Search Results (107)

This study aims to investigate the predictive value of pre-treatment multi-phasic contrast-enhanced computed tomography (CECT) radiomic features for treatment resistance in patients with rat sarcoma virus (RAS)-mutated colorectal liver metastases (CRLMs) receiving bevacizumab-based chemotherapy. Seventy-three samples with RAS-mutated CRLMs receiving bevacizumab-combined chemotherapy regimens were evaluated. Radiomic features were extracted from arterial phase (AP), portal venous phase (PVP), AP-PVP subtraction image, and Delta phase (DeltaP, calculated as AP-to-PVP ratio) images. Three groups of radiomics features were extracted for each phase, including peritumor, core tumor, and whole-tumor regions. For each of the four phases, a two-sided independent Mann–Whitney U test with the Bonferroni correction and K-means clustering was applied to the remnant features for each phase. Subsequently, the Least Absolute Shrinkage and Selection Operator (LASSO) algorithm was then applied for further feature selection. Six machine learning algorithms were then used for model development and validated on the independent testing cohort. Results showed peritumoral radiomic features and features derived from Laplacian of Gaussian (LoG) filtered images were dominant in all the compared machine learning algorithms; NB models yielded the best-performing prediction (Avg. training AUC: 0.731, Avg. testing AUC: 0.717) when combining all features from different phases of CECT images. This study demonstrates that peritumoral radiomic features and LoG-filtered pre-treatment multi-phasic CECT images were more predictive of treatment response to bevacizumab-based chemotherapy in RAS-mutated CRLMs compared to core tumor features. Full article

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. Full article

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. Full article

Background: Colorectal cancer (CRC) frequently metastasizes to the liver (CRLM), where M2-polarized macrophages shape an immunosuppressive pre-metastatic niche. The molecular cues driving this polarization remain unclear. Methods and Results: Using integrated transcriptomics, patient cohorts, and mouse models, we investigated the role of tissue inhibitor of metalloproteinases-1 (TIMP1) in CRLM. TIMP1 was consistently overexpressed in CRC tissues and associated with poor overall survival. CRC cells secreted TIMP1 into the tumor microenvironment, where it induced M2-like macrophage polarization and increased the expression of immunosuppressive mediators such as CSF1 and IRF4. In vivo, TIMP1 overexpression enhanced, whereas its knockdown reduced, liver metastatic burden. Immune profiling and depletion experiments indicated that these pro-metastatic effects were largely macrophage-dependent. Mechanistically, TIMP1 engaged CD63/β1-integrin on macrophages, activating AKT/mTOR signaling and stabilizing the M2 phenotype. Conclusions: CRC-derived TIMP1 remodels liver macrophages via the CD63/β1-integrin–AKT/mTOR pathway to promote a hepatic pre-metastatic niche. Pharmacologic inhibition of this signaling axis with the integrin antagonist cilengitide suppressed macrophage M2 markers and liver colonization in mice, supporting TIMP1–integrin signaling as a potential therapeutic target. Full article

Background: Surgical resection (SR) and liver transplantation (LT) are the main curative options for non-hepatocellular carcinoma (non-HCC) liver malignancies, including colorectal liver metastases (CRLMs), intrahepatic cholangiocarcinoma (iCCA), hilar cholangiocarcinoma (hCCA), and neuroendocrine tumor liver metastases (NETLMs). Resection aims for negative margins and adequate hepatic reserve, while LT offers treatment for unresectable disease but is limited by donor scarcity, immunosuppression, and ethical constraints. Methods: A targeted literature search (2005–2025) was conducted using PubMed and Google Scholar with predefined MeSH terms combining “liver resection,” “hepatectomy,” and “liver transplantation” across non-HCC malignancies. Relevant studies, reviews, and guidelines were included. Results: For CRLMs, SR remains standard with 5-year overall survival (OS) up to 58%, while LT offers 60–83% in highly selected unresectable cases. In iCCA, resection achieves median survival around 40 months, and LT yields OS up to 69% in very early or neoadjuvant-controlled disease. For hCCA, the Mayo protocol combining neoadjuvant therapy with LT provides 5-year OS of 65–80%. In NETLMs, LT achieves 63–97% OS under strict criteria. Conclusions: SR remains first-line for resectable non-HCC malignancies, while LT provides superior outcomes in unresectable yet biologically favorable disease, emphasizing careful selection and organ allocation. Full article

