Calculus bovis inhibits M2 tumor-associated macrophage polarization via Wnt/β-catenin pathway modulation to suppress liver cancer

BACKGROUND Calculus bovis(CB),used in traditional Chinese medicine,exhibits anti-tumor effects in various cancer models.It also constitutes an integral component of a compound formulation known as Pien Tze Huang,which is indicated for the treatment of liver cancer.However,its impact on the liver cancer tumor microenvironment,particularly on tumor-associated macrophages(TAMs),is not well understood.AIM To elucidate the anti-liver cancer effect of CB by inhibiting M2-TAM polarization via Wnt/β-catenin pathway modulation.METHODS This study identified the active components of CB using UPLC-Q-TOF-MS,evaluated its anti-neoplastic effects in a nude mouse model,and elucidated the underlying mechanisms via network pharmacology,transcriptomics,and molecular docking.In vitro assays were used to investigate the effects of CB-containing serum on HepG2 cells and M2-TAMs,and Wnt pathway modulation was validated by real-time reverse transcriptase-polymerase chain reaction and Western blot analysis.RESULTS This study identified 22 active components in CB,11 of which were detected in the bloodstream.Preclinical investigations have demonstrated the ability of CB to effectively inhibit liver tumor growth.An integrated approach employing network pharmacology,transcriptomics,and molecular docking implicated the Wnt signaling pathway as a target of the antineoplastic activity of CB by suppressing M2-TAM polarization.In vitro and in vivo experiments further confirmed that CB significantly hinders M2-TAM polarization and suppresses Wnt/β-catenin pathway activation.The inhibitory effect of CB on M2-TAMs was reversed when treated with the Wnt agonist SKL2001,confirming its pathway specificity.CONCLUSION This study demonstrated that CB mediates inhibition of M2-TAM polarization through the Wnt/β-catenin pathway,contributing to the suppression of liver cancer growth.

Comprehensive review of hepatocellular carcinoma with portal vein tumor thrombus:State of art and future perspectives

Background:Despite advances in the diagnosis of patients with hepatocellular carcinoma(HCC),70%-80%of patients are diagnosed with advanced stage disease.Portal vein tumor thrombus(PVTT)is among the most ominous signs of advanced stage disease and has been associated with poor survival if untreated.Data sources:A systematic search of MEDLINE(PubMed),Embase,Cochrane Library and Database for Systematic Reviews(CDSR),Google Scholar,and National Institute for Health and Clinical Excellence(NICE)databases until December 2022 was conducted using free text and MeSH terms:hepatocellular carcinoma,portal vein tumor thrombus,portal vein thrombosis,vascular invasion,liver and/or hepatic resection,liver transplantation,and systematic review.Results:Centers of surgical excellence have reported promising results related to the individualized surgical management of portal thrombus versus arterial chemoembolization or systemic chemotherapy.Critical elements to the individualized surgical management of HCC and portal thrombus include precise classification of the portal vein tumor thrombus,accurate identification of the subgroups of patients who may benefit from resection,as well as meticulous surgical technique.This review addressed five specific areas:(a)formation of PVTT;(b)classifications of PVTT;(c)controversies related to clinical guidelines;(d)surgical treatments versus non-surgical approaches;and(e)characterization of surgical techniques correlated with classifications of PVTT.Conclusions:Current evidence from Chinese and Japanese high-volume centers demonstrated that patients with HCC and associated PVTT can be managed with surgical resection with acceptable results.

Liver transplantation and resection in patients with hepatocellular cancer and portal vein tumor thrombosis: Feasible and effective?

Patients with locally advanced hepatocellular cancer(HCC)and portal vein tumor thrombosis(PVTT)have a dismal prognosis since limited treatment options are available for them.In recent years,effective systemic therapy,and advances in the understanding of technicalities and effectiveness of ablative therapies especially radiotherapy,have given some hope to prolong survival in them.This review summarized recent evidence in literature regarding the possible role of liver resection(LR)and liver transplantation(LT)in patients with locally advanced HCC and PVTT with no extrahepatic disease.Downstaging therapies have helped make curative resection or LT a reality in selected patients.This review emphasizes on the key points to focus on when considering surgery in these patients,who are usually relegated to palliative systemic therapy alone.Meticulous patient selection based on tumor biology,documented downstaging based on imaging and decrease in tumor marker levels,and an adequate waiting period to demonstrate stable disease,may help obtain satisfactory long-term outcomes post LR or LT in an intention to treat strategy in patients with HCC and PVTT.

