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Background: Neuroendocrine tumors (NET) constitute a heterogeneous group of malignancies whose incidence has been on the rise over the past two decades, currently documented at 5.25 per 100,000. Liver metastasis develops in over 60% of NET patients. Even after resection recurrence rates are high, underscoring the importance of parenchymal-sparing interventions. In this study, we conducted 105 surgical microwave ablations and examined outcomes related to survival and local recurrence. Methods: Retrospective review of patients who underwent a surgical microwave ablation (MWA) at a single-center, high-volume institution from September 2007 through December 2022 using a prospective database. Primary outcome was overall survival. Results: A total of 105 operations were performed on 94 patients, with 397 tumors undergoing MWA. Median tumor size was 1.3 cm (range 0.3–8.0), and the median number of tumors ablated was 2 (range 1–12). Laparoscopic approach was utilized 69.5% of the time. The most common concomitant procedure performed was hepatectomy (33.3%) and cholecystectomy (23.8%). Clavien–Dindo grade III or IV complications occurred in 9 patients (9.6%). Mortality within 30 days occurred in 1 patient (1.1%). The rate of incomplete ablation was 0.3% per tumor. Local recurrence occurred in 2.8% of tumors. Median OS was 9.43 years [95% CI 4.23–14.63 years], with a 5- and 10-year survival probability of 70.2% and 48.2%, respectively. Conclusion: Surgical MWA offers an efficacious, parenchymal-sparing treatment of hepatic metastasis of NET, with low rates of incomplete ablation and local recurrence per tumor. [ABSTRACT FROM AUTHOR]

Breast cancer (BC) remains one of the most common malignant diseases affecting female patients, and it can metastasize to nearly every part of the body. BC is rare in men, and therefore men rarely develop BC liver metastases (BCLMs). However, the present study reports a 55-year-old male patient who underwent surgery 5 years ago for BC. After treatment, the patient was actively followed up regularly. Recently, the patient was examined for chest tightness, and liver space-occupying lesions were found. The upper abdominal enhanced computed tomography images of the patient showed that the liver density was not uniform and that the liver had a mass. A crude needle biopsy was used to examine the liver tumour under the guidance of ultrasound. The pathology revealed that the patient was positive for E-cadherin, oestrogen receptor, progesterone receptor, human epidermal growth factor receptor 2, GATA binding protein 3 and CK7. The patient was subsequently diagnosed with BCLM. The patient was treated with doxorubicin hydrochloride, cyclophosphamide, Docetaxel and followed up regularly. The present case report emphasizes that BC is found not only in women but also in an increasing number of men, and that liver metastasis can occur in males with BC. BCLM is a complex process, and therefore it is hoped this case report will improve the understanding of male BCLM and the mechanism of this disease. [ABSTRACT FROM AUTHOR]

Metastasis to the liver is a leading cause of death in patients with colorectal cancer. To investigate the characteristics of cancer cells prone to metastasis, we utilized an isogenic model of BALB/c and colon tumor 26 (C26) cells carrying an active KRAS mutation. Liver metastatic (LM) 1 cells were isolated from mice following intrasplenic transplantation of C26 cells. Subsequent injections of LM1 cells generated LM2 cells, and after four cycles, LM4 cells were obtained. In vitro, using a perfusable capillary network system, we found comparable extravasation frequencies between C26 and LM4 cells. Both cell lines showed similar growth rates in vitro. However, C26 cells showed higher glucose consumption, whereas LM4 cells incorporated more fluorescent fatty acids (FAs). Biochemical analysis revealed that LM4 cells had higher cholesterol levels than C26 cells. A correlation was observed between fluorescent FAs and cholesterol levels detected using filipin III. LM4 cells utilized FAs as a source for cholesterol synthesis through acetyl‐CoA metabolism. In cellular analysis, cholesterol accumulated in punctate regions, and upregulation of NLRP3 and STING proteins, but not mTOR, was observed in LM4 cells. Treatment with a cholesterol synthesis inhibitor (statin) induced LM4 cell death in vitro and suppressed LM4 cell growth in the livers of nude mice. These findings indicate that colorectal cancer cells prone to liver metastasis show cholesterol‐dependent growth and that statin therapy could help treat liver metastasis in immunocompromised patients. [ABSTRACT FROM AUTHOR]

Lipid metabolism reprogramming stands as a fundamental hallmark of cancer cells. Unraveling the core regulators of lipid biosynthesis holds the potential to find promising therapeutic targets in pancreatic ductal adenocarcinoma (PDAC). Here, it is demonstrated that platelet‐derived growth factor C (PDGFC) orchestrated lipid metabolism, thereby facilitated the malignant progression of PDAC. Expression of PDGFC is upregulated in PDAC cohorts and is corelated with a poor prognosis. Aberrantly high expression of PDGFC promoted proliferation and metastasis of PDAC both in vitro and in vivo. Mechanistically, PDGFC accelerated the malignant progression of PDAC by upregulating fatty acid accumulation through sterol regulatory element‐binding protein 1 (SREBP1), a key transcription factor in lipid metabolism. Remarkably, Betulin, an inhibitor of SREBP1, demonstrated the capability to inhibit proliferation and metastasis of PDAC cell lines, along with attenuating the process of liver metastasis in vivo. Overall, the study underscores the pivotal role of PDGFC‐mediated lipid metabolism in PDAC progression, suggesting PDGFC as a potential biomarker for PDAC metastasis. Targeting PDGFC‐induced lipid metabolism emerges as a promising therapeutic strategy for metastatic PDAC, with the potential to improve clinical outcomes. [ABSTRACT FROM AUTHOR]

Inflammatory signals lead to recruitment of circulating monocytes and induce their differentiation into pro-inflammatory macrophages. Therefore, whether blocking inflammatory monocytes can mitigate disease progression is being actively evaluated. Here, we employ multiple lineage-tracing models and show that monocyte-derived macrophages (mo-mac) are the major population of immunosuppressive, liver metastasis-associated macrophages (LMAM), while the proportion of Kupffer cells (KC) as liver-resident macrophages is diminished in metastatic nodules. Paradoxically, genetic ablation of mo-macs results in only a marginal decrease in LMAMs. Using a proliferation-recording system and a KC-tracing model in a monocyte-deficient background, we find that LMAMs can be replenished either via increased local macrophage proliferation or by promoting KC infiltration. In the latter regard, KCs undergo transient proliferation and exhibit substantial phenotypic and functional alterations through epigenetic reprogramming following the vacating of macrophage niches by monocyte depletion. Our data thus suggest that a simultaneous blockade of monocyte recruitment and macrophage proliferation may effectively target immunosuppressive myelopoiesis and reprogram the microenvironment towards an immunostimulatory state. In liver metastasis of cancer, the inflammatory macrophage niche is dominated by both circulating monocytes and local expansion, but the nature and dynamic of this niche is still unclear. Here the authors use mouse genetic models and lineage-tracing tools to show that, under the condition of monocyte depletion, Kupffer cells pursue epigenetic reprogramming to contribute to this niche. [ABSTRACT FROM AUTHOR]

Background: Anorectal malignant melanoma (ARMM) has an extremely poor prognosis, and there is no report of resection of liver metastases so far. We report herein a rare case of postoperative laparoscopic partial hepatic S7 resection for rectal malignant melanoma. Case presentation: A 51-year-old female patient with a diagnosis of an ARMM underwent a laparoscopic rectal amputation. Eleven months later, computed tomography (CT) revealed a 14-mm nodule in liver segment 7 (S7), which was diagnosed as a hepatic recurrence of the ARMM. Because no other recurrences were found, a laparoscopic partial resection of S7 was performed. Pathological analysis found intracellular melanin deposition, and immunostaining was S-100 (+), HMB-45 (+), and SOX-10 (+). Based on these findings, a liver metastasis of malignant melanoma was diagnosed. The patient is alive 7 months after the second surgery and has so far experienced no recurrences. Conclusion: We reported an extremely rare case of a laparoscopic resection of a liver metastasis following surgery for ARMM. [ABSTRACT FROM AUTHOR]

Objective: This study focused on the analysis of the correlation between common gene mutation types and metastatic sites in NSCLC patients. Methods: We retrospectively studied 1586 NSCLC patients and used fluorescence Polymerase chain reaction (PCR) to detect EGFR, ALK, ROS1, RET, MET, BRAF, HER2, KRAS, NRAS, and PIK3CA gene mutations, and also investigated sex, smoking status, age at diagnosis, histological type and TNM stage. In addition, we analyzed the site of metastasis in patients with stage IV NSCLC. Results: The EGFR-mutation group more frequently metastasized to lung (18.9%, P = 0.004), brain (18.9%, P = 0.001) and bone (27.1%, P = 0.004) than wild-type patients. ALK-mutation group (71.0%, P < 0.001), BRAF-mutation group (82.4%, P = 0.005) and NRAS-mutation group (100%, P = 0.025) were more likely to metastasize than the wild-type group. In the ALK mutation, lung metastasis (24.2%, P = 0.013), brain (24.2%, P = 0.007), bone metastasis (32.3%, P = 0.024), liver metastasis (19.4%, P = 0.001), and pleural metastasis (29.0%, P = 0.021) were common. In the KRAS-mutation group, lung metastasis (21.7%, P = 0.012) and brain metastasis (23.3%, P = 0.001) were more common. Less metastasis occurred in the HER2-mutation group (28.3%, P = 0.014). There was no difference in the RET, MET and PIK3CA mutations. Conclusion: Patients with ALK mutant, BRAF mutant or NRAS mutant were more prone to metastasis, while the HER 2 mutation group was less metastatic. Patients with EGFR mutant NSCLC are more likely to develop bone, lung, or brain metastasis. [ABSTRACT FROM AUTHOR]

