Ex vivo liver resection and auto-transplantation and special systemic therapy in perihilar cholangiocarcinoma treatment

This editorial contains comments on the article“Systematic sequential therapy for ex vivo liver resection and autotransplantation:A case report and review of li-terature”in the recent issue of World Journal of Gastrointestinal Surgery.It points out the actuality and importance of the article and focuses primarily on the role and place of ex vivo liver resection and autotransplantation(ELRAT)and systemic therapy,underlying molecular mechanisms for targeted therapy in perihilar cho-langiocarcinoma(pCCA)management.pCCA is a tough malignancy with a high proportion of advanced disease at the time of diagnosis.The only curative option is radical surgery.Surgical excision and reconstruction become extremely com-plicated and not always could be performed even in localized disease.On the other hand,ELRAT takes its place among surgical options for carefully selected pCCA patients.In advanced disease,systemic therapy becomes a viable option to prolong survival.This editorial describes current possibilities in chemotherapy and reveals underlying mechanisms and projections in targeted therapy with ki-nase inhibitors and immunotherapy in both palliative and adjuvant settings.Fi-broblast grow factor and fibroblast grow factor receptor,human epidermal grow-th factor receptor 2,isocitrate dehydrogenase,and protein kinase cAMP activated catalytic subunit alpha(PRKACA)and beta(PRKACB)pathways have been ac-tively investigated in CCA in last years.Several agents were introduced and approved by the Food and Drug Administration.They all demonstrated mean-ingful activity in CCA patients with no global change in outcomes.That is why every successfully treated patient counts,especially those with advanced disease.In conclusion,pCCA is still hard to treat due to late diagnosis and extremely complicated surgical options.ELRAT also brings some hope,but it could be performed in very carefully selected patients.Advanced disease requires systemic anticancer treatment,which is supposed to be individualized according to the genetic and molecular features of cancer cells.Targeted therapy in combination with chemo-immunotherapy could be effective in susceptible patients.

Research progress in tumor angiogenesis and drug resistance in breast cancer

Angiogenesis is considered a hallmark pathophysiological process in tumor development. Aberrant vasculature resulting from tumor angiogenesis plays a critical role in the development of resistance to breast cancer treatments, via exacerbation of tumor hypoxia, decreased effective drug concentrations within tumors, and immune-related mechanisms. Antiangiogenic therapy can counteract these breast cancer resistance factors by promoting tumor vascular normalization. The combination of antiangiogenic therapy with chemotherapy, targeted therapy, or immunotherapy has emerged as a promising approach for overcoming drug resistance in breast cancer. This review examines the mechanisms associated with angiogenesis and the interactions among tumor angiogenesis, the hypoxic tumor microenvironment, drug distribution, and immune mechanisms in breast cancer. Furthermore, this review provides a comprehensive summary of specific antiangiogenic drugs, and relevant studies assessing the reversal of drug resistance in breast cancer. The potential mechanisms underlying these interventions are discussed, and prospects for the clinical application of antiangiogenic therapy to overcome breast cancer treatment resistance are highlighted.

Systemic therapy in gastrointestinal stromal tumors

Gastrointestinal stromal tumors(GISTs)are the most common type of soft tissue sarcoma in the gastrointestinal tract.Most GISTs have been attributed to activated gain-of-function mutations in either KIT or platelet-derived growth factor receptorα,making these molecular features essential targets for therapeutic interventions.Although surgery is the standard treatment for localized GISTs,patients often experience relapse and disease progression even after surgery.In recent years,targeted therapy has significantly improved the prognosis of patients with advanced GISTs.Imatinib mesylate,a KIT inhibitor,is the first-line treatment for advanced GISTs and has revolutionized the treatment of this disease.However,drug resistance remains a major issue with imatinib treatment,as a significant majority of patients become resistant to imatinib either after initiation or after 2–3 years of treatment.Consequently,novel tyrosine kinase inhibitors such as sunitinib,regorafenib,ripretinib,and avapritinib have been introduced to address drug resistance.Immunotherapy has emerged as a potential approach for the treatment of advanced GISTs.This review comprehensively summarizes the pathogenesis of GISTs and the development of targeted therapies and immunotherapies,provides an overview of the emergence of drug resistance in advanced GISTs,and discusses the challenges and prospects associated with the treatment of GISTs.

