Search Results (21)

(1) Background: In 2022, the World Stroke Organization said there were more than 12.2 million new cases of stroke each year, between all ages and sexes. Six and a half million people die each year from stroke. Ischemic stroke accounts for 7.6 million (62%) cases, with 3.3 million (51%) deaths. Stroke is mainly linked to the atherosclerosis of a large artery. (2) Objective: Since the carotid artery directly supplies the brain, we used age-dependent mechanical mapping on the healthy common carotid artery (CCA) with the aim of being able to predict and thus potentially prevent ischemic stroke. (3) Methods: We assessed the CCA stiffness of 95 healthy control (CTL) females (2.23–39.46 years) and 107 healthy CTL males (2.85–40 years). Cine-loops of B-mode CCA data were digitally recorded with conventional medical ultrasound devices. Arterial wall elastic moduli were estimated offline using a proprietary non-invasive imaging-based biomarker algorithm (ImBioMark). Statistical analyzes were carried out with Excel software. (4) Results: Females showed a linear regression profile of CCA elastic moduli ranging from 41 ± 2 kPa to 54 ± 17 kPa (R² = 0.88), while males showed one ranging from 38 ± 5 kPa to 63 ± 22 kPa (R² = 0.83). For qualitative and quantitative illustrations, the elastic modulus data of CTLs were compared with those of subjects with Kawasaki disease and subjects born prematurely, respectively. (5) Conclusions: This study introduced some fundamental features of the mechanical evolution of the CCA as a function of age (2–40 years). Since atherosclerotic arteriopathy starts early in life, this gives the ability to predict risks of stroke and other cardiovascular diseases with the possibility of applying a more comprehensive range of potential preventive measures early in life. This is consistent with preventive medicine objectives which aim to be more predictive to implement pre-emptive measures as opposed to diagnostic and curative approaches. Full article

Introduction: Colorectal cancer liver metastasis (CRCLM) remains a lethal diagnosis, with an overall 5-year survival rate of 5–10%. Two distinct histopathological growth patterns (HGPs) of CRCLM are known to have significantly differing rates of patient survival and response to treatment. We set out to review the results of 275 patients who underwent liver resection for CRCLM at the McGill University Health Center (MUHC) and analyze their clinical outcome, mutational burden, and pattern of cancer progression in light of their HGPs, and to consider their potential effect on surgical decision making. Methods: We performed a retrospective multivariate analysis on clinical data from patients with CRCLM (n = 275) who underwent liver resection at the McGill University Health Center (MUHC). All tumors were scored using international consensus guidelines by pathologists trained in HGP scoring. Results: A total of 109 patients (42.2%) were classified as desmoplastic and angiogenic, whereas 149 patients (57.7%) were non-desmoplastic and vessel co-opting. The 5-year survival rates for angiogenic patients compared with vessel co-opting patients were 47.1% and 13%, respectively (p < 0.0001). Multivariate analysis showed patients with vessel co-opting CRCLM had a higher incidence of extrahepatic metastatic disease (p = 0.0215) compared with angiogenic CRCLM. Additionally, KRAS mutation status was a marker of increased likelihood of disease recurrence (p = 0.0434), as was increased number of liver tumors (p = 0.0071) and multiple sites of extrahepatic metastatic disease (p < 0.0001). Conclusions: Multivariate analysis identified key clinical prognostic and molecular features correlating with the two HGPs. Determining liver tumor HGPs is essential for patient prognostication and treatment optimization. Full article

The current management of colorectal cancer liver metastasis (CRCLM) patients involves a multidisciplinary approach, with surgical resection remaining the primary curative option. The advances in liver surgery have improved outcomes, enabling more patients to undergo surgery successfully. In addition, the development of imaging software has improved the preoperative planning and patient selection for surgery and other interventions. Systemic therapies, such as targeted therapies and immunotherapies, have enhanced the chances of complete resection. Targeted agents, in combination with chemotherapy, have shown efficacy in downstaging tumors and increasing resectability. The algorithm approach for these patients continues to evolve, driven by a deeper understanding of the underlying biology. Personalized medicine, guided by molecular profiling and the potential of liquid biopsies in this field, may lead to more tailored treatment strategies. A greater understanding of the immune microenvironment in CRLM may unlock the potential for immune checkpoint inhibitors and novel immunotherapies to become more prominent in the treatment landscape. This review explores the current state-of-the-art treatment of CRCLM and discusses promising future perspectives. Full article