The quest to understand the molecular mechanisms of tumour metastasis and identify pivotal biomarkers for cancer therapy is increasing in importance. Single-omics analyses, constrained by their focus on a single biological layer, cannot fully elucidate the complexities of tumour molecular profiles and can thus overlook crucial molecular targets. In response to this limitation, we developed a multiobjective recommendation system (RJH-Metastasis 1.0) anchored in a multiomics knowledge graph to integrate genome, transcriptome, and proteome data and corroborative literature evidence and then conducted comprehensive analyses of colorectal cancer with liver metastasis (CRCLM). A total of 25 key genes significantly associated with CRCLM were recommended by our system, and GNB1, GATAD2A, GBP2, MACROD1, and EIF5B were further highlighted. Specifically, GNB1 presented fewer mutations but elevated RNA transcription and protein expression in CRCLM patients. The role of GNB1 in promoting the malignant behaviours of colon cancer cells was demonstrated via in vitro and in vivo studies. Aberrant expression of GNB1 could be regulated by METTL1-driven m7G modification. METTL1 knockdown decreased m7G modification in the 3' UTR of GNB1, increasing its mRNA transcription and translation during liver metastasis. Furthermore, GNB1 induced the formation of an immunosuppressive microenvironment by promoting the CLEC2C-KLRB1 interaction between memory B cells and KLRB1+PD-1+CD8+ cells. GNB1 expression and the efficacy of PD-1 antibody-based treatment in CRCLM patients were significantly correlated. In summary, our recommendation system can be used for effective exploration of key molecules in colorectal cancer, among which GNB1 was identified as a critical CRCLM promoter and immunotherapy biomarker in colorectal cancer patients. [ABSTRACT FROM AUTHOR]

Background: Tumours that metastasize to the ovary can occur in conjunction with other ovarian lesions, including benign sex cord stroma tumours like fibroma or fibrothecoma. This case report presents a unique instance of metastatic signet ring carcinoma involving the ovary in a background of fibroma in a Black African woman. Patient presentation: A 46-year-old gravida 3, para 0 (2 alive), patient was referred from the general outpatient clinic to the gynecology clinic due to progressive abdominal swelling over the past eight months. Abdominal examination revealed marked distension with massive ascites. Physical examination of the chest demonstrated dullness to percussion over both lung bases, with increased dullness noted on the right. Auscultation revealed decreased air entry in the right middle and lower lung zones, with normal to increased air entry in the remaining lung fields. Abdominopelvic ultrasound revealed a large irregularly marginated homogeneous solid mass in the right adnexa measuring 16.4 × 11.7 × 12.7 cm. An abdominal CT scan revealed bilateral pleural effusion, which was more pronounced on the right, ascites, and evidence of pulmonary and hepatic metastasis. Serum chemistry revealed abnormal levels of several analytes, including elevated CA 125 at 1,108.8 (normal range 0–35) U/L and CA 19–9 at 63.8 (normal range 0–35) U/L. She subsequently underwent staging laparotomy with total abdominal hysterectomy and bilateral salpingo-oophorectomy, without any postoperative complications. The histologic sections of the right and left ovaries revealed a moderately cellular lesion composed of intersecting bundles of spindle cells in a fascicular and storiform pattern. Additionally, pockets of small round to oval-shaped cells with intracytoplasmic clear vacuoles pushing the nucleus to the periphery (signet ring cells) were identified in a few foci. These cells were initially thought to be ovarian stroma or theca cells. Microscopic examination revealed signet ring cells with cytoplasmic positivity for periodic acid-Schiff (PAS) staining. The histopathological diagnosis was metastatic signet ring cell carcinoma involving the ovary, with an underlying ovarian fibroma. Conclusions: Ovarian metastatic signet ring carcinoma in a background of fibroma can pose a significant diagnostic challenge, as signet ring cells can mimic the ovarian stroma or theca cells, especially if they are only observed in a few foci of the sections. [ABSTRACT FROM AUTHOR]

Background: Recent evidence has demonstrated the vital roles of circular RNAs (circRNAs) in the progression of colorectal cancer (CRC); however, their functions and mechanisms in CRC need to be further explored. This study aimed to uncover the biological function of circXPO1 in CRC progression. Methods: CircXPO1 was identified by Sanger sequencing, RNase R, and actinomycin D treatment assays. Colony formation, scratch, transwell assays, and mouse xenograft models were adopted to evaluate CRC cell growth and metastasis in vitro and in vivo. Subcellular expression of circXPO1 was detected by FISH and nuclear-cytoplasmic separation assays. Molecular mechanisms were investigated by MeRIP, RIP, and RNA pull-down assays. Target molecular expression was detected by RT-qPCR, Western blotting and immunohistochemical staining. Results: circXPO1 was up-regulated in CRC tissues and cells, which indicated a poor prognosis of CRC patients. circXPO1 deficiency delayed the growth, EMT, and metastasis of CRC cells. Mechanistical experiments indicated that down-regulation of ALKBH5 enhanced IGF2BP2-mediated m6A modification of circXPO1 to increase circXPO1 expression. Furthermore, circXPO1 interacted with FMRP to reduce the mRNA stability of WWC2, which consequently resulted in Hippo-YAP pathway activation. Rescue experiments suggested that WWC2 overexpression abrogated circXPO1-mediated malignant capacities of CRC cells. The in vivo growth and liver metastasis of CRC cells were restrained by circXPO1 depletion or WWC2 overexpression. Conclusions: m6A-modified circXPO1 by ALKBH5/IGF2BP2 axis destabilized WWC2 via interaction with FMRP to activate Hippo-YAP pathway, thereby facilitating CRC growth and metastasis. Targeting circXPO1 might be a potential therapeutic strategy for CRC. [ABSTRACT FROM AUTHOR]

Distal metastases result from metastatic microenvironment and tumour epithelial cell interactions, the cellular heterogeneity of primary colorectal cancer (CRC) and liver metastases (LM) was evaluated by integrating single‐cell sequencing data, and the collected gene expression data from metastatic epithelial cell subsets was used to construct a prognostic model and to identify intercellular receptor‐ligand interactions between epithelial and immune cells in CRC and LM. Multiplex immunofluorescence staining, and in vitro wound healing, cell migration and cell apoptosis assays were performed to further explore the biological relevance of identified potential regulatory molecules. In this study, approximately 17 epithelial cell subtypes were detected, with Epi‐11 cells being highly expressed in LM tissues compared with CRC samples. Furthermore, patients with high expression of the metastasis‐related genetic profile of Epi‐11 had a poorer prognosis. By predicting receptor–ligand interactions, Epi‐11 cells were found to interact more with myeloid and T/natural killer cells in LM tissues when compared to primary CRC samples, which was mediated by the PLXNB1/SEMA4D axis. In addition, high SEMA4D expression was correlated with decreased overall survival of patients with CRC, whereas PLXNB1 was not. SEMA4D knockdown prevented the migration and promoted the apoptosis of HCT116 cells in vitro. In summary, Epi‐11 cells, an important subset of epithelial cells, may drive the LM of CRC and act by crosstalk with immune cells through the PLXNB1/SEMA4D signalling axis. [ABSTRACT FROM AUTHOR]

The abundance and biological contribution of natural killer (NK) cells in cancer are controversial. Here, we aim to uncover clinical relevance and cellular roles of NK cells in colon cancer liver metastasis (CCLM). Here, we integrated single- cell RNA- sequencing, spatial transcriptomics (ST), and bulk RNA- sequencing datasets to investigate NK cells' biological properties and functions in the microenvironment of primary and liver metastatic tumors. Results were validated through an in vitro co- culture experiment based on bioinformatics analysis. Useing single- cell RNA- sequencing and ST, we mapped the immune cellular landscape of colon cancer and well- matched liver metastatic cancer. We discovered that GZMK+ resting NK cells increased significantly in tumor tissues and were enriched in the tumor regions of both diseases. After combining bulk RNA and clinical data, we observed that these NK cell subsets contributed to a worse prognosis. Meanwhile, KIR2DL4+ activated NK cells exhibited the opposite position and relevance. Pseudotime cell trajectory analysis revealed the evolution of activated to resting NK cells. In vitro experiments further confirmed that tumor- cell- co- cultured NK cells exhibited a decidual- like status, as evidenced by remarkable increasing CD9 expression. Functional experiments finally revealed that NK cells exhibited tumoractivating characteristics by promoting the dissociation of SCF (stem cell factor) on the tumor cells membrane depending on cell- to- cell interaction, as the supernatant of the co- culture system enhanced tumor progression. In summary, our findings revealed resting NK cells exhibited a clinical relevance with CCLM, which may be exploited for novel strategies to improve therapeutic outcomes for patients with CCLM. [ABSTRACT FROM AUTHOR]

