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Objective:To study the safety and treatment outcomes of portal vein embolization (PVE) combined with lenvatinib plus an anti-programmed death-1(PD-1) antibody to treat patients with initially unreasectable hepatocellular carcinoma (uHCC).Methods:This study retrospectively analyzed the data of six patients with uHCC who received first-line combined systemic therapy with lenvatinib plus an anti-PD-1 antibody, and then underwent pre-hepatectomy PVE at the Department of Liver Surgery at Zhongshan Hospital, Fudan University from May 2019 to November 2020. All enrolled patients were males, aged (54.6±6.2) (ranged 46 to 63) years. Tumor response and liver volume were evaluated by medical imagings once every 2 months (±2 weeks) and evaluated using the Response Evaluation Criteria in Solid Tumours (version 1.1). Patients were followed-up by outpatient interviews or by phone calls to record their survival and tumor outcome status.Results:Three of the six enrolled patients had Barcelona Clinic Liver Cancer stage A and three had stage B disease. One patient achieved a partial response and five patients had stable diseases. The mean ± s. d. future liver remnant (FLR) percentage was (29.0±8.9) % before PVE and the combination therapy, and was (41.3±10.8) % before the last evaluation for liver surgery ( t=10.79, P<0.001). Hepatectomy was carried out in five patients, and one patient who failed to develop significant FLR hypertrophy did not undergo hepatectomy. Grade B post-hepatectomy liver failure and major postoperative complications (i.e. pleural effusion requiring additional percutaneous drainage) occurred in one patient. After a median post-operative follow-up of 4.5 (range: 1.0-12.3) months, all five patients were alive and were tumor free. Conclusion:PVE followed by hepatectomy is feasible in a uHCC patients receiving systemic therapy with lenvatinib and an anti-PD-1 antibody.
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Cancer is an internal disorder, as cancer cells come from normal cells, unlike infectious diseases. Therefore, "War on Can-cer" should be renamed as "Cancer Control War". Cancer Control War would need to emphasize on six integrations: integration of elim-ination and transformation strategies, integration of individual combat and comprehensive treatment, integration of quick decision in battle and lasting strategy, integration of passive treatment and active participation, integration of advanced technology and effi-cient, economical results, and integration of foreign service and Chinese mindset.
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Mutations detection of circulating tumor DNA can be divided into quantitative and qualitative classifications:the forumer mainly detects the total amount of circulating DNA (serum or plasma),whereas the latter mainly detects the specific genetic variations in serum or plasma DNA,such as gene mutations,methylations of tumor suppressor genes,and microsatellite alterations,etc.Both of them may reflect the tumor presence and disease severity.In this paper,mutations detection and its clinical significance of circulating tumor DNA in patients with hepatocellular carcinoma are reviewed.
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The development and progression of tumors are closely related to the tumor microenvironment.As one of the most important com-ponents in tumor microenvironment,cancer-associated fibroblasts (CAFs)play an important role in carcinogenesis,angiogenesis,inva-sion,and metastasis of tumors.The role of CAFs in the development and progression of hepatocellular carcinoma (HCC)is reviewed by dis-cussing how CAFs are recruited and activated in the tumor microenvironment and how CAFs promote tumor angiogenesis and regulate tumor immunity.This review may provide new approaches for the treatment of HCC.