Colorectal cancer liver metastases (CRCLMs) have two main histopathological growth patterns (HPGs): desmoplastic (DHGP) and replacement (RHGP). The vascularization in DHGP tumours is angiogenic, while the RHGP tumours exert vessel co-option vasculature. The presence of vessel co-option tumours is associated with poor response to anti-angiogenic agents and chemotherapy, as well as a worse prognosis. Metformin has been shown to influence the progression and vasculature of tumours in different cancers. However, its role in CRCLM is poorly understood. Herein, we conducted a retrospective cohort study to examine the role of metformin in CRCLM. A dataset of 108 patients was screened, of which 20 patients used metformin. The metformin user patients did not use metformin as an anticancer agent. We noticed a significantly lower percentage of CRCLM patients with vessel co-opting RHGP tumours in the population that used metformin compared to CRCLM patients who did not use metformin. Similar results were obtained when we compared the ratio of recurrence and extrahepatic metastases incidence. Moreover, the metformin user patients had significantly higher survival outcome compared to nonusers. Collectively, our data suggest that metformin administration is likely associated with better prognosis of CRCLM. Full article

There is a clear association between the molecular profile of colorectal cancer liver metastases (CRCLM) and the degree to which aggressive progression of the disease impacts patient survival. However, much of our knowledge of the molecular behaviour of colorectal cancer cells comes from experimental studies with, as yet, limited application in clinical practice. In this article, we review the current advances in the understanding of the molecular behaviour of CRCLM and present possible future therapeutic applications. This review focuses on three important steps in CRCLM development, progression and treatment: (1) the dissemination of malignant cells from primary tumours and the seeding to metastatic sites; (2) the response to modern regimens of chemotherapy; and (3) the possibility of predicting early progression and recurrence patterns by molecular analysis in liquid biopsy. Full article

An early evaluation of colorectal cancer liver metastasis (CRCLM) is crucial in determining treatment options that ultimately affect patient survival rates and outcomes. Radiomics (quantitative imaging features) have recently gained popularity in diagnostic and therapeutic strategies. Despite this, radiomics faces many challenges and limitations. This study sheds light on these limitations by reviewing the studies that used radiomics to predict therapeutic response in CRCLM. Despite radiomics’ potential to enhance clinical decision-making, it lacks standardization. According to the results of this study, the instability of radiomics quantification is caused by changes in CT scan parameters used to obtain CT scans, lesion segmentation methods used for contouring liver metastases, feature extraction methods, and dataset size used for experimentation and validation. Accordingly, the study recommends combining radiomics with deep learning to improve prediction accuracy. Full article

Resistance to anti-angiogenic therapy is a major challenge in the treatment of colorectal cancer liver metastases (CRCLMs). Vessel co-option has been identified as a key contributor to anti-angiogenic therapy resistance in CRCLMs. Recently, we identified a positive correlation between the expression of Angiopoietin1 (Ang1) in the liver and the development of vessel co-opting CRCLM lesions in vivo. However, the mechanisms underlying its stimulation of vessel co-option are unclear. Herein, we demonstrated Ang1 as a positive regulator of actin-related protein 2/3 (ARP2/3) expression in cancer cells, in vitro and in vivo, which is known to be essential for the formation of vessel co-option in CRCLM. Significantly, Ang1-dependent ARP2/3 expression was impaired in the cancer cells upon Tie2 or PI3K/AKT inhibition in vitro. Taken together, our results suggest novel mechanisms by which Ang1 confers the development of vessel co-option in CRCLM, which, targeting this pathway, may serve as promising therapeutic targets to overcome the development of vessel co-option in CRCLM. Full article

Purpose: The aim of this study is to assess MRI features of mucinous liver metastases compared to non-mucinous metastases and hepatic hemangioma. Methods: A radiological archive was assessed from January 2017 to June 2021 to select patients subjected to liver resection for CRCLM and MRI in the staging phase. We selected 20 patients with hepatic hemangioma (study group B). We evaluated (a) the maximum diameter of the lesions, in millimeters, on T1-W flash 2D in phase and out phase, on axial HASTE T2-W and on portal phase axial VIBE T1 W; and (b) the signal intensity (SI) in T1-W sequences, in T2-W sequences, Diffusion-Weighted Imaging (DWI) sequences and apparent diffusion coefficient (ADC) maps so as to observe (c) the presence and the type of contrast enhancement during the contrast study. The chi-square test was employed to analyze differences in percentage values of the categorical variable, while the non-parametric Kruskal–Wallis test was used to test for statistically significant differences between the median values of the continuous variables. A p-value < 0.05 was considered statistically significant. Results: The final study population included 52 patients (33 men and 19 women) with 63 years of median age (range 37–82 years) and 157 metastases. In 35 patients, we found 118 non-mucinous type metastases (control group), and in 17 patients, we found 39 mucinous type metastases (study group A). During follow-up, recurrence occurred in 12 patients, and three exhibited mucinous types among them. In the study group, all lesions (100%) showed hypointense SI on T1-W, very high SI (similar to hepatic hemangioma) in T2-W with restricted diffusion and iso-hypointense signals in the ADC map. During the contrast study, the main significant feature is the peripheral progressive enhancement. Full article

