RESUMO
ETHNOPHARMACOLOGICAL RELEVANCE: Dahuang Zhechong pill (DHZCP), a traditional Chinese medicine, was derived from the famous book Unk "Synopsis of Prescriptions of the Golden Chamber" during the Han dynasty. Owing to its ability to invigorate the circulation of blood in Chinese medicine, DHZCP is usually used for treating liver cirrhosis (LC) and hepatocellular carcinoma (HCC). Clinical application have shown that DHZCP exhibits satisfactory therapeutic effects in HCC adjuvant therapy; however, little is known about its underlying mechanisms. AIM OF THE STUDY: We aimed to clarify the mechanism of DHZCP against hepatic sinusoidal capillarization in rats with LC and HCC by inhibiting the MK/integrin signaling pathway of liver sinusoidal endothelial cells (LSECs). MATERIALS AND METHODS: The contents of 29 characteristic components in DHZCP were determined by ultraperformance liquid chromatography-tandem mass spectrometry. DEN (Diethylnitrosamine)-induced LC and HCC rat models were constructed, and DHZCP was administered when the disease entered the LC stage. After 4 or 12 weeks of administration, hematoxylin and eosin staining, Masson staining, Metavir score, and SSCP (Single strand conformation polymorphism) gene mutation detection were used to confirm tissue fibrosis and cancer. The levels of NO, ET-1 and TXA2, which can regulate vasomotor functions and activate the MK/Itgα6/Src signaling pathway were evaluated by using immunohistochemistry, chemiluminescence, immunofluorescence, Western blot analysis, and enzyme-linked immunosorbent assay (ELISA). Similar methods were also used to evaluate the levels of VEGF, VEGFR, Ang-2 and Tie, which can promote pathological angiogenesis and activate the MK/Itgα4/NF-κB signaling pathway. In vitro cell experiments were performed using potential pharmacodynamic molecules targeting integrins in DHZCP were selected by molecular docking, and the effects of these molecules on the function of LSECs were studied by Itgα4+ and Itgα6+ cell models. RESULTS: At the stage of LC, the animal experiments demonstrated that DHZCP mainly inhibited the MK/Itgα6 signaling pathway to increase the number and size of hepatic sinus fenestration, reversed the ET-1/NO and TXA2/NO ratios, regulated hepatic sinus relaxation and contraction balance, reduced the portal vein pressure, and inhibited cirrhotic carcinogenesis. At the HCC stage, DHZCP could also significantly inhibit the MK/Itgα4 signaling pathway, reduce pathological angiogenesis, and alleviate disease progression. The results of the cell experiments showed that Rhein, Naringenin, Liquiritin and Emodin-8-O-ß-D-glucoside (PMEG) were involved in vascular regulation by affecting the MK/integrin signaling pathway. Liquiritin and PMEG mainly blocked the MK/α6 signal, which is important in regulating the vasomotor function of the liver sinus. Naringenin and Rhein mainly acted by blocked the signaling of MK/α4 action signal, which are potent molecules that inhibit pathological angiogenesis. CONCLUSIONS: DHZCP could improve the hepatic sinusoidal capillarization of LC and HCC by inhibiting the MK/Itgα signaling pathway and inhibited disease progression. Rhein, Naringenin, Liquiritin and PMEG were the main active molecules that affected the MK/Itgα signaling pathway.
Assuntos
Carcinoma Hepatocelular , Medicamentos de Ervas Chinesas , Cadeias alfa de Integrinas , Cirrose Hepática , Neoplasias Hepáticas , Neovascularização Patológica , Animais , Ratos , Carcinoma Hepatocelular/irrigação sanguínea , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/patologia , Progressão da Doença , Células Endoteliais/patologia , Cirrose Hepática/tratamento farmacológico , Cirrose Hepática/patologia , Neoplasias Hepáticas/irrigação sanguínea , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/patologia , Simulação de Acoplamento Molecular , Neovascularização Patológica/tratamento farmacológico , Neovascularização Patológica/patologia , Transdução de Sinais , Medicamentos de Ervas Chinesas/farmacologia , Medicamentos de Ervas Chinesas/uso terapêutico , Capilares/efeitos dos fármacos , Fígado/irrigação sanguínea , Fígado/efeitos dos fármacos , Cadeias alfa de Integrinas/genética , Cadeias alfa de Integrinas/metabolismoRESUMO
to explore the value of transcatheter arterial chemoembolization (TACE) combined with targeted nanoparticle delivery system for sorafenib (SFB) to treat hepatocellular carcinoma (HCC) with microvascular invasion. 42 HCC patients with microvascular invasion after liver cancer surgery were selected from our hospital from December 2020 and February 2021. Patients were divided into experimental group and control group based on their willingness. Patients in experimental group (18 cases) were treated with combination therapy of TACE and Ab-SFB-NP system; while patients in control group (24 cases) took TACE and non-nano drug delivery system. There was no obvious difference in liver function and blood test results between two groups of patients before treatment and one month after treatment (P > 0.05). Three months after treatment, differences of alanine aminotransferase (ALT) were statistically significant (P < 0.05); while differences of other test results were not (P > 0.05). The disease control rate (DCR) of patients in experimental group was higher slightly (P > 0.05). The incidence of adverse reactions of patients in experimental group was lower than the control group and the differences were statistically significant (P < 0.05). After three months of TACE, the DCR in the experimental group was significantly higher compared to control group. The toxic reactions of taking SFB with Ab-SFB-NP nano-drug delivery system mainly included hand-foot syndrome, diarrhea, and bleeding, the toxic reactions were mainly at level 1 ~ 2. After symptomatic treatment, the toxicity was effectively controlled, so the security was high.