Background: Liver metastasis is one of the primary causes of poor prognosis in colon adenocarcinoma (COAD) patients, but there are few studies on its biomarkers. Methods: The Cancer Genome Atlas (TCGA)-COAD, GSE41258, and GSE49355 datasets were acquired from the public database. Differentially expressed genes (DEGs) between liver metastasis and primary tumor samples in COAD were identified by limma, and functional enrichment analysis were performed. MuTect2 and maftools were used to measure somatic mutation rates, while ADTEx was used to measure copy number variations (CNVs). The intersection of three machine learning methods, support vector machine (SVM), Random Forest, and least absolute shrinkage and selection operator (LASSO), is utilized to screen biomarkers, and their diagnostic performance is subsequently validated. The correlation between biomarkers and immune cells infiltration was analyzed by Spearman method. Results: 47 DEGs between liver metastasis and primary tumor samples in COAD were obtained, which were mainly enriched in the complement and coagulation, extracellular matrix (ECM), and peptidase regulator activity, etc. 38 out of 47 DEGs had mutations and exhibited a high frequency of CNV amplification or deletion. Furthermore, 3 biomarkers (MMP3, MAB21L2, and COLEC11) were screened, which showed good diagnostic performance. The proportion of multiple immune cells, such as B cells naive, T cells CD4 naive, Monocytes, and Dendritic cells resting, was higher in liver metastasis samples than that in primary tumor samples. Meanwhile, MMP3, MAB21L2, and COLEC11 exhibited an outstanding correlation with immune cells infiltration. Conclusion: In short, 3 biomarkers with good diagnostic efficacy were identified, providing a new perspective of therapeutic targets for liver metastasis in COAD. [ABSTRACT FROM AUTHOR]

Background: Although surgical resection is the curative treatment for colorectal liver metastases (CRLM), the efficacy of neoadjuvant chemotherapy (NAC) has been discussed due to recent remarkable advances in chemotherapy. The definition of borderline resectable (BR) is most important, where neoadjuvant chemotherapy should be administered. This study aimed to examine a new definition of BR CRLM based on the results of the treatment outcomes. Methods: This study included 127 patients who underwent liver resection for CRLM after exclusion of conversion cases between April 2010 and December 2023. Upfront resection was performed for synchronous and single liver metastasis or metachronous liver metastases. NAC was administered for multiple synchronous liver metastases. In order to find a new definition of BR, we examined the prognostic factors obtained from the treatment outcomes. Results: CA19-9 level > 37.0 was the only prognostic factor in the upfront group [hazard ratio (HR) 2.386, 95% CI, 1.583–4.769; p = 0.049]. in the NAC group, a maximum tumor diameter ˃3 cm (HR 2.248, 95% CI 1.038–4,867, p = 0.040), CA19-9 level > 37.0 (HR 2.239, 95% CI 1.044–4.800, p = 0.038), and a right-sided primary tumor in the colon (HR 2.770, 95% CI 1.284–5.988, p = 0.009) were identified as significant prognostic factors. Conclusions: In cases of CRLM, patients with CA19-9 levels > 37.0, or CA19-9 level with < 37.0 but with a primary tumor in the right colon or a maximum tumor diameter of > 3 cm can be defined as BR CRLM and should be treated with NAC. [ABSTRACT FROM AUTHOR]

Background: The study aimed to identify the optimal model for predicting rectal cancer liver metastasis (RCLM). This involved constructing various prediction models to aid clinicians in early diagnosis and precise decision-making. Methods: A retrospective analysis was conducted on 193 patients diagnosed with rectal adenocarcinoma were randomly divided into training set (n = 136) and validation set (n = 57) at a ratio of 7:3. The predictive performance of three models was internally validated by 10-fold cross-validation in the training set. Delineation of the tumor region of interest (ROI) was performed, followed by the extraction of radiomics features from the ROI. The least absolute shrinkage and selection operator (LASSO) regression algorithm and multivariate Cox analysis were employed to reduce the dimensionality of radiomics features and identify significant features. Logistic regression was employed to construct three prediction models: clinical, radiomics, and combined models (radiomics + clinical). The predictive performance of each model was assessed and compared. Results: KRAS mutation emerged as an independent predictor of liver metastasis, yielding an odds ratio (OR) of 8.296 (95%CI: 3.471–19.830; p < 0.001). 5 radiomics features will be used to construct radiomics model. The combined model was built by integrating radiomics model with clinical model. In both the training set (AUC:0.842, 95%CI: 0.778–0.907) and the validation set (AUC: 0.805; 95%CI: 0.692–0.918), the AUCs for the combined model surpassed those of the radiomics and clinical models. Conclusions: Our study reveals that KRAS mutation stands as an independent predictor of RCLM. The radiomics features based on MR play a crucial role in the evaluation of RCLM. The combined model exhibits superior performance in the prediction of liver metastasis. Clinical Trial Number: Not applicable. [ABSTRACT FROM AUTHOR]

Hyperprogressive disease (HPD) is described as the unexpected rapid growth of a tumour accompanied by a decline in performance status. While immune checkpoint inhibitors (ICIs) have improved outcomes in advanced melanoma, HPD remains a significant challenge in a subset of patients. Although HPD has been extensively studied in various solid tumours, research specifically focusing on advanced melanoma remains limited. We analysed 158 advanced melanoma patients, with 66.5% (n = 105) receiving anti-PD-1 and 33.5% (n = 53) receiving nivolumab plus ipilimumab. The median overall survival was 4.9 months for patients with HPD compared to 8.9 months for those with progressive disease without HPD (p = 0.014). Factors associated with HPD included liver metastasis (p = 0.002), three or more metastatic sites (p < 0.001), elevated lactate dehydrogenase levels (p = 0.004), and Eastern cooperative oncology group performance status ≥2 (p = 0.023). Multivariate analysis identified the Royal Marsden Hospital score (HR 3.675, 95% CI: 1.166–11.580, p = 0.026) as an independent risk factor for HPD, with the MDA-ICI score also trending towards significance (HR 4.466, 95% CI: 0.947–21.061, p = 0.059). This study provides valuable insights into the frequency and factors associated with HPD in advanced melanoma patients treated with ICIs, highlighting the relevance of clinical markers and scoring systems in predicting HPD risk. [ABSTRACT FROM AUTHOR]

A Prognostic Index for Liver Radiation (PILiR) for improved patient selection for stereotactic liver-directed radiotherapy (SBRT) was developed. Using a large single-center database, 195 patients treated with SBRT for local control, including 66 with hepatocellular carcinoma (HCC) and 129 with metastatic liver disease, were analyzed. Only patients ineligible for alternative treatments were included. Overall survival was 11.9 months and 9.4 months in the HCC group and metastatic groups, respectively. In the combined dataset, Child–Pugh Score (CPS) (p = 0.002), serum albumin (p = 0.039), and presence of extrahepatic disease (p = 0.012) were significant predictors of early death on multivariable analysis and were included in the PILiR (total score 0 to 5). Median survival was 23.8, 9.1, 4.5, and 2.6 months for patients with 0, 1–2, 3, and 4–5 points, respectively. In the HCC dataset, CPS (p < 0.001) and gross tumor volume (p = 0.013) were predictive of early death. In the metastatic dataset, serum albumin (p < 0.001) and primary disease site (p = 0.003) were predictive of early death. The AUC for the combined, HCC, and metastatic datasets are 0.78, 0.84, and 0.80, respectively. Poor liver function (defined by CPS and serum albumin) and extrahepatic disease were most predictive of early death, providing clinically important expected survival information for patients and caregivers. [ABSTRACT FROM AUTHOR]

The management of patients with colorectal liver metastases (CRLM) has transformed over the past 2 decades. Advances in surgical techniques, systemic therapies, and local treatments have resulted in a paradigm shift. Disease that would once have been considered terminal is now frequently treated aggressively with both a disease-free and overall survival benefit. In line with the expanding range of treatment options, there has been an increase in the volume and complexity of imaging required in the management of these patients to ensure optimal patient selection and outcome. The radiologist plays a pivotal role in interpreting these studies, conveying the relevant information and informing the discussion at multidisciplinary team meetings. The purpose of this review is to provide an update for radiologists on the current surgical management of patients with CRLM highlighting specific imaging information that is required by the multidisciplinary team when assessing resectability and/or the need for additional liver-directed therapies. [ABSTRACT FROM AUTHOR]

Colorectal cancer (CRC), a pervasive and lethal malignancy of gastrointestinal cancer, imposes significant challenges due to the occurrence of distant metastasis in advanced stages. Understanding the intricate regulatory mechanisms driving CRC distant metastasis is of paramount importance. CRISPR‐Cas9 screening has emerged as a powerful tool for investigating tumor initiation and progression. However, its application in studying CRC distant metastasis remains largely unexplored. To establish a model that faithfully recapitulates CRC liver metastasis in patients, we developed an in vivo genome‐wide CRISPR‐Cas9 screening approach using a spleen‐injected liver metastasis mouse model. Through comprehensive screening of a whole‐genome sgRNA library, we identified ANKRD42 as a pivotal regulatory gene facilitating CRC liver metastasis. Analysis of the TCGA database and our clinical cohorts unveiled heightened ANKRD42 expression in metastases. At the cellular level, the attenuation of ANKRD42 impaired the migration and invasion processes of tumor cells. In vivo experiments further validated these observations, highlighting the diminished liver metastatic capacity of tumor cells upon ANKRD42 knockdown. To unravel the specific mechanisms by which ANKRD42 regulates CRC distant metastasis, we leveraged patient‐derived organoid (PDO) models. Depleting ANKRD42 in PDOs sourced from liver metastases precipitated the downregulation of pivotal genes linked to epithelial‐mesenchymal transition (EMT), including CDH2 and SNAI2, thereby effectively suppressing tumor metastasis. This study not only establishes a conceptual framework but also identifies potential therapeutic avenues for advanced‐stage distant metastasis in CRC patients. [ABSTRACT FROM AUTHOR]