Vessel co-option is correlated with resistance against anti-angiogenic therapy in colorectal cancer liver metastases (CRCLM). Vessel co-opting lesions are characterized by highly motile cancer cells that move toward and along the pre-existing vessels in the surrounding nonmalignant tissue and co-opt them to gain access to nutrients. To access the sinusoidal vessels, the cancer cells in vessel co-opting lesions must displace the hepatocytes and occupy their space. However, the mechanisms underlying this displacement are unknown. Herein, we examined the involvement of apoptosis, autophagy, motility, and epithelial–mesenchymal transition (EMT) pathways in hepatocyte displacement by cancer cells. We demonstrate that cancer cells induce the expression of the proteins that are associated with the upregulation of apoptosis, motility, and EMT in adjacent hepatocytes in vitro and in vivo. Accordingly, we observe the upregulation of cleaved caspase-3, cleaved poly (ADP-ribose) polymerase-1 (PARP-1) and actin-related protein 2/3 (ARP2/3) in adjacent hepatocytes to cancer cell nests, while we notice a downregulation of E-cadherin. Importantly, the knockdown of runt-related transcription factor 1 (RUNX1) in cancer cells attenuates the function of cancer cells in hepatocytes alterations in vitro and in vivo. Altogether, our data suggest that cancer cells exploit various mechanisms to displace hepatocytes and access the sinusoidal vessels to establish vessel co-option. Full article

Colorectal cancer liver metastases (CRC-LM) present differential histologic growth patterns (HGP) that determine the interaction between immune and tumor cells. We explored the spatial distribution of lymphocytic infiltrates in CRC-LM in the context of the HGP using multispectral digital pathology. We did not find statistically significant differences of immune cell densities in the central regions of desmoplastic (_dHGP) and non-desmoplastic (_ndHGP) metastases. The spatial evaluation reported that _dHGP-metastases displayed higher infiltration by CD8⁺ and CD20⁺ cells in peripheral regions as well as CD4⁺ and CD45RO⁺ cells in _ndHGP-metastases. However, the reactive stroma regions at the invasive margin (IM) of _ndHGP-metastases displayed higher density of CD4⁺, CD20⁺, and CD45RO⁺ cells. The antitumor status of the TIL infiltrates measured as CD8/CD4 reported higher values in the IM of encapsulated metastases up to 400 μm towards the tumor center (p < 0.05). Remarkably, the IM of _dHGP-metastases was characterized by higher infiltration of CD8⁺ cells in the epithelial compartment parameter assessed with the ratio CD8^epithelial/CD8^stromal, suggesting anti-tumoral activity in the encapsulating lesions. Taking together, the amount of CD8⁺ cells is comparable in the IM of both HGP metastases types. However, in _dHGP-metastases some cytotoxic cells reach the tumor nests while remaining retained in the stromal areas in _ndHGP-metastases. Full article

A novel multi-mode thermal therapy was developed for local tumor ablation and the systemic stimulation of anti-tumor immunity, consisting of a rapid liquid nitrogen freezing, and followed by the radiofrequency heating of target tumor tissue. This pilot study aimed to compare the therapeutic effects of the new therapy with conventional radiofrequency ablation (RFA) on patients with colorectal cancer liver metastasis (CRCLM). From August 2016 to September 2019, thirty-one patients with CRCLM received either multi-mode thermal therapy (n = 17) or RFA (n = 14). Triphasic contrast-enhanced magnetic resonance imaging (MRI), routine blood tests, and peripheral blood immune responses were evaluated before the treatment and in 1, 3, 6, and 12 months after. Local tumor response and progression-free survival (PFS) were assessed using the Kaplan-Meier method, and pre- and post-treatment immune cell counts were analyzed using Mann-Whitney U and Wilcoxon tests. A significantly longer PFS was observed in the multi-mode thermal therapy group in comparison to that of the conventional RFA group (median, 11.4 versus 3.4 months, p = 0.022). It was found that multi-mode therapy induced the functional maturation of dendritic cells, promoted CD4⁺ T cell-mediated antitumor responses, and decreased regulatory T cells, contributing to better therapeutic efficacy in CRCLM patients. Full article

