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.

Wingless/It/β-catenin signaling in liver metastasis from colorectal cancer:A focus on biological mechanisms and therapeutic opportunities

The liver is the most common site of metastases in patients with colorectal cancer.Colorectal liver metastases(CRLMs)are the result of molecular mechanisms that involve different cells of the liver microenvironment.The aberrant activation of Wingless/It(Wnt)/β-catenin signals downstream of Wnt ligands initially drives the oncogenic transformation of the colon epithelium,but also the progression of metastatization through the epithelial-mesenchymal transition/mesenchymalepithelial transition interactions.In liver microenvironment,metastatic cells can also survive and adapt through dormancy,which makes them less susceptible to pro-apoptotic signals and therapies.Treatment of CRLMs is challenging due to its variability and heterogeneity.Advances in surgery and oncology have been made in the last decade and a pivotal role for Wnt/β-catenin pathway has been recognized in chemoresistance.At the state of art,there is a lack of clear understanding of why and how this occurs and thus where exactly the opportunities for developing anti-CRLMs therapies may lie.In this review,current knowledge on the involvement of Wnt signaling in the development of CRLMs was considered.In addition,an overview of useful biomarkers with a revision of surgical and non-surgical therapies currently accepted in the clinical practice for colorectal liver metastasis patients were provided.

Comprehensive Treatment Uncertainty Analysis and PTV Margin Estimation for Fiducial Tracking in Robotic Liver Stereotactic Body Radiation Therapy

Objective This study aims to quantify the uncertainties of CyberKnife Synchrony fiducial tracking for liver stereotactic body radiation therapy(SBRT)cases,and evaluate the required planning target volume(PTV)margins.Methods A total of 11 liver tumor patients with a total of 57 fractions,who underwent SBRT with synchronous fiducial tracking,were enrolled for the present study.The correlation/prediction model error,geometric error,and beam targeting error were quantified to determine the patient-level and fraction-level individual composite treatment uncertainties.The composite uncertainties and multiple margin recipes were compared for scenarios with and without rotation correction during treatment.Results The correlation model error-related uncertainty was 4.3±1.8,1.4±0.5 and 1.8±0.7 mm in the superior-inferior(SI),left-right,and anterior-posterior directions,respectively.These were the primary contributors among all uncertainty sources.The geometric error significantly increased for treatments without rotation correction.The fraction-level composite uncertainties had a long tail distribution.Furthermore,the generally used 5-mm isotropic margin covered all uncertainties in the left-right and anterior-posterior directions,and only 75%of uncertainties in the SI direction.In order to cover 90%of uncertainties in the SI direction,an 8-mm margin would be needed.For scenarios without rotation correction,additional safety margins should be added,especially in the superior-inferior and anterior-posterior directions.Conclusion The present study revealed that the correlation model error contributes to most of the uncertainties in the results.Most patients/fractions can be covered by a 5-mm margin.Patients with large treatment uncertainties might need a patient-specific margin.

The history of interventional therapy for liver cancer in China

In China interventional therapy of liver cancer started in the 1980s. It is well-known that Professor Lin Gui is the founding father of Interventional radiology. Under the leadership of Lin Gui and other professors, interventional therapy of liver cancer has swiftly progressed in China. Indeed, TAI, TAE, TACE and ablation therapy have witnessed great innovations in hardware facil ities, technical means, and therapeutic philosophy, while incorporating Chinese characteristics. As with the development of combined interventional therapy in China, interventional treatment of liver cancer has gradually started the process of precision and individualization. Actually, multidisciplinary, multimodal, and polymorphic treatments will be the most suitable pattern for liver cancer in the future, among which combination of interventional therapy with targeted, immunological treatments and information technology(IT) tools may bring a revolutionary breakthrough in liver cancer treatment.

