumor DNA (ctDNA) was tested for NPY and SEPT9 methylation. Results: The study was prematurely terminated due to FUDR production halt in China. Ninety-two patients were randomized and seventy-seven patients (38 in the HAI group and 39 in the non-HAI group) were eventually included in our mITT analysis. After a median follow-up of 35.8 months, there were 22 (57.9%) and 25 (64.1%) recurrences in the HAI and non-HAI groups, respectively. The median relapse-free survival was 20.0 months in the HAI group and 11.7 months in the non-HAI group (p = 0.14; HR 0.65; 95% confidence interval [CI] 0.37 to 1.16). No significant difference was found in terms of overall survival between the two groups (p = 0.461). Our subgroup analysis revealed that patients with multiple liver metastases (p &lt; 0.01) and RAS/BRAF mutation (p &lt; 0.01) could benefit from adjuvant HAI treatment. Based on ctDNA status, patients with positive postoperative ctDNA methylation benefited from adjuvant HAI treatment (p &lt; 0.01), while those with negative postoperative ctDNA methylation status (p = 0.95) did not. Chemotherapy-related adverse events were comparable between the two groups. Conclusions: Adjuvant chemotherapy intensification using HAI did not significantly reduce recurrence following CRLM resection. However, patients with multiple liver metastases, RAS/BRAF mutation and those with positive postoperative ctDNA might benefit from adjuvant HAI treatment. Clinical trial information: NCT03500874 .

Development and validation of a nomogram to predict which patients with colorectal cancer liver metastases would benefit from primary tumor resection.

The use of primary tumor resection (PTR) in the treatment of colorectal cancer liver metastases (CRLM) patients has become increasingly controversial. Our goal is to establish a nomogram to screen for the candidates that would benefit from PTR in CRLM patients. The Surveillance, Epidemiology, and End Results (SEER) database was searched for 8366 patients with colorectal liver cancer metastases (CRLM) from 2010 to 2015. Overall survival (OS) rates were calculated using the Kaplan-Meier curve. After propensity score matching (PSM), predictors were analyzed by logistic regression analysis, and a nomogram was created to predict for survival benefit of PTR using R software. After PSM, there were 814 patients in both PTR group and non-PTR group, respectively. The median OS time in the PTR group was 26months (95%CI = 23.33 ~ 28.67) and the median OS time in the non-PTR group was 15months (95%CI = 13.36 ~ 16.64). The Cox regression analysis found that PTR was an independent predictive factor (HR = 0.46, 0.41 ~ 0.52) for OS. Additionally, logistic regression was used to study the factors impacting PTR benefit, and the results showed that CEA (P = 0.016), chemotherapy (P < 0.001), N stage (P < 0.001), histological grade (P < 0.001), and lung metastasis (P = 0.001) are independent predictive factors affecting the therapeutic outcome of PTR in patients with CRLM. The developed nomogram displayed good discriminative ability in predicting the beneficial probability of PTR surgery, with the area under the curve (AUC) values of 0.801 in training set and 0.739 in validation set respectively. We developed a nomogram that predicts the survival benefits of PTR in CRLM patients with relatively high accuracy, and quantifies the predictive factors for PTR-related benefits.

CtDNA as a prognostic biomarker in resectable CLM: Systematic review and meta-analysis.

Cell-free circulating tumor DNA (ctDNA) is synthesized by tumor cells, including metastatic tumors, and circulates in the bloodstream. Evidence suggests that ctDNA is a potential predictive and prognostic biomarker for colorectal cancer (CRC), but its predictive efficacy in detecting CRC liver metastasis (CLM) remains unclear. Additionally, its utility in the clinical setting needs further investigation. We conducted a meta-analysis to determine the utility of ctDNA as a biomarker for predicting the prognosis of CLM and investigate the relationship between CLM and ctDNA positivity. A literature search was performed in electronic databases to identify relevant studies published up to March 19, 2022. We retrieved data on overall survival (OS), disease-free survival (DFS), and recurrence-free survival (RFS) for both ctDNA-positive and ctDNA-negative colorectal liver metastasis (CLM) patients from the selected articles. Hazard ratios (HRs) were also calculated for these survival outcomes analysis was also performed. The stability of the combined meta-analysis was verified by sensitivity analysis and publication bias evaluation. Ten trials were included, and 615 patients were evaluated. In patients with CLM, pooled HRs revealed a substantial link between ctDNA positivity and RFS/DFS. Subgroup analysis revealed that ctDNA had a prospective detection value. Sensitivity analysis and publication bias evaluation indicated stable results. Although the results on pooled HR for OS suggested that ctDNA-positive patients had a shorter survival time, their pooled HRs had a relatively evident heterogeneity, and sensitivity analysis and publication bias evaluation indicated that pooled HRs were extremely unstable. In conclusion, our results demonstrate that ctDNA appears to be a prognostic biomarker for resectable CLM patients.