Purpose: The prognostic and predictive value of RAS mutations in patients with colorectal liver metastases (CRLM) who have undergone hepatectomy holds substantial importance. The present study aimed to investigate the impact of different RAS codon mutations on long‐term survival in CRLM patients. Methods: A retrospective analysis was conducted on clinicopathological data from 399 CRLM patients with RAS mutations who underwent hepatectomy between January 2000 and December 2020. The RAS mutation gene status was assessed in KRAS codons (G12, G13, Q61, and A146) and NRAS codons (G12, G13, and Q61). Survival curves were generated using the Kaplan–Meier plotter and compared using the log‐rank test. Univariate and multivariate analyses were performed to analyze the clinicopathological data. Results: In the entire cohort, patients with KRAS G12 mutations exhibited the most favorable prognosis (p = 0.018). Comparatively, patients harboring KRAS Q61 mutations experienced poorer overall survival (OS) with a median of 15 months versus 33 months (p = 0.011) when compared to those with KRAS G12 mutations. Moreover, patients with NRAS Q61 mutations also showed decreased OS with a median of 26 months versus 33 months (p = 0.020) in comparison to KRAS G12 mutation patients. The results of multivariate analysis showed that both KRAS Q61 mutation (HR 2.130; 95% CI 1.088–4.168; p = 0.027) and NRAS Q61 mutation (HR 2.877; 95% CI 1.398–5.922; p = 0.004) were independent influencing factors of OS. Based on all identified risk factors, patients with RAS mutation were divided into high‐risk and low‐risk groups. Notably, in the high‐risk group, the incorporation of postoperative chemotherapy was associated with longer OS, while it did not improve the survival of patients in the low‐risk group. Conclusions: KRAS Q61 and NRAS Q61 mutations are promising predictors for OS in CRLM patients after hepatectomy. Postoperative chemotherapy may significantly benefit CRLM patients with RAS mutations, particularly those identified as high‐risk. [ABSTRACT FROM AUTHOR]

Tumor-associated macrophages (TAMs) take on pivotal and complex roles in the tumor microenvironment (TME); however, their heterogeneity in the TME remains incompletely understood. ETS proto-oncogene 1 (ETS1) is a transcription factor that is mainly expressed in lymphocytes. However, its expression and immunoregulatory role in colorectal cancer (CRC)-associated macrophages remain unclear. In the study, the expression levels of ETS1 in CD68+ macrophages in the CRC microenvironment were significantly higher than those in matched paracarcinoma tissues. Importantly, ETS1 increased the levels of chemokines C-C motif chemokine ligand 2 (CCL2) and C-X-C motif chemokine ligand 10 (CXCL10) in lipopolysaccharide-stimulated THP-1 cells. It also boosted the migration and invasion of CRC cells during the in vitro co-culture. In the ETS1 conditional knockout mouse model, ETS1 deficiency in macrophages ameliorated the histological changes in DSS-induced ulcerative colitis mouse models and prolonged the survival in an azomethane/dextran sodium sulfate (AOM/DSS)-induced CRC model. ETS1 deficiency in macrophages substantially inhibited tumor formation, reduced F4/80+TIM4+ macrophages in the mesenteric lymph nodes, and decreased CCL2 and CXCL10 protein levels in tumor tissues. Moreover, ETS1 deficiency in macrophages effectively prevented liver metastasis of CRC and reduced the infiltration of TAMs into the metastasis sites. Subsequent studies have indicated that ETS1 upregulated the expression of T-cell immunoglobulin mucin receptor 4 in macrophages through the signal transducer and activator of the transcription 1 signaling pathway activated by the autocrine action of CCL2/CXCL10. Collectively, ETS1 deficiency in macrophages potentiates antitumor immune responses by repressing CCL2 and CXCL10 expression, shedding light on potential therapeutic strategies for CRC. [ABSTRACT FROM AUTHOR]

Objectives: The aim of our study was to evaluate the cooccurrence of capsular liver lesions along with peritoneal carcinomatosis and hematogenous metastases in other regions of the body in ovarian cancer patients on follow-up F-18 fluorodeoxyglucose (18F-FDG) positron emission tomography/ computed tomography (PET/CT) studies. Methods: Consecutive 18F-FDG PET/CT studies of 54 women with ovarian cancer between August 2012 and January 2020 and a total of 192 scans were analysed retrospectively. All patients had at least one hepatic and/or capsular lesion with high 18F-FDG uptake and at least two PET/ CT examinations. Results: According to interpretation, of 54 patients with hepatic or capsular lesions, 44 (81.4%), 5 (9.3%) and 5 (9.3%) of them were concluded as perihepatic implants, hematogenous liver metastases and both, respectively. Accompanying peritoneal carcinomatosis on follow-up PET/CT images was found in 42 (95.4%) and 3 (60%) patients with solely capsular lesions and solely hematogenous liver metastases, respectively. Extrahepatic hematogenous organ metastases on follow-up PET/CT images were seen in 4 (9.0%) and 3 (60%) patients with solely capsular lesions and solely hematogenous liver metastases, respectively. Lungs, bones, spleen and brain were detected metastases sites. Conclusion: Cooccurrence of peritoneal carcinomatosis in other regions of abdomen was found to be higher in comparison to hematogenous organ metastases on consecutive PET/CT studies of ovarian cancer patients with capsular liver lesions. The primary opinion of the nuclear medicine physician is essential along with the other patient data for differential diagnosis and treatment approach in this particular patient group. [ABSTRACT FROM AUTHOR]

Photoacoustic (PA) tomography is an emerging biomedical imaging technology for precision cancer medicine. Conventional small‐molecule PA probes usually exhibit a single PA signal and poor tumor targeting that lack the imaging reliability. Here, we introduce a series of cyanine/hemicyanine interconversion dyes (denoted Cy‐HCy) for PA/fluorescent dual‐mode probe development that features optimized ratiometric PA imaging and tunable tumor‐targeting ability for precise diagnosis and resection of colorectal cancer (CRC). Importantly, Cy‐HCy can be presented in cyanine (inherent tumor targeting and long NIR PA wavelength) and hemicyanine (poor tumor targeting and short NIR PA wavelength) by fine‐tuning torsion angle and the ingenious transformation between cyanine and hemicyanine through regulation optically tunable group endows the NIR ratiometric PA and tunable tumor‐targeting properties. To demonstrate the applicability of Cy‐HCy dyes, we designed the first small‐molecule tumor‐targeting and NIR ratiometric PA probe Cy‐HCy‐H2S for precise CRC liver metastasis diagnosis, activated by H2S (a CRC biomarker). Using this probe, we not only visualized the subcutaneous tumor and liver metastatic cancers in CRC mouse models but also realized PA and fluorescence image‐guided tumor excision. We expect that Cy‐HCy will be generalized for creating a wide variety of inherently tumor‐targeting NIR ratiometric PA probes in oncological research and practice. [ABSTRACT FROM AUTHOR]

A 78-year-old man with a history of GI stromal tumor (GIST) in the stomach with metastasis to the liver presented with progressive shortness of breath, dry cough, and subjective fever that started 1 week after radioembolization of liver metastatic lesions. His initial diagnosis of GIST was 10 years before, for which he underwent surgical resection; however, more recently he was noted to have hepatic lesions biopsy-proven to be metastatic GIST lesions. He stated that he did not have any respiratory symptoms before the radioembolization procedure and denied having a history of pulmonary disease. His medical history was otherwise notable for coronary artery disease post coronary artery bypass graft in 2002, heart failure with reduced ejection fraction, and atrioventricular block after pacemaker placement. After the diagnosis of liver metastasis, he began treatment with imatinib 6 months earlier and consequently received radioembolization with yttrium-90 (Y-90) microspheres. [ABSTRACT FROM AUTHOR]

Background: The treatment and prognosis of de novo metastatic hormone-sensitive prostate cancer (mHSPC) vary. We established and validated a novel prognostic model for predicting cancer-specific survival (CSS) in patients with mHSPC using retrospective data from a contemporary cohort. Methods: 1092 Japanese patients diagnosed with de novo mHSPC between 2014 and 2020 were registered. The patients treated with androgen deprivation therapy and first-generation anti-androgens (ADT/CAB) were assigned to the Discovery (N = 467) or Validation (N = 328) cohorts. Those treated with ADT and androgen-receptor signaling inhibitors (ARSIs) were assigned to the ARSI cohort (N = 81). Results: Using the Discovery cohort, independent prognostic factors of CSS, the extent of disease score ≥ 2 or the presence of liver metastasis; lactate dehydrogenase levels > 250U/L; a primary Gleason pattern of 5, and serum albumin levels ≤ 3.7 g/dl, were identified. The prognostic model incorporating these factors showed high predictability and reproducibility in the Validation cohort. The 5-year CSS of the low-risk group was 86% and that of the high-risk group was 22%. Approximately 26.4%, 62.7%, and 10.9% of the patients in the Validation cohort defined as high-risk by the LATITUDE criteria were further grouped into high-, intermediate-, and low-risk groups by the new model with significant differences in CSS. In the ARSIs cohort, high-risk group had a significantly shorter time to castration resistance than the intermediate-risk group. Conclusions: The novel model based on prognostic factors can predict patient outcomes with high accuracy and reproducibility. The model may be used to optimize the treatment intensity of de novo mHSPC. [ABSTRACT FROM AUTHOR]

