Search Results (8,184)

Artificial intelligence encompasses the capacity of machines to emulate human faculties, including reasoning, learning, planning, and creativity. Presently, chronic liver disease, liver cirrhosis, primary liver tumors, and liver metastasis represent significant and escalating causes of mortality worldwide. Consequently, there is a growing demand for more efficient and minimally invasive tools to enhance the diagnostic and therapeutic approaches for these ailments. Over recent years, endeavors have been directed towards employing artificial intelligence within hepatology to advance the diagnosis and treatment of liver diseases. This paper aims to outline the latest developments in the application of artificial intelligence within the realm of liver disease. Full article

Study Aim: Patients with high-risk Ewing sarcoma (ES) have dismal outcomes despite aggressive multimodal therapy. This phase II, single-institution study evaluated the response rate to two up-front cycles of irinotecan, temozolomide, and temsirolimus (ITT) and assessed the tolerability of maintenance therapy following standard treatment in high-risk ES. Methods: Eligible patients had newly diagnosed high-risk ES (age ≥14 years old, metastatic disease, or primary pelvic tumor). The therapy included two cycles of window therapy (ITT) followed by interval-compressed chemotherapy (vincristine, doxorubicin, and cyclophosphamide alternating with ifosfamide and etoposide) and maintenance therapy (cyclophosphamide, sorafenib, and bevacizumab). A two-stage sequential design was employed to assess a >50% WHO response (CR or PR) with 80% power. Patients who required emergent radiation were excluded from receiving window therapy. Results: Sixteen patients (median age 12.2 years; range 4.8–23.6 years) were enrolled (12 evaluable for overall response, 10 for primary tumor response). Only three achieved a PR to window therapy, leading to study closure. All evaluable patients demonstrated a decline in their primary tumor volume (mean decline: 32.5%, standard deviation: 17.6%, p-value: 0.0005) and SUV peak (mean decline: 49.9%, standard deviation: 21.1%, p-value: 0.002). Maintenance therapy was well tolerated, with only 2/13 patients discontinuing due to toxicity. Conclusions: ITT did not achieve the prespecified response rate of 50%, according to WHO criteria; however, all patients exhibited decreased volume and metabolic activity, highlighting the limitations of conventional response assessments. Maintenance therapy was feasible and well tolerated. Although limited by small sample size, heterogeneous disease presentations, and the absence of a control arm, this study supports further evaluation of ITT and a maintenance approach in larger, randomized trials for high-risk ES. Full article

Objectives: Papillary thyroid carcinoma (PTC) frequently presents with cervical lymph node metastasis, even in small tumors, and lateral lymph node involvement serves as an important prognostic factor. Therapeutic lateral neck dissection is typically recommended when nodal metastasis is clinically evident, usually including levels II–V. However, the necessity of routine level II dissection in patients without clinical or radiologic evidence of level II involvement remains controversial, given its association with increased surgical morbidity, particularly injury to the spinal accessory nerve. Identifying reliable clinicopathological predictors of occult level II metastasis may enable more selective surgical approaches that minimize unnecessary dissection while preserving oncologic safety. Therefore, this study aimed to identify clinicopathological risk factors associated with occult level II lymph node metastasis in patients with PTC who have clinically positive lateral nodes but no clinical evidence of level II involvement. Methods: We retrospectively analyzed 1247 patients who underwent thyroidectomy for PTC between 2015 and 2022. Of these, 67 patients with clinically positive lateral lymph node metastasis and clinically negative Level II nodes who underwent therapeutic lateral neck dissection were included. Clinicopathological features were compared between patients with and without occult Level II metastasis. Univariate and multivariate logistic regression analyses were performed to identify independent risk factors. Results: Among the 67 patients analyzed, 24 (35.8%) had occult Level II metastasis. Compared to those without, patients with occult Level II metastasis had significantly larger primary tumors (2.18 ± 1.31 cm vs. 1.51 ± 1.02 cm, p = 0.024), a greater number of central lymph node metastases (5.88 ± 4.41 vs. 3.37 ± 2.66, p = 0.005), larger maximum size of metastatic central lymph node (1.44 ± 1.07 cm vs. 0.87 ± 0.48 cm, p = 0.004), and a higher number of metastatic lateral lymph nodes (7.63 ± 3.75 vs. 3.19 ± 2.21, p < 0.001). Multivariate analysis identified the number of metastatic lateral lymph node as the only independent predictor of occult Level II involvement (OR = 1.57, 95% CI: 1.213–2.044, p = 0.001). The final multivariate model demonstrated a Nagelkerke R² of 0.46. ROC curve analysis confirmed good predictive performance (AUC = 0.85), and the optimal cut-off value was ≥ 5 metastatic lateral lymph nodes. Conclusions: A substantial proportion of patients with clinically negative Level II nodes harbor occult metastasis. The number of metastatic lateral lymph nodes is an independent predictor of occult Level II involvement and may assist in tailoring the extent of lateral neck dissection in patients with PTC. Full article