Chimeric antigen receptor-engineered T-cell therapy for liver cancer

Background: Chimeric antigen receptor-engineered T-cell(CAR-T) therapy is a newly developed immunotherapy used in the treatment of cancers. Because CAR-T therapy has shown great success in treating CD19-positive hematological malignancies, its application has been explored in the treatment of solid tumors, such as liver cancer. In this review, we discuss the immune characteristics of liver cancer, the obstacles encountered during the application of CAR-T therapy, and preclinical and clinical progress in the use of CAR-T therapy in patients with liver cancer.Data sources: The data on CAR-T therapy related to liver cancers were collected by searching Pub Med and the Web of Science databases prior to December 2017 with the keywords "chimeric antigen receptor","CAR-T", "liver cancer", "hepatocellular carcinoma", and "solid tumor". Additional articles were identified by manual search of references found in the primary articles. The data for clinical trials were collected by searching Clinical Trials.gov.Results: The liver has a tolerogenic nature in the intrahepatic milieu and its tumor microenvironment significantly affects tumor progression. The obstacles that reduce the efficacy of CAR-T therapy in solid tumors include a lack of specific tumor antigens, limited trafficking and penetration of CAR-T cells to tumor sites, and an immunosuppressive tumor microenvironment. To overcome these obstacles, several strategies have emerged. In addition, several strategies have been developed to manage the side effects of CAR-T, including enhancing the selectivity of CARs and controlling CAR-T activity. To date, no clinical trials of CAR-T therapy against HCC have been completed. However, preclinical studies in vitro and in vivo have shown potent antitumor efficacy. Glypican-3, mucin-1, epithelial cell adhesion molecule, carcinoembryonic antigen, and other targets are currently being studied.Conclusions: The application of CAR-T therapy for liver cancer is just beginning to be explored and more research is needed. However, we are optimistic that CAR-T therapy will offer a new approach for the treatment of liver cancers in the future.

Polyethylene glycol microspheres loaded with irinotecan for arterially directed embolic therapy of metastatic liver cancer

AIM To study tumor response, and tolerability of arterially directed embolic therapy(ADET) with polyethylene glycol embolics loaded with irinotecan for the treatment of colorectal cancer liver metastases(CRC-LM). Secondary objectives were to monitor quality of life, time to progression and survival of patients.METHODS Patients were included in the study if they were affected by CRC-LM, refractory to systemic chemotherapy, treated with ADET using polyethylene glycol embolics, and had liver involvement < 50%. Tumor response, performance status(PS), tumor marker antigens, and quality of life(QoL) were monitored at 1, 3 and 6 mo after ADET. QoL was assessed with the Palliative Performance Scale(PPS).RESULTS We treated 50 consecutive CRC-LM patients with ADET using polyethylene glycol embolics. Their tumor response one month after ADET was: 28% of complete response(CR), 48% of partial response(PR), 8% stable disease(SD), and 16% of progression. Tumor response 3 mo after ADET was CR 24%, PR 38%, SD 19% and progression disease(PD) 19%. Tumor response 6 mo after ADET was CR 18%, PR 44%, SD 21% and PD 18%. QoL was 90% PPS at each time point. Median time to progression for patients who progressed was 2.5 mo(range 0.8-6). Median follow-up was 14 mo(0.8-25 range). ADETs were performed with no complications. Observed side effects(mild or moderate intensity) were: Pain in 32% of patients, increase of transaminase levels in 20% and fever in 14%, whereas 30% of patients did not complain any adverse event. CONCLUSION The treatment of unresectable CRC-LM with ADET using polyethylene glycol microspheres loaded with irinotecan was effective in tumor response and resulted in mild toxicity, and good QoL.