An elevated preoperative cholesterol-to-lymphocyte ratio predicts unfavourable outcomes in colorectal cancer liver metastasis patients receiving simultaneous resections: a retrospective study

BackgroundTo explore the clinical prognostic utility of the preoperative cholesterol-to-lymphocyte ratio (CLR) in outcomes for colorectal cancer liver metastasis (CRLM) patients receiving simultaneous resection of the primary lesion and liver metastases.MethodsA total of 444 CRLM patients receiving simultaneous resections were enrolled. The optimal cut-off value for CLR was determined using the highest Youden’s index. Patients were divided into the CLR < 3.06 group and the CLR≥3.06 group. Propensity score matching analysis (PSM) and the inverse probability of treatment weighting (IPTW) method were conducted to eliminate bias between the two groups. The outcomes included short-term outcomes and long-term outcomes. Kaplan–Meier curves and log-rank tests were used to analyse progression-free survival (PFS) and overall survival (OS).ResultsIn the short-term outcome analysis, after 1:1 PSM, 137 patients were distributed to the CLR < 3.06 group and CLR≥3.06 group. No significant difference was noted between the two groups (P > 0.1). Compared with patients with CLR < 3.06, patients with CLR≥3.06 had comparable operation times (320.0 [272.5–421.0] vs. 360.0 [292.5-434.5], P = 0.088), blood loss (200.0 [100.0-400.0] vs. 200.0 [150.0-450.0], P = 0.831), postoperative complication rates (50.4% vs. 46.7%, P = 0.546) and postoperative ICU rates (5.8% vs. 11.7%, P = 0.087). In the long-term outcome analysis, Kaplan–Meier analysis showed that compared with patients with CLR < 3.06, patients with CLR≥3.06 had worse PFS (P = 0.005, median: 10.2 months vs. 13.0 months) and OS (P = 0.002, median: 41.0 months vs. 70.9 months). IPTW-adjusted Kaplan–Meier analysis showed that the CLR≥3.06 group had worse PFS (P = 0.027) and OS (P = 0.010) than the CLR < 3.06 group. In the IPTW-adjusted Cox proportional hazards regression analysis, CLR≥3.06 was an independent factor for PFS (HR = 1.376, 95% CI 1.097–1.726, P = 0.006) and OS (HR = 1.723, 95% CI 1.218–2.439, P = 0.002). IPTW-adjusted Cox proportional hazards regression analysis including postoperative complications, operation time, intraoperative blood loss, intraoperative blood transfusion and postoperative chemotherapy revealed that CLR≥3.06 was an independent factor for PFS (HR = 1.617, 95% CI 1.252–2.090, P < 0.001) and OS (HR = 1.823, 95% CI 1.258–2.643, P = 0.002).ConclusionsThe preoperative CLR level predicts unfavourable outcomes in CRLM patients receiving simultaneous resection of the primary lesion and liver metastases and should be taken into consideration when developing treatment and monitoring strategies.

Comparison of the therapeutic efficacy between systemic chemotherapy with and without radiofrequency ablation for colorectal cancer liver metastases: A propensity score matching study.

