Degradation of FAK-targeting by proteolytic targeting chimera technology to inhibit the metastasis of hepatocellular carcinoma

Liver cancer is a prevalent malignant cancer,ranking third in terms of mortality rate.Metastasis and recurrence primarily contribute to the high mortality rate of liver cancer.Hepatocellular carcinoma(HCC)has low expression of focal adhesion kinase(FAK),which increases the risk of metastasis and recurrence.Nevertheless,the efficacy of FAK phosphorylation inhibitors is currently limited.Thus,investigating the mechanisms by which FAK affects HCC metastasis to develop targeted therapies for FAK may present a novel strategy to inhibit HCC metastasis.This study examined the correlation between FAK expression and the prognosis of HCC.Additionally,we explored the impact of FAK degradation on HCC metastasis through wound healing experiments,transwell invasion experiments,and a xenograft tumor model.The expression of proteins related to epithelial-mesenchymal transition(EMT)was measured to elucidate the underlying mechanisms.The results showed that FAK PROTAC can degrade FAK,inhibit the migration and invasion of HCC cells in vitro,and notably decrease the lung metastasis of HCC in vivo.Increased expression of E-cadherin and decreased expression of vimentin indicated that EMT was inhibited.Consequently,degradation of FAK through FAK PROTAC effectively suppressed liver cancer metastasis,holding significant clinical implications for treating liver cancer and developing innovative anti-neoplastic drugs.

PDCD6 Promotes Hepatocellular Carcinoma Cell Proliferation and Metastasis through the AKT/GSK3β/β-catenin Pathway

Objective Programmed cell death 6(PDCD6), a Ca~(2+)-binding protein, has been reported to be aberrantly expressed in all kinds of tumors. The aim of this study was to explore the role and mechanism of PDCD6 in hepatocellular carcinomas(HCCs).Methods The expression levels of PDCD6 in liver cancer patients and HCC cell lines were analyzed using bioinformatics and Western blotting. Cell viability and metastasis were determined by methylthiazol tetrazolium(MTT) and transwell assays, respectively. And Western blotting was used to test related biomarkers and molecular pathway factors in HCC cell lines. LY294002, a PI3K inhibitor inhibiting AKT, was used to suppress the AKT/GSK3β/β-catenin pathway to help evaluate the role of this pathway in the HCC carcinogenesis associated with PDCD6.Results The analysis of The Cancer Genome Atlas Database suggested that high PDCD6 expression levels were relevant to liver cancer progression. This was consistent with our finding of higher levels of PDCD6 expression in HCC cell lines than in normal hepatocyte cell lines. The results of MTT, transwell migration, and Western blotting assays revealed that overexpression of PDCD6 positively regulated HCC cell proliferation, migration, and invasion. Conversely, the upregulation of PDCD6 expression in the presence of an AKT inhibitor inhibited HCC cell proliferation, migration, and invasion. In addition, PDCD6promoted HCC cell migration and invasion by epithelial-mesenchymal transition. The mechanistic investigation proved that PDCD6 acted as a tumor promoter in HCC through the AKT/GSK3β/β-catenin pathway, increasing the expression of transcription factors and cellular proliferation and metastasis.Conclusion PDCD6 has a tumor stimulative role in HCC mediated by AKT/GSK3β/β-catenin signaling and might be a potential target for HCC progression.

TNFR2 is a potent prognostic biomarker for post-transplant lung metastasis in patients with hepatocellular carcinoma