Assuntos
Carcinoma Hepatocelular/irrigação sanguínea , Carcinoma Hepatocelular/tratamento farmacológico , Cateterismo , Quimioembolização Terapêutica , Neoplasias Hepáticas/tratamento farmacológico , Microvasos/patologia , Nanopartículas/química , Sorafenibe/uso terapêutico , Carcinoma Hepatocelular/sangue , Carcinoma Hepatocelular/fisiopatologia , Quimioembolização Terapêutica/efeitos adversos , Feminino , Humanos , Fígado/patologia , Fígado/fisiopatologia , Neoplasias Hepáticas/sangue , Neoplasias Hepáticas/irrigação sanguínea , Neoplasias Hepáticas/fisiopatologia , Masculino , Pessoa de Meia-Idade , Invasividade Neoplásica , Sorafenibe/efeitos adversosRESUMO
BACKGROUND: Transarterial chemoembolization (TACE) is an effective locoregional therapy in hepatocellular carcinoma (HCC). However, it is difficult to predict the tumour response (TR) of TACE intraprocedurally. The aim of this study was to predict the TR after TACE (1-3 months) in HCC patients using intraprocedural intraarterial contrast enhanced ultrasound (IA-CEUS). METHODS: In this case-control study, consecutive patients who received TACE in our hospital from September 2018 to May 2019 were enrolled. IA-CEUS was performed before and after TACE. Postoperative contrast-enhanced liver MRI was performed 1-3 months after TACE as the gold standard. According to the modified Response Evaluation Criteria in Solid Tumours (mRECIST), ultrasonic manifestations were compared between the complete remission (CR) group and non-CR group by univariate and multivariate analyses. A logistic predictive model was established and validated, and its diagnostic efficiency was evaluated. RESULTS: Forty-four patients with sixty-one lesions were enrolled in the study. Multivariate analysis identified, the risk factors as a large lesion diameter (OR: 1.84; 95% confidence interval [CI]: 1.009, 3.080; P = 0.020), a larger dimension of non-enhancing area in superior mesenteric artery (SMA)-CEUS than the size in B-mode ultrasound preoperatively (OR: 3.379; 95% CI: 1.346,8.484; P = 0.010), presence of corona enhancement in hepatic artery (HA)-CEUS postoperatively (OR: 6.642; 95% CI: 1.214, 36.331; P = 0.029), and decreased corona enhancement thickness (per centimetre) postoperatively (OR: 0.025; 95% CI: 0.006,0.718; P = 0.025). The area under the receiver operating characteristic curve (AUROC) of the predictive model was 0.904 (95% CI: 0.804, 0.966; P < 0.001). The sensitivity, specificity, accuracy, positive predictive value, and negative predictive value were 81.08, 91.67, 85.25, 93.75, and 75.86%, respectively. Leave-one-out cross-validation (LOOCV) showed that the accuracy was 77.05%. CONCLUSIONS: Intraprocedural IA-CEUS can be used to predict the TR in HCC patients after TACE.
Assuntos
Carcinoma Hepatocelular/terapia , Quimioembolização Terapêutica , Meios de Contraste/administração & dosagem , Óleo Etiodado/administração & dosagem , Neoplasias Hepáticas/terapia , Ultrassonografia/métodos , Análise de Variância , Carcinoma Hepatocelular/irrigação sanguínea , Carcinoma Hepatocelular/patologia , Estudos de Casos e Controles , Feminino , Artéria Hepática/diagnóstico por imagem , Humanos , Injeções Intra-Arteriais , Neoplasias Hepáticas/irrigação sanguínea , Neoplasias Hepáticas/patologia , Modelos Logísticos , Imageamento por Ressonância Magnética/métodos , Imageamento por Ressonância Magnética/normas , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Curva ROC , Critérios de Avaliação de Resposta em Tumores Sólidos , Sensibilidade e Especificidade , Resultado do Tratamento , Carga TumoralRESUMO
Despite multimodal treatment strategies, clinical outcomes of advanced stage colorectal cancer (CRC) patients remain poor. Neoadjuvant/adjuvant chemotherapy efficacy is limited due to chemoresistance, toxicity, and negative side effects. Since both melatonin and glycine have anti-cancer activities without relevant side effects, this study was designed to investigate their combined effects in experimental CRC liver metastases. CRC metastasis with CC531 cells were induced in male Wistar rats. Melatonin and glycine alone or their combination were supplemented for 14 days (n = 100). Blood parameters, a micro-computed tomography scan (tumor volume over time), and immunohistochemistry for Ki67 and CD31 expression in tumor tissue were compared between groups. Melatonin and glycine alone significantly reduced the tumor volume by 63.2% (p = 0.002) and 43% (p = 0.044) over time, respectively, while tumor volume increased by 8.7% in the controls. Moreover, treatment with melatonin and glycine alone reduced the tumor proliferation index. Most interestingly, the combination therapy did not have any influence on the above-mentioned tumor parameters. The leukocyte count was significantly increased with melatonin at the end of the experiment (p = 0.012) which was due to a high lymphocytes count. Tumor microvascular density was significantly reduced in all treatment groups. The results of this study suggest an inhibitory function for melatonin and glycine alone in the case of CRC liver metastasis growth by acting as natural antiangiogenic molecules, followed by angiogenesis-dependent cancer proliferation and immunomodulation.