Advances in postoperative adjuvant therapy for primary liver cancer

Hepatocellular carcinoma(HCC)is a highly heterogeneous,invasive,and conventional chemotherapy-insensitive tumor with unique biological characteristics.The main methods for the radical treatment of HCC are surgical resection or liver transplantation.However,recurrence rates are as high as 50%and 70%at 3 and 5 years after liver resection,respectively,and even in Milan-eligible recipients,the recurrence rate is approximately 20%at 5 years after liver transplantation.Therefore,reducing the postoperative recurrence rate is key to improving the overall outcome of liver cancer.This review discusses the risk factors for recurrence in patients with HCC radical surgical resection and adjuvant treatment options that may reduce the risk of recurrence and improve overall survival,including local adjuvant therapy(e.g.,transcatheter arterial chemoembolization),adjuvant systemic therapy(e.g.,molecular targeted agents and immunotherapy),and other adjuvant therapies(e.g.,antiviral and herbal therapy).Finally,potential research directions that may change the paradigm of adjuvant therapy for HCC are analyzed.

Gene therapy of liver cancer

The application of gene transfer technologies to the treatment of cancer has led to the development of new experimental approaches like gene directed enzyme/pro- drug therapy (GDEPT), inhibition of oncogenes and restoration of tumor-suppressor genes. In addition, gene therapy has a big impact on other fields like cancer immunotherapy, anti-angiogenic therapy and virotherapy. These strategies are being evaluated for the treatment of primary and metastatic liver cancer and some of them have reached clinical phases. We present a review on the basis and the actual status of gene therapy approaches applied to liver cancer.

Application of Paclitaxel-loaded EGFR Peptide-conjugated Magnetic Polymeric Liposomes for Liver Cancer Therapy

Developing the methodologies that allow for safe and effective delivery of therapeutic drugs to target sites is a very important research area in cancer therapy.In this study,polyethylene glycol(PEG)-coated magnetic polymeric liposome(MPL)nanoparticles(NPs)assembled from octadecyl quatemized carboxymethyl chitosan(OQC),PEGylated OQC,cholesterol,and magnetic NPs,and functionalized with epithelial growth factor receptor(EGFR)peptide,were successfully prepared for in-vivo liver targeting.The two-step liver targeting strategy,based on both magnetic force and EGFR peptide conjugation,was evaluated in a subcutaneous hepatocellular carcinoma model of nude mouse.The results showed that EGFR-conjugated MPLs not only accumulated in the liver by magnetic force,but could also diffuse into tumor cells as a result of EGFR targeting.In addition,paclitaxel(PTX)was incorporated into small EGFR-conjugated MPLs(102.0土0.7 nm),resulting in spherical particles with high drug encapsulation efficiency(>90%).The use of the magnetic targeting for enhancing the transport of PTX-loaded EGFR-conjugated MPLs to the tumor site was further confirmed by detecting PTX levels.In conclusion,PTX-loaded EGFR-conjugated MPLs could potentially be used as an effective drug delivery system for targeted liver cancer therapy.

A review of the literature on the use of CRISPR/Cas9 gene therapy to treat hepatocellular carcinoma

Noncoding RNAs instruct the Cas9 nuclease to site speifillyl cleave DNA in the CRISPR/Cas9 system.Despite the high incidence of hepatocellular carcinoma(HCC),the patient's outcome is poor.As a result of the emergence of therapeutic resistance in HCC patients,dlinicians have faced difficulties in treating such tumor.In addition,CRISPR/Cas9 screens were used to identify genes that improve the dlinical response of HCC patients.It is the objective of this article to summarize the current understanding of the use of the CRISPR/Cas9 system for the treatment of cancer,with a particular emphasis on HCC as part of the current state of knowledge.Thus,in order to locate recent developments in oncology research,we examined both the Scopus database and the PubMed database.The ability to selectively interfere with gene expression in combinatorial CRISPR/Cas9 screening can lead to the discovery of new effective HCC treatment regimens by combining clinically approved drugs.Drug resistance can be overcome with the help of the CRISPR/Cas9 system.HCC signature genes and resistance to treatment have been uncovered by genome-scale CRISPR activation screening although this method is not without limitations.It has been extensively examined whether CRISPR can be used as a tool for disease research and gene therapy.CRISPR and its applications to tumor research,particularly in HCC,are examined in this study through a review of the literature.