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<p><b>BACKGROUND</b>The MAPK phosphatases (MKPs) are a family of dual-specificity phosphatases (DUSPs) that can dephosphorylate both phosphothreonine and phosphotyrosine residues, thus inactivating MAPK signaling. DUSP6 is a cytoplasmic MKP that can inactivate ERK. DUSP6 has been implicated in the development of some tumors. The aim of this research was to investigate the expression of DUSP6 in hepatocellular carcinoma (HCC) and the correlation of DUSP6 with mitogen-activated protein kinases (MAPKs), clinicopathological characteristics, and prognosis.</p><p><b>METHODS</b>Tissues from 305 patients who had undergone hepatectomy for HCC was used in this study. The expression of DUSP6, p-ERK, p-JNK, and p-p38α was determined using tissue microarrays for immunohistochemical analysis. The prognostic value of DUSP6 and other clinicopathological factors were evaluated.</p><p><b>RESULTS</b>The expression of DUSP6 was significantly higher in the tumor tissue when compared to the peritumor or normal liver tissue (P < 0.001). Tumor DUSP6 expression was significantly associated with disease-free survival (DFS) (P = 0.013). Tumor DUSP6 expression was an independent prognostic factor for DFS (Hazard ratio = 1.635, P = 0.006).</p><p><b>CONCLUSIONS</b>DUSP6 is over expressed in tumor tissue compared to peritumor or normal liver tissue. Higher expression of DUSP6 in tumor tissue, than in peritumor tissue, is associated with the recurrence after curative resection of HCC, and the relative tumor DUSP6 expression has good power to predict the recurrence of HCC.</p>
Subject(s)
Adult , Aged , Aged, 80 and over , Female , Humans , Male , Middle Aged , Young Adult , Carcinoma, Hepatocellular , Metabolism , Dual Specificity Phosphatase 6 , Metabolism , Immunohistochemistry , Liver Neoplasms , Metabolism , Neoplasm Recurrence, Local , Metabolism , Tissue Array AnalysisABSTRACT
The 5-year survival rates of small liver cancer resection were no longer improved in the past 40 years,indicating the importance of studies on cancer metastasis.Several important issues of cancer metastasis will be delineated:(1)Changing concepts of cancer metastasis:Cancer metastasis is a systemic issue,metastatic potential of cancer originated from pri-mary tumor,cancer stem cell is the key component of cancer metastasis,metastatic potential also influenced by immuneinflammatory microenvironment,metastatic potential is an alterable event.(2) The pro-metastatic effect of cancer eradication:In Liver Cancer Institute of Fudan University,experimental studies using human hepatocellular carcinoma nude mice model with high metastatic potential indicated that palliative resection,radiotherapy,chemotherapy,hepatic artery ligation and molecular targeted therapies that target to VEGF (eg.Sorafenib) promoted the metastatic potential of residual cancer,mainly via hypoxia,inflammation and immuno-suppression with different molecular alterations.Interestingly,effective intervention that inhibits metastasis and prolongs survival has been found using clinical available drugs in experimental studies.Such as cytokine (interferon),anti-inflammatories (aspirin and zoledronic acid),herbal medicine (Songyou Yin) and Tanshinone Ⅱ A,a novel tripeptide-tyroserleutide,etc.(3) Systemic intervention,including nervous system,immunotherapy,endocrinal intervention,as well as metabolic intervention,etc.were briefly discussed.
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Objective To evaluate the prognosis and management of recurrent primary clear cell carcinoma of liver (PCCCL).Methods 214 patients with PCCCL treated by curative resection from January 1996 to March 2006 were retrospectively studied.Tumour recurrences were classified into early (≤1 year) and late (＞1 year) recurrences.Results Of 99 patients who developed recurrences,28 developed early recurrence while 71 developed late recurrence.The patients with recurrences were treated with re-resection (n=33),percutaneous ethanol injection (PEI,n=7),radiofrequency ablation (RFA,n=10),transcatheter arterial chemoembolization (TACE,n =27),systemic chemotherapy (n=1),Chinese medicine (n=1),and conservative management (n=20).The re-resection rate was higher in the late than in the early recurrence group (P=0.04).In this study,reresection,PEI,and RFA were considered as curative therapies.There was no significant difference in the overall survival (OS) for patients who received these different curative therapeutic procedures (P=0.68).The 1,3-,and 5-year OS of patients with recurrences who were treated with curative treatment were comparable to those patients who did not develop recurrences (100％,86.0％,63.5％ vs 85.2％,72.2％,64.3％,P=0.71).The 1-,3-,and 5-year OS of patients who received TACE for recurrences were 100％,66.7％,and 44.4％ respectively.The results were poorer than patients who received curative treatment for recurrences (P=0.03),but were better than those who received conservative management after recurrences (80.0 ％,25.0 ％,and 10.0 ％,P＜ 0.01).Conclusions Reresection,PEI and RFA are optimal curative methods for recurrent PCCCL.TACE plays an important role in the management of patients with recurrent PCCCL who cannot be treated with curative methods.