Assuntos
Inibidores da Angiogênese/administração & dosagem , Neoplasias Colorretais/patologia , Glicina/administração & dosagem , Neoplasias Hepáticas/dietoterapia , Neoplasias Hepáticas/secundário , Melatonina/administração & dosagem , Animais , Linhagem Celular Tumoral , Dieta , Contagem de Leucócitos , Neoplasias Hepáticas/irrigação sanguínea , Neoplasias Hepáticas/patologia , Masculino , Microvasos , Transplante de Neoplasias , Ratos , Ratos Wistar , Carga TumoralRESUMO
Hepatocellular carcinoma (HCC) is a typical hyper-vascular solid tumor; aberrantly rich in tumor vascular network contributes to its malignancy. Conventional anti-angiogenic therapies seem promising but transitory and incomplete efficacy on HCC. Vasculogenic mimicry (VM) is one of functional microcirculation patterns independent of endothelial vessels which describes the plasticity of highly aggressive tumor cells to form vasculogenic-like networks providing sufficient blood supply for tumor growth and metastasis. As a pivotal alternative mechanism for tumor vascularization when tumor cells undergo lack of oxygen and nutrients, VM has an association with the malignant phenotype and poor clinical outcome for HCC, and may challenge the classic anti-angiogenic treatment of HCC. Current studies have contributed numerous findings illustrating the underlying molecular mechanisms and signaling pathways supporting VM in HCC. In this review, we summarize the correlation between epithelial-mesenchymal transition (EMT), cancer stem cells (CSCs) and VM, the role of hypoxia and extracellular matrix remodeling in VM, the involvement of adjacent non-cancerous cells, cytokines and growth factors in VM, as well as the regulatory influence of non-coding RNAs on VM in HCC. Moreover, we discuss the clinical significance of VM in practice and the potential therapeutic strategies targeting VM for HCC. A better understanding of the mechanism underlying VM formation in HCC may optimize anti-angiogenic treatment modalities for HCC.
Assuntos
Inibidores da Angiogênese/uso terapêutico , Carcinoma Hepatocelular/irrigação sanguínea , Carcinoma Hepatocelular/tratamento farmacológico , Neoplasias Hepáticas/irrigação sanguínea , Neoplasias Hepáticas/tratamento farmacológico , Neovascularização Patológica/tratamento farmacológico , Inibidores da Angiogênese/farmacologia , Animais , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patologia , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Humanos , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Terapia de Alvo Molecular , Neovascularização Patológica/metabolismo , Neovascularização Patológica/patologia , Transdução de Sinais/efeitos dos fármacosRESUMO
PURPOSE: Overexpression of fibroblast growth factor receptor (FGFR) contributes to tumorigenesis, metastasis, and poor prognosis of hepatocellular carcinoma (HCC). Infigratinib-a pan-FGFR inhibitor-potently suppresses the growth of high-FGFR-expressing HCCs in part via alteration of the tumor microenvironment and vessel normalization. In this study, we aim to assess the utility of dynamic contrast-enhanced (DCE) magnetic resonance imaging (MRI) as a non-invasive imaging technique to detect microenvironment changes associated with infigratinib and sorafenib treatment in high-FGFR-expressing HCC xenografts. PROCEDURES: Serial DCE-MRIs were performed on 12 nude mice bearing high-FGFR-expressing patient-derived HCC xenografts to quantify tumor microenvironment pre- (day 0) and post-treatment (days 3, 6, 9, and 15) of vehicle, sorafenib, and infigratinib. DCE-MRI data were analyzed using extended generalized kinetic model and two-compartment distributed parameter model. After treatment, immunohistochemistry stains were performed on the harvested tumors to confirm DCE-MRI findings. RESULTS: By treatment day 15, infigratinib induced tumor regression (70 % volume reduction from baseline) while sorafenib induced relative growth arrest (185 % volume increase from baseline versus 694 % volume increase from baseline of control). DCE-MRI analysis revealed different changes in microcirculatory parameters upon exposure to sorafenib versus infigratinib. While sorafenib induced microenvironment changes similar to those of rapidly growing tumors, such as a decrease in blood flow (F), fractional intravascular volume (vp), and permeability surface area product (PS), infigratinib induced the exact opposite changes as early as day 3 after treatment: increase in F, vp, and PS. CONCLUSIONS: Our study demonstrated that DCE-MRI is a reliable non-invasive imaging technique to monitor tumor microcirculatory response to FGFR inhibition and VEGF inhibition in high-FGFR-expressing HCC xenografts. Furthermore, the microcirculatory changes from FGFR inhibition manifested early upon treatment initiation and were reliably detected by DCE-MRI, creating possibilities of combinatorial therapy for synergistic effect.
Assuntos
Biomarcadores Tumorais/metabolismo , Carcinoma Hepatocelular/tratamento farmacológico , Meios de Contraste/química , Neoplasias Hepáticas/tratamento farmacológico , Imageamento por Ressonância Magnética , Neovascularização Patológica/tratamento farmacológico , Compostos de Fenilureia/uso terapêutico , Pirimidinas/uso terapêutico , Receptores de Fatores de Crescimento de Fibroblastos/metabolismo , Animais , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Apoptose/efeitos dos fármacos , Carcinoma Hepatocelular/irrigação sanguínea , Proliferação de Células/efeitos dos fármacos , Humanos , Cinética , Neoplasias Hepáticas/irrigação sanguínea , Camundongos SCID , Perfusão , Sorafenibe/farmacologia , Sorafenibe/uso terapêutico , Microambiente Tumoral/efeitos dos fármacos , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Hepatocellular carcinoma (HCC) is among the leading causes of cancer-related mortality worldwide. Our previous study identified a novel alternative splicing variant of prenyl diphosphate synthase subunit 2 (PDSS2) in HCC characterized by a deletion of exon 2, named PDSS2-Del2, which is devoid of the tumor-suppressive function of full-length PDSS2 (PDSS2-FL). To better understand the clinical significance of PDSS2-Del2, we performed a BaseScope™ assay on an HCC tissue microarray and found that positive staining for PDSS2-Del2 predicted a worse overall survival in patients with HCC (P = 0.02). PDSS2-Del2 levels correlated significantly with microvessel counts in HCC tumor tissues. Importantly, PDSS2-Del2 overexpression functionally promoted HCC metastasis, as demonstrated by in vitro and in vivo migration assays. In vivo assays also demonstrated that PDSS2-Del2 increased angiogenesis in xenografts. Furthermore, we discovered that elevated PDSS2-Del2 expression in HCC tumor cells decreased fumarate levels and activated the canonical nuclear factor-κB pathway. The epithelial-to-mesenchymal transition (EMT) and WNT/ß-catenin signaling pathways were also activated by overexpression. Dimethyl fumarate (DMF), a fumaric acid ester, effectively reduced the metastasis induced by PDSS2-Del2 as observed with in vivo spleen-liver metastasis animal experiments. DMF is a prescribed oral therapy for multiple sclerosis and it might be a potential treatment for metastasis of patients with HCC. Early clinical trials are needed to validate its potential in this context.