Objective:Lung metastasis is a common and fatal complication of liver transplantation for hepatocellular carcinoma(HCC).The precise prediction of post-transplant lung metastasis in the early phase is of great value.Methods:The mRNA profiles of primary and paired lung metastatic lesions were analyzed to determine key signaling pathways.We enrolled 241 HCC patients who underwent liver transplantation from three centers.Tissue microarrays were used to evaluate the prognostic capacity of tumor necrosis factor(TNF),tumor necrosis factor receptor 1(TNFR1),and TNFR2,particularly for post-transplant lung metastasis.Results:Comparison of primary and lung metastatic lesions revealed that the TNF-dependent signaling pathway was related to lung metastasis of HCC.The expression of TNF was degraded in comparison to that in para-tumor tissues(P<0.001).The expression of key receptors in the TNF-dependent signaling pathway,TNFR1 and TNFR2,was higher in HCC tissues than in para-tumor tissues(P<0.001).TNF and TNFR1 showed no relationship with patients’outcomes,whereas elevated TNFR2 in tumor tissue was significantly associated with worse overall survival(OS)and increased recurrence risk(5-year OS rate:31.9%vs.62.5%,P<0.001).Notably,elevated TNFR2 levels were also associated with an increased risk of post-transplant lung metastasis(hazard ratio:1.146;P<0.001).Cox regression analysis revealed that TNFR2,Hangzhou criteria,age,and hepatitis B surface antigen were independent risk factors for post-transplant lung metastasis,and a novel nomogram was established accordingly.The nomogram achieved excellent prognostic efficiency(area under time-dependent receiver operating characteristic=0.755,concordance-index=0.779)and was superior to conventional models,such as the Milan criteria.Conclusions:TNFR2 is a potent prognostic biomarker for predicting post-transplant lung metastasis in patients with HCC.A nomogram incorporating TNFR2 deserves to be a helpful prognostic tool in liver transplantation for HCC.

Global trends in hepatitis C-related hepatocellular carcinoma mortality:A public database analysis(1999-2019)

BACKGROUND Hepatitis C is the leading cause of chronic liver disease worldwide and it significantly contributes to the burden of hepatocellular carcinoma(HCC).However,there are marked variations in the incidence and mortality rates of HCC across different geographical regions.With the advent of new widely available treatment modalities,such as direct-acting antivirals,it is becoming increasingly imperative to understand the temporal and geographical trends in HCC mortality associated with Hepatitis C.Furthermore,gender disparities in HCC mortality related to Hepatitis C are a crucial,yet underexplored aspect that adds to the disease's global impact.While some studies shed light on gender-specific trends,there is a lack of comprehensive data on global and regional mortality rates,particularly those highlighting gender disparities.This gap in knowledge hinders the development of targeted interventions and resource allocation strategies.DISCUSSION The results of our study show an overall decline in the mortality rates of patients with hepatitis C-related HCC over the last two decades.Notably,females exhibited a remarkable decrease in mortality compared to males.Regionally,East Asia and the Pacific displayed a significant decline in mortality,while Europe and Central Asia witnessed an upward trend.Latin America and the Caribbean also experienced an increase in mortality rates.However,no significant difference was observed in the Middle East and North Africa.North America exhibited a notable upward trend.South Asia and Sub-Saharan Africa significantly declined throughout the study period.This raises the hope of identifying areas for implementing more targeted resources.Despite some progress,multiple challenges remain in meeting the WHO 2030 goal of eliminating viral hepatitis[24].

Long-term survival of patients with hepatocellular carcinoma with hepatic,pulmonary,peritoneal and rare colon metastasis:A case report

BACKGROUND Hepatocellular carcinoma(HCC)is a highly malignant cancer that often metastasizes and has a poor prognosis.Gastrointestinal tract metastases are rare,and colon metastases are even rarer.The long-term survival of patients with multiple intrahepatic and extrahepatic metastases,especially to the colon,has not been previously reported.CASE SUMMARY We present an atypical clinical case of a patient with liver,right lung,peritoneal,and colon metastases diagnosed successively following hepatic resection for primary HCC.Comprehensive treatment,including partial liver,lung and colon resection,palliative management such as systemic chemotherapy,trans-arterial chemoembolization,targeted therapy with sorafenib,and cryotherapy were attempted.Despite his early metastases,the patient remained relatively healthy for 8 years after diagnosis.CONCLUSION This case indicates that comprehensive treatment is beneficial for certain patients with metastatic HCC.Clinicians should be alert as to the possibility of rare site metastatic tumors that may be easily misdiagnosed as primary tumors.