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Complete resection of liver cancer is the main approach for achieving radical resection,and sufficient remnant liver is essential for avoiding hepatic failure after operation.With the aim of increasing remnant liver volume,a new two-stage technique,associating liver partition and portal vein ligation for staged hepatectomy (ALPPS),recently has been developed.In this article,the initial experience with 1 case of hepatocellular carcinoma who underwent ALPPS at the Zhongshan Hospital in April 2013 was reported.In the first stage,the right portal vein branch was ligated and subsequently the liver parenchyma was dissected along the falciform ligament to isolate the segment Ⅳ and the left lateral lobe.On postoperative day 7,the remnant liver volume was increased from 291 ml to 579 ml,and on postoperative day 8,the second stage operation was performed.During the second stage,the extended right lobe was removed.ALPPS induces a great and fast hypertrophy of the remnant liver,and R0 resection could be performed on patients which was considered unresectable because of small remnant liver volume,without severe postoperative liver failure and has a low mortality.
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Objective To investigate the risk factors influencing early and late recurrences after resection of primary clear cell carcinoma of the liver (PCCCL).Methods 214 PCCCL patients treated by curative resection from January 1996 to March 2006 were retrospectively analyzed.Recurrences were classified into early (≤1 year) and late (＞1 year) recurrences.Results 99 patients developed recurrences,with early recurrence in 28 patients and late recurrence in 71 patients.The 3-and 5-year overall survival (OS) rates for recurrent PCCCL were significantly worse than those with no recurrence (68.7％ and 46.2％ vs 72.2％ and 64.3％,P=0.003).The 1-,3-and 5-year OS rates for late recurrence were 100％,80.3％ and 54.6％,which were significantly better than those with early recurrence (85.7％,39.3％ and 25.0％,P=0.001).On multivariate analysis,aminoleucine transferase (ALT) level and vascular invasion were independent risk factors for early recurrence,while age was the only significant risk factor for late recurrence.Conclusions The time to recurrence was the main determinant for prognosis of recurrent PCCCL,Clarifying the different risk factors for early and late recurrences will help postoperative follow-up,early detection of recurrence,and hopefully will improve survival.
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Objective To investigate the effects of inhibiting epithelial mesenchymal transition (EMT) on metastastic potential of hepatocellular carcinoma (HCC) enhanced by hepatic arterial occlusion in mice. Methods Using a metastatic human HCC orthotopic nude mice model (MHCC97),the effects of hepatic artery ligation (HAL) alone,combination of HAL and phosphatidylinositol 3-kinase (PI3K)inhibitor LY294002,or combination of HAL and interferon-α (IFN-α) on the growth of planted human HCC cells and pulmonary metastasis were evaluated,respectively.The cells and tumor tissues specimens were analyzed through expression of Akt,p-Akt,E-cadhein,N-cadherin and Twist. Results HAL inhibits tumor growth (2002.97 ± 331.28 ) mm3 vs.( 3921.23 ± 786.21 ) mm3,t =4.052,P ＜ 0.01 ),while promoting pulmonary metastatsis ( 10/12 vs.4/12,P ＜ 0.05).HAL combined with LY294002 represses significantly enhanced pulmonary metastasis rate by HAL alone (0/6 vs.6/6,P ＜ 0.01 ).Moderate-dose IFN-α (7.5 × 106 U/kg) combined with HAL failed to further reduce tumor volume compared with that of HAL alone,but inhibited markedly pulmonary metastasis (2/6 vs.6/6,P ＜ 0.05 ).The augmented level of N-cadherin and Twist in tumor tissues due to HAL reduced by LY294002 or 7.5 × 106 U/kg IFN-α.The arrest of EMT by LY294002 or IFN-α in HAL-treated xenografts was further demonstrated by the in vitro response of hypoxic cells to both agents. Conclusions Inhibition of EMT in HCC cells could repress enhanced metastastic potential due to hepatic arterial occlusion.