Assuntos
Alquil e Aril Transferases/metabolismo , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patologia , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , NF-kappa B/metabolismo , Neovascularização Patológica/metabolismo , Adulto , Idoso , Animais , Carcinoma Hepatocelular/irrigação sanguínea , Linhagem Celular Tumoral , Movimento Celular , Suplementos Nutricionais , Transição Epitelial-Mesenquimal , Feminino , Fumaratos/farmacologia , Humanos , Neoplasias Hepáticas/irrigação sanguínea , Masculino , Camundongos Endogâmicos BALB C , Camundongos Nus , Microvasos/patologia , Pessoa de Meia-Idade , Metástase Neoplásica , Análise de Sobrevida , Via de Sinalização Wnt , Adulto JovemRESUMO
BACKGROUND/AIM: To examine the factors influencing the introduction of the second-line chemotherapy and discuss the selection of first-line agent for hepatocellular carcinoma (HCC). PATIENTS AND METHODS: We retrospectively studied 154 patients with HCC who received sorafenib therapy. RESULTS: A total of 109 (70.8%) patients, maintained Child-Pugh grade A and Eastern Cooperative Oncology Group performance status (ECOG-PS) ≤1 upon sorafenib discontinuation. Multivariate analysis revealed that the up-to-seven criteria status in the hepatic lesion [p=0.019; odds ratio=OR, 2.685], albumin-bilirubin (ALBI) grade (p=0.002; OR=3.589), and macroscopic vascular invasion (MVI) (p=0.008; OR=2.972) were significant factors at sorafenib initiation that influenced the maintenance of Child-Pugh grade A and ECOG-PS ≤1 upon therapy discontinuation. CONCLUSION: Not only ALBI grade and MVI, but also up-to-seven criteria status in the hepatic lesion influence the introduction of second-line therapy, and could affect the selection of the first-line therapy.
Assuntos
Carcinoma Hepatocelular/tratamento farmacológico , Neoplasias Hepáticas/tratamento farmacológico , Sorafenibe/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/uso terapêutico , Carcinoma Hepatocelular/irrigação sanguínea , Carcinoma Hepatocelular/patologia , Feminino , Humanos , Neoplasias Hepáticas/irrigação sanguínea , Neoplasias Hepáticas/patologia , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Estudos Retrospectivos , Índice de Gravidade de Doença , Resultado do Tratamento , Carga TumoralRESUMO
OBJECTIVE: Systemic therapy, such as sorafenib, has been used clinically to treat patients with advanced stage or Barcelona Clinic Liver Cancer staging system (BCLC) stage C hepatocellular carcinoma (HCC). The aim of the study was to evaluate the therapeutic benefit of combined sorafenib and transarterial chemoembolization (TACE) in this group of patients. METHODS: Data on patients with HCC at BCLC stage C from August 2012 to September 2017 were collected. Patients who were given sorafenib alone were classified as the monotherapy group and those taking sorafenib and TACE were classed as the combined therapy group. RESULTS: A total of 118 patients were enrolled. There were 65 and 53 patients in the monotherapy and the combined therapy group, respectively. The groups' general characteristics were similar. Compared with the monotherapy group the combined therapy group experienced prolonged time-to-progression (TTP) (mean 6.42 mo vs 3.63 mo, P = 0.003) and overall survival (OS) (mean 11.21 mo vs 5.98 mo, P = 0.001). A subgroup analysis found that patients with macroscopic vascular invasion (MVI) also had prolonged TTP and OS in the combined therapy group than the monotherapy group (mean TTP, 7.93 mo vs 3.43 mo, P = 0.007; mean OS, 13.41 mo vs 5.50 mo, P = 0.001), however, these significant differences did not exist for those with extrahepatic spread (EHS). CONCLUSION: Combined sorafenib and TACE therapy has significant better outcomes than sorafenib alone in patients with stage C HCC, particularly those with MVI.
Assuntos
Antineoplásicos/uso terapêutico , Carcinoma Hepatocelular/terapia , Quimioembolização Terapêutica/métodos , Neoplasias Hepáticas/terapia , Sorafenibe/uso terapêutico , Idoso , Carcinoma Hepatocelular/irrigação sanguínea , Terapia Combinada , Feminino , Humanos , Neoplasias Hepáticas/irrigação sanguínea , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Resultado do TratamentoRESUMO
ETHNOPHARMACOLOGICAL RELEVANCE: Hypervascularity has been considered as one of the major features of many solid tumors. Green tea is one of the commonly drink resources in China, and its active component, Epigallocatechin gallate (EGCG), exhibits antiangiogenic activities in various experimental tumor models. However, EGCG has many shortages, e.g., relatively unstable, low lipid solubility, poor bioavailability, and short duration of action. AIM OF THE STUDY: To overcome the shortages of EGCG for antiangiogenic antitumor usage, our study developed a novel EGCG derivate, Y6(5,3',4',3â³,4â³,5â³-6-0-ethyl-EGCG). The underlying mechanism was also elucidated. MATERIAL AND METHODS: we evaluated the effects of EGCG, Y6 on HCC and angiogenesis in vivo and in vitro. Moreover, to understand their antitumor mechanisms, key factors within angiogenesis-related signaling pathways (MAPK/ERK1/2, PI3K/AKT, HIF-1 VEGF) were analyzed by using western blot, immunohistochemistry (IHC), quantitative real-time quantitative PCR (RT-PCR). HepG2 xenograft model and the chorioallantoic membrane (CAM) were used to investigate the effects of Y6 and EGCG on tumors and anti-angiogenesis in vivo. Micro-vessel density (MVD) was analyzed by IHC of CD34 staining. IHC, qRT-PCR and Western blot were used to detect the expression of HIF-1α and VEGF protein in tumor tissues. The protein levels of MAPK/ERK1/2, PI3K/AKT, HIF-1α, and VEGF in tumor tissues were detected by western blot. RESULTS: Our results demonstrated that both EGCG and Y6 displayed antiangiogenetic and antitumor effects against HCC cells in vitro and in vivo. We found that rather than equal amount of EGCG, Y6 displayed better abilities in inhibiting the growth of HCC tumor cells, as well as inhibiting the growth of neovascularization in the chick embryos and HepG2 xenograft tumors bearing-mice, based on the data obtained from MTT assay, immunohistochemistry (IHC), chick chorioallantoic membrane (CAM) assays. In the comparison of equivalent dose of EGCG, qRT-PCR data showed that Y6 induced more significant decrease of the mRNA levels of HIF-1α and VEGF in supernatant-treated SMMC-7721â¯cells under hypoxic condition, as well as in the in xenograft tumor tissues; whereas Y6 also significantly reduced the protein levels of MAPK/ERK1/2, PI3K/AKT, HIF-1α, and VEGF to a greater extent than EGCG, determined by western blotting assay. CONCLUSIONS: our work suggests that the new EGCG derivate Y6 could significantly inhibit tumor growth and angiogenesis which is possibly involved with the signaling intervention of MAPK/ERK1/2 and PI3K/AKT/HIF-1α/VEGF pathways, and is supposed to be a potential therapeutic reagent for anti-angiogenesis treatment of solid tumors.