Objective [ 177 Lu]Lu-prostate-specific membrane antigen (PSMA)-617 radioligand therapy (RLT) shows promise for metastatic castration-resistant prostate cancer (mCRPC) patients with positive PSMA positron emission tomography (PET) imaging. Identifying high-risk patients is crucial. We evaluated pretherapeutic PSMA PET-derived parameters to predict prostate-specific antigen (PSA) response in patients undergoing [ 177 Lu]Lu-PSMA-617 RLT. Materials and Methods We conducted a retrospective analysis among 27 patients (mean age: 71.0 ± 9.5 years; range: 52–85 years) who underwent PSMA PET/computed tomography (CT) and subsequent [ 177 Lu]Lu-PSMA-617 RLT between March 2019 and January 2023. After excluding patients with liver metastases, the number of patients left for analysis was 21 (14 responders and 7 nonresponders). Tumors were semiautomatically delineated with calculation of total tumor volume (PSMA-TV), lesion uptake (PSMA-TLU = PSMA-TV * standardized uptake value [SUV]mean), and lesion quotient (PSMA-TLQ = PSMA-TV/SUVmean) for each patient. Semiquantitative parameters were analyzed only in patients with mCRPC and no liver metastasis. Results In total, 17/27 patients (62.96%) had a decline in PSA levels; 15/27 patients (55.56%) experienced a decline of > 50%. Pretherapeutic PSMA PET/CT results revealed significant differences in PSMA-TV (p = 0.003), PSMA-TLU (p = 0.013), and PSMA-TLQ (p = 0.011) between responders and nonresponders. SUVmax was significantly correlated to the best percentage change in PSA response after 177 Lu-PSMA-617 treatment (r = −0.79, p = 0.006). No association was observed between PSMA-TV (p = 0.367), PSMA-TLU (p = 0.128), and PSMA-TLQ (p = 0.556), with the best percentage change in PSA response after 177 Lu-PSMA-617 therapy. Conclusion Pretherapeutic PSMA PET-derived PSMA-TV, PSMA-TLU, and PSMA-TLQ were significant negative predictors of PSA response in patients with mCRPC and no liver metastasis receiving [ 177 Lu]Lu-PSMA-617 RLT. [ABSTRACT FROM AUTHOR]

Objective: Our objective was to evaluate the predictive factors and metastatic time for liver and lung metastasis in locally advanced rectal cancer (RC) patients. Methods: Univariate and multivariate analysis were performed to identify risk factors and prognostic factors for liver metastasis and lung metastasis in RC. Survival probabilities were calculated using the Kaplan–Meier model and compared using the log-rank test between groups. The probability of time-to-event occurrence was calculated using the random survival forest model. Finally, the SEER database was used to verify our findings. Results: Our results indicated that pathological T stage and pathological N stage were independent predictive factors for liver metastasis. Furthermore, CEA level, pathological T stage, and tumor deposit were independent predictive factors for lung metastasis. Based on the results of a multivariate Cox analysis, we categorized patients with liver and lung metastasis into three groups based on their scores. The results revealed that patients with higher scores had a higher probability of experiencing metastasis. For liver metastasis, Groups 1, 2, and 3 all exhibited higher occurrence rates within the first 24 months. However, for lung metastasis, Group 4 showed the highest occurrence rate at the 12th month, while Groups 5 and 6 exhibited the highest occurrence rates at the 15th month. Conclusions: In summary, we developed predictive models to determine the likelihood of liver and lung metastasis in RC patients. It is crucial to implement a more intensive surveillance program for patients with unfavorable risk profiles in order to facilitate early detection of metastasis. [ABSTRACT FROM AUTHOR]

Purpose: This study aimed to determine the diagnostic efficacy of various indicators and models for the prediction of gastric cancer with liver metastasis. Methods: Clinical and spectral computed tomography (CT) data from 80 patients with gastric adenocarcinoma who underwent surgical resection were retrospectively analyzed. Patients were divided into metastatic and non-metastatic groups based on whether or not to occur liver metastasis, and the region of interest (ROI) was measured manually on each phase iodine map at the largest level of the tumor. Iodine concentration (IC), normalized iodine concentration (nIC), and clinical data of the primary gastric lesions were analyzed. Logistic regression analysis was used to construct the clinical indicator (CI) and clinical indicator-spectral CT iodine concentration (CI-Spectral CT-IC) Models, which contained all of the parameters with statistically significant differences between the groups. Receiver operating characteristic (ROC) curves were constructed to evaluate the accuracy of the models. Results: The metastatic group showed significantly higher levels of Cancer antigen125 (CA125), carcinoembryonic antigen (CEA), IC, and nIC in the arterial phase, venous phase, and delayed phase than the non-metastatic group (all p < 0.05). Normalized iodine concentration Venous Phase (nICVP) exhibited a favorable performance among all IC and nIC parameters for forecasting gastric cancer with liver metastasis (area under the curve (AUC), 0.846). The combination model of clinical data with significant differences and nICVP showed the best diagnostic accuracy for predicting liver metastasis from gastric cancer, with an AUC of 0.897. Conclusion: nICVP showed the best diagnostic efficacy for predicting gastric cancer with liver metastasis. Clinical Indicators-normalized ICVP model can improve the prediction accuracy for this condition. [ABSTRACT FROM AUTHOR]

Metastatic breast cancer (mBC) remains incurable and liver metastases (LM) are observed in approximately 50% of all patients with mBC. In some cases, surgical resection of breast cancer liver metastases (BCLM) is associated with prolonged survival. However, there are currently no validated marker to identify these patients. The interactions between the metastatic cancer cells and the liver microenvironment result in two main histopathological growth patterns (HGP): replacement (r-HGP), characterized by a direct contact between the cancer cells and the hepatocytes, and desmoplastic (d-HGP), in which a fibrous rim surrounds the tumor cells. In patients who underwent resection of BCLM, the r-HGP is associated with a worse postoperative prognosis than the d-HGP. Here, we aim at unraveling the biological differences between these HGP within ten patients presenting both HGP within the same metastasis. The transcriptomic analyses reveal overexpression of genes involved in cell cycle, DNA repair, vessel co-option and cell motility in r-HGP while angiogenesis, wound healing, and several immune processes were found overexpressed in d-HGP LM. Understanding the biology of the LM could open avenues to refine treatment of BC patients with LM. [ABSTRACT FROM AUTHOR]

Purpose: Advances in surgical procedures and immunosuppressive therapies have considerably improved the outcomes of patients who have undergone liver transplantation in the past few decades. In 2020, the Italian Liver Transplant Working Group published practice-oriented algorithms for immunosuppressive therapy (IT) in adult liver transplant (LT) recipients. Due to the rapidly evolving LT field, regular updates to the recommendations are required. This review presents a consensus- and evidence-based update of the 2020 recommendations. Methods: The Italian Liver Transplant Working Group set out to address new IT issues, which were discussed based on supporting literature and the specialists' personal experiences. The panel deliberated on and graded each statement before consensus was reached. Results: A series of consensus statements were formulated and finalized on: (i) oncologic indications for LT; (ii) management of chronic LT rejection; (iii) combined liver–kidney transplantation; (iv) immunosuppression for transplantation with an organ donated after circulatory death; (v) transplantation in the presence of frailty and sarcopenia; and (vi) ABO blood group incompatibility between donor and recipient. Algorithms were updated in the following LT groups: standard patients, critical patients, oncology patients, patients with specific etiology, and patients at high immunologic risk. A steroid-free approach was generally recommended, except for patients with autoimmune liver disease and those at high immunologic risk. Conclusion: The updated consensus- and evidence-based 2024 recommendations for immunosuppression regimens in adult patients with ABO-compatible LT address a range of clinical variables that should be considered to optimize the choice of the immunosuppression treatment in clinical practice in Italy. [ABSTRACT FROM AUTHOR]

The presence of Fusobacterium nucleatum is associated with an immunosuppressive tumor immune microenvironment (TIM) in primary colorectal cancer (CRC), contributing to tumor progression. Its persistence in CRC liver metastasis tissues raises questions about its role in modulating local and systemic immune responses and influencing recurrence patterns. This retrospective cohort study of 218 patients with CRC liver metastasis investigated the association of F. nucleatum in CRC liver metastasis tissues with systemic inflammation, TIM alterations, and the number of metastatic organs involved in recurrence. Two‐step polymerase chain reaction (PCR), including digital PCR, detected F. nucleatum in 42% (92/218) of fresh‐frozen specimens of CRC liver metastases. Compared with the F. nucleatum‐none group, the F. nucleatum‐high group showed higher C‐reactive protein levels (0.82 vs. 0.22 mg/dL; Ptrend = 0.02), lower numbers of CD8+ cells (33.2 vs. 65.3 cells/mm2; Ptrend = 0.04) and FOXP3+ cells (11.3 vs. 21.7 cells/mm2; Ptrend = 0.01) in the TIM, and a greater number of metastatic organs involved in recurrence (1.6 vs. 1.1; p < 0.001). The presence of F. nucleatum in CRC liver metastasis tissues was associated with increased systemic inflammation, TIM alterations, and a greater number of metastatic organs involved in recurrence. These findings suggest a potential contribution of F. nucleatum to the metastatic propensity of CRC cells and could inform future research to enhance understanding of the interaction between tumor, host, and microbes in the metastatic process. [ABSTRACT FROM AUTHOR]