Background: Ovarian cancer is often diagnosed at advanced stages due to the absence of specific early symptoms, resulting in high mortality rates. This study aims to develop a robust and interpretable machine learning (ML) model for the early detection of ovarian cancer, enhancing its transparency through the use of the Contrastive Explanation Method (CEM), an advanced technique within the field of explainable artificial intelligence (XAI). Methods: An open-access dataset of 349 patients with ovarian cancer or benign ovarian tumors was used. To improve reliability, the dataset was augmented via bootstrap resampling. A three-layer deep neural network was trained on normalized demographic, biochemical, and tumor marker features. Model performance was measured using accuracy, sensitivity, specificity, F1-score, and the Matthews correlation coefficient. CEM was used to explain the model’s classification results, showing which factors push the model toward “Cancer” or “No Cancer” decisions. Results: The model achieved high diagnostic performance, with an accuracy of 95%, sensitivity of 96.2%, and specificity of 93.5%. CEM analysis identified lymphocyte count (CEM value: 1.36), red blood cell count (1.18), plateletcrit (0.036), and platelet count (0.384) as the strongest positive contributors to the “Cancer” classification, with lymphocyte count demonstrating the highest positive relevance, underscoring its critical role in cancer detection. In contrast, age (change from −0.13 to +0.23) and HE4 (change from −0.43 to −0.05) emerged as key factors in reversing classifications, requiring substantial hypothetical increases to shift classification toward the “No Cancer” class. Among benign cases, a significant reduction in RBC count emerged as the strongest determinant driving a shift in classification. Overall, CEM effectively explained both the primary features influencing the model’s classification results and the magnitude of changes necessary to alter its outputs. Conclusions: Using CEM with ML allowed clear and trustworthy detection of early ovarian cancer. This combined approach shows the promise of XAI in assisting clinicians in making decisions in gynecologic oncology. Full article

Background: Recent studies highlight the role of microsatellite instability (MSI) in tumor progression. This study examines the link between MSI, type of loss of function, and disease progression in low-grade endometrial carcinoma clinically confined to the uterus, focusing on myometrial infiltration. Materials and Methods: This retrospective case-control study analyzed data from 144 women treated for clinical stage I low-grade endometrial carcinoma at two university hospitals. Patients were divided into two groups based on microsatellite status: 118 with microsatellite stability (MSS) and 26 with MSI. Immunohistochemical profiling assessed MMR proteins (MLH1, PMS2, MSH2, MSH6). The primary outcome was the presence of myometrial infiltration, and the secondary outcome was the deepness of infiltration. Data were statistically analyzed using Fisher’s exact, Chi-square, and Wilcoxon tests, with logistic regression applied to evaluate the impact of MSI on these outcomes. Results: Myometrial infiltration was present in 96% of MSS and 98% of MSI cases (p = 0.5). However, deep infiltration (≥50%) was more frequent in patients with MSI (38% vs. 19%, p = 0.042). Stratification by heterodimer loss revealed that loss of MLH1/PMS2 was associated with a higher rate of deep infiltration (47%), while loss of MSH2/MSH6 correlated with lower infiltration risk (14%). In multivariate analysis, MSH2/MSH6 loss remained negatively associated with infiltration (OR 0.88; 95% CI 0.80–0.98; p = 0.020), independent of grade and LVSI. Conclusions: In low-grade endometrial carcinomas clinically confined to the uterus, MSI does not increase the overall prevalence of myometrial infiltration but is associated with deeper invasion, especially in cases with MLH1/PMS2 loss. MSI profiling could aid in risk stratification and therapeutic planning, particularly in candidates for fertility-sparing treatment. Full article