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Objective To investigate the clinicopathologic characteristics and prognostic factors of primary clear cell carcinoma of the liver(PCCCL). Methods A total of 214 PCCCL patients treated by curative resection from January 1996 to March 2006 were retrospectively analyzed. Results The 1-,3-,and 5-year overall survival (OS) rates for PCCCL patients were significantly better than those of non-clear cell hepatocellular carcinoma ( NHCC ) patients ( 90.2％,70.6％,and 55.9％ vs 82.8％,62.7％ and 47.7％,P =0.001 ).Tumor size was significantly smaller in PCCCL group than in NHCC group ( x2 =4.37,P =0.04 ).Tumors of PCCCL group had a lower incidence of vascular invasion ( x2 =9.42,P =0.002) and a better differentiation than those of NHCC group ( x2 =4.30,P =0.04).Serum a-fetoprotein (AFP) level,tumor size,liver cirrhosis,and vascular invasion were independent risk factors impacting OS and disease-free survival (DFS) of PCCCL. Conclusions PCCCL is an uncommon subtype of HCC and has different clinicopathologic characteristics from NHCC. Complete surgical resection is the optimal treatment for PCCCL and its prognosis is much better than that of NHCC.
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ObjectiveTo explore the role of β-catenin in the proinvasive consequences of hypoxia in hepatocellular carcinoma (HCC).MethodsWe established in vitro and in vivo hypoxic models using the highly metastatic MHCC97 and the stable red fluorescent protein-expressing MHCC97-R cells.The role of β-catenin in hypoxia-mediated aggressiveness was investigated by β-catenin knockdown.ResultsHypoxia caused a pronounced arrest of proliferation in MHCC97 cells,suppressed tumor growth in MHCC97-R xenografts,but promoted in vitro invasiveness and in vivo metastasis.β-Catenin-silencing by short hairpin significantly inhibited the enhanced invasiveness of MHCC97 cells due to hypoxia,reduced the increase in distant metastasis by hepatic arterial ligation,but failed to further restrain cell proliferation.Conclusionβ-Catenin in HCC cells plays an essential role in the hypoxia-induced metastatic potential.A reduction of βcatenin expression inhibited the proinvasive consequences of hypoxia in HCC.
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ObjectiveTo study the role and mechanism of low-dose aspirin with IFN-α in inhibiting growth and metastasis of hepatocellular carcinoma (HCC).MethodsMHCC97L cells were cultured and a metastatic model of human HCC was established by orthotopic implantation of histologically intact human HCC tissue into the liver of nude (nu/nu) mice.After administration of different doses of Aspirin and IFN-α for 40 days,the mice bearing xenografts in liver were killed,and the tumor volume and lung metastasis were evaluated.Cell proliferation and MMP-2 activity were measured by MTT and gelatin zymography,respectively.The expressions of VEGF and MMP-2 were measured by western blot and ELISA.ResultsCompared to the control group,there were no significant differences in the high-dose Aspirin [45 mg/(kg · d)] treated group regarding tumor volume [(1.89 ±0.88) cm3 vs (3.12±0.85) cm3,P＞0.05] and incidence of lung metastases (58.3％ vs 66.7％,P＞0.05),but the tumor volume and incidence of lung metastasis were significantly inhibited in the highdose IFN-α group [1.5 × 107/(kg · d)],the high-dose IFN-α combined with high-dose Aspirin group,and the low-dose IFN-α [7.5 × 106 / (kg · d) ] combined with low-dose Aspirin [15 mg/(kg · d] group (P＜0.05).2 mmol/L Aspirin did not inhibit the proliferation of MHCC97 cells (P＞0.05),but inhibited the activities and expressions of MMP-2 and VEGF.Low-dose IFN-α combined with low-dose Aspirin significantly decreased the expressions of MMP-2 and VEGF in nude mice (P＜0.05).ConclusionLow-dose Aspirin combined with low-dose IFN-α significantly inhibited the growth and metastasis of HCC through suppressing the expressions of MMP-2 and VEGF.