Functionalized magnetic nanoparticles for drug delivery in tumor therapy

The side effects of chemotherapy are mainly the poor control of drug release. Magnetic nanoparticles(MNPs) have super-paramagnetic behaviors which are preferred for biomedical applications such as in targeted drug delivery, besides, in magnetic recording, catalysis, and others. MNPs, due to high magnetization response, can be manipulated by the external magnetic fields to penetrate directly into the tumor, thus they can act as ideal drug carriers. MNPs also play a crucial role in drug delivery system because of their high surface-to-volume ratio and porosity. The drug delivery in tumor therapy is related to the sizes, shapes, and surface coatings of MNPs as carriers. Therefore, in this review, we first summarize the effects of the sizes, shapes, and surface coatings of MNPs on drug delivery, then discuss three types of drug release systems, i.e., p H-controlled, temperature-controlled, and magnetic-controlled drug release systems, and finally compare the principle of passive drug release with that of active drug release in tumor therapy.

Recent progress on nanoparticle-based drug delivery systems for cancer therapy

The development of cancer nanotherapeutics has attracted great interest in the recent decade. Cancer nanotherapeutics have overcome several limitations of conventional therapies, such as nonspecific biodistribution, poor water solubility, and limited bioavailability. Nanoparticles with tuned size and surface characteristics are the key components of nanotherapeutics, and are designed to passively or actively deliver anti-cancer drugs to tumor cells. We provide an overview of nanoparticle-based drug delivery methods and cancer therapies based on tumor-targeting delivery strategies that have been developed in recent years.

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.

Adeno-associated virus mediated endostatin gene therapy in combination with topoisomerase inhibitor effectively controls liver tumor in mouse model

AIM:rAAV mediated endostatin gene therapy has been examined as a new method for treating cancer.However, a sustained and high protein delivery is required to achieve the desired therapeutic effects.We evaluated the impact of topoisomerase inhibitors in rAAV delivered endostatin gene therapy in a liver tumor model. METHODS:rAAV containing endostatin expression cassettes were transduced into hepatoma cell lines.To test whether the topoisomerase inhibitor pretreatment increased the expression of endostatin,Western blotting and ELISA were performed.The biologic activity of endostatin was confirmed by endothelial cell proliferation and tube formation assays. The anti-tumor effects of the rAAV-endostatin vector combined with a topoisomerase inhibitor,etoposide,were evaluated in a mouse liver tumor model. RESULTS:Topoisomerase inhibitors,including camptothecin and etoposide,were found to increase the endostatin exPression level in vitro.The over-expressed endostatin, as a result of pretreatment with a topoisomerase inhibitor, was also biologically active.In animal experiments,the combined therapy of topoisomerase inhibitor,etoposide with the rAAV-endostatin vector had the best tumor- suppressive effect and tumor foci were barely observed in livers of the treated mice.Pretreatment with an etoposide increased the level of endostatin in the liver and serum of rAAV-endostatin treated mice.Finally,the mice treated With rAAV-endostatin in combination with etoposide showed the longest survival among the experimental models. CONCLUSION:rAAV delivered endostatin gene therapy in combination with a topoisomerase inhibitor pretreatment is an effective modality for anticancer gene therapy.

Novel insights into mTOR signalling pathways: A paradigm for targeted tumor therapy

As a crucial protein kinase,the mammalian target of rapamycin(mTOR)intimately controls essential cellular processes like cell development,proliferation,metabolism,and other crucial activities.Different cancers and disorders have been linked to imbalances in mTOR's regulatory systems.Multiple mTOR inhibitor therapy has recently acquired popularity as a method of treating cancers brought on by abnormal signal transduction pathways.We also explore potential processes behind tumor cell resistance to mTOR inhibitors and suggest workarounds to overcome this challenge.We hold the potential to pioneer cutting-edge methods for tumor therapy by methodically examining the complex mTOR signaling system and its regulatory complexity.Increasing our knowledge of mTOR-related mechanisms not only creates opportunities for cutting-edge methods to target and treat cancers but also has the potential to improve patient outcomes and general quality of life significantly.This review paper explores the most recent developments in understanding mTOR signaling pathways and the use of mTOR inhibitors in treating tumors.