Xiaoaiping injection affects the invasionand metastasis of hepatocellular carcinomaby controlling AFP expression

Objective Xiaoaiping (XAP) is a traditional Chinese medicine that is a commonly used as an anticancerdrug in clinical practice owing to its high efficiency and low toxicity. Specifically, XAP can effectively inhibitthe growth of hepatocellular carcinoma (HCC). Alpha-fetoprotein (AFP) is a key HCC diagnostic marker andis closely related to certain malignant cytological behaviors of HCC. However, whether AFP expression andXAP treatment are related to the invasion and metastasis of HCC remains unclear. In the present study, weaimed to evaluate the effects and underlying mechanism of XAP on the invasion and metastasis of HCC..Methods Using a cell scratch assay, Transwell technology, and western blotting we detected the differentinvasion and metastatic abilities of Hep3B cells in XAP treatment and blank control groups. This allowedcomparison of the invasion and metastatic abilities of Hep3B cells with differing levels of AFP expression.AFP mRNA sequencing technology was used to analyze the mechanism of tumor invasion and metastasisassociated with AFP and XAP treatment.Results Cell invasion and metastasis abilities in the XAP group were significantly lower than those in thecontrol group (P < 0.05). Additionally, compared to the control group, the expression of AFP significantlydecreased after XAP treatment (P < 0.05). The ability of Hep3B cells to invade and metastasize waspromoted when AFP expression was up-regulated, whereas it was inhibited when AFP was silenced. XAPinjection and AFP regulate the invasion and metastatic ability of HCC by affecting matrix metalloproteinases(MMPs).Conclusion XAP injection inhibits the invasion and metastatic ability of HCC by influencing the expressionof AFP;additionally, this inhibition of AFP is achieved by affecting MMPs.

Three-in-one incidence of hepatocellular carcinoma,cholangiocellular carcinoma,and neuroendocrine carcinoma:A case report

BACKGROUND Primary hepatic neuroendocrine carcinoma(NEC)is rare,and a combination with hepatocellular carcinoma(HCC)and cholangiocarcinoma(CCA)is extremely rare.To date,only four combination cases have been reported.The present paper describes the fifth patient.CASE SUMMARY A 32-year-old Chinese man with chronic hepatitis B was hospitalized for persistent upper abdominal pain.Abdominal computed tomography(CT)examination revealed a liver mass.The tumor was located in the 7th and 8th segments of the liver,and CT and magnetic resonance imaging findings were consistent with the diagnosis of HCC.Laboratory examinations revealed the following:Alanine aminotransferase,243 U/L;aspartate aminotransferase,167 U/L;alpha-fetoprotein,4519μg/L.Laparoscopic right lobe hepatectomy was performed on the liver mass.Postoperative pathology showed low differentiation HCC plus medium and low differentiation CCA combined with NEC.One month after the surgery,the patient suffered from epigastric pain again.Liver metastasis was detected by CT,and tumor transcatheter arterial chemoembolization was performed.Unfortunately,the liver tumor was progressively increased and enlarged,and after 1 mo,the patient died of liver failure.CONCLUSION This is a rare case,wherein the tumor is highly aggressive,grows rapidly,and metastasizes in a short period.Imaging and laboratory tests can easily misdiagnose or miss such cases;thus,the final diagnosis relies on pathology.

The Relationship between 67KD Laminin Receptor Expression and Metastasis of Hepatocellular Carcinoma

The 67KD laminin receptor (LN-R ) that binds laminin (LN) is involved in the metastasis cascade. Using immunohistochemical technique, in situ hybridization and reverse transcription polymerase chain reaction(RT-PCR), we studied LN-R protein and RNA levels in 30 cases of human hepatocellular carcinoma (HCC) to further understand its role in the metastasis of HCC. In our 14 cases of HCC with metastasis, its positive rates were 71. 4 %, 57. 1%, 85.7% respectively, whereas its positive expression in 16 cases without metastasis were 31.3 %, 18. 8 %, 50. 0 % respectively. The significant difference was found between these two groups. The results suggest that the 67KD LN-R expression plays a very important role in the metastasis of HCC.