ABSTACT: Gastrointestinal stromal tumors (GISTs) originate from the gastrointestinal tract. GISTs originate outside the gastrointestinal tract, referred to as extra GISTs, which is rare. Primary liver gastrointestinal stromal tumor (PLGIST) and liver metastasis of gastrointestinal stromal tumor (LMGIST) may present isolated liver lesion, making it difficult to determine their origin. A 38‐year‐old man who presented with isolated multiple giant cystic‐solid liver lesions, ultimately diagnosed as liver GIST through CT‐guided fine‐needle aspiration. However, distinguishing between PLGIST and LMGIST in this case is challenging due to the absence of detailed medical records of emergency small intestine resection 5 years ago. Over 2‐year follow‐up period, the maximum lesion size increased from 16 to 21 cm, still, no extra liver lesions were observed. This study aims to provide a review to enhance understanding of this rare liver entity, aiding in tumor diagnosis and staging. [ABSTRACT FROM AUTHOR]

Uveal melanoma (UM), the primary intraocular tumor in adults, arises from eye melanocytes and poses a significant threat to vision and health. Despite its rarity, UM is concerning due to its high potential for liver metastasis, resulting in a median survival of about a year after detection. Unlike cutaneous melanoma, UM responds poorly to immune checkpoint inhibition (ICI) due to its low tumor mutational burden and PD-1/PD-L1 expression. Tebentafusp, a bispecific T cell engager (TCE) approved for metastatic UM, showed potential in clinical trials, but the objective response rate remains modest. To enhance TCE efficacy, we explored quantitative systems pharmacology (QSP) modeling in this study. By integrating a TCE module into an existing QSP model and using clinical data on UM and tebentafusp, we aimed to identify and rank potential predictive biomarkers for patient selection. We selected 30 important predictive biomarkers, including model parameters and cell concentrations in tumor and blood compartments. We investigated biomarkers using different methods, including comparison of median levels in responders and non-responders, and a cutoff-based biomarker testing algorithm. CD8+ T cell density in the tumor and blood, CD8+ T cell to regulatory T cell ratio in the tumor, and naïve CD4+ density in the blood are examples of key biomarkers identified. Quantification of predictive power suggested a limited predictive power for single pre-treatment biomarkers, which was improved by early on-treatment biomarkers and combination of predictive biomarkers. Ultimately, this QSP model could facilitate biomarker-guided patient selection, improving clinical trial efficiency and UM treatment outcomes. [ABSTRACT FROM AUTHOR]

AbstractThis study aimed to create a prognostic nomogram to predict the risk of liver metastasis (LM) in thyroid cancer (TC) patients and assess survival outcomes for those with LM. Data were collected from the SEER database, covering TC patients from 2010 to 2020, totaling 110,039 individuals, including 142 with LM. Logistic regression and stepwise regression based on the Akaike information criterion (AIC) identified significant factors influencing LM occurrence: age, histological type, tumor size, bone metastasis, lung metastasis, and T stage (p < 0.05). A nomogram was constructed using these factors, achieving a Cindex of 0.977, with ROC curve analysis showing an area under the curve (AUC) of 0.977. For patients with TCLM, follicular TC, medullary TC, papillary TC, and examined regional nodes were associated with better prognosis (p < 0.001, HR < 1), while concurrent brain metastasis indicated poorer outcomes (HR = 2.747, p = 0.037). In conclusion, this nomogram effectively predicts LM risk and evaluates prognosis for TCLM patients, aiding clinicians in personalized treatment decisions [ABSTRACT FROM AUTHOR]

Background: Patient-derived tumour organoids (PDOs) are highly advanced in vitro models for disease modelling, yet they lack vascularisation. To overcome this shortcoming, organoids can be inoculated onto the chorioallantoic membrane (CAM); the highly vascularised, not innervated extraembryonic membrane of fertilised chicken eggs. Therefore, we aimed to (1) establish a CAM patient-derived xenograft (PDX) model based on PDOs generated from the liver metastasis of a colorectal cancer (CRC) patient and (2) to evaluate the translational pipeline (patient – in vitro PDOs – in vivo CAM-PDX) regarding morphology, histopathology, expression of C-X-C chemokine receptor type 4 (CXCR4), and radiotracer uptake patterns. Results: The main liver metastasis of the CRC patient exhibited high 2-[18F]FDG uptake and moderate and focal [68Ga]Ga-Pentixafor accumulation in the peripheral part of the metastasis. Inoculation of PDOs derived from this region onto the CAM resulted in large, highly viable, and extensively vascularised xenografts, as demonstrated immunohistochemically and confirmed by high 2-[18F]FDG uptake. The xenografts showed striking histomorphological similarity to the patient's liver metastasis. The moderate expression of CXCR4 was maintained in ovo and was concordant with the expression levels of the patient's sample and in vitro PDOs. Following in vitro re-culturing of CAM-PDXs, growth, and [68Ga]Ga-Pentixafor uptake were unaltered compared to PDOs before transplantation onto the CAM. Although [68Ga]Ga-Pentixafor was taken up into CAM-PDXs, the uptake in the baseline and blocking group were comparable and there was only a trend towards blocking. Conclusions: We successfully established an in vivo CAM-PDX model based on CRC PDOs. The histomorphological features and target protein expression of the original patient's tissue were mirrored in the in vitro PDOs, and particularly in the in vivo CAM-PDXs. The [68Ga]Ga-Pentixafor uptake patterns were comparable between in vitro, in ovo and clinical data and 2-[18F]FDG was avidly taken up in the patient's liver metastasis and CAM-PDXs. We thus propose the CAM-PDX model as an alternative in vivo model with promising translational value for CRC patients. [ABSTRACT FROM AUTHOR]

Background: Irreversible electroporation has been proved as a feasible and safe method against tumor in liver. However, few studies focused on tumors adjacent to perihepatic important structure like vessels, biliary system and gall bladder. These structures limit the effectiveness of conventional treatments. The aim of this article is to analyze the clinical outcomes of patients with hepatic tumors at the special sites who received IRE treatment and provide reliable evidence for broadening the scope of IRE's clinical application. Methods: The clinical information of patients who underwent IRE ablation for tumors adjacent to perihepatic important structure between February 2017 and December 2021 was collected and retrospectively analyzed. All patients underwent contrast-enhanced CT or MRI for further evaluation at the 1-month follow-up and every 3 months thereafter. Post-ablation complications, recurrence, progression-free survival and overall survival were evaluated to analyze the prognosis of IRE ablation adjacent to perihepatic important structure. Categorical variables are presented as numbers followed by percentages. Continuous data are presented as the mean ± deviation. The tumor size and IRE ablation size were evaluated by the maximum diameters. Results: Thirty-two patients who underwent IRE ablation for tumor adjacent to perihepatic important structure were studied in this research. There were 39 lesions in 32 patients treated with IRE ablation. Fourteen of them (35.9%) were located adjacent to the porta hepatis, and 8 of them (20.5%) were located adjacent to the hepatocaval confluence. Subcapsular lesions accounted for 15.4% (6 of 39 lesions). The other 11 lesions were in the para gallbladder (5 of 39 lesions, 12.8%), the caudate lobe (5 of 39 lesions, 12.8%) and the colonic hepatic flexure (1 of 39 lesions, 2.6%). According to the Clavien-Dindo classification system for complications, all relative patients with cancer experienced complications below class III except one patient who developed postoperative hemorrhagic shock and improved after timely treatment. Recurrence in situ was observed in 5 of 32 (15.6%) patients. The median PFS of the patients who received IRE ablation was 384 days, and the median OS was 571 days. Conclusion: IRE ablation is a feasible and safe treatment strategy for tumors adjacent to perihepatic important structure. With improved equipment, optimized therapeutic parameters and long-term clinical trials, IRE will play an increasingly important role in the treatment of tumors in liver. [ABSTRACT FROM AUTHOR]

Epithelioid inflammatory myofibroblastic sarcoma (EIMS) is a rare subtype of inflammatory myofibroblastic tumor, characterized to be an aggressive disease with high frequency of ALK rearrangement, rapid recurrence, and poor prognosis. Primary EIMS of thoracic origin is rarely observed. Herein, we described a case of 28-year-old female developed primary EIMS in the anterior mediastinum with hepatic metastasis. The EIMS displayed sheet-like growth of epithelioid and spindle cells with enlarged nuclei, abundant and eosinophilic cytoplasm, and infiltration of inflammatory cells. Immunohistochemical staining revealed positive expression of ALK in the nuclear membrane, and ALK rearrangement was identified by polymerase chain reaction assay. Alectinib showed partial response, and achieved a meaningful survival benefit for four months. Based on this case report and literature review, ALK inhibitor reveals promising activity on the rare but aggressive EIMS. Awareness of EIMS in thoracic disease and its clinicopathological features is essential to avoid erroneous diagnosis. [ABSTRACT FROM AUTHOR]

Background: About half of the patients with esophageal cancer are presenting with metastasis at initial diagnosis. However, few studies have concerned on the prognostic factors of metastatic esophageal adenocarcinoma (mEAC). This research aimed to investigate the effects of single bone metastasis (BM) and single liver metastasis (LM) on prognosis of mEAC patients. Methods: Data were obtained from the National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) Program database. We compared the effects of LM and BM on overall survival (OS), EAC-specific survival (CSS), and EAC-specific death (EASD) by multivariate Cox regression, Kaplan-Meier analysis, and competing risk regression models. Results: A total of 1,278 EAC patients were recruited in this study. Of which 78.95% (1009/1278) were EASD, and 12.68% (162/1278) were non-EAC-specific death (non-EASD). In multivariate Cox regression analysis, surgery, chemotherapy, and AJCC.T2 (vs. T1) were identified as protective factors for OS&CSS, while divorced/separated, single/unmarried (vs. married), grade III-IV (vs. grade I-II) and BM (vs. LM) were identified as risk factors. Competing risk regression analysis further confirmed that surgery and chemotherapy were beneficial to the patients with mEAC, and BM (vs. LM) was a risk factor for mEAC patients when considering the existence of the competitive risk events. Conclusion: Our study indicated that mEAC patients with BM face a worse prognosis compared to those with LM. Additionally, surgery and chemotherapy emerge as protective factors for mEAC patients. These findings offer evidence-based insights for clinical management and contribute to the field. [ABSTRACT FROM AUTHOR]