STAT3-specific nanocarrier for shRNA/drug dual delivery and tumor synergistic therapy

Non-small cell lung cancer(NSCLC)is a major disease with high incidence,low survival rate and prone to develop drug resistance to chemotherapy.The mechanism of secondary drug resistance in NSCLC chemotherapy is very complex,and studies have shown that the abnormal activation of STAT3(Signal Transducer and Activator of Transcription 3)plays an important role in it.In this study,the pGPU6/GFP/Neo STAT3-shRNA recombinant plasmid was constructed with STAT3 as the precise target.By modifying hydrophilic and hydrophobic blocks onto chitosan,a multifunctional vitamin E succinate-chitosan-polyethylene glycol monomethyl ether histidine(VES-CTS-mPEG-His)micelles were synthesized.The micelles could encapsulate hydrophobic drug doxorubicin through self-assembly,and load the recombinant pGPU6/GFP/Neo STAT3-shRNA(pDNA)through positive and negative charges to form dual-loaded nanoparticles DOX/VCPH/pDNA.The co-delivery and synergistic effect of DOX and pDNA could up-regulate the expression of PTEN(Phosphatase and Tensin Homolog),down-regulate the expression of CD31,and induce apoptosis of tumor cells.The results of precision targeted therapy showed that DOX/VCPH/pDNA could significantly down-regulate the expression level of STAT3 protein,further enhancing the efficacy of chemotherapy.Through this study,precision personalized treatment of NSCLC could be effectively achieved,reversing its resistance to chemotherapy drugs,and providing new strategies for the treatment of drug-resistant NSCLC.

Pathologic complete response to conversion therapy in hepatocellular carcinoma using patient-derived organoids:A case report

BACKGROUND For primary liver cancer,the key to conversion therapy depends on the effectiveness of drug treatment.Patient-derived tumor organoids have been demonstrated to improve the efficacy of conversion therapy by identifying individualtargeted effective drugs,but their clinical effects in liver cancer remain unknown.CASE SUMMARY We described a patient with hepatocellular carcinoma(HCC)who achieved pathologic complete response(pCR)to conversion therapy guided by the patientderived organoid(PDO)drug sensitivity testing.Despite insufficiency of the remaining liver volume after hepatectomy,the patient obtained tumor reduction after treatment with the PDO-sensitive drugs and successfully underwent radical surgical resection.Postoperatively,pCR was observed.CONCLUSION PDOs contributes to screening sensitive drugs for HCC patients to realize the personalized treatment and improve the conversion therapy efficacy.

Prevention of metastasis to liver by using 5-FU intraperitoneal chemotherapy in nude mice inoculated with human colonic cancer cells

AIMS Using a new approach of regional adjuvant chemotherapy to prevent cancer cells hepatic metasta- sis after radical surgery of large bowel cancer. METHODS A model of liver with metastasis of hu- man colonic cancer (HCC) cells in nude mice was used to observe the effect in prevention of metastasis of HCC cells inoculated via spleen applied with early postoper- ative intraperitoneal (IP) chemotherapy using large dose of 5-FU. RESULTS The incidence of metastasis to liver was decreased by 40%,the mean number of metastatic liv- er nodules in each animal was reduced by 50.89% and the mean survival times of each animal was prolonged by 48.21% by using 5-FU 40 mg/NS 40 ml/kg IP for two consecutive days as compared with the controls. CONCLUSIONS IP is a new and more effective re- gional adjuvant chemotheraputic approach in the pre- vention of liver metastasis HCC cells after radical surgery of large bowel cancer.

Post reperfusion syndrome during liver transplantation:From pathophysiology to therapy and preventive strategies

This review aims at evaluating the existing evidence regarding post reperfusion syndrome, providing a description of the pathophysiologic mechanisms involved and possible management and preventive strategies. A Pub Med search was conducted using the Me SH database, "Reperfusion" AND "liver transplantation" were the combined Me SH headings; EMBASE and the Cochrane library were also searched using the same terms. 52 relevant studies and one ongoing trial were found. The concept of post reperfusion syndrome has evolved through years to a multisystemic disorder. The implications of the main organ, recipient and procedure related factors in the genesis of this complex syndrome are discussed in the text as the novel pharmacologic and technical approaches to reduce its incidence. However the available evidence about risk factors, physiopathology and preventive measures is still confusing, the presence of two main definitions and the numerosity of possible confounding factors greatly complicates the interpretation of the studies.