Current status of yttrium-90 microspheres radioembolization in primary and metastatic liver cancer

Liver malignancy,including primary liver cancer and metastatic liver cancer has become one of the most common causes of cancer-related death worldwide due to the high malignant degree and limited systematic treatment strategy.Radioembolization with yttrium-90(^(90)Y)-loaded microspheres is a relatively novel technology that has made significant progress in the local treatment of liver malignancy.The different steps in the extensive work-up of radioembolization for patients with an indication for treatment with^(90)Y microspheres,from patient selection to follow up,both technically and clinically,are discussed in this paper.It describes the application and development of^(90)Y microspheres in the treatment of liver cancer.

Unraveling the efficacy network: A network meta-analysis of adjuvant external beam radiation therapy methods after hepatectomy

BACKGROUND Primary liver cancer is a malignant tumor with a high recurrence rate that significantly affects patient prognosis.Postoperative adjuvant external radiation therapy(RT)has been shown to effectively prevent recurrence after liver cancer resection.However,there are multiple RT techniques available,and the differ-ential effects of these techniques in preventing postoperative liver cancer re-currence require further investigation.AIM To assess the advantages and disadvantages of various adjuvant external RT methods after liver resection based on overall survival(OS)and disease-free survival(DFS)and to determine the optimal strategy.METHODS This study involved network meta-analyses and followed the PRISMA guidelines.The data of qualified studies published before July 10,2023,were collected from PubMed,Embase,the Web of Science,and the Cochrane Library.We included relevant studies on postoperative external beam RT after liver resection that had OS and DFS as the primary endpoints.The magnitudes of the effects were determined using risk ratios with 95%confidential intervals.The results were analyzed using R software and STATA software.RESULTS A total of 12 studies,including 1265 patients with hepatocellular carcinoma(HCC)after liver resection,were included in this study.There was no significant heterogeneity in the direct paired comparisons,and there were no significant differences in the inclusion or exclusion criteria,intervention measures,or outcome indicators,meeting the assumptions of heterogeneity and transitivity.OS analysis revealed that patients who underwent stereotactic body radiotherapy(SBRT)after resection had longer OS than those who underwent intensity modulated radiotherapy(IMRT)or 3-dimensional conformal RT(3D-CRT).DFS analysis revealed that patients who underwent 3D-CRT after resection had the longest DFS.Patients who underwent IMRT after resection had longer OS than those who underwent 3D-CRT and longer DFS than those who underwent SBRT.CONCLUSION HCC patients who undergo liver cancer resection must consider distinct advantages and disadvantages when choosing between SBRT and 3D-CRT.IMRT,a RT technique that is associated with longer OS than 3D-CRT and longer DFS than SBRT,may be a preferred option.

Combination therapy of murine liver cancer with IL-12 gene and HSV-TK gene

Objective: To investigate the synergistic anti-tumor effects of murine IL-12 gene and HSV-TK gene therapy in mice bearing liver cancer. Methods: Mouse liver cancer MM45T. Li (H-2d) cells were transfected with retroviral vector containing IL-12 gene or HSV-TK gene insert. Gene-modified liver cancer cells, MM45T. Li/IL-12 and MM45T. Li/TK, with stable expression of IL-12 and TK were obtained. Balb/c mice were inoculated subcutaneously with 2′105 MM45T. Li cells. When the tumor reached a size of 0.5-1.0 cm, a mixture of MM45T.Li/TK cells and 60Co-irradiated MM45T. Li/IL-12 cell were injected intratumoraly. Ganciclovir (GCV) was injected ip (40 mg.kg-1.d-1) for 10 days. Intratumoral injection of 60Co-irradiated MM45T. Li/IL-12 cells was repeated twice in one week apart. Mice with distant tumors were treated according to the same protocol. CTL activity of spleen cells was measured by 51Cr-release assay and phenotype of tumor infiltrating lymphocytes by immunohistochemical staining. Results: In mice treated with MM45T. Li/IL-12 or MM45T. Li/TK+GCV individually led to moderate reduction in tumor growth, but neither could eradicate the tumor completely, while in 60% of mice treated with a mixture of MM45T. Li/IL-12 and MM45T. Li/TK cells plus GCV, complete tumor regression was observed, with no tumor recurrence for two months. The growth of distant tumor was also inhibited significantly in mice similarly treated. Most of the mice received combined gene therapy plus GCV had abundant CD4+, CD8+T lymphocyte infiltration. Their CTL activity was significantly higher than in mice received single gene therapy. Conclusion Combination therapy with IL-12 gene and HSV-TK gene plus GCV is effective for mouse liver cancer.