Anti-programmed cell death ligand 1-based immunotherapy in recurrent hepatocellular carcinoma with inferior vena cava tumor thrombus and metastasis:Three case reports

BACKGROUND Recurrent hepatocellular carcinoma(HCC)with inferior vena cava tumor thrombus is a great challenge for oncologists and has a poor prognosis.To date,the safety and efficacy of programmed cell death ligand 1(PD-L1)inhibitors are still unknown.CASE SUMMARY A 59-year-old male was identified as having a tumor thrombus in the inferior vena cava 3 years after surgery.The patient underwent a second surgery and adjuvant chemotherapy.However,the level of alpha-fetoprotein was elevated after 2 mo,and lung metastases and mediastinal lymph node metastases were identified.The expression of PD-L1 in HCC and inferior vena cava tumor thrombus tissues was analyzed by immunohistochemistry.Then,the patient received atezolizumab immunotherapy.The level of alpha-fetoprotein dropped to normal,the mediastinal lymph node metastases decreased in size and the lung metastases disappeared after 3 mo of immunotherapy.The patient had no signs of recurrence at 21 mo of follow-up.A 60-year-old male underwent left hepatic tumor resection,inferior vena cava incision and thrombus removal,followed by regular chemotherapy.The patient developed lung and splenic metastases after surgery.Pembrolizumab was used for six courses,and the splenic metastasis shrank,after which splenectomy was performed.The patient continued to receive pembrolizumab for thirteen courses,and the lung metastases showed no progression.A 34-year-old male was diagnosed with liver cancer with inferior vena cava tumor thrombus.The patient underwent right hepatectomy and received tislelizumab for three courses.He is still receiving immunotherapy and in good condition.CONCLUSION Anti-PD-L1 therapy in HCC patients with inferior vena cava tumor thrombus and metastasis is associated with relatively good patient outcomes.

Perivascular epithelioid cell tumors of the liver misdiagnosed as hepatocellular carcinoma:Three case reports

BACKGROUND Hepatic perivascular epithelioid cell neoplasms(PEComas)are rare.Diagnostic and treatment experience with hepatic PEComa remains insufficient.CASE SUMMARY Three hepatic PEComa cases are reported in this paper:One case of primary malignant hepatic PEComa,one case of benign hepatic PEComa,and one case of hepatic PEComa with an ovarian mature cystic teratoma.During preoperative imaging and pathological assessment of intraoperative frozen samples,patients were diagnosed with hepatocellular carcinoma(HCC),while postoperative pathology and immunohistochemistry subsequently revealed hepatic PEComa.Patients with hepatic PEComa which is misdiagnosed as HCC often require a wider surgical resection.It is easy to mistake them for distant metastases of hepatic PEComa and misdiagnosed as HCC,especially when it’s combined with tumors in other organs.Three patients eventually underwent partial hepatectomy.After 1-4 years of follow-up,none of the patients experienced recurrence or metastases.CONCLUSION A clear preoperative diagnosis of hepatic PEComa can reduce the scope of resection and prevent unnecessary injuries during surgery.

Relationship between expression of CD44v6 and nm23-H1 and tumor invasion and metastasis in hepatocellular carcinoma

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Role of autophagy in tumorigenesis,metastasis,targeted therapy and drug resistance of hepatocellular carcinoma

Autophagy is a "self-degradative" process and is involved in the maintenance of cellular homeostasis and the control of cellular components by facilitating the clearance or turnover of long-lived or misfolded proteins, protein aggregates, and damaged organelles. Autophagy plays a dual role in cancer, including in tumor progression and tumor promotion, suggesting that autophagy acts as a double-edged sword in cancer cells. Liver cancer is one of the greatest leading causes of cancer death worldwide due to its high recurrence rate and poor prognosis. Especially in China, liver cancer has become one of the most common cancers due to the high infection rate of hepatitis virus. In primary liver cancer, hepatocellular carcinoma (HCC) is the most common type. Considering the perniciousness and complexity of HCC, it is essential to elucidate the function of autophagy in HCC. In this review, we summarize the physiological function of autophagy in cancer, analyze the role of autophagy in tumorigenesis and metastasis, discuss the therapeutic strategies targeting autophagy and the mechanisms of drug-resistance in HCC, and provide potential methods to circumvent resistance and combined anticancer strategies for HCC patients.

