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Abstract Background Microwave ablation (MWA) is widely used to eliminate colorectal liver metastases (CRLM). However, the risk of tumor recurrence is difficult to predict due to lack of reliable clinical and biological markers. Elevation of gamma-glutamyl transferase (GGT) and aspartate transaminase (AST) provides signals for liver inflammation and cancer progression. The present study evaluated the association between pre-ablation GGT to AST ratio index (GSR) and hepatic recurrence in patients with CRLM after MWA. Methods A retrospectively analyzed 192 CRLM patients who underwent MWA from January 2013 to December 2017. Pre-ablation GSR was classified into high (≤ 2.34) or low (> 2.34) using the upper quartile value. The prognostic value of GSR and other risk factors for liver progression-free survival (LPFS) and cancer-specific survival (CSS) were evaluated by univariate and multivariate analyses. Results High GSR was significantly associated with males (P = 0.041), the presence of cholelithiasis (P = 0.012), but not pre-ablation chemotherapy (P = 0.355), which caused significantly increased levels of GGT (P = 0.015) and AST (P = 0.008). GSR showed a significant association with LPFS and CSS through univariate analysis (P = 0.002 and 0.006) and multivariate analysis (P = 0.043 and 0.037). The subgroup analysis demonstrated no interaction between GSR and all variables except for distribution in the sub-analysis of LPFS. Conclusions Our findings suggest that the pre-ablation GSR can be considered as a promising prognostic indicator for poor prognosis of patients with CRLM underwent MWA. Trial registration Not applicable.

Background: Transanal total mesorectal excision has emerged as a potential solution to certain limitations associated with laparoscopic total mesorectal excision in rectal cancer patients. Differences in surgical approaches have raised questions regarding their impact on the risk of postoperative urinary retention, with limited data available from large scale randomized clinical study. Objective: To report incidence of postoperative urinary retention and evaluate the associated risk factors for transanal total mesorectal excision. Design: In this randomized controlled trial (ClinicalTrials. gov NCT06147492), we retrieved 524 patients who received total mesorectal excision (TME) for stage I–III rectal cancer between June 2019 and April 2022, and the patients were randomly assigned in a 1:1 ratio to undergo either taTME or laTME. Patients: We enrolled 524 patients who underwent total mesorectal excision for stage I–III rectal cancer between June 2019 and April 2022. Main outcome measures: The incidence of postoperative urinary retention. Results: Among the 524 enrolled patients, 261 were randomized to the laTME group, while 263 were were randomized the taTME group. The median age was 58 years, and 340 participants (64.8 %) were male. Notably, 37 individuals (7.0 %) experienced postoperative urinary retention during the follow-up period, with no significant disparity was observed between the taTME and laTME groups (6.8 % and 7.2 %, respectively, P = 0.98). Risk factors associated with PUR in patients following taTME encompassed early removal of the urinary catheter (P = 0.006), net infusion rate >4.09 ml kg−1.h−1 (P = 0.006), and an age surpassing 65 years (P = 0.0321). Limitations: The generalizability of the findings outside specialist rectal cancer centers may be limited. Conclusions: Transanal total mesorectal excision was not found to heighten the risk of postoperative urinary retention. Nonetheless, it is advisable removing postoperative catheter beyond the initial day and exercising caution in the administration of intravenous fluids in clinical practice for taTME procedures.

Abstract Background Adenosquamous carcinoma is a rare sub-type of colorectal cancer with a poor prognosis. Little is known about its clinicopathological and molecular characteristics in Asian populations. This study aimed to investigate these features in a cohort of patients with adenosquamous carcinoma in the colorectum. Methods Tumor cases pathologically diagnosed with colorectal adenosquamous carcinoma were retrieved from the Sixth Affiliated Hospital, Sun Yat-sen University tissue archive between December 2012 and June 2020. Clinicopathological features, molecular characteristics, and oncology outcomes were analyzed. Results Among 18,139 cases of colorectal cancer, 11 were diagnosed with adenosquamous carcinoma, providing an incidence rate of 0.061%. The median overall survival (OS) was 14 months, and the expected 3-year OS rate was 29.6%. As of October 14, 2022, four cases had local recurrence and five had distant metastasis. KRAS gene mutations were found in four of seven patients (57.1%), and three out of eleven (27.3%) patients had mismatch repair-deficient (dMMR) tumors. Conclusions Adenosquamous carcinoma is associated with a poor prognosis. Compared to other sub-types of colorectal cancer, a higher proportion of patients with dMMR and KRAS mutations were observed. These findings suggested that more patients with adenosquamous carcinoma could benefit from targeted therapies, such as immunotherapy.