Background: Robotic liver surgery is emerging as a key advancement in minimally invasive techniques, though it still faces several challenges. Meanwhile, colorectal cancer (CRC) continues to be a leading cause of cancer deaths, with liver metastases affecting 25–30% of patients. These metastases significantly burden healthcare systems by raising costs and resource demands. Methods: A narrative literature review was performed, resulting in the inclusion of 14 studies in our analysis. Fourteen studies met the inclusion criteria and were analyzed with attention to patient characteristics, surgical details, perioperative outcomes, and reporting limitations. For consistency, simultaneous robotic-assisted resection (RAR) refers to cases in which the colorectal primary and liver metastasectomy were performed during the same operative session. Results: The 14 studies included a total of 771 patients (520 males and 251 females), aged between 31 and 88, undergoing simultaneous robotic-assisted resection (RAR). Most were affected by rectal cancer (76%) and unilobar liver metastases (82%). All surgeries using the DaVinci system are represented by 62% wedge resection and 38% anatomical (21.39% major and 16.61% minor). Patients’ BMI ranged from 19.5 to 40.4 kg/m², the average blood loss was 181.5 mL (30–780), the median hospital stay was 7 days (range 2–28), and the mean operative time ranged from 30 to 682 min. Data on POLF (postoperative liver failure) are reported in two studies: Rocca et al., 1/90 patients; Marino et al., 1/40 patients. Biliary leak is reported in one case by Marino et al., while Winckelmans et al. reported a 2.6% incidence of biliary leak in the laparoscopic group and 3.4% in the robotic group. Conclusions: As research advances and new therapies emerge for colorectal liver metastasis (CRLM), surgery remains the mainstay of treatment. However, evidence is limited by small sample sizes, heterogeneous study designs, inconsistent reporting of perioperative chemotherapy, timing of surgery, metastasis localization, and complications. Robotic liver surgery has become a well-established technique and possibly represents the future for managing colorectal liver metastases. Further prospective and comparative studies with standardized outcome reporting are needed to define optimal patient selection and long-term effectiveness. Full article

Colorectal liver metastases (CRLM) management remains a complex conundrum in the context of potential curable disease. The combination of systemic therapy and surgery, with overall survival outcomes up to 58% at five years, has become the gold standard. Locoregional therapies have gained evidence in complementing surgery or even substituting it in selected cases. Adequate patient selection is paramount, but prognostic models have certain limitations that prevent their full implementation in clinical practice. A plethora of prognostic factors exists, with variable evidence supporting their definitive role. Thus, CRLM management decisions frequently vary depending on multidisciplinary team experience and hospital access to systemic and locoregional treatments. Definition of resectability has evolved in recent years due to technical developments in surgical and non-surgical approaches. Complexity is added when trying to fully understand the integration between local and systemic treatment. Whereas evidence in the context of resectable disease has been attempted in several phase III trials, definitive conclusions regarding the best approach to potentially resectable disease cannot be drawn. In addition, liver transplantation has gained evidence and is proposed in selected patients, raising a challenge regarding its integration and wider implementation. In this review, current standards in the management of CRLM regarding patient selection, resectability, surgical and non-surgical locoregional strategies, as well as the best systemic approach are covered. Full article