Somatic mutations in KRAS and TP53 are among the most common genetic alterations in pancreatic ductal adenocarcinoma (PDAC). Advances in PCR-based technologies now enable the detection of these mutations in tumor tissue and cell-free DNA (cfDNA), providing a minimally invasive approach to assess tumor burden. However, in resectable PDAC, circulating tumor DNA (ctDNA) may represent less than 0.1% of total cfDNA, requiring highly sensitive detection methods. The aim of our study was to assess two PCR-based assays—competitive allele-specific PCR (castPCR) and digital PCR (dPCR)—for detecting selected somatic mutations in tumor tissue, cfDNA, and extracellular vesicle-associated DNA (EV-DNA) from plasma. Matched primary tumor and preoperative plasma samples were collected from 50 patients undergoing upfront resection for PDAC. CastPCR was used for detecting selected KRAS, TP53, SMAD4, and CDKN2A mutations in tumor DNA. Additionally, dPCR was used to analyze KRAS and TP53 mutations in tumor DNA as well as cfDNA and EV-DNA. The concordance between both platforms was 71.4% for KRAS p.G12D and 58.3% for the analysis of TP53 p.R273H mutations in tumor tissue. However, dPCR detected these mutations in an additional 28.6% and 39.6% of samples, respectively. In cfDNA, dPCR identified KRAS p.G12D in 10.2% and TP53 p.R273H in 2.0% of samples. Mutation detection in EV-DNA was limited by low DNA yield. Both platforms proved effective for tumor DNA analysis, with dPCR offering greater sensitivity. Somatic mutation detection from liquid biopsy using dPCR further supports its potential utility in the preoperative setting. Full article

Background: Conservative mastectomy with prepectoral breast reconstruction is becoming increasingly widespread and validated in recent years. Today, while aesthetic advantages and improvement in quality-of-life outcomes are widely acknowledged, oncological safety remains subject of debate. There is limited evidence on residual breast tissue after conservative mastectomy, and it still represents an unknown risk for local recurrence. The recent spread of this surgical technique precludes a standardized surgical approach in case of local recurrence of ipsilateral breast cancer, and the lack of evidence in the literature complicates the decision-making process. The objective of this study is to describe the surgical treatment of local relapses for breast cancer patients following conservative mastectomy and prepectoral implant-based reconstruction. Methods: Between January 2018 and May 2024 at a single institution, 648 consecutive patients underwent conservative mastectomy and prepectoral reconstruction as their primary treatment. We identified 12 patients with T1-2 breast cancer who subsequently had histologically confirmed ipsilateral breast cancer recurrence and a local wide excision or radical mastectomy were performed. Each clinical case was discussed in a multidisciplinary meeting to define the most appropriate surgical treatment. At time of diagnosis of recurrence, patients with lymph node metastasis or systemic involvement were excluded from the study. Results: Among 648 consecutive patients who underwent conservative mastectomy, 12 with histologically confirmed ipsilateral breast cancer recurrence were included. The mean interval to recurrence was 43 months (range 10–76 months) from the primary operation. Recurrence sites were as follows: upper outer quadrant in four patients (33.4%), upper inner quadrant in three (25.0%), lower inner quadrant in two (16.6%), lower outer quadrant in one (8.4%), and central quadrant with nipple involvement in two (16.6%). Of the 12 patients, 9 (75%) underwent wide local excision, including 2 who also received partial capsulectomy, while 3 (25%) required radical mastectomy with implant removal. Adjuvant radiation therapy was administered to 6 patients (50%)—5/6 (83.3%) in the excision group and 1/6 (16.7%) in the mastectomy group. No significant differences were observed in distant disease–free survival or overall survival between the two groups. Conclusions: Currently, surgical treatment of ipsilateral breast tumor recurrence following conservative mastectomy and prepectoral breast reconstruction is not reported in the literature, and this study represents the first instance where wide local excision is described. The management of ipsilateral recurrence should be discussed in multidisciplinary meetings and could be performed safely in selected cases, sparing the prosthesis and avoiding radical mastectomy. Full article

