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.

Hypofractionated and intensity-modulated radiotherapy combined with systemic therapy in metastatic hepatocellular carcinoma:A case report

BACKGROUND Liver cancer treatment is characterized by multidisciplinary participation and coexistence of multiple treatment methods.Hypofractionated and intensity-modulated radiotherapy is a new precise radiotherapy technique applied to the treatment of systemic malignant tumors.There is a lack of understanding of hypofractionated and intensity-modulated radiotherapy combined with systemic therapy in metastatic hepatocellular carcinoma(HCC).CASE SUMMARY We report a case of metastatic HCC treated with hypofractionated and intensity-modulated radiotherapy combined with systemic therapy.A 41-year-old man was diagnosed with metastatic HCC(T3N1M1 stage IVB).Because it was found to be in the late stage of cancer and had already metastasized,it was impossible to undergo surgical treatment.In addition to aggressive comprehensive treatment for the primary lesion,local treatment for metastatic cancer can improve the patient's survival potential.Hypofractionated and intensity-modulated radiotherapy can provide a larger single treatment dose within a shorter overall treatment time,and improve the local control rate of the tumor.Follow-up examination demonstrated that the tumor and metastatic lesions had shrunk after therapy.The treatment has showed good efficacy.The patient survived for 18 months without disease progression and stable disease persisted for>38 months.CONCLUSION Targeted therapy and immunotherapy followed by hypofractionated and intensity-modulated radiotherapy are also effective for advanced metastatic HCC.

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].

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.

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.

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.

Positron emission tomography/computer tomography in guidance of extrahepatic hepatocellular carcinoma metastasis management

Hepatocellular carcinoma （HCC） is one of the most common primary cancers in the world. Surgery is the gold standard for treatment of patients with HCC. Recurrence and metastasis are the major obstacles to further improve the prognosis of HCC. Most recurrences are intrahepatic. However, 30% of the recurrences are extrahepatic. The role of resection in intrahepatic recurrences is widely accepted. The role of resection in extrahepatic HCC recurrence and metastasis is not well established. 18F fluorodeoxyglucose （18F-FDG） positron emission tomography/computer tomography （PET/CT） is useful in detecting distant metastasis from a variety of malignancies and shows superior accuracy to conventional imaging modalities in identification of intrahepatic and extrahepatic metastasis. We present one patient with one new isolated omental lymph node metastasis, who had a history of huge HCC resected six years ago. The metastatic focus was identified with 18 F-FDG PET/CT and resected. The follow-up revealed good prognosis with a long-term survival potential after resection of the omental lymphatic metastasis.

Inhibitory effects of genistein on metastasis of human hepatocellular carcinoma

AIM： To investigate the inhibitory effects of genistein on metastasis of MHCC97-H hepatocellular carcinoma cells and to explore the underlying mechanism. METHODS： MHCC97-H hepatocellular carcinoma cells were exposed to genistein. A cell attachment assay was carried out in a microculture well pre-coated with fibronectin. The invasive activity of tumor cells was assayed in a transwell cell culture chamber, and cell cycle and apoptosis were evaluated by a functional assay. In addition, the expression and phosphorylation of FAK were detected by Western blotting. In situ xenograft transplantation of hepatocellular carcinoma was performed in 12 nude mice and lung metastasis of hepatocellular carcinoma was observed. RESULTS： Genistein significantly inhibited the growth of MHCC97-H cells in vitro. Adhesion and invasiveness of MHCC97-H cells were inhibited in a concentrationdependent fashion, and the inhibitory effect of genistein was more potent in the 10 i^g/mL and 20 i^g/ mL genistein-treated groups. Genistein caused G0/G1 cell cycle arrest, an S phase decrease, and increased apoptosis. The expression and phosphorylation of FAK in MHCC-97H cells were significantly decreased. In situ xenograft transplantation of hepatocellular carcinoma was also significantly suppressed by genistein. The number of pulmonary micrometastatic loci in the genistein group was significantly lower compared with the control group （12.3 ± 1.8 vs 16.6± 2.6, P 〈 0.05）. CONCLUSION： Genistein appears to be a promising agent in the inhibition of metastasis of hepatocellular carcinoma.

SF/HGF-c-Met autocrine and paracrine promote metastasis of hepatocellular carcinoma

AIM: To explore the role of SF/HGF-Met autocrine and paracrine in metastasis of hepatocellular carcinoma (HCC). METHODS: SF/HGF and c-met transcription and protein expression in HCC were examined by RT-PCR and Western Blot in 4 HCC cell lines, including HepG2, Hep3B, SMMC7721 and MHCC-1, the last cell line had a higher potential of metastasis. sf/hgf cDNA was transfected by the method of Lipofectin into SMMC7721. SF/HGF and c-met antibody were used to stimulate and block SF/HGF-c-met signal transduction. Cell morphology, mobility, and proliferation were respectively compared by microscopic observation, wound healing assay and cell growth curve. RESULTS: HCC malignancy appeared to be relative to its met-SF/HGF expression. In MHCC-1, c-met expression was much stronger than that in other cell lines with lower potential of metastasis and only SF/HGF autocrine existed in MHCC-1. After sf/hgf cDNA transfection or conditioned medium of MHCC-1 stimulation, SMMC7721 changed into elongated morphology, and the abilities of proliferation (P 【 0.05) and mobility increased. Such bio-activity could be blocked by c-met antibody (P 【 0.05). CONCLUSION: The system of SF/HGF-c-met autocrine and paracrine played an important role in development and metastasis potential of HCC. Inhibition of SF/HGF-c-met signal transduction system may reduce the growth and metastasis of HCC.