Background: Liver metastases are a leading cause of cancer-associated deaths in patients affected by colorectal cancer (CRC). The multidisciplinary strategy to treat CRC is more effective when the radiological diagnosis is accurate and early. Despite the evolving technologies in radiological accuracy, the radiological diagnosis of Colorectal Cancer Liver Metastases (CRCLM) is still a key point. The aim of our study was to define a new patient representation different by Artificial Intelligence models, using Formal Methods (FMs), to help clinicians to predict the presence of liver metastasis when still undetectable using the standard protocols. Methods: We retrospectively reviewed from 2013 to 2020 the CT scan of nine patients affected by CRC who would develop liver lesions within 4 months and 8 years. Seven patients developed liver metastases after primary staging before any liver surgery, and two patients were enrolled after R0 liver resection. Twenty-one patients were enrolled as the case control group (CCG). Regions of Interest (ROIs) were identified through manual segmentation on the medical images including only liver parenchyma and eventual benign lesions, avoiding major vessels and biliary ducts. Our predictive model was built based on formally verified radiomic features. Results: The precision of our methods is 100%, scheduling patients as positive only if they will be affected by CRCLM, showing a 93.3% overall accuracy. Recall was 77.8%. Conclusion: FMs can provide an effective early detection of CRCLM before clinical diagnosis only through non-invasive radiomic features even in very heterogeneous and small clinical samples. Full article

Background: Unfortunately, the majority of patients with colorectal cancer liver metastases (CRCLM) experience disease recurrence following hepatic surgery. The key challenge is therefore optimal patient selection, which currently relies on anatomical and clinical parameters. Exploring a potential molecular signature may be predictive for seeing a clinical benefit from CRCLM resection. Methods: Consecutive patients who underwent CRCLM resection at our medical center between 2006 and 2016 were divided into cohorts of “good prognosis” (GP) or “poor prognosis” (PP) based on the time interval between their resection and disease recurrence. Proteomic analysis was performed on the surgical specimen and correlation analysis was carried out with demographics and clinical outcomes. Results: Proteomic analysis revealed 99 differentially expressed proteins of which a third were associated with extracellular matrix (ECM) pathways as the matrix metalloproteinases (MMPs). Multivariate analysis yielded a statistically differential proteomic pattern between the cohort regardless of perioperative treatment. Conclusion: Our results indicate a different proteomic landscape in the cohort of patients who had a clinical benefit from CRCLM resection which appears to be correlated with ECM pathways. Further prospective studies are needed to define the role of ECM pathways in prognostics and patient selection for surgical procedures for CRCLM. Full article

Metastatic liver tumors have presented challenges with the use of checkpoint inhibitors (CPIs), with only limited success. We hypothesize that regional delivery (RD) of CPIs can improve activity in the liver and minimize systemic exposure, thereby reducing immune-related adverse events (irAE). Using a murine model of colorectal cancer liver metastases (LM), we confirmed high levels of PD-L1 expression on the tumor cells and liver myeloid-derived suppressor cells (L-MDSC). In vivo, we detected improved LM response at 3 mg/kg on PTD7 via portal vein (PV) regional delivery as compared to 3 mg/kg via tail vein (TV) systemic delivery (p = 0.04). The minimal effective dose at PTD7 was 5 mg/kg (p = 0.01) via TV and 0.3 mg/kg (p = 0.02) via PV. We detected 6.7-fold lower circulating CPI antibody levels in the serum using the 0.3 mg/kg PV treatment compared to the 5 mg/kg TV cohort (p < 0.001) without increased liver toxicity. Additionally, 3 mg/kg PV treatment resulted in increased tumor cell apoptotic signaling compared to 5 mg/kg TV (p < 0.05). Therefore, RD of an anti-PD-1 CPI therapy for CRCLM may improve the therapeutic index by reducing the total dose required and limiting the systemic exposure. These advantages could expand CPI indications for liver tumors. Full article

The aim of this study was to correlate the pre-procedural magnetic-resonance-imaging-based hepatic fat fraction (hFF) with the degree of hypertrophy after portal vein embolization (PVE) in patients with colorectal cancer liver metastases (CRCLM). Between 2011 November and 2020 February, 68 patients with CRCLM underwent magnetic resonance imaging (MRI; 1.5 Tesla) of the liver before PVE. Using T1w chemical shift imaging (DUAL FFE), the patients were categorized as having a normal (<5%) or an elevated (>5%) hFF. The correlation of hFF, age, gender, initial tumor mass, history of chemotherapy, degree of liver hypertrophy, and kinetic growth rate after PVE was investigated using multiple regression analysis and Spearman’s test. A normal hFF was found in 43/68 patients (63%), whereas 25/68 (37%) patients had an elevated hFF. The mean hypertrophy and kinetic growth rates in patients with normal vs. elevated hFF were 24 ± 31% vs. 28 ± 36% and 9 ± 9 % vs. 8 ± 10% (p > 0.05), respectively. Spearman’s test showed no correlation between hFF and the degree of hypertrophy (R = −0.04). Multivariable analysis showed no correlation between hFF, history of chemotherapy, age, baseline tumor burden, or laterality of primary colorectal cancer, and only a poor inverse correlation between age and kinetic growth rate after PVE. An elevated hFF in a pre-procedural MRI does not correlate with the hypertrophy rate after PVE and should therefore not be used as a contraindication to the procedure in patients with CRCLM. Full article