Current landscape of preoperative neoadjuvant therapies for initial resectable colorectal cancer liver metastasis

Colorectal cancer liver metastasis(CRLM)presents a clinical challenge,and optimizing treatment strategies is crucial for improving patient outcomes.Surgical resection,a key element in achieving prolonged survival,is often linked to a heightened risk of recurrence.Acknowledging the potential benefits of preoperative neoadjuvant chemotherapy in managing resectable liver metastases,this approach has gained attention for its role in tumor downsizing,assessing biological behavior,and reducing the risk of postoperative recurrence.However,the use of neoadjuvant chemotherapy in initially resectable CRLM sparks ongoing debates.The balance between tumor reduction and the risk of hepatic injury,coupled with concerns about delaying surgery,necessitates a nuanced approach.This article explores recent research insights and draws upon the practical experiences at our center to address critical issues regarding considerations for initially resectable cases.Examining the criteria for patient selection and the judicious choice of neoadjuvant regimens are pivotal areas of discussion.Striking the right balance between maximizing treatment efficacy and minimizing adverse effects is imperative.The dynamic landscape of precision medicine is also reflected in the evolving role of gene testing,such as RAS/BRAF and PIK3CA,in tailoring neoadjuvant regimens.Furthermore,the review emphasizes the need for a multidisciplinary approach to navigate the comp-lexities of CRLM.Integrating technical expertise and biological insights is crucial in refining neoadjuvant strategies.The management of progression following neoadjuvant chemotherapy requires a tailored approach,acknowledging the diverse biological behaviors that may emerge.In conclusion,this review aims to provide a comprehensive perspective on the considerations,challenges,and advancements in the use of neoadjuvant chemotherapy for initially resectable CRLM.By combining evidencebased insights with practical experiences,we aspire to contribute to the ongoing discourse on refining treatment paradigms for improved outcomes in patients with CRLM.

Identification of colorectal cancer metastasis markers by an angiogenesis-related cytokine-antibody array

AIM： To investigate the angiogenesis-related protein expression profile characterizing metastatic colorectal cancer （mCRC） with the aim of identifying prognostic markers.METHODS： The expression of 44 angiogenesis- secreted factors was measured by a novel cytokine antibody array methodology. The study evaluated vas- cular endothelial growth factor （VEGF） and its soluble vascular endothelial growth factor receptor （sVEGFR）-I protein levels by enzyme immunoassay （EIA） in a panel of 16 CRC cell lines, mRNA VEGF and VEGF-A isoforms were quantified by quantitative reverse-transcription polymerase chain reaction （Q-RT-PCR） and vascular en- dothelial growth factor receptor （VEGFR）-2 expressionwas analyzed by flow cytometry.

Identification of metastasis-associated genes in colorectal cancer through an integrated genomic and transcriptomic analysis

Objective： Identification of colorectal cancer （CRC） metastasis genes is one of the most important issues in CRC research. For the purpose of mining CRC metastasis-associated genes, an integrated analysis of mJcroarray data was presented, by combined with evidence acquired from comparative genornic hybridization （CGH） data. Methods： Gene expression profile data of CRC samples were obtained at Gene Expression Omnibus （GEO） website. The 15 important chromosomal aberration sites detected by using CGH technology were used for integrated genomic and transcriptomic analysis. Significant Analysis of Microarray （SAM） was used to detect significantly differentially expressed genes across the whole genome. The overlapping genes were selected in their corresponding chromosomal aberration regions, and analyzed by using the Database for Annotation, Visualization and Integrated Discovery （DAVID）. Finally, SVM-T-RFE gene selection algorithm was applied to identify ted genes in CRC. Results： A minimum gene set was obtained with the minimum number [14] of genes, and the highest classification accuracy （100%） in both PRI and META datasets. A fraction of selected genes are associated with CRC or its metastasis. Conclusions- Our results demonstrated that integration analysis is an effective strategy for mining cancer- associated genes.