Colorectal cancer (CRC) remains a leading cause of cancer-related mortality worldwide, with liver metastases (CRLM) representing a common and often incurable manifestation. While surgical resection combined with chemotherapy remains the standard for resectable disease, a significant subset of patients presents with unresectable CRLM. Recent advances have positioned liver transplantation (LT) as a promising therapeutic option for select patients with unresectable CRLM. This review synthesizes current evidence from landmark studies—including the SECA and TRANSMET trials—and emerging data from North American cohorts, highlighting the evolution of patient selection criteria, prognostic indicators such as the Oslo score and metabolic tumor volume, and the role of living-donor and extended-criteria grafts. Outcomes from recent studies demonstrate that LT can achieve 5-year overall survival rates exceeding 70% in well-selected patients, rivaling those of traditional transplant indications. Ongoing trials such as SECA-III and SOULMATE aim to refine indications and address organ allocation challenges. Collectively, these findings suggest that LT can offer long-term survival benefits comparable to traditional transplant indications, marking a paradigm shift in the management of metastatic CRC. Full article

Historically, colorectal liver metastases (CRLMs) have been considered a contraindication for liver transplantation (LT), primarily due to limited organ availability and concerns about oncologic efficacy. However, emerging evidence indicates that highly selected patients with unresectable CRLM can achieve long-term survival following LT—often with outcomes superior to those obtained through conventional systemic therapies. To evaluate the evolving role of LT in this setting, we conducted a scoping review of the literature. A comprehensive search was performed across PubMed, Embase, Web of Science, Scopus, and ClinicalTrials.gov, as well as ProQuest Dissertations & Theses and Google Scholar to capture gray literature. The search included English-language articles published between January 2015 and April 2025. Eligible studies included those reporting on the application of LT for patients with unresectable CRLM. This scoping review synthesizes current evidence on patient selection criteria, overall and disease-free survival, recurrence patterns, and emerging biomarkers that may guide transplant eligibility. In addition, we explore innovations in organ utilization—including living donor LT and machine perfusion technologies—that aim to expand access while addressing ethical concerns related to organ allocation. As LT for CRLM transitions from investigational use to clinical implementation, this review outlines the key challenges and future opportunities that will shape its role in the landscape of transplant oncology. Full article

Background/Objective: At least 25% of colorectal cancer (CRC) patients develop liver metastases (CRLM), and chemotherapeutic regimens based on the fluoropyrimidine (FP) drug 5-fluorouracil (5-FU) provide a survival advantage, but long-term survival is uncommon. The primary molecular target of FP drugs is thymidylate synthase (TS). Methods: A TS/Top1 dual-targeting cytotoxic mechanism for CF10/LV was confirmed by TS ternary complex detection by Western blot and by immunofluorescence detection of Top1 cleavage complexes. CF10/LV activated the ATR/Chk1 pathway consistent with enhanced replication stress and induced apoptosis. In vivo studies showed CF10 and CF10/LV eradicated liver metastasis in a CRLM model without scarring or weight loss, displaying therapeutic advantages relative to legacy FPs. Results: We demonstrated that a nanoscale FP polymer, CF10, displayed greater potency than expected based on FP content in part through more direct conversion to the TS-inhibitory metabolite, FdUMP. In this study, we tested CF10 for potency advantages relative to 5-FU and trifluorothymidine (TFT, the FP component of TAS-102) and confirmed a general potency advantage for CF10 in CRC cell lines in the Broad Institute PRISM screen. We demonstrated that this potency advantage is retained in CRC cells cultured with human-like folate levels and is enhanced by LV co-treatment to a similar extent as that by 5-FU. Our results confirm CF10 development proceeding as a CF10/LV combination. Mechanistically, CF10 cytotoxicity closely correlates with poisons of DNA topoisomerase 1 (Top1) in the PRISM screen relative to 5-FU and TFT. Conclusions: Our pre-clinical data support an early-phase clinical trial for CF10 for treating liver-metastatic CRC. Full article