Glioblastoma multiforme (GBM), the most aggressive primary brain tumor in adults, has a poor prognosis due to rapid recurrence and treatment resistance. This review examines the evolution of radiotherapy (RT) for GBM management, from whole-brain RT to modern techniques like intensity-modulated RT (IMRT) and volumetric modulated arc therapy (VMAT), guided by 2023 European Society for Radiotherapy and Oncology (ESTRO)-European Association of Neuro-Oncology (EANO) and 2025 American Society for Radiation Oncology (ASTRO) recommendations. The standard Stupp protocol (60 Gy/30 fractions with temozolomide [TMZ]) improves overall survival (OS) to 14.6 months, with greater benefits in O6-methylguanine-DNA methyltransferase (MGMT)-methylated tumors (21.7 months). Tumor Treating Fields (TTFields) extend median overall survival (mOS) to 31.6 months in MGMT-methylated patients and 20.9 months overall in supratentorial GBM (EF-14 trial). However, 80–90% of recurrences occur within 2 cm of the irradiated field due to tumor infiltration and radioresistance driven by epidermal growth factor receptor (EGFR) amplification, phosphatase and tensin homolog (PTEN) mutations, cyclin-dependent kinase inhibitor 2A/B (CDKN2A/B) deletions, tumor hypoxia, and tumor stem cells. Pseudoprogression, distinguished using Response Assessment in Neuro-Oncology (RANO) criteria and positron emission tomography (PET), complicates response evaluation. Targeted therapies (e.g., bevacizumab; PARP inhibitors) and immunotherapies (e.g., pembrolizumab; oncolytic viruses), alongside advanced imaging (multiparametric magnetic resonance imaging [MRI], amino acid PET), support personalized RT. Ongoing trials evaluating reirradiation, hypofractionation, stereotactic radiosurgery, neoadjuvant therapies, proton therapy (PT), boron neutron capture therapy (BNCT), and AI-driven planning aim to enhance efficacy for GBM IDH-wildtype, but phase III trials are needed to improve survival and quality of life. Full article

Cisplatin remains a cornerstone chemotherapeutic agent; however, its off-target gonadotoxicity poses a significant risk for premature ovarian failure (POF) and infertility in young women. Strategies to preserve ovarian function during chemotherapy are critically needed. To investigate the protective effects of krill oil supplementation against cisplatin-induced ovarian damage in a rat model, with a focus on oxidative stress, inflammation, follicular dynamics, and stromal fibrosis. Twenty-one adult female Wistar albino rats were randomized into three groups: control, cisplatin-treated, and cisplatin + krill oil-treated. Ovarian toxicity was induced via intraperitoneal injection of cisplatin (2.5 mg/kg, twice weekly for four weeks). Krill oil (4 mL/kg/day) was administered orally during the same period. Ovarian histopathology, follicle counts (primordial, primary, secondary, tertiary), stromal fibrosis, and biochemical markers, including plasma anti-Müllerian hormone (AMH), malondialdehyde (MDA), tumor necrosis factor-alpha (TNF-α), interleukin-1 beta (IL-1β), and ovarian levels of nuclear factor erythroid 2-related factor 2 (Nrf2), Toll-like receptor 4 (TLR4), TNF-α, NOD-like receptor family pyrin domain containing 3 (NLRP3), and IL-1β were evaluated. Cisplatin significantly reduced primordial, primary, secondary, and tertiary follicle counts while increasing stromal fibrosis (p < 0.001). Krill oil co-treatment notably ameliorated follicular depletion—improving follicle counts by 38.16%, 54.74%, 62.5%, 40.43%, respectively—and reduced fibrosis (p = 0.017). Biochemically, cisplatin decreased AMH levels and Nrf2 expression while elevating MDA, TNF-α, TLR4, NLRP3, and IL-1β levels (p < 0.001). Krill oil supplementation restored AMH (p = 0.002) and Nrf2 (p = 0.003) levels, while reducing MDA (p = 0.009), NLRP3 (p < 0.001), ovarian IL-1β (p = 0.005), plasma IL-1β (p < 0.001), TLR4 (p = 0.001), plasma TNF-α (p = 0.001), and ovarian TNF-α (p < 0.001), compared to the cisplatin group. Krill oil exerts significant antioxidant and anti-inflammatory effects, offering a promising strategy to mitigate cisplatin-induced ovarian damage and preserve fertility in young cancer patients. Full article