Suppression of colorectal cancer metastasis by nigericin through inhibition of epithelial-mesenchymal transition

AIM: To evaluate the effect of nigericin on colorectal cancer and to explore its possible mechanism. METHODS: The human colorectal cancer (CRC) cell lines HT29 and SW480 were treated with nigericin or oxaliplatin under the conditions specified. Cell viability assay and invasion and metastasis assay were performed to evaluate the effect of nigericin on CRC cells. Sphereforming assay and soft agar colony-forming assay were implemented to assess the action of nigericin on the cancer stem cell properties of CRC cells undergone epithelial-mesenchymal transition (EMT). RESULTS: Compared with oxaliplatin, nigericin showed more toxicity for the HT29 cell line (IC50, 12.92 ± 0.25 μmol vs 37.68 ± 0.34 μmol). A similar result was also obtained with the SW116 cell line (IC50, 15.86 ± 0.18 μmol vs 41.02 ± 0.23 μmol). A Boyden chamber assay indicated that a significant decrease in the number of HT29 cells migrating through polyvinylidene fluoride membrane was observed in the nigericin-treated group, relative to the vehicle-treated group [11 ± 2 cells per high-power field (HPF) vs 19.33 ± 1.52 cells per HPF, P < 0.05]. Compared to the control group, the numbers of HT29 cells invading through the Matrigel-coated membrane also decreased in the nigericin-treated group (6.66 ± 1.52 cells per HPF vs 14.66 ± 1.52 cells per HPF, P < 0.05). Nigericin also reduced the proportion of CD133+ cells from 83.57% to 63.93%, relative to the control group (P < 0.05). Nigericin decreased the number of spheres relative to the control group (0.14 ± 0.01 vs 0.35 ± 0.01, P < 0.05), while oxaliplatin increased the number of spheres relative to the control group (0.75 ± 0.02 vs 0.35 ± 0.01; P < 0.05). Nigericin also showed a decreased ability to form colonies under anchorage-independent conditions in a standard soft agar assay after 14 d in culture, relative to the control group (1.66 ± 0.57 vs 7 ± 1.15, P < 0.05), whereas the colony numbers were higher in the oxaliplatin group relative to the vehicle-treated controls (14.33 ± 0.57 vs 7 ± 1.15, P < 0.05). We further detected the expression of E-cadherin and vimentin in cells treated with nigericin and oxaliplatin. The results showed that HT29 cells treated with nigericin induced an increase in E-cadherin expression and a decrease in the vimentin expression relative to vehicle controls. In contrast, oxaliplatin downregulated the expression of E-cadherin and upregulated the expression of vimentin in HT29 cells relative to vehicle controls. CONCLUSION: This study demonstrated that nigericin could partly reverse the EMT process during cell invasion and metastasis.

Prognostic role of serum carcinoembryonic antigen in patients receiving liver resection for colorectal cancer liver metastasis:A meta-analysis

BACKGROUND Carcinoembryonic antigen(CEA)is a broad-spectrum tumor marker for differential diagnosis,monitoring,and response assessment of a variety of malignancies.AIM To evaluate whether serum CEA could predict the prognosis in patients with colorectal cancer liver metastasis(CRCLM)before and after liver resection(LR).METHODS PubMed,Embase,Cochrane,and Web of Science were systematically searched to retrieve literature,with a search cut-off date of February 27,2023.Articles were strictly screened for inclusion according to pre-specified inclusion and exclusion criteria.Data were pooled and analyzed using Stata 16.0.RESULTS This meta-analysis included 36 studies involving a total of 11143 CRCLM patients.The results showed that a high pre-LR serum CEA level was correlated with poor overall survival(OS)[hazard ratio(HR)=1.61,95%confidence interval(CI):1.49-1.75,P<0.001]and recurrence-free survival(HR=1.27,95%CI:1.11-1.45,P<0.001)in CRCLM patients.A high post-LR serum CEA level predicted poor OS(HR=2.66,95%CI:2.10-3.38,P<0.001).A comparison by treatment modality,analysis modality,patient source,and cutoff-value showed that overall,high preoperative and postoperative serum CEA levels remained correlated with a poor prognosis.CONCLUSION This study concluded that high pre-LR and post-LR serum CEA levels were significantly correlated with a poor prognosis in CRCLM patients.