Abstract Background Hepatocellular carcinoma (HCC) cells undergo reprogramming of glucose metabolism to support uncontrolled proliferation, of which the intrinsic mechanism still merits further investigation. Although regulatory factor X6 (RFX6) is aberrantly expressed in different cancers, its precise role in cancer development remains ambiguous. Methods Microarrays of HCC tissues were employed to investigate the expression of RFX6 in tumour and adjacent non‐neoplastic tissues. Functional assays were employed to explore the role of RFX6 in HCC development. Chromatin immunoprecipitation, untargeted metabolome profiling and sequencing were performed to identify potential downstream genes and pathways regulated by RFX6. Metabolic assays were employed to investigate the effect of RFX6 on glycolysis in HCC cells. Bioinformatics databases were used to validate the above findings. Results HCC tissues exhibited elevated expression of RFX6. High RFX6 expression represented as an independent hazard factor correlated to poor prognosis in patients with HCC. RFX6 deficiency inhibited HCC development in vitro and in vivo, while its overexpression exerted opposite functions. Mechanistically, RFX6 bound to the promoter area of phosphoglycerate mutase 1 (PGAM1) and upregulated its expression. The increased PGAM1 protein levels enhanced glycolysis and further promoted the development of HCC. Conclusions RFX6 acted as a novel driver for HCC development by promoting aerobic glycolysis, disclosing the potential of the RFX6–PGAM1 axis for therapeutic targeting.

Abstract Current literature highlights the need for precise histological quantitative assessment of fibrosis which cannot be achieved by conventional scoring systems, inherent to their discontinuous values and reader-dependent variability. Here we used an automated image analysis software to measure fibrosis deposition in two relevant preclinical models of liver fibrosis, and established correlation with other quantitative fibrosis descriptors. Longitudinal quantification of liver fibrosis was carried out during progression of post-necrotic (CCl4-induced) and metabolic (HF-CDAA feeding) models of chronic liver disease in mice. Whole slide images of picrosirius red-stained liver sections were analyzed using a fully automated, unsupervised software. Fibrosis was characterized by a significant increase of collagen proportionate area (CPA) at weeks 3 (CCl4) and 8 (HF-CDAA) with a progressive increase up to week 18 and 24, respectively. CPA was compared to collagen content assessed biochemically by hydroxyproline assay (HYP) and by standard histological staging systems. CPA showed a high correlation with HYP content for CCl4 (r = 0.8268) and HF-CDAA (r = 0.6799) models. High correlations were also found with Ishak score or its modified version (r = 0.9705) for CCl4 and HF-CDAA (r = 0.9062) as well as with NASH CRN for HF-CDAA (r = 0.7937). Such correlations support the use of automated digital analysis as a reliable tool to evaluate the dynamics of liver fibrosis and efficacy of antifibrotic drug candidates in preclinical models.

Abstract Background Colorectal cancer is a malignant gastrointestinal cancer, in which some advanced patients would develop cancer cachexia (CAC). CAC is defined as a multi-factorial syndrome characterized by weight loss and muscle loss (with or without fat mass), leading to progressive dysfunction, thereby increasing morbidity and mortality. ApcMin/+ mice develop spontaneous intestinal adenoma, which provides an established model of colorectal cancer for CAC study. Upon studying the ApcMin/+ mouse model, we observed a marked decrease in weight gain beginning around week 15. Such a reduction in weight gain was rescued when ApcMin/+ mice were crossed with MMP12−/− mice, indicating that MMP12 has a role in age-related ApcMin/+-associated weight loss. As a control, the weight of MMP12−/− mice on a weekly basis, their weight were not significantly different from those of WT mice. Methods ApcMin/+; MMP12−/− mice were obtained by crossing ApcMin/+ mice with MMP12 knockout (MMP12 −/−) mice. Histological scores were assessed using hematoxylin-eosin (H&E) staining. MMP12 expression was confirmed by immunohistochemistry and immunofluorescence staining. ELISA, protein microarrays and quantitative Polymerase Chain Reaction (qPCR) were used to investigate whether tumor could up-regulate IL-6. Cell-based assays and western blot were used to verify the regulatory relationship between IL-6 and MMP12. Fluorescence intensity was measured to determine whether MMP12 is associated with insulin and insulin-like growth factor 1 (IGF-1) in vitro. MMP12 inhibitors were used to explore whether MMP12 could affect the body weight of ApcMin/+ mice. Results MMP12 knockout led to weight gain and expansion of muscle fiber cross-sectional area (all mice had C57BL/6 background) in ApcMin/+ mice, while inhibiting MMP12 could suppress weight loss in ApcMin/+ mice. MMP12 was up-regulated in muscle tissues and peritoneal macrophages of ApcMin/+ mice. IL-6 in tumor cells and colorectal cancer patients is up-regulation. IL-6 stimulated MMP12 secretion of macrophage. Conclusions MMP12 is essential for controlling body weight of Apc Min/+ mice. Our study shows that it exists the crosstalk between cancer cells and macrophages in muscle tissues that tumor cells secrete IL-6 inducing macrophages to up-regulate MMP12. This study may provide a new perspective of MMP12 in the treatment for weight loss induced by CAC.