To compare therapeutic efficacy between systemic chemotherapy (SC) alone and preoperative SC followed by radiofrequency ablation (SC+RFA) in patients with colorectal cancer liver metastases (CRLM). This study identified a cohort of patients with CRLM after treatment between 2010 and 2016. Patients who received SC+RFA were compared with SC patients by propensity score matching. Overall survival (OS) and intrahepatic progression-free survival (PFS) were compared using stratified log-rank test. The outcomes after SC and SC+RFA were also assessed in patient subgroups. This study identified 338 patients with CRLM who had underwent SC and had different response to chemotherapy, including non-progressive disease (non-PD) or progressive disease (PD). Of this cohort, 64 patients in SC+RFA group were matched by propensity score to 64 patients who received SC alone. Compared with SC cohort, the SC+RFA cohort yielded better OS (HR, 0.403; 95% CI, 0.271-0.601) and PFS (HR, 0.190; 95% CI, 0.113-0.320). The estimated OS rates at 1, 3 and 5 years were 93.8%, 51.6% and 15.6% for SC+RFA group and 81.3%, 26.6% and 10.9% for SC group (p＜0.001). The cumulative PFS rates at 1, 3, and 5 years were 43.8 %, 14.1% and 3.1% for the SC+RFA group and 1.6%, 0 and 0% for SC group (p＜0.0001). In subgroup analysis, compared with patients with PD response, patients with non-PD response could gain better PFS (HR, 0.207; 95% CI, 0.121-0.354) and OS (HR, 0.390; 95% CI, 0.246-0.617). RFA was associated with improved OS and intrahepatic PFS in CRLM patients with preoperative SC,especially in non-PD response subgroup after SC. The addition of RFA was advocated for CRLM patients with preoperative SC. This study will provide important reference and evidence to better perform the management of unresectable CRLM.

Combined ablation and resection (CARe) for resectable colorectal cancer liver Metastases-A propensity score matching study

BackgroundThe efficacy of combining ablation and resection (CARe) in treating unresectable colorectal cancer liver metastases (CRLM) was well established. This study aimed to investigate the surgical and oncological outcomes of CARe strategy focusing on initially resectable CRLM. Patients and methodsA total of 971 patients with resectable CRLM from a retrospective database of 1414 CRLM patients were enrolled, including 120 in the CARe group and 851 in the hepatectomy alone group. Short- and long-term outcomes were compared between groups using propensity score matching analysis. ResultsAfter propensity score matching, 96 matched pairs of patients from each group were included. General characteristics of primary tumour and liver metastases were not statistically different between the CARe group and hepatectomy alone group. Disease-free survival (p = 0.257), intrahepatic recurrence-free survival (p = 0.329), and overall survival (p = 0.358) were similar between the two groups. Patients in CARe group had significantly reduced rate of major hepatectomy (5.2% vs. 21.9%, p = 0.001), lower incidence of postoperative hepatic insufficiency (0.0% vs. 5.2%, p = 0.023), and shortened postoperative hospital stay (7 d vs. 8 d, p = 0.019). Multivariate analysis showed that surgical approach did not affect oncologic outcome; liver metastasis with diameter >3 cm was an independent prognostic factor for hepatic recurrence-free and disease-free survival, and RAS status and lymph node metastasis at the primary site were independent prognostic factors for overall survival. ConclusionFor patients with resectable CRLM, CARe may be a better treatment strategy than hepatectomy alone, as it could avoid major hepatectomy and get better surgical outcomes, while providing the similar oncologic results.

Hepatocellular carcinoma (HCC) tumor microenvironment is more suppressive than colorectal cancer liver metastasis (CRLM) tumor microenvironment