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Hepatocellular carcinoma(HCC)is a major cause of cancer mortality worldwide,and liver transplantation (LT)has the potential to improve the survival for patients with HCC.However,tumor recurrence after LT remains the main obstacles for long-term survival.Selection of the ideal recipients based on Milan criteria or Shanghai Fudan criteria is a key point to reduce the incidence of recurrence.C,enomics and proteomics combined with tumor specific tumor markers detection are helpful to screen out the recipients.The norms of rumor-free operation should be strictly followed intraoperatively.Preventive chemotherapy and evaluation of immune function should be considered postoperatively to reduce the risks of tumor recurrence and metastasis.
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Post-transplant tumor recurrence and metastasis remain the main obstacles for long-term survival after liver transplantation (LT) for hepatocellular carcinoma (HCC). Measures to explore the HCC biological characteristics and the relationship between post-transplant immuno-suppression and tumor recurrence, to determine precisely the prognostic factors associated with post-transplant recurrence, to intervene effectively for those with high risk of recurrence, and to use individualized multimodality treatment for recurrence and metastasis may improve the therapeutic results of LT for HCC.
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Objective To investigate the role and mechanism of TMPRSS4 in radiation induced metastasis of hepatocellular carcinoma (HCC).Methods Metastatic model of human HCC was established by orthotopic implantation of histologically intact human HCC tissue into the liver of nude mice.Mice bearing xenografts in liver were killed after radiation and the residual tumors were resected and reimplanted into the liver of normal nude mice.At the end of sixth week,the mice were killed and the histopathological features,tumor volume,intrahepatic and lung metastasis were evaluated.Expression of epithelial-mesenchymal transition (EMT) related genes including N-cadherin,Vimentin,SIP1 and TMPRSS4 were measured by Western blotting and RT-PCR.Results The tumor volume and frequency of lung metastasis of control group was 2.25±0.52 cm3 and 66.7％,respectively.Compared to control group,tumor diameter (1.61±0.51 cm3,P＜0.05) and lung metastasis (12.5％,P＜0.05) were significantly inhibited 2 days after radiation.Whereas,30 days after radiation,tumor growth recovered (2.60±0.61 cm3,P＞0.05) and lung metastasis was enhanced (100％,P＜0.05).There were no intrahepatic metastasis in the control group and in the group of reimplantation of HCC 2 days after radiation,while the tumors from those 30 days after radiation showed enhanced intrahepatic metastasis (18 ± 8.05,P＜ 0.01 ),with overexpression of SIP1,N-cadherin,Vimentin and TMPRSS4,and reduced expression of E-cadherin.Conclusion The metastasis potential of residual HCC after radiation was first inhibited and then promoted.Overexpression of TMPRSS4 plays a critical role in radiation induced long-term metastasis of HCC by facilitating EMT.
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Objective To investigate the mechanism of pseudomonasaeruginosa mannose sensitive hamemagglutination vaccine (PA-MSHA) in inducing apoptosis in hepatocellular carcinoma (HCC).MethodsA metastatic model of human hepatocellular carcinoma (HCC) was established by orthotopic implantation of histologically intact human HCC tissue into the liver of nude mice.Mice bearing xenografts in liver were randomly divided into three groups:control group,PA-MSHA intraperitoneal administration group,and PA-MSHA subcutaneous administration group.The agent was administered every day after the third day post-tumor implantation.At the end of the sixth week,the mice were killed.Serum levels of TNF-α,IL-4,IL-6 and IFN-γ were measured by ELISA and the activities of caspase 3,caspase 8 and caspase 9 in the tumor samples were tested by spectrophotometric method.Fas/FasL expressions were evaluated by Western blotting.ResultsSerum TNF-α levels in the control group,PA-MSHA subcutaneous administration group and PA-MSHA intraperitoneal administration group were 25.24±3.22 pg/ml,25.50±4.55 pg/ml(P＞0.05) and 34.22±2.42 pg/ml (P＜0.01),respectively,while there were no significant differences in serum IL-4,IL-6 and IFN-γ among these three groups(P＞0.01).Compared with the control group,the activities of caspase 3,caspase 8 and caspase 9 in tumors in the intraperitoneal administration group increased by 4.1,2.3 and 1.9 fold(P＜0.01),respectively,and Fas/FasL expressions were significantly elevated in the intraperitoneal administration group and subcutaneous administration group.ConclusionWhen given intraperitoneally,PA-MSHA can induce apoptosis in HCC by promoting the secretion of TNF-α and expression of Fas/FasL,thereby inhibiting HCC growth and metastasis.