Background: Metastasis is the primary cause of lung cancer-related death. Primary cancer cells invade through the lymphatic or blood vessels to distant sites. Recently, it was proposed that lymphatic metastasis was more a hallmark of tumor aggressiveness or metastatic potential than a gateway to metastases. Therefore, the underlying molecular mechanism of metastasis is not entirely clear. Objectives: This study aimed to explore the genetic mechanisms underlying liver metastases from lung cancer and to evaluate the efficacy of different therapies in these patients. Design: We retrospectively analyzed the mutation spectrum of different biopsy samples including primary lung tumors, liver, lymph node metastasis, and circulating tumor DNA (ctDNA) from 1090 non-small-cell lung cancer (NSCLC) patients with liver metastasis between the years 2017 and 2022. Methods: Demographic and disease characteristics were summarized using descriptive parameters. Time to treatment discontinuation was used to analyze the clinical outcome. Results: More liquid biopsies were performed than tissue biopsies, especially in the treated advanced NSCLC patients. Liver metastasis before treatment was associated with poor response to immune checkpoint inhibitors and targeted therapy. Liver and lymph node metastasis had higher levels of single nucleotide variants and copy number variants than primary lung tumors. In paired lung and liver, lymph nodes, and simultaneous ctDNA, we found actionable mutations were always shared, while metastasis samples had multiple private mutations. Serial ctDNA analysis identifies potential resistant mutations and describes the evolution of tumor cells. Conclusion: Liver and lymph node metastasis in NSCLC showed shared actionable mutations. Of note, the discrepancy of private mutations in liver and lymph node metastases indicated that liver metastases are mainly seeded by the primary tumor rather than the earlier colonized lymph node metastases. [ABSTRACT FROM AUTHOR]

Introduction: Colorectal cancer (CRC) is one of the most common malignancies, with liver metastasis being its most common form of metastasis. The diagnosis of colorectal cancer liver metastasis (CRCLM) mainly relies on imaging techniques and puncture biopsy techniques, but there is no simple and quick early diagnosisof CRCLM. Methods: This study aims to develop a method for rapidly detecting the risk of liver metastasis in CRC patients through blood test indicators based on machine learning (ML) techniques, thereby improving treatment outcomes. To achieve this, blood test indicators from 246 CRC patients and 256 CRCLM patients were collected and analyzed, including routine blood tests, liver function tests, electrolyte tests, renal function tests, glucose determination, cardiac enzyme profiles, blood lipids, and tumor markers. Six commonly used ML models were used for CRC and CRCLM classification and optimized by using a feature selection strategy. Results: The results showed that AdaBoost algorithm can achieve the highest accuracy of 89.3% among the six models, which improved to 91.1% after feature selection strategy, resulting with 20 key markers. Conclusions: The results demonstrate that the combination of machine learning techniques with blood markers is feasible and effective for the rapid diagnosis of CRCLM, significantly im-proving diagnostic ac-curacy and patient prognosis. [ABSTRACT FROM AUTHOR]

Introduction: Biology-guided radiotherapy (BgRT) is a novel radiation delivery approach utilizing fluorodeoxyglucose (FDG) activity on positron emission tomography (PET) imaging performed in real-time to track and direct RT. Our institution recently acquired the RefleXion X1 BgRT system and sought to assess the feasibility of targeting metastatic sites in various organs, including the liver. However, in order for BgRT to function appropriate, adequate contrast in FDG activity between the tumor and the background tissue, referred to as the normalized SUV (NSUV), is necessary for optimal functioning of BgRT. Methods: We reviewed the charts of 50 lung adenocarcinoma patients with liver metastases. The following variables were collected: SUVmax and SUVmean for each liver metastasis, SUVmean and SUVmax at 5 and 10 mm radially from the lesion, and NSUV at 5 mm and 10 mm (SUVmax of the liver metastasis divided by SUV mean at 5 mm at 10 mm respectively). Results: 82 measurable liver metastases were included in the final analysis. The average SUVbackground of liver was 2.26 (95% confidence interval [CI] 2.17–2.35); average SUVmean for liver metastases was 5.31 (95% CI 4.87–5.75), and average SUVmax of liver metastases was 9.19 (95% CI 7.59–10.78). The average SUVmean at 5 mm and 10 mm radially from each lesion were 3.08 (95% CI 3.00-2.16) and 2.60 (95% CI 2.52–2.68), respectively. The mean NSUV at 5 mm and 10 mm were 3.13 (95% CI 2.53–3.73) and 3.69 (95% CI 3.00-4.41) respectively. Furthermore, 90% of lesions had NSUV greater than 1.45 at 5 mm and greater than 1.77 at 10 mm. Conclusions: This is the first study to comprehensively characterize FDG contrast between the liver tumor and background, referred to as NSUV. Due to the high background SUV normally found in the liver, this work will be valuable for guiding optimization of BgRT for treating liver metastases in the future using the RefleXion® X1 and potentially other similar BgRT platforms. [ABSTRACT FROM AUTHOR]

Background: Absolute lymphocyte count (ALC) is a predictive and prognostic factor for various tumor types, including breast cancer. Palbociclib is a CDK4/6 inhibitor widely used for the treatment of metastatic estrogen receptor (ER)-positive, HER2-negative breast cancer. However, predictive biomarkers of the efficacy of palbociclib remain unelucidated. We conducted a retrospective study to examine the predictive value of the baseline ALC in patients treated with palbociclib. Methods: The medical records of patients with ER-positive, HER2-negative breast cancer treated with palbociclib plus hormonal therapy between December 2017 and December 2021 were analyzed retrospectively. The cutoff value of ALC was set at 1800 cells/μL at the initiation of palbociclib treatment. The clinical benefit rate (CBR) was defined as the rate of complete or partial response or stable disease for at least 6 months. Progression-free survival (PFS) rates were estimated using the Kaplan–Meier method and compared using the log-rank test. Univariate and multivariate analyses were performed using Cox proportional hazards regression. Results: All of the 202 patients were women, with a median age of 59 years and a performance status (PS) of ≤ 2. The median numbers of lines of chemotherapy and endocrine therapy before palbociclib treatment were 0 (range, 0–9) and 1 (range, 0–7), respectively. Fifty-one patients had liver metastases. Forty-six patients tested negative for progesterone receptor (PgR) expression. The median follow-up time was 9.1 months. The CBR was significantly higher in the ALC-high group than in the ALC-low group (79% vs. 60%; P = 0.018). The median PFS was significantly longer in the ALC-high group than in the ALC-low group (26.8 months vs. 8.4 moths, respectively; P = 0.000013). ALC, age, PS, PgR status, prior chemotherapy, prior endocrine therapy, and liver metastasis were entered into the multivariate analysis. ALC was identified as an independent factor for PFS (P = 0.00085), along with liver metastasis (P = 0.0020), PS (P = 0.026), and prior endocrine therapy (P = 0.019). Conclusion: ALC can serve as a predictor of palbociclib efficacy in patients with metastatic ER-positive, HER2-negative breast cancer. [ABSTRACT FROM AUTHOR]

Colorectal cancer (CRC) is the second common cause of cancer mortality worldwide, and it still lacks effective approaches for relapsed and metastatic CRC. Recently, oncolytic virus has been emerged as a promising immune therapeutic strategy. In this study, we develop a novel oncolytic adenovirus, rAd.mDCN.mCD40L, which drive oncolytic activity by telomerase reverse transcriptase promoter (TERTp). rAd.mDCN.mCD40L expressed both mouse genes of decorin (mDCN) and CD40 ligand (mCD40L), and produced effective cytotoxicity in both human and mouse CRC cells. Moreover, oncolytic adenovirus mediated mDCN over-expression inhibited Met expression in vitro. In CT26 subcutaneous tumor model, intratumorally delivery of oncolytic adenoviruses could inhibit tumor growth and liver metastasis, while mDCN and/or mCD40L armed oncolytic adenoviruses produced much more impressive responses. No obvious toxicity was detected in lung, liver and spleen. Moreover, mDCN and/or mCD40L armed oncolytic adenoviruses altered the immune state to activate anti-tumor responses, including increasing CD8+ T effector cells and CD4+ memory T cells, reducing MDSCs and Tregs in peripheral blood. Furthermore, mDCN and/or mCD40L armed oncolytic adenoviruses mediated mDCN and/or mCD40L expression in tumors, and up-regulated Th1 cytokines and reduced Th2 cytokines in tumors, which will be benefit for remodeling tumor microenvironment. Importantly, rAd.mDCN.mCD40L and rAd.mCD40L prevented tumor liver metastasis much more effectively than rAd.Null and rAd.mDCN. Therefore, rAd.mDCN.mCD40L and rAd.mCD40L are promising approaches for CRC therapy. [ABSTRACT FROM AUTHOR]