Association between vascular endothelial growth factor and metastasis after transcatheter arterial chemoembolization in patients with hepatocellular carcinoma

BACKGROUND: Hypoxia up-regulates vascular endothelialgrowth factor (VEGF) and stimulates the growth of hepa-tocellular carcinoma (HCC) cells. This study was designedto investigate the association between changes in plasmaVEGF levels after transcatheter arterial chemoembolization(TACE) and HCC progression, especially in relation tometastasis.METHODS: Plasma VEGF levels were measured by quati-tative sandwich enzyme-linked immunosorbent assay(ELISA R&D system). Plasma VEGF levels were measuredbefore, 3 days and 4 weeks after TACE in 30 patients withHCC. The development of metastasis was evaluated at theend of the third month after TACE.RESULTS: The plasma VEGF levels of the 30 patients withHCC were 154.47±90.17 pg/ml. The total plasma VEGFlevels after TACE increased compared with their basal levels(P<0.05), and the plasma VEGF levels had a tendency toincrease in patients with heterogenous uptake of iodizdoiland portal vein thrombosis. Follow-up for six monthsshowed metastatic foci in 20 patients (74%) with increasedplasma VEGF, but none of the patients with decreased plas-ma VEGF developed metastasis.CONCLUSION: Increased plasma VEGF expression is asso-ciated with the development of metastasis in HCC after TA-CE.

Expression of nm23 gene in hepatocellular carcinoma tissue and its relation with metastasis

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Efficacy of capecitabine and oxaliplatin regimen for extrahepatic metastasis of hepatocellular carcinoma following local treatments

AIM: To investigate the efficacy and safety of capecitabine and oxaliplatin (CapeOx) for extrahepatic metastasis after local treatment of hepatocellular carcinoma (HCC). METHODS: Thirty-two patients with extrahepatic metastasis of HCC after local treatment were prospectively enrolled. The CapeOx regimen consisted of capecitabine 1000 mg/m 2 taken orally twice daily on days 1-14, and oxaliplatin was administered at a total dose of 100 mg/m 2 on day 1. The treatment was repeated every 3 wk until disease progression or unaccetablle toxicity. Efficacy and safety were assessable for all enrolled patients. The primary objective of this study was to assess the overall response rate. The secondary objectives were to evaluate the overall survival (OS), the time to tumor progression (TTP) and the toxicity profile of the combined strategy. TTP and OS were assessed by the Kaplan-Meier method and differences between the curves were analyzed using the log-rank test. The statistical software SPSS version 15.0 for Windows (SPSS Inc., Chicago, IL, United States) was used for statistical analysis. All P values were 2-tailed, with statistical significance defined byP ≤ 0.05. RESULTS: Thirty-two patients were assessable for efficacy and toxicity. The median follow-up duration was 15 mo (range, 12-20 mo). At the cut-off date of March 31, 2012, 27 patients died due to tumor progression and one patient died of myocardial infarction. Four patients were still alive (three patients with disease progression). OR was 21.9% (n = 7), the stabilization rate was 40.6% (n = 13), and the disease control rate was 62.5%. The responses lasted from 4 to 19 mo (median, 6 mo). Median TTP was 4.2 mo (95%CI: 2.5-7.4), and the median OS time was 9.2 mo (95%CI: 6.5-17.8). The 1-year survival rate was 43.6% (95%CI: 29.0-66.0). In a multivariate analysis, OS was significantly longer in patients with a Child-Pugh class A compared with class B patients (P = 0.014), with a median OS of 10.1 mo vs 5.4 mo, and there were trends towards longer OS (P = 0.065) in patients without portal vein tumor thrombosis. There were no significant effects of age, gender, performance status, cirrhosis, metastatic sites, and level of alpha fetoprotein (AFP) or hepatitis B virus-DNA on OS. Among the 22 patients with elevated AFP levels at baseline (≥ 400 ng/mL), the level fell by more than 50% during treatment in 6 patients (27.3%). The most frequent treatment-related grade 3 to 4 toxicities included leucopenia/neutropenia, transient elevation of aminotransferases, handfoot syndrome and fatigue. CONCLUSION: CapeOx showed modest anti-tumor activity in metastatic HCC. However, the manageable toxicity profile and the encouraging disease control rate deserve further study for these patients.