The value of postoperative hepatic regional chemotherapy in prevention of recurrence after radical resection of primary liver cancer

INTRODUCTIONIn China,primary liver cancer (PLC) ranks secondin cancer mortality since the 1990s.In the field ofPLC treatment,surgical resection remains the best,which includes large PLC resection,small PLCresection,re-resection of subclinical recurrence,aswell as cytoreduction and sequential resection forunresectable PLC.However,recurrence

Hepatic cancer stem cells and drug resistance: Relevance in targeted therapies for hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is one of most common malignancies in the world. Systemic treatments for HCC, particularly for advanced stages, are limited by the drug resistance phenomenon which ultimately leads to therapy failure. Recent studies have indicated an association between drug resistance and the existence of the cancer stem cells (CSCs) as tumor initiating cells. The CSCs are resistant to conventional chemotherapies and might be related to the mechanisms of the ATP Binding Cassette (ABC) transporters and alterations in the CSCs signaling pathways. Therefore, to contribute to the development of new HCC treatments, further information on the characterization of CSCs, the modulation of the ABC transporters expression and function and the signaling pathway involved in the self renewal, initiation and maintenance of the cancer are required. The combination of transporters modulators/inhibitors with molecular targeted therapies may be a potent strategy to block the tumoral progression. This review summarizes the association of CSCs, drug resistance, ABC transporters activities and changes in signaling pathways as a guide for future molecular therapy for HCC.

Cholestatic liver diseases:An era of emerging therapies

Recently the field of cholestasis has expanded enormously reflecting an improved understanding of the molecular mechanisms underlying bile secretion and its perturbation in chronic cholestatic disease. Novel anti-cholestatic therapeutic options have been developed for patients not favorably responding to ursodeoxycholic acid (UDCA), the current standard treatment for cholestatic liver disease. Important novel treatment targets now also include nuclear receptors involved in bile acid (BA) homoeostasis like farnesoid X receptor and G proteincoupled receptors e.g., the G-protein-coupled BA receptor “transmembrane G coupled receptor 5”. Fibroblast growth factor-19 and enterohepatic BA transporters also deserve attention as additional drug targets as does the potential treatment agent norUDCA. In this review, we discuss recent and future promising therapeutic agents and their potential molecular mechanisms in cholestatic liver disorders.

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.

Outcomes of loco-regional therapy for down-staging of hepatocellular carcinoma prior to liver transplantation

BACKGROUND: The number of loco-regional therapies (LRTs) for hepatocellular carcinoma (HCC) has increased dramatically during the past decade. Many patients with HCC who were beyond the Milan criteria were allowed to receive a liver transplantation (LT) once the HCC was successfully down-staged. This retrospective study aimed to analyze the outcomes of LRTs prior to LT in patients with HCC beyond the Milan criteria. METHODS: We analyzed 56 patients treated from June 2006 to March 2010: 22 met the Milan criteria (T1+T2, 39.3%), 16 had T3 tumors (28.6%), and 11 had T4a tumors (19.6%), while 7 were suspected of tumor vascular invasion (T4b, 12.5%). All patients underwent preoperative LRTs, including transcatheter arterial chemoembolization, radiofrequency ablation, percutaneous ethanol injection, liver resection, and/or microwave coagulation therapy. The number of the patients who were successfully down-staged before LT, the types of LRTs used before LT, and their outcomes after LT were recorded. RESULTS: Eleven patients had necrotic tumors (pT0, 19.6%); 6 had pT1 tumors (10.7%), 22 had pT2 tumors (39.3%), 6 had pT3 tumors (10.7%), 5 had pT4a tumors (8.9%), and 6 had pT4b tumors (10.7%). The histopathologic tumors of 39 patients (69.6%) were down-staged and met the established Milan criteria (pT0-2). Imaging-proven under-staging was present in 5 HCC patients (8.9%) who had tumors involving the intrahepatic venous system. Twenty-three patients (41.1%) had stable HCC and 10 (17.9%) died. The 1-, 3- and 4-year survival rates were 96%, 73% and 61%, respectively, with a mean survival time of 22.29±1.63 months. Six patients died of tumorrecurrence. The 1-, 3- and 4-year recurrence-free survival (RFS) rates were 88%, 75% and 66%, respectively. The 3-year RFS of patients with pT0-2 tumors was 82%, which was markedly greater than that of patients with pT3 tumors (63%, P=0.018) or pT4 tumors (17%, P=0.000). Although the 3-year RFS of patients with pT3 tumors was greater than that of patients with pT4 tumors, the difference was not significant. CONCLUSIONS: Successful down-staging of HCCs can be achieved in the majority of carefully selected patients by LRTs. Importantly, patients who are successfully down-staged and undergo LT may have a higher RFS rate.