Potential of nano carriers as cancer cell-specific drug delivery systems in photodynamic therapy

Photodynamic therapy (PDT) in combination with chemotherapy has great potential for cancer treatment (1, 2)However,there have been very few attempts to develop cancer-targeted co-delivery systems of photosensitizers and anticancer drugs.We developed hematoporphyrin (HP)-modified doxorubicin(DOX)-loaded bovine serum albumin nanoparticles (HP-NPs) in an attempt to improve the therapeutic effect of PDT in treating liver cancer.

Association between liver targeted antiviral therapy in colorectal cancer and survival benefits:An appraisal

In colorectal cancer(CRC),liver metastasis remains a major contributor to the cause of cancer-related death.Putative biomarkers,therapeutic efficacy,and drug insensitivity still pose clinical challenges for metastatic CRC patients.Interestingly,previous studies indicated that tumor cells in CRC did not metastasize to the injured liver,which included hepatitis or cirrhotic liver.The benefits of antiviral therapy on hepatocellular carcinoma have also been identified.This review discusses the role of antiviral therapy on the liver.Antiviral therapy may reduce potential liver metastasis associated with CRC in several mechanistic aspects.

Neoadjuvant chemotherapy for metastatic colorectal cancer to the liver: from chemotherapy to targeting therapy

Despite the advances in surgical techniques, adjuvant chemotherapy and targeted therapy, approximately 40%-70% of patients with progressive colorectal cancer will develop liver metastases, of whom one-third are found at the time of diagnosis.[1] Surgical resection is now the standard treatment and also the only potentially curative treatment for resectable lesions.

Therapy Response of Chinese Herbal Medicine in Advanced Liver Cancer： A Retrospective Observational Clinical Trial

Aiming at starting the ball rolling and contributing humble effort to promote CTM （Chinese traditional medicine）, we performed the present study to assess the therapy response of Chinese herbal decoction compared to conventional therapy on critical ill patients of advanced liver cancer. A total of 6 patients （1 female and 5 males） with histologically confirmed liver cancer were included in this retrospective observational clinical trial. We administered Chinese medicine （Gan Decoction, mixed with a variety of effective herbal components） to help them to recover from poor condition. In the meantime, conventional treatment of surgical resection and artery catheterization chemotherapy was applied in cases compared. In 3 cases of CTM combined treatment, the tumor marker level decreased. Residual intrahepatic metastatic sites reduced according to ultrasonography/CT imaging, and the patients felt free from the complaint of abdominal discomfort. The quality of life has been improved, we managed to have prolonged the PFS （Progression-Free-Survival） and TTP （Time-to-Progression） from the onset to date. While in 3 cases with conventional treatment only of surgical resection and artery catheterization chemotherapy, we were not able to decrease the level of tumor marker, metastatic lesions increased according to ultrasonography/CT imaging, and the patient＇s condition worsen more. We failed in having prolonged the PFS and TTP in the compared cases of conventional treatment only. The retrospective clinical study showed no OS （overall survival） benefit for liver cancer patients treated with Gan Decoction, while the QOL （quality of life） evaluation seemed to predict survival better. Chinese herbs might be an additional choice with its better benefits and tolerability in the treatment of primary liver cancer.