ATP-citrate lyase regulates stemness and metastasis in hepatocellular carcinoma via the Wnt/β-catenin signaling pathway

Background: Hepatocellular carcinoma(HCC) is one of the most highly malignant tumors. Liver tumor-initiating cells(LTICs) have been considered to contribute to HCC progression and metastasis. ATP-citrate lyase(ACLY), as a key enzyme for de novo lipogenesis, has been reported to be upregulated in various tumors. However, its expression and role in HCC and LTICs remain unknown. Methods: The expressions of ACLY in HCC tissues were detected by quantitative real-time PCR(q RT-PCR), Western blotting and immunohistochemistry. Kaplan-Meier curves and Chi-square test were used to determine the clinical significance of ACLY expression in HCC patients. A series of assays were performed to determine the function of ACLY on stemness, migration and invasion of HCC cells. Luciferase reporter assay, Western blotting and immunoprecipitation were used to study the regulation of the Wnt/β-catenin signaling by ACLY. Rescue experiments were performed to investigate whether β-catenin was the mediator of ACLY-regulated stemness and migration in HCC cells. Results: ACLY was highly expressed in HCC tissues and LTICs. Overexpression of ACLY was significantly correlated with poor prognosis, progression and metastasis of HCC patients. Knockdown of ACLY remarkably suppressed stemness properties, migration and invasion in HCC cells. Mechanistically, ACLY could regulate the canonical Wnt pathway by affecting the stability of β-catenin, and Lys49 acetylation of β-catenin might mediate ACLY-regulated β-catenin level in HCC cells. Conclusions: ACLY is a potent regulator of Wnt/β-catenin signaling in modulating LTICs stemness and metastasis in HCC. ACLY may serve as a new target for the diagnosis and treatment of HCC.

Misdiagnosis of left supraclavicular lymph node metastasis of hepatocellular carcinoma:A case report

Left supraclavicular lymph node metastasis is a rare presentation of hepatocellular carcinoma (HCC).This phenomenon is easily neglected in the clinic.A 56-yearold man presented with HCC.On examination,a 1cm long left supraclavicular lymph node was palpated.Auxiliary examination indicated a lesion located in the right lobe of the liver.Fine needle aspiration cytology (FNAC) of the enlarged lymph node was performed;however,only necrosis was found.Hepatectomy was performed and HCC was confirmed by Hematoxylin-Eosin staining.However,14 d after surgery,significantly enlarged left supraclavicular lymph nodes,a new intrahepatic lesion,and pulmonary and mediastinal metastasis appeared.An excisional biopsy of the left supraclavicular lymph node was performed,and its findings confirmed metastatic HCC.The patient's HCC rapidly progressed and he died one month later.It is possible for HCC tometastasize to the left supraclavicular lymph node.Surgeons should always consider an overall physical examination.When left supraclavicular lymphadenopathy of unknown origin is encountered,FNAC should be performed initially.If the results are negative,an excisional biopsy and subsequent Positron emission tomography computed tomography scanning should be performed.These are very important for making the correct diagnosis and for selecting reasonable therapies.

Expression of Vascular Endothelial Growth Factor in Hepatocellular Carcinoma and Its Relationship to Tumor Growth and Metastasis

To understand the relationship between the expression of vasCular endothelial growth factor (VEGF) and the growth, metastasis of hepatocellular car cinoma (HCC), immunohistochemistry and Northern blot were used to investigate VEGF protein and mRNA in 21 cases of HCC with and without rnetastasis.VEGF protein was found in 8 of 9 cases with metastasis, whereas only in 4 of 12 cases without rnetastasis. The Positive rate of the former was significantly higher than that in the latter. VEGF mRNA was detectable in both carcinoma and its surrounding liver tissues, but its level in the former was 2 - 3 times higher than that in the latter. In carcinoma with metastasis, the mRNA level was 5-6 times higher than that without metastasis. It is concluded that VEGF Is closely related to the growth of HCC as well as its metastasis and it might be a useful indicator for the metastatic potential of HCC.