Assuntos
Inibidores da Angiogênese/farmacologia , Carcinoma Hepatocelular/tratamento farmacológico , Catequina/análogos & derivados , Neoplasias Hepáticas/tratamento farmacológico , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Animais , Carcinoma Hepatocelular/irrigação sanguínea , Carcinoma Hepatocelular/metabolismo , Catequina/farmacologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Embrião de Galinha , Membrana Corioalantoide/patologia , Células Hep G2 , Células Endoteliais da Veia Umbilical Humana , Humanos , Neoplasias Hepáticas/irrigação sanguínea , Neoplasias Hepáticas/metabolismo , Camundongos , Quinases de Proteína Quinase Ativadas por Mitógeno/metabolismo , Neovascularização Patológica/tratamento farmacológico , Fosfatidilinositol 3-Quinases/metabolismo , Fator A de Crescimento do Endotélio Vascular/metabolismo , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
BACKGROUND: Sorafenib represents one of the therapeutic strongholds for advanced hepatocellular carcinoma (HCC), but unfortunately, predictive factors are lacking. We previously reported that the VEGF single nucleotide polymorphisms (SNPs) rs2010963 and rs4604006 might correlate with clinical outcomes in sorafenib-treated HCC patients. OBJECTIVE: The objective of the ALICE-2 study is to define a prognostic angiogenesis profile to better identify HCC patients who are more likely to benefit from sorafenib treatment. PATIENTS AND METHODS: From 2008 to 2015, all consecutive HCC patients receiving sorafenib according to the Italian label were tested for specific HIF-1α, VEGF, and VEGFR SNPs. Results from angiogenesis genotyping were then correlated with clinical outcome parameters. RESULTS: Globally, a total of 210 patients were enrolled. At multivariate analysis rs12434438 of HIF1α, rs2010963 of VEGF-A, and rs4604006 of VEGF-C were confirmed as independent predictive factors. At the combined analysis of significant SNPs, the presence of two favourable alleles of rs2010963 and rs4604006 of VEGF compared to only one or to none favourable alleles, was able to identify three separate patients populations with different time-to-progression (TTP) (10.8 vs. 5.6 vs. 3.7 months, respectively; p < 0.0001) and overall survival (OS) (19.0 vs. 13.5 vs. 7.5 months, respectively; p < 0.0001). Furthermore, the presence of the GG genotype of rs12434438 (HIF-1α) seemed able to select a population with a particularly poor outcome, independently from the clinical effect of the two VEGF SNPs (TTP: 2.6 months, HR: 0.54, p = 0.0374; OS: 6.6 months, p = 0.0061, HR: 0.43). CONCLUSIONS: Our findings show that polymorphism analysis of HIF-1α, VEGF, and VEGFR genes may represent a prognostic panel to better identify HCC patients who are more likely to benefit from sorafenib treatment.
Assuntos
Carcinoma Hepatocelular/irrigação sanguínea , Carcinoma Hepatocelular/tratamento farmacológico , Neoplasias Hepáticas/irrigação sanguínea , Neoplasias Hepáticas/tratamento farmacológico , Sorafenibe/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma Hepatocelular/genética , Feminino , Genótipo , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Neoplasias Hepáticas/genética , Masculino , Pessoa de Meia-Idade , Neovascularização Patológica/tratamento farmacológico , Neovascularização Patológica/genética , Polimorfismo de Nucleotídeo Único , Prognóstico , Estudos Retrospectivos , Sorafenibe/efeitos adversos , Fator A de Crescimento do Endotélio Vascular/genética , Receptor 1 de Fatores de Crescimento do Endotélio Vascular/genéticaRESUMO
Transcatheter arterial embolization (TAE) plays an important role in clinical liver tumor therapy. However, hypoxia after TAE limit the medium-long term efficacy of TAE. Thus, in our study, we explored the treatment effect and mechanism of combining transcatheter arterial embolization with adopted iodized oil containing Apatinib on suppressing tumor growth and metastasis. We simulated the changing of tumor microenvironment before and after TAE both in vitro and in vivo models. The anti-angiogenic effect of Apatinib was explored by bioassays in human umbilical vein endothelial cells (HUVECs), including cell migration, invasion and apoptosis, tube formation, and wound healing. Further experiments showed that Apatinib inhibited tumor microangiogenesis to achieve the aims of inhibiting tumor growth and recurrence by means of down-regulating the phosphorylation of the RAF-mek-erk, PI3K-akt and P38MAPK pathways. The antitumor growth and anti-angiogenic effect of Apatinib was further validated by the animal experiment. Taken together, we concluded that Apatinib inhibits the angiogenesis and growth of liver cancer by down-regulating the PI3K-akt, RAF-mek-erk and P38MAPK pathways, and has a stronger inhibitory effect in hypoxic environments. Combining TAE with adopted iodized oil containing Apatinib has a stronger inhibitory effect in VX2 liver tumor growth and metastasis, which suggesting such combinations may provide a new target and strategy for interventional therapy of liver cancer.