Transcatheter arterial chemoembolization combined with PD-1 inhibitors and Lenvatinib for hepatocellular carcinoma with portal vein tumor thrombus

BACKGROUND Hepatocellular carcinoma(HCC)patients complicated with portal vein tumor thrombus(PVTT)exhibit poor prognoses and treatment responses.AIM To investigate efficacies and safety of the combination of PD-1 inhibitor,transcatheter arterial chemoembolization(TACE)and Lenvatinib in HCC subjects comorbid with PVTT.METHODS From January 2019 to December 2020,HCC patients with PVTT types Ⅰ-Ⅳ were retrospectively enrolled at Beijing Ditan Hospital.They were distributed to either the PTL or TACE/Lenvatinib(TL)group.The median progression-free survival(mPFS)was set as the primary endpoint,while parameters like median overall survival,objective response rate,disease control rate(DCR),and toxicity level served as secondary endpoints.RESULTS Forty-one eligible patients were finally recruited for this study and divided into the PTL(n=18)and TL(n=23)groups.For a median follow-up of 21.8 months,the DCRs were 88.9%and 60.9%in the PTL and TL groups(P=0.046),res-pectively.Moreover,mPFS indicated significant improvement(HR=0.25;P<0.001)in PTL-treated patients(5.4 months)compared to TL-treated(2.7 months)patients.There were no treatment-related deaths or differences in adverse events in either group.CONCLUSION A triplet regimen of PTL was safe and well-tolerated as well as exhibited favorable efficacy over the TL regimen for advanced-stage HCC patients with PVTT types Ⅰ-Ⅳ.

Predictive value of NLR, Fib4, and APRI in the occurrence of liver failure after hepatectomy in patients with hepatocellular carcinoma

BACKGROUND Neutrophil-lymphocyte ratio(NLR),fibrosis index based on four factors(Fib4),aspartate aminotransferase-to-platelet ratio index(APRI)can be used for prognostic evaluation of hepatocellular carcinoma.However,no study has established an individualized prediction model for the prognosis of hepatocellular carcinoma based on these factors.AIM To screen the factors that affect the prognosis of hepatocellular carcinoma and establish a nomogram model that predicts postoperative liver failure after hepatic resection in patients with hepatocellular carcinoma.METHODS In total,220 patients with hepatocellular carcinoma treated in our hospital from January 2022 to January 2023 were selected.They were divided into 154 participants in the modeling cohort,and 66 in the validation cohort.Comparative analysis of the changes in NLR,Fib4,and APRI levels in 154 patients with hepatocellular carcinoma before liver resection and at 3 mo,6 mo,and 12 mo postoperatively was conducted.Binary logistic regression to analyze the influencing factors on the occurrence of liver failure in hepatocellular carcinoma patients,roadmap prediction modeling,and validation,patient work characteristic curves(ROCs)to evaluate the predictive efficacy of the model,calibration curves to assess the consistency,and decision curve analysis(DCA)to evaluate the model’s validity were also conducted.RESULTS Binary logistic regression showed that Child-Pugh grading,Surgical site,NLR,Fib4,and APRI were all risk factors for liver failure after hepatic resection in patients with hepatocellular carcinoma.The modeling cohort built a column-line graph model,and the area under the ROC curve was 0.986[95%confidence in terval(CI):0.963-1.000].The patients in the validation cohort utilized the column-line graph to predict the probability of survival in the validation cohort and plotted the ROC curve with an area under the curve of the model of 0.692(95%CI:0.548-0.837).The deviation of the actual outcome curves from the calibration curves of the column-line plots generated by the modeling and validation cohorts was small,and the DCA confirmed the validity.CONCLUSION NLR,Fib4,and APRI independently influence posthepatectomy liver failure in patients with hepatocellular carcinoma.The column-line graph prediction model exhibited strong prognostic capability,with substantial concordance between predicted and actual events.