Skull metastasis from hepatocellular carcinoma with chronic hepatitis B

A 56-year-old male visited our hospital for evaluation of an occipital mass.Contrast computed tomography showed hypervascular enhancement with osteolytic change in the skull and a huge enhanced mass in the liver.Magnetic resonance imaging showed bone metastasis in the thoracic vertebrae.Assays for hepatitis B surface antigen and hepatitis B core antibody were positive and his liver condition was Child-Pugh grade A.Our diagnosis was hepatocellular carcinoma(HCC) with skull and vertebrae metastases on chronic hepatitis B.He was treated with radiation therapy for bone metastases and transcatheter arterial chemoembolization for HCC.But he developed acute respiratory failure because of aspiration pneumonia,congestion and oedema with haemorrhage of the lungs and died.Dissection showed HCC with multiple bone metastases.The liver tumor was categorized as well-differentiated HCC,Edmondson classification Ⅰ,trabecular type and pseudoglandular type.In the liver mild infiltration of lymphocytes was seen in Glisson's capsules which were signif icantly enlarged with well preserved limiting plates.Piecemeal necrosis was not obvious.No fibrosis was noted.An 8 cm × 7 cm × 3 cm metastatic lesion had formed in the left occipitotemporal part of the cranial bone.The lesion was osteolytic and showed invasion into the dura mater.Neither the subdural cavity nor the brain showed involvement from the metastatic tumor.However,skull metastasis from HCC is very rare and it affects the patient's prognosis and the quality of life.Therefore,it is very important to make an early diagnosis and carry out proper management of skull metastasis from HCC.

Features of extrahepatic metastasis after radiofrequency ablation for hepatocellular carcinoma

BACKGROUND Extrahepatic metastasis(EHM)of hepatocellular carcinoma(HCC)is associated with poor outcomes.However,the clinical features and risk factors of EHM of HCC after radiofrequency ablation(RFA)remain unclear.AIM To elucidate the characteristics and risk factors of EHM after RFA for HCC.METHODS From January 2008 to December 2017,we retrospectively enrolled 661 patients who underwent RFA as first-line treatment for HCC at 2 tertiary hospitals.The inclusion criteria were age≥18 years,a diagnosis of HCC,and treatment-naivety.Abdominal computed tomography(CT)or magnetic resonance imaging(MRI)and alpha-fetoprotein measurements were routinely performed at 1 mo after RFA and followed-up at intervals of 3-6 mo.Univariate analyses were performed using the chi-squared test or Student’s t-test,and univariate and multivariate analyses were performed via logistic regression,as appropriate.RESULTS EHM was diagnosed in 44 patients(6.7%)during a median follow-up period of 1204 days.The 10-year cumulative rate of HCC recurrence and EHM was 92.7%and 33.7%,respectively.Initial recurrence was most often intrahepatic,and the rate of extrahepatic recurrence at initial recurrence was only 1.2%.The median time to the diagnosis of EHM was 2.68 years,and 68.2%of patients developed EHM within 2 years of the first recurrence,regardless of recurrence-free survival and 75.0%of patients developed EHM within 5 years after first recurrence.EHM was mostly diagnosed via abdominal CT/MRI in 33(75.0%)and 38 of 44 patients(86.4%)with EHM had either positive abdominal CT scan results or serum AFP level elevation.In multivariate analysis,recurrence-free survival<2 years,ablation zone/tumor size<2,and alpha-fetoprotein level>400 IU/mL were associated with a high EHM risk.CONCLUSION EHM occurs following multiple intrahepatic recurrences after RFA and combined contrast-enhanced abdominal CT and serum AFP were useful for surveillance.Patients especially with high-risk factors require close follow-up for EHM.