We wished to understand the metabolic reprogramming underlying liver fibrosis progression in mice. Administration to male C57BL/6J mice of the hepatotoxins carbon tetrachloride (CCl4), thioacetamide (TAA), or a 60% high-fat diet, choline-deficient, amino-acid-defined diet (HF-CDAA) was conducted using standard protocols. Livers collected at different times were analyzed by gas chromatography–mass spectrometry-based metabolomics. RNA was extracted from liver and assayed by qRT-PCR for mRNA expression of 11 genes potentially involved in the synthesis of ascorbic acid from hexoses, Gck, Adpgk, Hk1, Hk2, Ugp2, Ugdh, Ugt1a1, Akr1a4, Akr1b3, Rgn and Gulo. All hepatotoxins resulted in similar metabolic changes during active fibrogenesis, despite different etiology and resultant scarring pattern. Diminished hepatic glucose, galactose, fructose, pentose phosphate pathway intermediates, glucuronic acid and long-chain fatty acids were compensated by elevated ascorbate and the product of collagen prolyl 4-hydroxylase, succinate and its downstream metabolites fumarate and malate. Recovery from the HF-CDAA diet challenge (F2 stage fibrosis) after switching to normal chow was accompanied by increased glucose, galactose, fructose, ribulose 5-phosphate, glucuronic acid, the ascorbate metabolite threonate and diminished ascorbate. During the administration of CCl4, TAA and HF-CDAA, aldose reductase Akr1b3 transcription was induced six- to eightfold, indicating increased conversion of glucuronic acid to gulonic acid, a precursor of ascorbate synthesis. Triggering hepatic fibrosis by three independent mechanisms led to the hijacking of glucose and galactose metabolism towards ascorbate synthesis, to satisfy the increased demand for ascorbate as a cofactor for prolyl 4-hydroxylase for mature collagen production. This metabolic reprogramming and causal gene expression changes were reversible. The increased flux in this pathway was mediated predominantly by increased transcription of aldose reductase Akr1b3.

Purpose: To analyze whether HBV infection can reduce the risk of colorectal liver metastasis (CRLM) in stage 2 colorectal cancer (CRC)., Methods: The data of postoperative pathological stage 2 CRC patients treated at the Sixth Affiliated Hospital of Sun Yat-sen University between 2013 and 2015 were analyzed. The patients were divided into an infection group (group A) and a non-infection group (group B). The correlations between HBV infection and CRLM, 5-year liver disease-free survival, and 5-year overall survival were compared., Results: A total of 884 patients who met the inclusion criteria were included in the study. Group A included 297 patients (33.60%), and 5 patients (1.68%) had CRLM. Group B included 587 patients (66.40%), and 31 patients (5.28%) had CRLM. The results of correlation analysis and logistic regression analysis showed that HBV infection (P = 0.013, HR = 0.29, 95% CI 0.11-0.77) was a protective factor for CRLM, while CEA > 5 ng/ml (P = 0.002, HR = 3.12, 95% CI 1.51-6.47) and hypertension (P = 0.010, HR = 3.50, 95% CI 1.34-9.09) were risk factors for CRLM. Group A had a significantly better 5-year liver disease-free survival than group B (P = 0.011, HR = 0.31, 95% CI 0.16-0.63), but there was no significant difference in the 5-year overall survival (P = 0.433)., Conclusion: HBV infection may reduce the risk of metachronous liver metastasis in stage 2 colorectal cancer.