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.

Misdiagnosis of hemangioma of left triangular ligament of the liver as gastric submucosal stromal tumor:Two case reports

BACKGROUND Extragastric lesions are typically not misdiagnosed as gastric submucosal tumor(SMT).However,we encountered two rare cases where extrinsic lesions were misdiagnosed as gastric SMTs.CASE SUMMARY We describe two cases of gastric SMT-like protrusions initially misdiagnosed as gastric SMTs by the abdominal contrast-enhanced computed tomography(CT)and endoscopic ultrasound(EUS).Based on the CT and EUS findings,the patients underwent gastroscopy;however,no tumor was identified after incising the gastric wall.Subsequent surgical exploration revealed no gastric lesions in both patients,but a mass was found in the left triangular ligament of the liver.The patients underwent laparoscopic tumor resection,and the postoperative diagnosis was hepatic hemangiomas.CONCLUSION During EUS procedures,scanning across different layers and at varying degrees of gastric cavity distension,coupled with meticulous image analysis,has the potential to mitigate the likelihood of such misdiagnoses.

Role of immunosuppression and tumor differentiation in predicting recurrence after liver transplantation for hepatocellular carcinoma: A multicenter study of 412 patients

AIM： To assess pre-orthotopic liver transplantation （OLT） factors that could be evaluated pre-operatively or controlled post-operatively associated with hepatocellular carcinoma （HCC） recurrence and disease-free survival after liver transplantation （LT）.METHODS： Four hundred and twelve patients transplanted for HCC between 1988 and 1998 in 14 French centers, who survived the postoperative period were studied. Kaplan Meier estimates were calculated for 24 variables potentially associated with recurrence of HCC. Uni- and multivariate analyses were conducted to identify independent predictors of recurrence. RESULTS： Overall 5-year disease-free survival was 57.1%. By univariate analysis, variables associated with disease-free survival were： presence of cirrhosis （P = 0.001）, etiology of liver disease （P = 0.03）, α fetoprotein level （〈 200, 200 to 2000, or 〉 2000; P 〈 0.0001）, y-GT activity （N, N to 2N or 〉 2N; P = 0.02）, the number of nodules （1, 2-3 or ≥ 4; P = 0.02）, maximal diameter of the largest nodule （〈 3 cm, 3 to 5 cm or 〉 5 cm; P 〈 0.0001）, the sum of the diameter of the nodules （〈 3 cm, 3 to 5 cm, 5 to 10 cm or 〉10 cm; P 〈 0.0001）, bilobar location （P = 0.01）, preoperative portal thrombosis （P 〈 0.0001）, peri-operative treatment of the tumor （P = 0.002） and chemoembolization （P = 0.03）, tumor differentiation （P = 0.01）, initial type of calcineurin inhibitor （P = 0.003）, the use of antilymphocyte antibodies （P = 0.02）, rejection episodes （P = 0.003） and period of LT （P 〈 0.0001）. By multivariate analysis, 6 variables were independently associated with HCC recurrence： maximal diameter of the largest nodule （P 〈 0.0001）, time of LT （P 〈 0.0001）, tumor differentiation （P 〈 0.0001）, use of anti-lymphocyte antibody （ATG） or anti-CD3 antibody （OKT3） （P = 0.005）, preoperative portal thrombosis （P = 0.06） and the number of nodules （P = 0.06）. CONCLUSION： This study identifies immunosuppression, through the use of ATG or OKT3, as a predictive factor of tumor recurrence, and confirms the prognostic value of tumor differentiation.

Primary liver transplantation vs liver resection followed by transplantation for transplantable hepatocellular carcinoma:Liver functional quality and tumor characteristics matter

Liver resection(LR) and primary liver transplantation(LT) are two potentially curative treatment modalities for patients with hepatocellular carcinoma(HCC).If an underlying chronic liver disease exists,however,making a decision on which method should be selected is difficult.If a patient has no chronic liver disease,LR may be the preferable option with salvage transplantation(ST) in mind in case of recurrence.Presence of a moderate-to-severe liver failure accompanying HCC usually warrants primary LT.The treatment of patients with HCC and early-stage chronic liver disease remains controversial.The advantages of "LR-followed-by-STif-needed" strategy include less complicated index operation,no need for immunosuppression,use of donor livers for other patients in today's organ shortage setting and comparable survival rates.However,primary LT has its own advantages as it also treats underlying chronic liver disease with carcinogenic potential,removes undetected tumor nodules and potentially eliminates need for a ST.An article recently published by Fuks et al in Hepatology offers an approach by which selecting between LR-followed-by-ST and immediate LT might be easier.Here we discuss the results of the aforementioned report in the light of currently available knowledge.