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Objective To summarize the techniques of anatomical liver resection for the treatment of hepatocellular carcinoma(HCC).Methods The clinical data of 125 patients with solitary HCC who underwent anatomical liver resection at the Zhongshan Hospital from January 2005 to December 2006 were retrospectively analysed.The inflow and outflow of hepatic segments to be resected were selectively clamped,then the main branches of portal vein and hepatic artery were ligated,and the ischemic hepatic segments were resected en bloc.Kelly forceps were used to crash and clamp the liver cut surface.The stumps of left and right hepatic ducts were continuously sutured with Prolene sutures.For tumors with the size above 10 cm in diameter,hepatectomy with anterior approach and liver hanging maneuver were adopted.Bile leakage was checked by injecting methylene blue or covering a gauze on the liver cut surface.Results The mean blood loss of all patients was 250 ml(100-6000 ml),and 32 of them needed blood transfusion.The morbidity was 23%(29/125).No patient died within 30 days after the operation,and 6%(5/83)of patients were found with residual tumor by postoperative arteriography.Conclusion Anatomical liver resection may improve the safety of operation,prevent the injury of great vessels and thus improve the efficacy.
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Objective To investigate the effects of Pseudomonas aeruginosa vaccine (PA) on proliferation and invasiveness of the hepatocellular carcinoma cell line MHCC97L with metastatic potential. Methods Proliferation, growth curve, plate efficiency, flow cytometry, transwell invasion assay, cell motility assay, scarification test, vascular endothelial growth factor (VEGF) and matrix metalloproteinase-2 (MMP2) protein activity were evaluated after cells were treated with PA at various concentrations. Results PA can inhibit the proliferation and plate efficiency of MHCC97L cell markedly in a dose-dependent manner. The IC50 of cells treated with PA for 48 h and 72 h was 3.1 ×108/ml and 1.9 × 108/ml, respectively. The doubling time increased and plate efficiency decreased gradually when cells treated with 0.5 × 108/ml, 1 × 108/ml and 2 × 108/ml PA (P＜0.01). PA could induce cell cycle arrest at the G1 phase in a dose-dependent manner by flow cytometric analysis. The average amount of invading cell per field in cell invasion assay and motility assay were 4. 8 ± 1.3 and 8. 8±2.2 when cells treated with 1× 108/ml PA, which was significantly lower than that of control group (8. 6±2. 1 and 15. 6±1.2 ) (P＜0.01) Scarification test showed that the metastatic ability of cells treated with 1 × 108/ml PA significantly lower than that in the control group. Comparison between cells treated with 1 × 108/ml PA and control group, no remarkable difference was found regarding expression of VEGF and MMP2 in supernatant of cell culture. Conclusion PA can inhibit proliferation and plate efficiency of HCC cell line MHCC97L, which is in part mediated by the cell cycle arrest at the G1 phase. PA could inhibit invasiveness of HCC cell line MHCC97L, which is unrelated to the VEGF and MMP2 protein activity.
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In the 20th century, major progresses were made for treatment of hepatocellular carcinoma: standard resection, radiotherapy and chemotherapy were applied in the 1950s; liver transplantation emerged in the 1960s, and the positive clinical results for the treatment of hepatocellular carcinoma were proved in the 1990s; the survival rates were significantly increased due to local resection for small liver cancer in the 1970s and local tumor therapies benefited the patients more in the 1980s. But the purpose of these procedures was only to destroy the tumors. In the past half century, the survival rate of liver cancer patients in our hospital increased every ten years. It is predicted that in the 21st century, the purpose of improving the outcome of treatment for liver cancer will elaborate to manipulating procedures between tumor and the human body on the basis of destroying the tumors. There are various ways to improve the therapeutic results for hepatocellular carcinoma. For example, these efforts can be achieved by developing and using new therapeutic methods. In the early 21st century, further biological study is the key point to influence the clinical progress for hepatocellular carcinoma. Although to destroy the tumors is basic and important, the most important thing is how to regulate the relationship between residual tumors and the human body.