Matrix metalloproteinase-9:A deleterious link between hepatic ischemia-reperfusion and colorectal cancer

Despite the advent of improved surgical techniques and the development of cytotoxic chemotherapeutic agents useful for the treatment of colorectal cancer,the primary clinical challenge remains that of preventing and combating metastatic spread.Surgical resection is the best treatment for colorectal metastases isolated to the liver.However,in rodent models,the hepatic ischemia-reperfusion(I/R) applied during the surgery accelerates the outgrowth of implanted tumors.Among the adverse effects of I/R on cellular function,several studies have demonstrated an over expression of the matrix metalloproteinase-9(MMP-9) in the ischemic liver.Since several studies showed high local levels of expression and activity of this proteolytic enzyme in the primary colorectal adenocarcinoma,the role of MMP-9 might be considered as a potential common mediator,favoring both growth of local tumor and the dissemination of colorectal carcinoma metastases.

Oncological outcomes and predictors of radiofrequency ablation of colorectal cancer liver metastases

BACKGROUND Surgical resection is considered the standard treatment option for long-term survival in colorectal cancer liver metastasis(CRLM)patients,but only a small number of patients are suitable for resection following diagnosis.Radiofrequency ablation(RFA)is an accepted alternative therapy for CRLM patients who are not suitable for resection.However,the relatively high rate of local tumor progression(LTP)is an obstacle to the more widespread use of RFA.AIM To determine the oncological outcomes and predictors of RFA in CRLM patients.METHODS A retrospective analyze was performed on the clinical data of 85 consecutive CRLM patients with a combined total of 138 liver metastases,who had received percutaneous RFA treatment at our institution from January 2013 to December 2018.Contrast-enhanced computed tomography was performed the first month after RFA to assess the technique effectiveness of the RFA and to serve as a baseline for subsequent evaluations.The Kaplan-Meier method was used to calculate overall survival(OS)and LTP-free survival(LTPFS).The log-rank test and Cox regression model were used for univariate and multivariate analyses to determine the predictors of the oncological outcomes.RESULTS There were no RFA procedure-related deaths,and the technique effectiveness of the treatment was 89.1%(123/138).The median follow-up time was 30 mo.The LTP rate was 32.6%(45/138),and the median OS was 36 mo.The 1-,3-,and 5-year OS rates were 90.6%,45.6%,and 22.9%,respectively.Univariate analysis revealed that tumor size and ablative margin were the factors influencing LTPFS,while extrahepatic disease(EHD),tumor number,and tumor size were the factors influencing OS.Multivariate analysis showed that tumor size larger than 3 cm and ablative margin of 5 mm or smaller were the independent predictors of shorter LTPFS,while tumor number greater than 1,size larger than 3 cm,and presence of EHD were the independent predictors of shorter OS.CONCLUSION RFA is a safe and effective treatment method for CRLM.Tumor size and ablative margin are the important factors affecting LTPFS.Tumor number,tumor size,and EHD are also critical factors for OS.

Is CA19-9 effective in predicting chemotherapeutic response in patients with synchronous liver metastases with colorectal cancer?

Evaluation of response to chemotherapy in colorectal cancer patients with synchronous liver metastases is important in terms of treatment management.In this Letter to the Editor,several issues in the article are discussed.For the comparison of carbohydrate antigen 19-9(CA19-9)values referenced in the study,the patient group was not matched for cancer stage.Therefore,it may be more appropriate to select and compare CA19-9 values in patients with same-stage cancer.