Impact of non-oncological factors on tumor recurrence after liver transplantation in hepatocellular carcinoma patients

Hepatocellular carcinoma (HCC) is the most common primary neoplasm of the liver and is one of the leading causes of cancer-related death worldwide. Liver transplantation (LT) has become one of the best curative therapeutic options for patients with HCC, although tumor recurrence after LT is a major and unaddressed cause of mortality. Furthermore, the factors that are associated with recurrence are not fully understood, and most previous studies have focused on the biological properties of HCC, such as the number and size of the HCC nodules, the degree of differentiation, the presence of hepatic vascular invasion, elevated serum levels of alpha-fetoprotein, and the tumor stage outside of the Milan criteria. Thus, little attention has been given to factors that are not directly related to HCC (i.e., &#x0201c;non-oncological factors&#x0201d;), which have emerged as predictors of tumor recurrence. This review was performed to assess the effects of non-oncological factors on tumor recurrence after LT. The identification of these factors may provide new research directions and clinical strategies for the prophylaxis and surveillance of tumor recurrence after LT, which can help reduce recurrence and improve patient survival.

Collision tumor of hepatocellular carcinoma and neuroendocrine carcinoma involving the liver: Case report and review of the literature

Primary hepatic neuroendocrine carcinoma(NEC) with concurrent occurrence of hepatocellular carcinoma(HCC) of the liver is very rare. Only 8 cases have been reported in the literature. Concurrent occurrence of HCC and NEC in the liver is classified as combined type or collision type by histological distributional patterns; only 2 cases have been reported. Herein, we report a case of collision type concurrent occurrence of HCC and NEC, in which primary hepatic NEC was in only a small portion of the nodule, which is different from the 2 previously reported cases. A 72-year-old male with chronic hepatitis C was admitted to our hospital for a hepatic mass detected by liver computed tomography(CT) at another clinic. Because the nodule was in hepatic segment 3 and had proper radiologic findings for diagnosis of HCC, including enhancement in the arterial phase and wash-out in the portal and delay phases, the patient was treated with laparoscopic left lateral sectionectomy. The pathology demonstrated that the nodule was 2.5 cm and was moderately differentiated HCC. However, a 3 mm-sized focal neuroendocrine carcinoma was also detected on the capsule of the nodule. The tumor was concluded to be a collision type with HCC and primary hepatic NEC. After the surgery, for follow-up, the patient underwent a liver CT every 3 mo. Five multiple nodules were found in the right hepatic lobe on the follow-up liver CT 6 mo post-operatively. As the features of the nodules in the liver CT and MRI were different from that of HCC, a liver biopsy was performed. Intrahepatic recurrent NEC was proven after the liver biopsy, which showed the same pathologic features with the specimen obtained 6 mo ago. Palliative chemotherapy with a combination of etoposide and cisplatin has been administered for 4 months, showing partial response.

Alpha-fetoprotein and 18F-FDG standard uptake value predict tumor recurrence after liver transplantation for hepatocellular carcinoma with portal vein tumor thrombosis:Preliminary experience