Background: Colorectal liver metastasis (CRLM) represents a major clinical challenge in oncology, affecting 25–50% of colorectal cancer patients and significantly impacting survival. While multimodal therapies—including surgical resection, systemic chemotherapy, and local ablative techniques—have improved outcomes, prognosis remains heterogeneous due to variations in tumor biology, patient factors, and institutional practices. Methods: This review synthesizes current evidence on prognostic factors influencing CRLM management, encompassing clinical (e.g., tumor burden, anatomic distribution, timing of metastases), biological (e.g., CEA levels, inflammatory markers), and molecular (e.g., RAS/BRAF mutations, MSI status, HER2 alterations) determinants. Results: Key findings highlight the critical role of molecular profiling in guiding therapeutic decisions, with RAS/BRAF mutations predicting resistance to anti-EGFR therapies and MSI-H status indicating potential responsiveness to immunotherapy. Emerging tools like circulating tumor DNA (ctDNA) and radiomics offer promise for dynamic risk stratification and early recurrence detection, while the gut microbiome is increasingly recognized as a modulator of treatment response. Conclusions: Despite advancements, challenges persist in standardizing resectability criteria and integrating multidisciplinary approaches. Current guidelines (NCCN, ESMO, ASCO) emphasize personalized strategies but lack granularity in terms of incorporating novel biomarkers. This exhaustive review underscores the imperative for the development of a unified, biomarker-integrated framework to refine CRLM management and improve long-term outcomes. Full article

Background: Colorectal liver metastases (CRLM) occur in up to 50% of colorectal cancer with a significant impact on patient survival, of whom only 20–30% will be considered suitable for surgical treatment. Despite the progress in systemic therapies, palliative chemotherapy alone results in a 5-year overall survival (OS) < 10%. Recently, liver transplantation (LT) has been reconsidered as an option and demonstrates improved survival in highly selected patients. This study assessed the impact of implementing a standardised patient selection protocol (LITORALE) on post-transplant outcomes for unresectable CRLM (uCRLM) at a high-volume single centre. Methods: This is a prospective observational study including all consecutive patients transplanted for uCRLM at our institution between July 2015 and September 2024. This prospective observational study evaluated the impact of the LITORALE protocol on post-transplant outcomes in uCRLM patients at a single centre. Patients who underwent LT between July 2015 and September 2024 were grouped into pre-LITORALE (2015–2021) and LITORALE (post-2021) cohorts. Recipient profiles, transplant variables, and post-transplant outcomes were compared. Results: Twenty-one patients were included (eight pre-LITORALE, thirteen LITORALE). The LITORALE group had a lower median number of lesions (4 vs. 17.5, p = 0.004), a smaller major lesion size (3 cm vs. 5.5 cm, p = 0.082), and a significantly lower tumour burden score (6.32 vs. 18.02, p = 0.002). Similar to recent major clinical trials, one- and three-years OS were 100% and 83%, respectively, after protocol introduction; recurrence patterns were significantly different, with reduced multi-site recurrences (7.7% vs. 50%, p = 0.048) and a higher incidence of lung-only recurrences in the LITORALE group (50% vs. 0%, p = 0.033). Conclusions: The introduction of the LITORALE protocol significantly influenced patient selection and recurrence patterns in LT for uCRLM. Although the limited number of patients and the short study timespan highlight the need for future validation, these preliminary results support the adoption of structured, multidisciplinary criteria to optimise oncologic outcomes. Full article