Advances in liver transplantation for unresectable colon cancer liver metastasis

It is estimated that 50%of patients with colorectal cancer will develop liver metastasis.Surgical resection significantly improves survival and provides a chance of cure for patients with colorectal cancer liver metastasis(CRLM).Increasing the resectability of primary unresectable liver metastasis provides more survival benefit for those patients.Considerable surgical innovations have been made to increase the resection rate and decrease the potential risk of hepatic failure postoperation.Liver transplantation(LT)has been explored as a potential curative treatment for unresectable CRLM.However,candidate selection criteria,chemotherapy strategies,refined immunity regimens and resolution for the shortage of grafts are lacking.This manuscript discusses views on surgical indication,peritransplantation anti-tumor and anti-immunity therapy and updated advances in LT for unresectable CRLM.A literature review of published articles and registered clinical trials in PubMed,Google Scholar,and Clinicaltrials.gov was performed to identify studies related to LT for CRLM.Some research topics were identified,including indications for LT for CRLM,oncological risk,antitumor regimens,graft loss,administration of anti-immunity drugs and solutions for graft deficiency.The main candidate selection criteria are good patient performance,good tumor biological behavior and chemosensitivity.Chemotherapy should be administered before transplantation but is not commonly administered posttransplantation for preventive purposes.Mammalian target of rapamycin regimens are recommended for their potential oncological benefit,although there are limited cases.In addition to extended criterion grafts,living donor grafts and small grafts combined with two-stage hepatectomy are efficient means to resolve organ deficiency.LT has been proven to be an effective treatment for selected patients with liver-only CRLM.Due to limited donor grafts,high cost and poorly clarified oncological risks,LT for unresectable CRLM should be strictly performed under a well-organized study plan in selected patients.Some vital factors,like LT indication and anti-tumor and anti-immune treatment,remain to be confirmed.Ongoing clinical trials are expected to delineate these topics.

Development and validation of a radiomics nomogram for preoperative prediction of lymph node metastasis in colorectal cancer

With the support by the National Natural Science Foundation of China,the research team jointly led by Porf.Liu Zaiyi(刘再毅)at Guangdong General Hospital and Prof.Tian Jie(田捷)at the Key Laboratory of Molecular Imaging,Chinese Academy of Sciences,developed a CT-based radiomics prediction model to preoperatively predict the lymph node metastasis in colorectal cancer(CRC),which was published

Enhanced recovery nursing and mental health education on postoperative recovery and mental health of laparoscopic liver resection

BACKGROUND Patients undergoing laparoscopic resection of liver metastases of colorectal cancer are prone to negative emotions and decrease of digestive function.Early nursing and psychological intervention are necessary.AIM To observe the effect of enhanced recovery nursing combined with mental health education on postoperative recovery and mental health of patients undergoing laparoscopic resection of liver metastases of colorectal cancer.METHODS One hundred and twenty patients who underwent laparoscopic resection of liver metastases of colorectal cancer at our hospital between March 2021 and March 2023,were selected as participants.The patients admitted from March 1,2021 to February 28,2022 were set as the control group,and they were given routine nursing combined with mental health education intervention.While the patients admitted from March 1,2022 to March 31,2023 were set as the observation group,they were given accelerated rehabilitation surgical nursing combined with mental health education intervention.The differences in postoperative recovery-related indices,complications and pain degrees,and mental health-related scores were compared between groups.The T lymphocyte subset levels of the two groups were also compared.RESULTS The postoperative exhaust,defecation,eating and drainage time of the observation group were shorter than those of the control group.The pain scores of the observation group were lower than those of the control group at 6,12,24,48,and 72 h after surgery.The cumulative complication rate of the observation group was lower than that of the control group(P<0.05).The CD4+/CD8+in the observation group was higher than that in the control group 3 d after surgery(P<0.05).After intervention,the self-rating depression scale,self-rating anxiety scale,avoidance dimension,and yielding dimension in Medical coping style(MCMQ)scores of the two groups were lower than those prior to intervention,and the scores in the observation group were lower than those in the control group(P<0.05).The face dimension score in the MCMQ score was higher than that before intervention,and that of the observation group was higher than that of the control group(P<0.05).After intervention,the total scores of the life function index scale(FLIC)and psychological well-being scores of cancer patients in the two groups,and the physical and social well-being scores in the observation group,were higher than those before intervention.The nursing satisfaction of the observation group was higher than that of the control group(P<0.05).The physical,psychological,and social well-being,and the total FLIC scores of the observation group were higher than those in the control group after surgery(P<0.05).CONCLUSION Enhanced recovery nursing combined with mental health education can promote the recovery of gastrointestinal function,improve the mental health and quality of life of patients after laparoscopic resection of colorectal cancer liver metastases,and reduce the incidence of complications.