Assuntos
Antineoplásicos/administração & dosagem , Carcinoma Hepatocelular/terapia , Quimioembolização Terapêutica/métodos , Neoplasias Hepáticas/terapia , Piridinas/administração & dosagem , Animais , Apoptose/efeitos dos fármacos , Carcinoma Hepatocelular/irrigação sanguínea , Carcinoma Hepatocelular/genética , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Células Hep G2 , Células Endoteliais da Veia Umbilical Humana , Humanos , Óleo Iodado/administração & dosagem , Neoplasias Hepáticas/irrigação sanguínea , Neoplasias Hepáticas/genética , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Camundongos , Neovascularização Patológica/terapia , Fosforilação/efeitos dos fármacos , Microambiente Tumoral/efeitos dos fármacos , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
BACKGROUND AND OBJECTIVES: During thermal heating surgical procedures such as electrosurgery, thermal ablative treatment and hyperthermia, soft tissue deformation due to surgical tool-tissue interaction and patient movement can affect the distribution of thermal energy induced. Soft tissue temperature must be obtained from the deformed tissue for precise delivery of thermal energy. However, the classical Pennes bio-heat transfer model can handle only the static non-moving state of tissue. In addition, in order to enable a surgeon to visualise the simulated results immediately, the solution procedure must be suitable for real-time thermal applications. METHODS: This paper presents a formulation of bio-heat transfer under the effect of soft tissue deformation for fast or near real-time tissue temperature prediction, based on fast explicit dynamics finite element algorithm (FED-FEM) for transient heat transfer. The proposed thermal analysis under deformation is achieved by transformation of the unknown deformed tissue state to the known initial static state via a mapping function. The appropriateness and effectiveness of the proposed formulation are evaluated on a realistic virtual human liver model with blood vessels to demonstrate a clinically relevant scenario of thermal ablation of hepatic cancer. RESULTS: For numerical accuracy, the proposed formulation can achieve a typical 10-3 level of normalised relative error at nodes and between 10-4 and 10-5 level of total errors for the simulation, by comparing solutions against the commercial finite element analysis package. For computation time, the proposed formulation under tissue deformation with anisotropic temperature-dependent properties consumes 2.518 × 10-4â ms for one element thermal loads computation, compared to 2.237 × 10-4â ms for the formulation without deformation which is 0.89 times of the former. Comparisons with three other formulations for isotropic and temperature-independent properties are also presented. CONCLUSIONS: Compared to conventional methods focusing on numerical accuracy, convergence and stability, the proposed formulation focuses on computational performance for fast tissue thermal analysis. Compared to the classical Pennes model that handles only the static state of tissue, the proposed formulation can achieve fast thermal analysis on deformed states of tissue and can be applied in addition to tissue deformable models for non-linear heating analysis at even large deformation of soft tissue, leading to great translational potential in dynamic tissue temperature analysis and thermal dosimetry computation for computer-integrated medical education and personalised treatment.
Assuntos
Temperatura Alta , Neoplasias Hepáticas/diagnóstico por imagem , Fígado/diagnóstico por imagem , Técnicas de Ablação , Algoritmos , Simulação por Computador , Eletrocirurgia , Análise de Elementos Finitos , Humanos , Hipertermia Induzida , Imageamento Tridimensional , Modelos Lineares , Fígado/irrigação sanguínea , Neoplasias Hepáticas/irrigação sanguínea , Modelos Anatômicos , Modelos CardiovascularesRESUMO
BACKGROUND: Advanced hepatocellular carcinoma (HCC) with macrovascular invasion has an extremely dismal prognosis. We report a rare case of multiple HCC with tumor thrombosis in the portal vein and inferior vena cava that was initially treated with hepatic arterial infusion chemotherapy (HAIC); later resection revealed pathological complete response. CASE PRESENTATION: A 75-year-old man presented with HCC in his right liver, with tumor thrombosis growing to the right portal vein and the inferior vena cava, and bilateral intrahepatic liver metastases. He underwent HAIC (5-fluorouracil [170 mg/m2] + cisplatin [7 mg/m2]) via an indwelling port. Although the tumor shrank and tumor marker levels decreased rapidly, we abandoned HAIC after one cycle because of cytopenia. We resumed HAIC 18 months later because of tumor progression, using biweekly 5-fluorouracil only [1000 mg] due to renal dysfunction. However, after 54 months, the HAIC indwelling port was occluded. The patient therefore underwent a right hepatectomy to resect the residual lesion. Histopathological findings showed complete necrosis with no viable tumor cells. The patient has been doing well without postoperative adjuvant therapy for more than 10 years after initially introducing HAIC and 6 years after the resection, without evidence of tumor recurrence. CONCLUSIONS: HAIC can be an effective alternative treatment for advanced HCC with macrovascular invasion.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Carcinoma Hepatocelular/tratamento farmacológico , Artéria Hepática/patologia , Neoplasias Hepáticas/tratamento farmacológico , Trombose Venosa/patologia , Idoso , Carcinoma Hepatocelular/irrigação sanguínea , Carcinoma Hepatocelular/patologia , Carcinoma Hepatocelular/cirurgia , Cisplatino/administração & dosagem , Terapia Combinada , Fluoruracila/administração & dosagem , Humanos , Infusões Intra-Arteriais , Neoplasias Hepáticas/irrigação sanguínea , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/cirurgia , Masculino , Resultado do TratamentoRESUMO