Pedunculated hepatocellular carcinoma and splenic metastasis

Only a few cases of pedunculated hepatocellular carcinoma (P-HCC) have been reported in the literature. The common sites of extrahepatic metastases in patients with HCC are the lungs, regional lymph nodes, kidney, bone marrow and adrenals. Metastasis to spleen is mostly via hematogenous metastasis, direct metastasis to spleen was very rare. We report a case of P-HCC presenting as a left upper abdominal lesions which involved the spleen that was actually a P-HCC with splenic metastasis. This case is unique as P-HCC directly involved the spleen which is not via hematogenous metastasis.

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.

Brain metastasis of hepatocellular carcinoma:A case report and review of the literature

Hepatocellular carcinoma (HCC) is one of the most frequent malignancies in the world. It is more common in far eastern countries and relatively rare in the United States and western European countries where at autopsy it accounts for only 1-2% of malignant rumors, The disease is usually manifested in the the 6^th and 7^th decade of life. HCC is one of the highly malignant neoplasms, Extrahepatic metastases are seen in 64% of patients with HCC. The lungs, regional lymph nodes, kidney, bone marrow and adrenals are common sites of HCC metastasis^[1-3], But, metastasis to brain and skull is extremely rare. Table I shows some of the reported cases of HCC with brain metastasis. These case reports reaffirms the complex and multidisciplinary care of these patients^[4-5].

Intraductal papillary neoplasm of the bile duct in liver cirrhosis with hepatocellular carcinoma

A case of intraductal papillary neoplasm of the bile duct (IPNB) arising in a patient with hepatitis B-related liver cirrhosis with hepatocellular carcinoma (HCC) is reported. A 76-year-old man was admitted to our hospital with recurrent HCC. Laboratory data showed that levels of carcinoembryonic antigen and carbohydrate antigen 19-9 were elevated. He died of progressive hepatic failure. At autopsy,in addition to HCCs,an intraductal papillary proliferation of malignant cholangiocytes with fibrovascular cores was found in the dilated large bile ducts in the left lobe,and this papillary carcinoma was associated with an invasive mucinous carcinoma (invasive IPNB). Interestingly,extensive intraductal spread of the cholangiocarcinoma was found from the reactive bile ductular level to the interlobular bile ducts and septal bile ducts and to the large bile ducts in the left lobe. Neural cell adhesion molecule,a hepatic progenitor cell marker,was detected in IPNB cells. It seems possible in this case that hepatic progenitor cells located in reactive bile ductules in liver cirrhosis may have been responsible for the development of the cholangiocarcinoma and HCC,and that the former could have spread in the intrahepatic bile ducts and eventually formed grossly visible IPNB.

Axl glycosylation mediates tumor cell proliferation, invasion and lymphatic metastasis in murine hepatocellular carcinoma