Radiofrequency ablation versus microwave ablation for colorectal liver metastases:long-term results of a retrospective cohort surgical experience

Background:Ablation is an alternative treatment modality for selected patients with colorectal liver metastases(CRLMs).Although initially widely performed via radiofrequency ablation(RFA),more recently,microwave ablation(MWA)is being preferred due to its perceived superiority in creating the ablation zones.The aim of this study is to compare the long-term efficacy of these two modalities performed surgically.Methods:Patients undergoing surgical liver ablation from 2005-2023 at a tertiary center by a single surgeon for CRLM were included in a retrospective institutional review board-approved study.Outcomes were compared using Wilcoxon,Chi-square,Kaplan-Meier,and Cox multivariate regression analyses.Continuous data are presented as median(interquartile range).Results:There were a total of 242 patients.Laparoscopic RFA was done in 121 patients with 303 lesions and laparoscopic MWA in 121 patients with 300 lesions.There was no difference between the groups regarding operative time(161 vs.147 minutes,respectively,P=0.4),perioperative morbidity(3%vs.8%,respectively,P=0.2)or hospital stay(1 vs.1 day,P=0.05).Local recurrence(LR)per lesion with at least 1 year of imaging follow-up was 29%in the RFA and 13%in the MWA group(P<0.001).Based on univariate survival analysis,tumor size,blood vessel proximity,ablation margin,and ablation modality were independent predictors of LR.To control these variables,direct matching was performed.Each cohort included 189 lesions.Kaplan-Meier analysis of these cohorts showed increased LR-free survival in the MWA group vs.the RFA group(P=0.005).Conclusions:This large study confirms our initial observation that local tumor control rate is better after MWA vs.RFA.

Liver transplantation for non-resectable colorectal metastases-an evolving paradigm in transplant oncology

A better understanding of colorectal liver metastasis(CRLM)onco-genomics and the improvement of systemic treatments,including targeted and immune therapies,have shifted the paradigm of CRLM prognosis over the past two decades.While 40%of the patients with colorectal cancers are likely to develop CRLM[and 50%of them to be non-resectable(nCRLM)],current oncologic management allows for the identification of a subset of CRLM patients with controlled diseases likely to highly benefit from curative resections and,perhaps,liver transplantation(LT).Indeed,the Norwegian SECA I trial in 2013(1)triggered a growing interest in LT as a curative treatment for non-resectable colorectal liver metastasis(nCRLM).This strategy is supported by several pilot studies reporting up to 80%of 5-year estimated overall survival(OS)after LT for CRLM,in contrast to the poor results obtained in the early 80’s series.

Aquaporin 9 is involved in CRC metastasis through DVL2-dependent Wnt/β-catenin signaling activation

Background:Aquaporin 9(AQP9)is permeable to water or other small molecules,and plays an important role in various cancers.We previously found that AQP9 was related to the efficacy of chemotherapy in patients with colorectal cancer(CRC).This study aimed to identify the role and regulatory mechanism of AQP9 in CRC metastasis.Methods:The clinical significance of AQP9 was analysed by using bioinformatics and tissue microarray.Transcriptome sequencing,Dual-Luciferase Reporter Assay,Biacore,and co-immunoprecipitation were employed to demonstrate the regulatory mechanism of AQP9 in CRC.The relationship between AQP9 and CRC metastasis was verified in vitro and in vivo by using real-time cell analysis assay,high content screening,and liver metastasis models of nude mice.Results:We found that AQP9 was highly expressed in metastatic CRC.AQP9 overexpression reduced cell roundness and enhanced cell motility in CRC.We further showed that AQP9 interacted with Dishevelled 2(DVL2)via the C-terminal SVIM motif,resulting in DVL2 stabilization and the Wnt/b-catenin pathway activation.Additionally,we identified the E3 ligase neural precursor cell expressed developmentally downregulated 4-like(NEDD4L)as a modulator regulating the ubiquitination and degradation of AQP9.Conclusions:Collectively,our study revealed the important role of AQP9 in regulating DVL2 stabilization and Wnt/β-catenin signaling to promote CRC metastasis.Targeting the NEDD4L–AQP9–DVL2 axis might have therapeutic usefulness in metastatic CRC treatment.