Background: There is no doubt that hyperthermia is one of the powerful radiosensitizers. Finding a proper mechanism working in hyperthermia/radiation combination is still pronounced challenge. Objectives: This study is focusing on the anti-cancer activities (anti-proliferative, anti-angiogenic and antiapoptotic) of thermoradiotherapy. Materials and Methods: Liver cancer cell line (HepG2) was treated by 37oC, 40oC and 43oC hyperthermia degrees combined with three radiation doses (2 Gy, 4 Gy and 8 Gy) for 24, 48 and 72 hrs. Cell viability, apoptotic/necrotic cell screening, apoptotic (BAX and FasL) and antiapoptotic (BCL-2 and GRP78) genes, and pro-angiogenic mediators [vascular endothelial- (VEGF) and Platelet derived-growth factors (PDGF) ware investigated. Results: Our data showed that 40oC temperature combined with 4 Gy radiation gives a significant decrease (p<0.05) in cell viability. Maximum cytotoxicity was reported 48 hr post-treatment followed by slight restoration of cell viability after 72 hr. Compared with untreated cells, only 5% of viable cells with a high percentage of apoptotic (31%) and necrotic (63%) cells were demonstrated in 40oC/4 Gy/48 hr group. Expression of pro-apoptotic genes (BAX and FasL) were increased after hyperthermia with apparent elevation in 40oC/4 Gy/48 hr group coincides with moderate expression of antiapoptotic BCL-2 and GRP78 genes. A significant reduction (p<0.001; p<0.05) in VEGF and PDGF levels; respectively was shown at 40oC/4 Gy/48 hr group. Conclusions: This pilot study proposed 40oC mild temperature hyperthermia as a favorable hyperthermal condition with 4 Gy radiotherapy in HCC treatment. A further research has to be performed considering an application of more than one session of radiothermal therapy at 40oC/4 Gy for total abrogation of cancer cells.
Assuntos
Apoptose , Carcinoma Hepatocelular/patologia , Proliferação de Células , Regulação Neoplásica da Expressão Gênica , Hipertermia Induzida/métodos , Neoplasias Hepáticas/patologia , Radioterapia/métodos , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Carcinoma Hepatocelular/irrigação sanguínea , Carcinoma Hepatocelular/terapia , Terapia Combinada , Chaperona BiP do Retículo Endoplasmático , Humanos , Neoplasias Hepáticas/irrigação sanguínea , Neoplasias Hepáticas/terapia , Projetos Piloto , Células Tumorais CultivadasRESUMO
INTRODUCTION: Significant intratumoral shunts between tumor-supplying arteries and portal or liver veins are a contraindication for transarterial therapy of HCC because interventional treatment of these shunts is frequently insufficient. Sorafenib has anti-angiogenic effects and is indicated for palliative treatment of patients with HCC. Here, we report our experience with the use of sorafenib for the closure of intratumoral shunts in patients scheduled for transarterial therapy of HCC. MATERIALS AND METHODS: Three patients with HCC, aged 65, 82 and 79 years, exhibited a significant intratumoral shunting from tumor artery to portal (n = 1) or liver veins (n = 2). In all cases, intratumoral shunting had already been suspected based on pre-interventional CT angiography, and DSA confirmed the shunt. Oral sorafenib (800 mg/day) was administered for at least four weeks, only and specifically to occlude the shunt. Hereafter, patients were re-evaluated by CT and DSA. RESULTS: All patients tolerated the full prescribed dose for at least 4 weeks. In one case, therapy was prolonged with an adapted dose (400 mg/day) due to sorafenib-related hand-foot syndrome. After sorafenib treatment, CT and DSA confirmed a complete closure of intratumoral shunts for all patients. No tumor progression was observed. All three patients hereafter underwent successful transarterial treatment by TACE (n = 2) or TARE (n = 1) without complications. Progression-free survival according to mRECIST was 501, 397 and 599 days, respectively. CONCLUSION: Even short-term oral sorafenib seems to effectively close intratumoral shunts in patients with HCC and thus might enable transarterial treatment of these patients.
Assuntos
Antineoplásicos/uso terapêutico , Carcinoma Hepatocelular/irrigação sanguínea , Neoplasias Hepáticas/irrigação sanguínea , Neovascularização Patológica/tratamento farmacológico , Sorafenibe/uso terapêutico , Idoso , Idoso de 80 Anos ou mais , Angiografia Digital , Antineoplásicos/administração & dosagem , Carcinoma Hepatocelular/complicações , Carcinoma Hepatocelular/diagnóstico por imagem , Quimioembolização Terapêutica , Feminino , Humanos , Infusões Intra-Arteriais , Fígado/irrigação sanguínea , Fígado/diagnóstico por imagem , Neoplasias Hepáticas/complicações , Neoplasias Hepáticas/diagnóstico por imagem , Masculino , Neovascularização Patológica/complicações , Neovascularização Patológica/diagnóstico por imagem , Estudos Retrospectivos , Sorafenibe/administração & dosagem , Tempo , Tomografia Computadorizada por Raios X , Resultado do TratamentoRESUMO
OBJECTIVE: It is difficult to control small hepatocellular carcinoma (HCC) nodules adjacent to the Glisson sheath (GS) by trans-arterial chemoembolization (TACE) probably due to multiple small tumor feeders directly branching from the trunk artery. The purpose of this study was to conduct a retrospective evaluation of a new TACE technique called the repeated alternate infusion of cisplatin solution and gelatin slurry distal to balloon occlusion (RAIB-TACE), for the treatment of small HCC nodules adjacent to GS. MATERIALS AND METHODS: Small nodules less than 4 cm attached to proximal portion of the subsegmental to lobar level portal branch were retrospectively selected. Between January 2011 and April 2014, 29 nodules in 29 patients were treated by super-selective lipiodol TACE/balloon-occluded TACE (B-TACE) (Lip-TACE group). Since April 2014, treatment protocols for small nodules adjacent to GS were changed, and 14 nodules in 12 patients were treated by RAIB-TACE (RAIB-TACE group). In RAIB-TACE group, alternate infusion of cisplatin solution and sparse gelatin slurry (mixture of 80 mg of gelatin fragments and 20 mL of contrast medium) were repeated until arterial flow was ceased. In Lip-TACE group, lipiodol was used as drug carrier and dense gelatin slurry (mixture of 80 mg of gelatin fragments and 2 mL of contrast medium) as embolization material. Dynamic CT/MRI was obtained 1-3 months after TACE, and response of each nodule was evaluated basing on modified RECIST criteria. RESULTS: In RAIB-TACE group, all 14 nodules (100%) were diagnosed as CR or PR. In Lip-TACE group, 18 of 29 (62.1%) were diagnosed as CR or PR. There was a statistically significant difference in objective response ratio between the groups (p=0.008, Fisher's test). Biloma (n=1) and benign stricture of the right hepatic duct (n=1) were seen in RAIB-TACE group. The biloma shrunk without treatment and the patient had no symptom, but the patient with biliary stricture repeated cholangitis and was treated by administration of antibiotics. CONCLUSION: The study results show that RAIB-TACE is more effective than lipiodol TACE/B-TACE for small hepatocellular carcinoma adjacent to GS. We speculate that one of the reasons to explain why Lip-TACE is inferior to RAIB-TACE is that viscous lipiodol or dense gelatin slurry could not flow into small tumor feeders effectively.