AIM: To investigate the effects of Axl deglycosylation on tumor lymphatic metastases in mouse hepatocellular carcinoma cell lines. METHODS: Western blotting was used to analyze the expression profile of Axl glycoprotein in mouse hepa-tocellular carcinoma cell line Hca-F treated with tunicamycin and PNGase F 3-(4,5)-dimethylthiazol(-zyl)-3,5- diphenyltetrazolium bromide (MTT) assay, extracellular matrix (ECM) invasion assay (in vitro ) and tumor metastasis assay (in vivo ) were utilized to evaluate the effect of Axl deglycosylation on the Hca-F cell proliferation, invasion and lymphatic metastasis. RESULTS: Tunicamycin and PNGase F treatment markedly inhibited Axl glycoprotein synthesis and expression, proliferation, invasion, and lymphatic metastasis both in vitro and in vivo . In the MTT assay, proliferation was apparent in untreated Hca-F cells compared with treated Hca-F cells. In the ECM invasion assay (in vitro ), treated cells passed through the ECMatrix gel in significantly smaller numbers than untreated cells (tunicamycin 5 μg/mL: 68 ± 8 vs 80 ± 9, P=0.0222; 10 μg/mL: 50 ± 6vs 80 ± 9,P=0.0003; 20 μg/mL: 41 ± 4 vs 80 ± 9, P=0.0001); (PNGase F 8 h: 66 ± 7 vs 82 ± 8, P=0.0098; 16 h: 49 ± 4 vs 82 ± 8, P=0.0001; 24 h: 34 ± 3 vs 82 ± 8, P=0.0001). In the tumor metastasis assay (in vivo ), average lymph node weights of the untreated Hca-F group compared with treated Hca-F groups (tunicamycin 5 μg/mL: 0.84 ± 0.21 g vs 0.72 ± 0.19 g, P=0.3237; 10 μg/mL: 0.84 ± 0.21 g vs 0.54 ± 0.11 g, P=0.0113; 20 μg/mL: 0.84 ± 0.21 g vs 0.42 ± 0.06 g, P=0.0008); (PNGase F 8 h: 0.79 ± 0.15 g vs 0.63 ± 0.13 g, P=0.0766; 16 h: 0.79 ± 0.15 g vs 0.49 ± 0.10 g, P=0.0022; 24 h: 0.79 ± 0.15 g vs 0.39 ± 0.05 g, P=0.0001). Also, average lymph node volumes of the untreated Hca-F group compared with treated Hca-F groups (tunicamycin 5 μg/mL: 815 ± 61 mm 3 vs 680 ± 59 mm 3 , P=0.0613; 10 μg/mL: 815 ± 61 mm 3 vs 580 ± 29 mm 3 , P=0.0001; 20 μg/mL: 815 ± 61 mm 3 vs 395 ± 12 mm 3 , P=0.0001); (PNGase F 8 h: 670 ± 56 mm 3 vs 581 ± 48 mm 3 , P=0.0532; 16 h: 670 ± 56 mm 3 vs 412 ± 22 mm 3 , P=0.0001; 24 h: 670 ± 56 mm 3 vs 323 ± 11 mm 3 , P=0.0001). CONCLUSION: Alteration of Axl glycosylation can at-tenuate neoplastic lymphatic metastasis. Axl N-glycans may be a universal target for chemotherapy.

Metabolic imaging for guidance of curative treatment of isolated pelvic implantation metastasis after resection of spontaneously ruptured hepatocellular carcinoma: A case report

Spontaneous rupture of hepatocellular carcinoma(HCC) is a life-threatening complication and its prognosis is significantly poor because of the high recurrence rate after initial hepatectomy. Resection of isolated extrahepatic metastasis of HCC has been advocated to obtain a possibility of long-term survival. However, it is a challenge for clinicians to detect implantation metastasis of spontaneously ruptured HCC. Accurate re-staging plays the most important role in making a decision on isolated metastasis resection. 18F-fluorodeoxyglucose(18F-FDG) positron emission tomography/computed tomography(PET/CT) is useful in detecting intraabdominal implantation metastasis from a variety of malignancies and shows superior accuracy to conventional imaging modalities in determining the location of metastasis. We present one patient with a new isolated pelvic implantation metastasis detected by 18F-FDG PET/CT and pathologically confirmed by PET/CT-guided percutaneous biopsy, who had a history of resection of spontaneously ruptured HCC two years ago. The patient's condition was stable at the 6-mo follow-up after resection of the isolated pelvic metastasis.

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

AIM To detect the expression of CD44v6 mRNA and nm23-H1 mRNA in hepatocellular carcinoma (HCC) by in situ hybridization, and to evaluate the relationship between their expression and also relationship between their expressions and tumor invasion and metastasis.METHODS CD44v6 cDNA probe was synthesized with PCR technique and the nm23-H1 cRNA probe by in vitro transcription. The expression of CD44v6 mRNA and nm23-H1 mRNA was detected by in situ hybridization.RESULTS In group with high invasion and metastasis potential, the positive rates of CD44v6 mRNA and nm23-H1 mRNA were 80% (8/10) and 40% (4/10), in group with poor invasion and metastasis potential, they were 21.7% (5/23) and 91.3% (21/23). There was a positive correlation between the expression of CD44v6 mRNA and tumor invasion and metastasis potential in HCC (P＜0.01), and a reverse correlation between the expression of nm23-H1 mRNA and tumor invasion and metastasis potential (P＜0.01) and a reverse correlation in the expression between CD44v6 mRNA and nm23-H1 mRNA in HCC (P＜0.01).CONCLUSION Detection of CD44v6 mRNA and nm23-H1 mRNA may be useful for tumor invasion and metastasis in HCC.INTRODUCTIONCD44 is a cell surface transmembrane glycoprotein. As a kind of adhesive molecule, it participates in cell-cell and cell-matrix adhesion and interactions. Many studies revealed a correlation between high-level expression of CD44, especially CD44v and tumor invasion, metastasis and prognosis. The exon 6v containing isoforms may be an independent diagnostic parameter[1,2]. Some other studies, however, had different results[3,4]. Some researches showed a reverse correlation between the expression of nm23-H1 mRNA and tumor metastasis[5,6]. In order to evaluate the relationship between the expression of CD44v6 mRNA and nm23-H1 mRNA and tumor invasive and metastatic potential in HCC and to evaluate the relationship in the expression between CD44v6 mRNA and nm23-H1 mRNA, we detected their expression in HCC by in situ hybridization.