Radical prostatectomy is the standard of care for the treatment of early, clinically localized prostate cancer (PC). In addition to known clinical prognosticators, perioperative conditions and the type of anesthesia may affect clinical outcomes through several mechanisms that favor a tumor-propagating state, including activation of the sympathetic system, increased opioid requirements, and inflammation. In this review, we provide an overview of the impact of the perioperative period on PC prognosis and patient outcomes. A non-systematic literature review was conducted to investigate the possible association between neuraxial anesthesia and outcomes after radical prostatectomy (RP) for prostate cancer. The following keywords were used: “cancer recurrence” OR “cancer prognosis” OR “metastasis” AND “neuraxial anesthesia” AND “prostate cancer”. Eligible studies were summarized in the form of a narrative review. In the era of limited use of ERAS protocols, the implementation of neuraxial anesthesia was found to reduce mortality after RP for primary prostate cancer when compared to general anesthesia. Although there was no significant association between anesthetic technique and radiological or biochemical-free survival, regional anesthesia may have an impact on short-term survival in patients with severe comorbidities, involving pulmonary complications and thrombosis. The effect of anesthetic technique on PC patient outcomes remains elusive, although preliminary retrospective evidence suggests a possible positive effect of neuraxial anesthesia on patient outcomes. As the perioperative period is considered a vulnerable timeframe for these patients, the role of the leadership dyad of surgeon and onco-anesthesiologist is crucial. Full article

Background/Objectives: Glioblastomas are a part of adult-type diffuse gliomas, the most common and most aggressive primary brain tumors in adults (glioblastoma, IDH-wildtype). The identification of the genetic factors associated with glioblastoma could be an important contribution to the diagnosis and early prevention of this disease. We compiled data from the global literature and analyzed clinically relevant variants implicated in glioblastoma risk. Methods: PubMed, Web of Science, and Scopus were used as databases. Associations between the SNPs and glioblastoma risk were calculated as a measure of pooled odds ratios (ORs) and 95% confidence intervals. Pearson’s analysis was used for epidemiological correlation (only p-values less than 0.05 were statistically significant), and data were obtained from the World Health Organization platform and the 1000 Genomes Project. Statistical analysis was performed using Review Manager (RevMan) 5.4 and BioEstat 5.0. Results: CCDC26 rs891835 G/T, G/G, and G/T-G/G genotypes were analyzed and determined to increase glioblastoma risk (G/T OR = 1.96, 95% CI: 1.38–2.77, p = 0.0002, I² = 0%; G/G OR = 1.33, 95% CI: 0.46–3.85, p = 0.60, I² = 0%; G/T − G/G OR = 1.96, 95% CI: 1.39–2.76, p = 0.0001, I² = 0%). Epidemiological correlation also demonstrated that the higher the frequency of the CCDC26 rs891835 variant, the higher the incidence of that variant in the European population. Conclusions: CCDC26 rs891835 may serve as a predictive biomarker for glioblastoma, IDH-wildtype risk and may influence higher glioblastoma incidence rates in the European population. Full article

Glioblastoma multiforme (GBM) remains the most aggressive primary brain tumor with median survival of 14.6 months, necessitating novel therapeutic approaches. Here, we report the biogenic synthesis of zinc oxide nanoparticles (ZnO NPs) using Bacillus licheniformis strain TT14s isolated from mining environments and demonstrate their selective anti-glioma efficacy. ZnO NPs exhibited hexagonal wurtzite structure (crystallite size: 15.48 nm) with spherical morphology (19.37 ± 5.28 nm diameter) as confirmed by XRD, HRTEM, and comprehensive physicochemical characterization. Colloidal stability analysis revealed an isoelectric point at pH 7.46, ensuring optimal dispersion in biological media. Cytotoxicity evaluation revealed remarkable selectivity: at 100 μg/mL, ZnO NPs reduced NG-108 glioblastoma cell viability to 36.07 ± 1.89% within 1 h while maintaining 78.9 ± 0.94% viability in primary retinal cells. The selective cytotoxicity was attributed to the interplay of convergent mechanisms acting under dark conditions, including defect-mediated ROS generation supported by photoluminescence analysis revealing a characteristic oxygen vacancy emission at 550 nm, pH-dependent dissolution enhanced in the acidic tumor microenvironment, and preferential cellular uptake by rapidly proliferating cancer cells with compromised antioxidant defenses. Time-course analysis demonstrated concentration-dependent effects with therapeutic windows favoring normal cell preservation. The intrinsic cytotoxic activity under dark laboratory conditions eliminates the need for external activation, providing practical advantages for therapeutic applications. These findings establish ZnO NPs as promising candidates for targeted glioblastoma therapy, warranting further in vivo validation and mechanistic elucidation for clinical translation. Full article