Background:Portal vein tumor thrombosis(PVTT)is regarded as a contraindication for liver transplantation(LT)in hepatocellular carcinoma(HCC).However,some of these patients may have a favorable prognosis after LT.In this study,we evaluated the biological behavior of HCC with PVTT using tumor biomarker(alpha-fetoprotein,AFP)and 18 F-FDG positron emission tomography(tumor standard uptake value)to identify a subset of patients who may be suitable for LT.Methods:Seventy-five HCC-PVTT liver recipients transplanted during February 2016 and June 2018 were analyzed.Different pre-transplant prognostic factors were identified by univariate and multivariate analyses.PVTT status was identified following Vp classification(Vp1-Vp4).Results:Three-year recurrence-free survival and overall survival rates were 40%and 65.4%in Vp2-Vp3 PVTT patients,21.4%and 30.6%in Vp4 PVTT patients(P<0.05).Total tumor diameter>8 cm,pretransplant AFP level>1000 ng/m L and intrahepatic tumor maximal standard uptake value(SUVmaxtumor>5)were independent risk factors for HCC recurrence and overall survival after LT in Vp2-3 PVTT patients.Low risk patients were defined as total tumor diameter≤8 cm;or if total tumor diameter more than 8 cm,with both pre-transplant AFP level less than 1000 ng/m L and intrahepatic tumor SUVmax less than 5,simultaneously.Twenty-two Vp2-3 PVTT HCC patients(46.8%)were identified as low risk patients,and their 3-year recurrence-free and overall survival rates were 67.6%and 95.2%,respectively.Conclusions:Patients with segmental or lobar PVTT and biologically favorable tumors defined by AFP and 18 F-FDG SUVmax might be suitable for LT.

Liver tumor infiltrating lymphocytes: Comparison of hepatocellular and cholangiolar carcinoma

AIM: To investigate the role of tumor inf iltrating lym-phocytes (TIL) in primary hepatocellular and cholangio-lar carcinomas of the liver.METHODS: Immunohistochemical analysis was per-formed including antibodies to CD3, CD4, CD8, CD20, CD56 and TIA-1 in formalin-f ixed and paraff in-embed-ded tissue of 35 liver resection specimens of hepatocel-lular or cholangiocellular carcinomas. Semiquantitative evaluation was performed with emphasis on the area of the tumor itself and of the tumor/liver interface.RESULTS: All hepatocellular carcinomas showed in-filtration of lymphocytes predominantly around the tumor in the tumor/liver interface consisting mainly of CD3+ CD4+ T lymphocytes [164.3/10 high power f ields (HPF)] and in the tumor itself of CD8+ cells (54.9/10 HPF). Cholangiocarcinomas contained a heterogeneous amount of TIL, composed mainly of CD3+ T cells with a predominance of CD8+ cells in the tumor tissue (52.6/10 HPF) and of CD4+ cells in the interface region (223.1/10 HPF). CD56+ cells of the innate immune system were scarce. There was no significant difference between hepatocellular or cholangiolar carcinoma. No correlation with the clinicopathological data was seen. CONCLUSION: Liver TIL consists of intratumoral CD8+ T cells and peritumoral CD4+ T cells indepen-dent of histogenetic origin. Different functions of lym-phocytes in these regions seem possible.

Cloning of differentially expressed genes in human hepatocellular carcinoma and nontumor liver

INTRODUCTIONThe mechanism of hepatocellular carcinoma(HCC)is still unclear,although some genes have been found to play a role in the transformation of liver cells,and a variety of studies have described differences in gene expression which distinguished tumor from nontumor[1-6].The new genes,especially the functional genes directly related with tumor are still worth being found.The purpose of our study is to find the different genes between human liver tumor and normal tissues using suppression subtractive hybridization.

Living donor liver transplantation does not increase tumor recurrence of hepatocellular carcinoma compared to deceased donor transplantation

AIM: to compare the recurrence-free survival (RFS) and overall survival (OS) of hepatitis B virus (HBV)-positive hepatocellular carcinoma (HCC) after living donor liver transplantation (LDLT) and deceased donor liver transplantation (DDLT). METHODS: We retrospectively collected clinical data from 408 liver cancer patients from February 1999 to September 2012. We used the chi-squared test or Fisher's exact test to analyze the characteristics of LDLT and DDLT. Kaplan-Meier analysis was used to compare the RFS and OS in HCC. RESULTS: Three hundred sixty HBV-positive patients (276 DDLT and 84 LDLT) were included in this study. The mean follow-up time was 27.1 mo (range 1.1-130.8 mo). One hundred eighty-five (51.2%) patients died during follow-up. The 1-, 3-, and 5-year RFS rates for LDLT were 85.2%, 55.7%, and 52.9%, respectively; for DDLT, the RFS rates were 73.2%, 49.1%, and 45.3% (P = 0.115). The OS rates were similar between the LDLT and DDLT recipients, with 1-, 3-, and 5-year survival rates of 81.8%, 49.5%, and 43.0% vs 69.5%, 43.0%, and 38.3%, respectively (P = 0.30). The outcomes of HCC according to the Milan criteria after LDLT and DDLT were not significantly different (for LDLT: 1-, 3-, and 5-year RFS: 94.7%, 78.7%, and 78.7% vs 89.2%, 77.5%, and 74.5%, P = 0.50; for DDLT: 86.1%, 68.8%, and 68.8% vs 80.5%, 62.2%, and 59.8% P = 0.53). CONCLUSION: The outcomes of LDLT for HCC are not worse compared to the outcomes of DDLT. LDLT does not increase tumor recurrence of HCC compared to DDLT. (C) 2014 Baishideng Publishing Group Inc. All rights reserved.