Effects of intensity modulated radiation therapy + local hyperthermia on the cancer cell apoptosis and invasion in liver cancer lesion

Objective: To investigate the effects of intensity modulated radiation therapy + local hyperthermia on the cancer cell apoptosis and invasion in liver cancer lesion. Methods:A total of 94 patients with middle-advanced primary liver cancer who were diagnosed and treated in this hospital between November 2015 and February 2017 were divided into control group (n=47) and experimental group (n=47) by random number table method. Control group received intensity modulated radiation therapy and experimental group received intensity modulated radiation therapy + local hyperthermia. Both groups accepted peritoneal lesion biopsy before and after treatment, and the expression of apoptosis and invasion genes in specimen tissue were detected by fluorescence quantitative PCR. Results: There was no statistically significant difference in apoptosis and invasion gene expression between the two groups of patients before treatment. After treatment, apoptosis genes Fas, caspase-3, Bax and p53 mRNA expression in lesion tissue of experimental group were higher than those of control group whereas FasL and Bcl-2 mRNA expression were lower than those of control group;invasion genes Cofilin-1, Bmi-1, STAT3 and SOX18 mRNA expression in lesion tissue of experimental group were lower than those of control group whereas Tip30 and TP53IP1 mRNA expression were higher than those of control group. Conclusion: intensity modulated radiation therapy + local hyperthermia can effectively promote cancer cell apoptosis and inhibit its invasion activity in patients with middle and advanced primary liver cancer.

Liver cancer stem cell markers: Progression and therapeutic implications

Cancer stem cells(CSCs) are a small subpopulation in cancer, have been proposed to be cancer-initiating cells, and have been shown to be responsible for chemotherapy resistance and cancer recurrence. The identification of CSC subpopulations inside a tumor presents a new understanding of cancer development because it implies that tumors can only be eradicated by targeting CSCs. Although advances in liver cancer detection and treatment have increased the possibility of curing the disease at early stages, unfortunately, most patients will relapse and succumb to their disease. Strategies aimed at efficiently targeting liver CSCs are becoming important for monitoring the progress of liver cancer therapy and for evaluating new therapeutic approaches. Herein, we provide a critical discussion of biological markers described in the literature regarding liver cancer stem cells and the potential of these markers to serve as therapeutic targets.

Nucleus-targeting orange-emissive carbon dots delivery adriamycin for enhanced anti-liver cancer therapy

Carbon dots(CDs)with precise targeting function show great potential in the field of drug delivery therapeutics.In this study,the functionalized nucleus-targeting orange-emissive CDs with nuclear localization sequence(NLS)were loaded with adriamycin(DOX)to obtain a nucleus-targeting orange-emissive CDs drug delivery system(CDs-NLS-DOX),which delivered DOX to tumor cell nuclei to enhance its anti-tumor activity.The drug carrier orange-emissive CDs showed excitation-independent behavior,stable and enhanced imaging capability and good biocompatibility in vitro and in vivo.Meanwhile,the CDs-NLS could target the nuclei efficiently,and the CDs-NLS-DOX complexes had a high drug loading rate(59.4%)after loading DOX,exhibiting p H-dependent DOX release behavior through breaking acylhydrazone bond in a weak acidic environment.In addition,the CDs-NLS-DOX complexes exhibited an enhanced killing activity against human hepatoma cells(HepG2).The in vivo therapeutic effects on HepG2 nude mice transplanted tumors indicated the CDs-NLS-DOX had a stronger ability to inhibit tumor growth compared to free DOX.In short,CDs-NLS-DOX is expected to be a precise and efficient nucleus-targeting nano-drug delivery system for tumor treatment.