Background and purposeWhile HCC is an inflammation-associated cancer, CRLM develops on permissive healthy liver microenvironment. To evaluate the immune aspects of these two different environments, peripheral blood-(PB), peritumoral-(PT) and tumoral tissues-(TT) from HCC and CRLM patients were evaluated.Methods40 HCC and 34 CRLM were enrolled and freshly TT, PT and PB were collected at the surgery. PB-, PT- and TT-derived CD4+CD25+ Tregs, M/PMN-MDSC and PB-derived CD4+CD25− T-effector cells (Teffs) were isolated and characterized. Tregs’ function was also evaluated in the presence of the CXCR4 inhibitor, peptide-R29, AMD3100 or anti-PD1. RNA was extracted from PB/PT/TT tissues and tested for FOXP3, CXCL12, CXCR4, CCL5, IL-15, CXCL5, Arg-1, N-cad, Vim, CXCL8, TGFβ and VEGF-A expression.ResultsIn HCC/CRLM-PB, higher number of functional Tregs, CD4+CD25hiFOXP3+ was detected, although PB-HCC Tregs exert a more suppressive function as compared to CRLM Tregs. In HCC/CRLM-TT, Tregs were highly represented with activated/ENTPD-1+Tregs prevalent in HCC. As compared to CRLM, HCC overexpressed CXCR4 and N-cadherin/vimentin in a contest rich in arginase and CCL5. Monocytic MDSCs were highly represented in HCC/CRLM, while high polymorphonuclear MDSCs were detected only in HCC. Interestingly, the function of CXCR4-PB-Tregs was impaired in HCC/CRLM by the CXCR4 inhibitor R29.ConclusionIn HCC and CRLM, peripheral blood, peritumoral and tumoral tissues Tregs are highly represented and functional. Nevertheless, HCC displays a more immunosuppressive TME due to Tregs, MDSCs, intrinsic tumor features (CXCR4, CCL5, arginase) and the contest in which it develops. As CXCR4 is overexpressed in HCC/CRLM tumor/TME cells, CXCR4 inhibitors may be considered for double hit therapy in liver cancer patients.

Early evaluation of liver metastasis using spectral CT to predict outcome in patients with colorectal cancer treated with FOLFOXIRI and bevacizumab

PurposeEarly evaluation of the efficacy of first-line chemotherapy combined with bevacizumab in patients with colorectal cancer liver metastasis (CRLM) remains challenging. This study used 2-month post-chemotherapy spectral computed tomography (CT) to predict the overall survival (OS) and response of CRLM patients with bevacizumab-containing therapy.MethodThis retrospective analysis was performed in 104 patients with pathologically confirmed CRLM between April 2017 and October 2021. Patients were treated with 5-fluorouracil, leucovorin, oxaliplatin or irinotecan with bevacizumab. Portal venous phase spectral CT was performed on the target liver lesion within 2 months of commencing chemotherapy to demonstrate the iodine concentration (IoD) of the target liver lesion. The patients were classified as responders (R +) or non-responders (R −) according to the Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 at 6 months. Multivariate analysis was performed to determine the relationships of the spectral CT parameters, tumor markers, morphology of target lesions with OS and response. The differences in portal venous phase spectral CT parameters between the R + and R − groups were analyzed. Receiver operating characteristic (ROC) curves were used to evaluate the predictive power of spectral CT parameters.ResultsOf the 104 patients (mean age ± standard deviation: 57.73 years ± 12.56; 60 men) evaluated, 28 (26.9%) were classified as R + . Cox multivariate analysis identified the iodine concentration (hazard ratio [HR]: 1.238; 95% confidence interval [95% CI]: 1.089–1.408; P < 0.001), baseline tumor longest diameter (BLD) (HR: 1.022; 95% CI: 1.005–1.038, P = 0.010), higher baseline CEA (HR: 1.670; 95% CI: 1.016–2.745, P = 0.043), K-RAS mutation (HR: 2.027; 95% CI: 1.192–3.449; P = 0.009), and metachronous liver metastasis (HR: 1.877; 95% CI: 1.179–2.988; P = 0.008) as independent risk factors for patient OS. Logistic multivariate analysis identified the IoD (Odds Ratio [OR]: 2.243; 95% CI: 1.405–4.098; P = 0.002) and clinical N stage of the primary tumor (OR: 4.998; 95% CI: 1.210–25.345; P = 0.035) as independent predictor of R + . Using IoD cutoff values of 4.75 (100ug/cm3) the area under the ROC curve was 0.916, sensitivity and specificity were 80.3% and 96.4%, respectively.ConclusionsSpectral CT IoD can predict the OS and response of patients with CRLM after 2 months of treatment with bevacizumab-containing therapy.