Proposal of new expanded selection criteria using total tumor size and ^(18)F-fluorodeoxyglucose- positron emission tomography/computed tomography for living donor liver transplantation in patients with hepatocellular carcinoma:The National Cancer Center K

AIM: To expand the living donor liver transplantation(LT) pool of eligible patients with hepatocellular carcinoma(HCC) using new morphological and biological criteria.METHODS: Patients with HCC who underwent living donor LT(LDLT) from March 2005 to May 2013 at the National Cancer Center Korea(NCCK) were enrolled. We performed the 18F-fluorodeoxyglucose positron emission tomography/computed tomography(PET/CT)before LDLT. Overall and disease-free survival analysis was done in patients to evaluate the usefulness of new NCCK criteria using PET/CT and total tumor size(10 cm).RESULTS: We enrolled a total of 280 patients who pathologically confirmed to have HCC and performed the PET/CT before transplantation. Among them, 164(58.6%) patients fulfilled the NCCK criteria and 132 patients(47.1%) met the Milan criteria. Five-year overall and disease-free survival rates for patients who fulfilled the NCCK criteria showed 85.2% and 84.0%, respectively, and were significantly higher than those beyond the NCCK criteria(60.2% and 44.4%, respectively; P < 0.001). The correlation analysis between preoperative imaging tests and pathologic reports using Cohen's Kappa demonstrated the better results in the NCCK criteria than those in the Milan criteria(0.850 vs 0.583). The comparison of diseasefree analysis among the NCCK, Milan, and University of California, San Francisco(UCSF) criteria using the receiver operating characteristics curves revealed the similar area under the curve value criteria(NCCK vs Milan, P = 0.484; NCCK vs UCSF, P = 0.189 at 5-years).CONCLUSION: The NCCK criteria using hybrid concept of both morphological and biological parameters showed an excellent agreement between preoperative imaging and pathological results, and favorable survival outcomes. These new criteria might select the optimal patients with HCC waiting LDLT and expand the selection pool.

Liver transplantation for hepatocellular carcinoma on cirrhosis:Strategies to avoid tumor recurrence

Hepatocellular carcinoma(HCC) is one of the most frequent neoplasms worldwide and in most cases it is associated with chronic liver disease.Liver transplantation(LT) is potentially the optimal treatment for those patients with HCC who have a poor functional hepatic reserve due to their underlying chronic liver disease.However,due to the limited availability of donors,only those patients whose oncologic profile is favorable can be considered for LT.Despite the careful selection of candidates based on strict rules,10 to 20%of liver transplant recipients who have HCC in the native cirrhotic liver develop tumor recurrence after transplantation.The selection criteria presently employed to minimize the risk of recurrence are based on gross tumor characteristics defined by imaging techniques;unfortunately,the accuracy of imaging is far from being optimal.Furthermore,microscopic tumor features that are strictly linked with prognosis can not be assessed prior to transplantation.Pre-transplantation tumor downstaging may allow transplantation in patients initially outside the selection criteria and seems to improve the prognosis;it also provides information on tumor biology.Themain peculiarity of the transplantation setting,when this is compared with other modalities of treatment,is the need for pharmacological immunosuppression:this is based on drugs that have been demonstrated to increase the risk of tumor development.As HCC is an aggressive malignancy,immunosuppression has to be handled carefully in patients who have HCC at the time of transplantation and new categories of immunosuppressive agents should be considered.Adjuvant chemotherapy following transplantation has failed to show any significant advantage.The aim of the present study is to review the possible strategies to avoid recurrence of HCC after liver transplantation based on the current clinical evidence and the more recent developments and to discuss possible future directions.