Purpose: To compare the efficacy of first‐line regimens based on programmed cell death (or ligand) [PD‐(L)1] blockade in extensive‐stage small‐cell lung cancer (ES‐SCLC) patients with or without liver metastases (LM), and to identify optimal treatment strategies. Methods: Network meta‐analysis of randomized controlled trials (RCTs) comparing chemo‐immunotherapy (CIT) and chemotherapy (CT) in ES‐SCLC patients stratified by LM. Overall survival (OS) and progression‐free survival (PFS) were evaluated using hazard ratios (HRs) and 95% confidence intervals (CIs). Results: Seven RCTs involving 3658 ES‐SCLC patients (1243 with LM, 2415 without LM) were analyzed. For patients with LM, the combination therapies of anti‐PD‐1 + CT (HR, 0.67; 95% CI, 0.54%–0.82%; p < 0.001) and anti‐PD‐L1 + CT + anti‐angiogenesis (HR, 0.84; 95% CI, 0.71%–0.99%; p = 0.042) demonstrated superior efficacy in prolonging OS compared to CT alone. The anti‐PD‐1 + CT regimen had the highest cumulative probability of 91.6% for extending OS in patients with LM. For patients without LM, all CIT regimens resulted in improved OS compared to CT alone, with the regimen of anti‐angiogenesis + anti‐PD‐L1 + CT ranking first and having the highest cumulative probability of 95.5% for prolonging OS. Conclusions: CIT is effective for ES‐SCLC patients regardless of LM status. For patients with LM, PD‐1 blockade combined with CT is the best option. For patients without LM, the most beneficial regimen is the combination of anti‐angiogenesis, PD‐L1 blockade, and CT. [ABSTRACT FROM AUTHOR]

Simple Summary: Due to the lack of cancer cell-specific markers in colorectal cancer (CRC), the utility of antibody-mediated therapies in this disease setting has been limited. Here, we evaluated whether markers of cancer-associated fibroblasts (CAFs) may more specifically target CRCs. We identified fibroblast activation protein (FAP) as a strong candidate for targeting CRC. FAP is highly expressed in a majority of cancers and is absent in over 90% of normal tissues. These data indicate that FAP may be a strong candidate for antibody conjugate therapy and support the continued development of FAP-targeting conjugate therapies. Additionally, we identified associations between CAF marker co-expression and immunostimulatory pathways. CAF markers might be useful as targets for immune engaging therapies, with combinations of CAF markers holding promise to identify those patients most likely to respond. Overall, these data provide the basis for potential further studies investigating the utility of CAF markers to target CRCs. In colorectal cancer (CRC), attempts to identify cancer cell-specific markers to guide antibody-mediated therapeutics have failed to uncover markers that are both exclusive to cancer tissues and abundant across CRCs. Alternatively, cancer-associated fibroblasts (CAFs), which are abundant in the tumor microenvironment and upregulate unique surface markers, are not found in healthy tissues. Here, we evaluated the expression patterns of CAF-associated proteins α-smooth muscle actin (αSMA), fibroblast activation protein (FAP), podoplanin (PDPN), matrix metalloproteinase-2 (MMP2), transgelin (TAGLN), and THY1. While αSMA and THY1 were abundant in cancer tissues, high abundance in normal tissues limited their targeting potential. FAP was present in 94.5% of primary and metastatic CRC tissues and absent in 93.7% of adjacent normal colon and liver tissues assessed. These results indicate that FAP is a promising target for antibody conjugates with potential for broad application in CRC. Co-expression analyses showed that CRCs simultaneously expressing high levels of PDPN, MMP2, and THY1 were enriched for immune-related signatures, indicating potential for antibody-mediated immune engagers. Overall, this work highlights the potential of CAF proteins to act as therapeutic targets for novel anticancer agents and become important therapeutic biomarkers. [ABSTRACT FROM AUTHOR]

Simple Summary: The survival of patients with colorectal cancer liver metastasis can be prognosticated based on the presence or absence of desmoplastic histopathologic growth patterns. Patient survival is improved if the liver tumor has at least a 50% desmoplastic histopathologic growth pattern. Determing the patients tumor histopathological features is essential to prognosis outcomes and treatment management. 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. [ABSTRACT FROM AUTHOR]

Dysregulation of the mitogen-activated protein kinase interacting kinases 1/2 (MNK1/2)-eukaryotic initiation factor 4E (eIF4E) signaling axis promotes breast cancer progression. MNK1 is known to influence cancer stem cells (CSCs); self-renewing populations that support metastasis, recurrence, and chemotherapeutic resistance, making them a clinically relevant target. The precise function of MNK1 in regulating CSCs, however, remains unexplored. Here, we generated MNK1 knockout cancer cell lines, resulting in diminished CSC properties in vitro and slowed tumor growth in vivo. Using a multiomics approach, we functionally demonstrated that loss of MNK1 restricts tumor cell metabolic adaptation by reducing glycolysis and increasing dependence on oxidative phosphorylation. Furthermore, MNK1-null breast and pancreatic tumor cells demonstrated suppressed metastasis to the liver, but not the lung. Analysis of The Cancer Genome Atlas (TCGA) data from breast cancer patients validated the positive correlation between MNK1 and glycolytic enzyme protein expression. This study defines metabolic perturbations as a previously unknown consequence of targeting MNK1/2, which may be therapeutically exploited. [ABSTRACT FROM AUTHOR]

Background: The prognostic implications of the RAS status in colorectal cancer liver metastasis (CRLM) remain unclear. This study investigated the prognostic significance of RAS status after curative hepatectomy, focusing on surgical controllability. Methods: This retrospective study included liver-only CRLM patients who underwent the first hepatectomy between 2015 and 2022 at the National Cancer Center Hospital. Recurrence-free survival (RFS), surgically controllable period (SCP), and overall survival (OS) were compared between RAS wild-type (RAS-wt) and mutant (RAS-mt) patients. Multivariate analyses were conducted to identify independent prognostic factors for each outcome and independent risk factors for less than 1 year SCP. Results: A total of 150 patients were evaluated, comprising 63 patients with RAS-mt status. There was no significant difference in RFS between RAS-mt and RAS-wt (7.00 vs. 8.03 months, p = 0.48). RAS-mt patients exhibited worse SCP (11.80 vs.21.13 months, p < 0.001) and OS (44.03 vs. 70.03 months, p < 0.001) compared to RAS-wt. Multivariate analysis identified RAS-mt as an independent prognostic factor for both OS (hazard ratio [HR]: 3.37, p < 0.001) and SCP (HR: 2.20, p < 0.001), and as an independent risk factor for less than 1 year of SCP (odds ratio, 2.31; p = 0.03). Conclusions: CRLM with RAS mutations should be considered for strict surgical indications with preoperative chemotherapy and thorough examination, considering the possibility of short SCP. [ABSTRACT FROM AUTHOR]

Background: Colorectal cancer ranks among the most prevalent malignancies globally. Accurate prediction of metachronous liver metastasis is crucial for optimizing postoperative management. Tripartite motif-containing protein 27 (TRIM27), an E3 ubiquitin ligase, is implicated in diverse cellular functions and tumorigenesis. Methods: This study aimed to develop and validate a TRIM27-based nomogram for prognostication in colorectal cancer patients. Transcriptome sequencing of five paired tumor and normal tissue samples identified TRIM27 as a potential prognostic biomarker. Immunohistochemistry was employed to assess TRIM27 expression in colorectal cancer cohorts from two institutions. Results: TRIM27 expression correlated significantly with both the prognosis of colorectal cancer patients and the occurrence of metachronous liver metastasis. A nomogram incorporating TRIM27 and clinical factors was constructed and demonstrated robust predictive accuracy in an independent validation cohort. Conclusion: The TRIM27-based nomogram is a valuable prognostic tool for predicting prognosis and metachronous liver metastasis in colorectal cancer patients, aiding in personalized treatment decisions. [ABSTRACT FROM AUTHOR]

Background: The netrin-1/CD146 pathway regulates colorectal cancer (CRC) liver metastasis, angiogenesis, and vascular development. However, few investigations have yet examined the biological function of netrin-1/CD146 complex in CRC. In this work, we investigated the relationship between the netrin-1/CD146 axis and S100 proteins in sentinel lymph node, and revealed a possible new clue for vascular metastasis of CRC. Methods: The expression levels of netrin-1 and CD146 proteins in CRC, as well as S100A8 and S100A9 proteins in the sentinel lymph nodes were determined by immunohistochemistry. Using GEPIA and UALCAN, we analyzed netrin-1 and CD146 gene expression in CRC, their association with CRC stage, and their expression levels and prognosis in CRC patients. Results: The expression level of netrin-1 in N1a+1b (CRC lymphatic metastasis groups, exculded N1c) was positively increased with N0 (p = 0.012). The level of netrin-1 protein was positively correlated with CD146 protein (p < 0.05). The level of S100A9 protein was positively correlated with CD146 protein (r = 0.492, p = 0.007). Moreover, netrin-1 expression was obviously correlated with S100A9 expression in the N1 stage (r = 0.867, p = 0.000). CD146 level was correlated with S100A9 level in the N2 stage (r = 0.731, p = 0.039). CD146 mRNA expression was higher in normal colorectal tissues than in CRC (p < 0.05). Netrin-1 and CD146 expression were not significantly associated with the tumor stages and prognosis of patients with CRC (p > 0.05). Conclusions: The netrin-1/CD146 and netrin-1/S100A9 axis in CRC tissues might related with early stage of lymph node metastasis, thus providing potential novel channels for blocking lymphatic metastasis and guiding biomarker discovery in CRC patients. [ABSTRACT FROM AUTHOR]