Given the promising outcomes of stereotactic body radiation therapy (SBRT) in treating colorectal cancer liver metastases (CRLMs), we proposed an innovative strategy combining surgery with planned liver SBRT for CRLMs. This retrospective study included patients who underwent curative-intent surgery combined with planned liver SBRT from July 2019 to October 2023. Planned liver SBRT was delivered to residual unresectable and unablatable lesions with maximum diameters of ≤5 cm. Outcomes included local failure (LF), intrahepatic recurrence-free survival (IHRFS), extrahepatic recurrence-free survival (EHRFS), progression-free survival (PFS), overall survival (OS), and radiation-related adverse events. A total of 69 patients were included. The 1-, and 2-year cumulative incidence rates of LF after SBRT were 7.7%, and 9.6%, respectively. The median PFS was 6.2 months, and the median OS was 45.8 months. Multivariate analysis identified RAS/BRAF mutations, extrahepatic metastases excluding lung involvement, and higher CEA as independent predictors of poorer OS. Intrahepatic recurrence was the predominant pattern of first disease progression after combination treatment. Acute grade 1–2 radiation-related adverse events occurred in 56.5% of patients, while grade 3 toxicities were reported in 4.3%. This approach offers favorable long-term outcomes, suggesting its potential to broaden the indications for curative-intent local treatments in CRLMs. Full article

Transposable elements (TEs) make up around half of the human genome. Their transcription is repressed in most somatic cells to maintain genome integrity and function. The repression is chiefly maintained by a combination of epigenetic modifications such as DNA methylation and histone modifications. However, recent research suggests that liver steatosis is associated with extensive changes to the hepatocyte epigenome. Furthermore, studies in mice have reported diet- and drug-induced changes to TE transcript levels in liver. The confirmation of these effects in human liver has not previously been undertaken. Here, we examined TE transcription in liver tissue from three patient cohorts with histologically confirmed liver steatosis caused by alcohol consumption or metabolic dysfunction. The quantitation of the number of transcripts with TE-homology in RNA-Seq data from a cohort of 90 bariatric surgery patients with metabolic dysfunction-associated steatotic liver disease (MASLD) revealed a trend for the reduction in TEs of all classes due to increasing steatosis, but no effect of fibrosis. This pattern was also present in a separate cohort of MASLD and HCC patients, as RT-qPCR also showed a reduction in Alu element transcripts in advanced steatosis, but again, no effect of fibrosis. Contrastingly, in a cohort of alcohol-related liver disease patients, the reduction in LINE-1 transcripts was associated with either increased steatosis or increased fibrosis. Moreover, the examination of LINE-1 DNA methylation levels in the MASLD and HCC cohort indicated that DNA methylation was also negatively associated with LINE-1 transcription in MASLD. This study suggests that TE transcript levels in human liver are slightly reduced by steatosis, that DNA methylation is an influential epigenetic regulator of LINE-1 retrotransposon transcription in steatosis, and that Alu transcript levels in background liver could be a new biomarker for HCC in cirrhotic and non-cirrhotic MASLD. Full article

Background: Hepatic resection is performed for liver lesions and requires careful preoperative planning to minimize bleeding. Blood type O, associated with lower von Willebrand factor (vWF) levels, may increase bleeding risk. This study investigates the relationship between the ABO blood type and perioperative bleeding in partial hepatectomy for colorectal liver metastases (CRLMs). Methods: Out of 563 patients who underwent hepatectomy, 135 cases were analyzed for CRLM at Carmel Medical Center (2013–2023). Patients were categorized into blood type O (61 patients) and non-O (74 patients) groups. Data on perioperative hemoglobin levels, blood loss, coagulation parameters, transfusion needs, and complications were assessed using χ², t-tests, and ANOVA (p < 0.05). Results: No significant differences were observed for estimated blood loss (474.3 ± 696 mL for O vs. 527.8 ± 599 mL for non-O; p = 0.29), intraoperative hemoglobin drop (p = 0.613), or transfusion rates (24.59% for O vs. 28.37% for non-O; p = 0.698). Although non-O patients had a higher postoperative INR (p = 0.035), this did not correlate with increased bleeding or transfusion needs. Conclusions: Blood type O does not significantly affect perioperative bleeding or transfusion requirements in partial hepatectomy for CRLM. Further research is needed to better understand the significance of the ABO blood type. Full article