Applications of Nanobiomaterials in the Therapy and Imaging of Acute Liver Failure

Acute liver failure(ALF),a fatal clinical disease featured with overwhelming hepatocyte necrosis,is a grand challenge in global health.However,a satisfactory therapeutic option for curing ALF is still absent,other than liver transplantation.Nanobiomaterials are currently being developed for the diagnosis and treatment of ALF.The liver can sequester most of nanoparticles from blood circulation,which becomes an intrinsic superiority for nanobiomaterials targeting hepatic diseases.Nanobiomaterials can enhance the bioavailability of free drugs,thereby significantly improving the therapeutic effects in ALF.Nanobiomaterials can also increase the liver accumulation of therapeutic agents and enable more effective targeting of the liver or specific liver cells.In addition,stimuli-responsive,optical,or magnetic nanomaterials exhibit great potential in the therapeutical,diagnostic,and imaging applications in ALF.Therefore,therapeutic agents in combination with nanobiomaterials increase the specificity of ALF therapy,diminish adverse systemic effects,and offer a multifunctional theranostic platform.Nanobiomaterial holds excellent significance and prospects in ALF theranostics.In this review,we summarize the therapeutic mechanisms and targeting strategies of various nanobiomaterials in ALF.We highlight recent developments of diverse nanomedicines for ALF therapy,diagnosis,and imaging.Furthermore,the challenges and future perspectives in the theranostics of ALF are also discussed.

Imaging response predictors following drug eluting beads chemoembolization in the neoadjuvant liver transplant treatment of hepatocellular carcinoma

BACKGROUND Drug-eluting bead transarterial chemoembolization(DEB-TACE)is an endovascular treatment to release chemotherapeutic agents within a target lesion,minimizing systemic exposure and adverse effects to chemotherapeutics.Therefore,identifying which patient characteristics may predict imaging response to DEB-TACE can improve treatment results while selecting the best candidates.Predictors of the response after DEB-TACE still have not been fully elucidated.This is the first prospective study performed with standardized DEBTACE technique that aim to identify predictors of radiological response,assessing patients clinical and laboratory characteristics,diagnostic imaging and intraprocedure data of the hepatocellular carcinoma treated in the neoadjuvant context for liver transplantation.AIM To identify pre-and intraoperative clinical and imaging predictors of the radiological response of drug-eluting bead transarterial chemoembolization(DEB-TACE)for the neoadjuvant treatment of hepatocellular carcinoma(HCC).METHODS This is prospective,cohort study,performed in a single transplant center,from 2011 to 2014.Consecutive patients with HCC considered for liver transplant who underwent DEB-TACE in the first session for downstaging or bridging purposes were recruited.Pre and post-chemoembolization imaging studies were performed by computed tomography or magnetic resonance.The radiological response of each individual HCC was evaluated by objective response using mRECIST and the percentage of necrosis.RESULTS Two hundred patients with 380 HCCs were examined.Analysis of the objective response(nodule-based analysis)demonstrated that HCC with pseudocapsules had a 2.01 times greater chance of being responders than those without pseudocapsules(P=0.01),and the addition of every 1mg of chemoembolic agent increased the chance of therapeutic response in 4%(P<0.001).Analysis of the percentage of necrosis through multiple linear regression revealed that the addition of each 1mg of the chemoembolic agent caused an average increase of 0.65%(P<0.001)in necrosis in the treated lesion,whereas the hepatocellular carcinoma with pseudocapsules presented 18.27%(P<0.001)increased necrosis compared to those without pseudocapsules.CONCLUSION The presence of a pseudocapsule and the addition of the amount of chemoembolic agent increases the chance of an objective response in hepatocellular carcinoma and increases the percentage of tumor necrosis following drug-eluting bead chemoembolization in the neoadjuvant treatment,prior to liver transplantation.

Biointerface engineering nanoplatforms for cancer-targeted drug delivery

Over the past decade,nanoparticle-based therapeutic modalities have become promising strategies in cancer therapy.Selective delivery of anticancer drugs to the lesion sites is critical for elimination of the tumor and an improved prognosis.Innovative design and advanced biointerface engineering have promoted the development of various nanocarriers for optimized drug delivery.Keeping in mind the biological framework of the tumormicroenvironment,biomembrane-camouflaged nanoplatforms have been a research focus,reflecting their superiority in cancer targeting.In this review,we summarize the development of various biomimetic cell membrane-camouflaged nanoplatforms for cancertargeted drug delivery,which are classified according to the membranes fromdifferent cells.The challenges and opportunities of the advanced biointerface engineering drug delivery nanosystems in cancer therapy are discussed.