Development of a nomogram for predicting liver transplantation prognosis in hepatocellular carcinoma

BACKGROUND At present,liver transplantation(LT)is one of the best treatments for hepatocellular carcinoma(HCC).Accurately predicting the survival status after LT can significantly improve the survival rate after LT,and ensure the best way to make rational use of liver organs.AIM To develop a model for predicting prognosis after LT in patients with HCC.METHODS Clinical data and follow-up information of 160 patients with HCC who underwent LT were collected and evaluated.The expression levels of alphafetoprotein(AFP),des-gamma-carboxy prothrombin,Golgi protein 73,cytokeratin-18 epitopes M30 and M65 were measured using a fully automated chemiluminescence analyzer.The best cutoff value of biomarkers was determined using the Youden index.Cox regression analysis was used to identify the independent risk factors.A forest model was constructed using the random forest method.We evaluated the accuracy of the nomogram using the area under the curve,using the calibration curve to assess consistency.A decision curve analysis(DCA)was used to evaluate the clinical utility of the nomograms.RESULTS The total tumor diameter(TTD),vascular invasion(VI),AFP,and cytokeratin-18 epitopes M30(CK18-M30)were identified as important risk factors for outcome after LT.The nomogram had a higher predictive accuracy than the Milan,University of California,San Francisco,and Hangzhou criteria.The calibration curve analyses indicated a good fit.The survival and recurrence-free survival(RFS)of high-risk groups were significantly lower than those of low-and middle-risk groups(P<0.001).The DCA shows that the model has better clinical practicability.CONCLUSION The study developed a predictive nomogram based on TTD,VI,AFP,and CK18-M30 that could accurately predict overall survival and RFS after LT.It can screen for patients with better postoperative prognosis,and improve longterm survival for LT patients.

Synergistic effect of bromocriptine and tumor necrosis factor-a on reversing hepatoceiiuiar carcinoma multidrug resistance in nude mouse MDRl model of liver neoplasm

AIM： To investigate the effect of bromocripUne （BCT） and tumor necrosis factor-α ClNF-α） on hepatocellular carcinoma （HCC） multidrug resistance （MDR） in nude mouse HDR model of liver neoplasm. METHODS： Human hepatocarcinoma cell line HepG2t drug resistant hepatocarcinoma cell line HepG2/adriamycin （ADM） and hepatocarcinoma cell line transfected with TNF-α gene HepG2JADM/TNF were injected into the liver of nude mice via orthotopic implantation and MDR model of liver neoplasm in vivo was established （HepG2t ADM, TNF, BCT groups）. Among these groups, BCT group and TNF group were treated with BCT through gastric canal. Each group was divided into control group and chemotherapy group. Size and weight of the tumor were measured. Furthermore, tumor his^logical character and growth of the nude mice were observed and their chemosensitivity was tested. MDR-associated genes and proteins （MRP, LRP） of implanted tumors were detected by immunohistochemistry, reverse transcriptase polymerase chain reaction, and apoptosis rate of hepatocarcinoma cells was detected by TUNEL assay. RESULTS： The nude mouse model of each cell line was inoculated successfully. The tumor growth rate and weight were significantly different among groups. After chemotherapy, abdominal cavity tumor growth inhibition rate was higher in BCT group （67%） compared to ADM and TNF groups, and similar to HepG2group （54%）. MDRI and LRPmRNA could be detected in all groups, but TNF-α was detected only in TNF and BCT groups. Furthermore, MDR1 and LRP protein expression of tumors in TNF and BCT groups was low similar to HepG2 group. The apoptosis rate of hepatocarcinoma cells was much higher in BCT group than in other groups with TUNEL assay. CONCLUSION： BCT and TNF-a can reverse HCC MDR in nude mouse MDR1 model of liver neoplasm. 2005 The WJG Press and Elsevier Inc. All rights reserved