Hepatocellular carcinoma (HCC) is the most common primary liver cancer. At the time of diagnosis, many HCC patients are not candidates for surgical resection and are considered for other locoregional therapies, including transarterial radioembolization (TARE) and stereotactic body radiation therapy (SBRT). To date only a few studies have explored the safety and efficacy of combining TARE and SBRT. Therefore, we aimed to evaluate it. Patients who received both SBRT and TARE from 2016 to 2024 were retrospectively evaluated for treatment-related toxicity based on criteria for adverse events (CTCAE v4.0). Treatment response was evaluated by modified response evaluation criteria for solid tumors (m-RECIST). We identified 12 patients with median age of 66.5 (range: 40, 87) and median follow up of 12 months. The median time between TARE and SBRT was 6.5 months (range: 1.5 to 24). Following the second treatment, ALBI grade remined the same among all patients at 3-month post treatment compared to baseline. Baseline CP was A among all patients and remained unchanged during follow-up and no higher than grade 3 clinical or biochemical toxicity was seen. The objective response rate (ORR) among patients receiving treatment to the same lesion was 100%. The combination treatment was consistent with prior studies in which the combination of TARE and SBRT has been shown to have good local control with few cases of grade 3 toxicity. Our study demonstrates that treatment with TARE and SBRT was safe and effective among our small sample of patients. Full article

Background/Objectives: Cancer-associated fibroblasts (CAFs) play a pivotal role in the tumor microenvironment. We conducted an analysis using RNA sequencing to identify specific markers for CAFs compared to normal fibroblasts (NFs) in non-small-cell carcinoma (NSCLC). Methods: CAFs and NFs were isolated and cultured from tumor tissues (primary tumor or metastatic lymph nodes) and matched non-tumor tissues, respectively. Bulk RNA sequencing was conducted on isolated CAFs and normal fibroblast NFs. Differential expressions, gene set enrichment, and CAF subpopulation prediction analyses were performed. Results: During the study period, 27 CAFs and 12 NFs were isolated and cultured from tumor and non-tumor tissues in patients with treatment-naïve NSCLC. Among them, 22 CAFs and 11 NFs were included in the RNA sequencing analysis. The 22 CAF samples consisted of 12 adenocarcinomas and 10 squamous cell carcinomas (SqCC), with 16 samples from the lungs and 6 samples from the lymph nodes. Notably, COL11A1, GREM1, CD36, and GAS6 showed a higher expression in CAFs than in NFs, whereas TNC and CXCL2 were more abundantly expressed in NFs. CD36 levels were elevated in CAFs from lymph nodes (LN-CAFs) compared with those from lung specimens (Lung-CAFs) and NFs. COL11A1 levels in Lung-CAFs surpassed those in LN-CAFs and NFs. Both GREM1 and GAS6 showed a strong expression in Lung-CAFs and LN-CAFs relative to NFs. CAFs exhibited features of the myofibroblast CAF subpopulation, whereas NFs displayed traits of the antigen-presenting CAF subtype. In the co-culture model of CAFs and THP-1 cells, the knockdown of GREM1 or GAS6 in CAFs significantly decreased the M2 marker expression in macrophages. Conclusions: In NSCLC, GREM1 and GAS6 can be valuable diagnostic targets for CAFs from primary tumors and metastatic sites; they warrant further study. Full article

Colorectal cancer (CRC) is a major global health burden and a leading cause of cancer-related mortality, with metastasis representing the primary cause of death. Angiogenesis plays a critical role in this process, and macrophages within the tumor microenvironment (TME) are its key regulators. Among these, Tie2-expressing macrophages (TEMs) constitute a distinct pro-angiogenic subset that localizes to perivascular regions and responds to angiopoietin2 (Ang2) signaling. Moreover, TEMs contribute to vessel destabilization and the formation of permissive niches for cancer cell intravasation, linking them to both angiogenic and non-angiogenic modes of malignant tumor progression. The significance of TEMs in CRC remains controversial. This controversy, as we noticed, stems from a confluence of methodological challenges, lack of standardized markers, small-scale studies, inconsistent findings across studies, and the inherent complexity of both CRC biology and macrophage biology. Evidence from preclinical models and patient samples highlights the correlation between Ang2/Tie2 activity, TEM infiltration, and poor prognosis in CRC. This review summarizes current knowledge on the role of TEMs and the Ang/Tie2 axis in CRC angiogenesis, metastasis, and resistance to anti-angiogenic therapies. Advancing our understanding of TEMs may enable novel macrophage-focused strategies to inhibit CRC progression and improve patient outcomes. Full article