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Carcinoma Hepatocelular/terapia , Quimioembolização Terapêutica , Cisplatino/administração & dosagem , Óleo Etiodado/administração & dosagem , Gelatina/administração & dosagem , Neoplasias Hepáticas/terapia , Idoso , Idoso de 80 Anos ou mais , Oclusão com Balão , Carcinoma Hepatocelular/irrigação sanguínea , Carcinoma Hepatocelular/patologia , Feminino , Humanos , Fígado/irrigação sanguínea , Fígado/patologia , Neoplasias Hepáticas/irrigação sanguínea , Neoplasias Hepáticas/patologia , Masculino , Pessoa de Meia-Idade , Estudos RetrospectivosRESUMO
BACKGROUND/AIM: The aim of the present study was to investigate the vascular normalization effect of traditional Chinese medicine Astragalus membranaceus (AM) and Curcuma wenyujin (CW) on tumor-derived endothelial cells (TECs). MATERIALS AND METHODS: TECs were isolated from the xenografted HCC cell line HepG2 expressing red fluorescent protein (RFP). The effect of AM and CW on TECs proliferation was measured using the CCK8 assay. The vascular normalization potential of AM and CW was assessed using a tube formation assay. Immunocytochemistry was performed to assess the effect of AM and CW on the expression of angiogenic maker CD34 and hypoxia-inducible factor HIF1a. RESULTS: The isolated TECs and endothelioma (EOMA) cells did not differ with regard to the expression levels of endothelial markers CD34, VEGFR-1, VEGFR-2, PDGFR-α and PDGFR-ß. All AM, CW, AM+CW and Nintedanib (Nin) showed a dose-dependent increasing inhibition effect on either TECs or EOMA cells. AM, CW and AM+CW significantly reduced HIF1a expression, increased CD34 expression and enhanced endothelial network formation in TECs or EOMA cells compared to the control. CONCLUSION: AM and CW promoted vascular normalization in tumor-derived endothelial cells of HCC, through increased expression of CD34 and reduced expression of HIF1a.
Assuntos
Antígenos CD34/metabolismo , Carcinoma Hepatocelular/metabolismo , Medicamentos de Ervas Chinesas/farmacologia , Células Endoteliais/citologia , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Neoplasias Hepáticas/metabolismo , Animais , Astragalus propinquus/química , Carcinoma Hepatocelular/irrigação sanguínea , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Curcuma/química , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/metabolismo , Células Endoteliais/patologia , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Células Hep G2 , Humanos , Neoplasias Hepáticas/irrigação sanguínea , Medicina Tradicional Chinesa , Camundongos , Transplante de Neoplasias , Transdução de Sinais/efeitos dos fármacosRESUMO
BACKGROUND: Neoangiogenesis is one of the key pathogenetic mechanisms in hepatocellular carcinoma (HCC). Modulation of the renin-angiotensin system (RAS) by angiotensin-converting enzyme inhibitors (ACE-Is) and angiotensin receptor blockers (ARBs) seems to be a possible adjuvant therapy for HCC, due to the anti-angiogenic and anti-fibrogenic activity of these drugs. AIM: To elucidate the role of ARBs and ACE-Is in HCC. METHODS: We performed an electronic search of the literature using the most accessed online databases (PubMed, Cochrane library, Scopus and Web of Science), entering the query terms "angiotensin-converting enzyme inhibitors" OR "ACE inhibitors" OR "ACE-I" AND "hepatocarcinoma*" OR "hepatocellular carcinoma; moreover "angiotensin II type 1 receptor blockers" OR "ARBs" AND "hepatocarcinoma*" OR "hepatocellular carcinoma". Eligibility criteria were: (1) prospective or retrospective clinical studies; (2) epidemiological studies; and (3) experimental studies conducted in vivo or in vitro. Abstracts, conference papers, and reviews were excluded a priori. We limited our literature search to articles published in English, in peer-reviewed journals. RESULTS: Thirty-one studies were selected. Three interventional studies showed that ACE-Is had a significant protective effect on HCC recurrence only when used in combination with vitamin K or branched chain aminoacids, without a significant increase in overall survival. Of six retrospective observational studies, mainly focused on overall survival, only one demonstrated a prolonged survival in the ACE-Is group, whereas the two that also evaluated tumor recurrence showed conflicting results. All experimental studies displayed beneficial effects of RAS inhibitors on hepatocarcinogenesis. Numerous experimental studies, conducted either on animals and cell cultures, demonstrated the anti-angiogenetic and antifibrotic effect of ACE-Is and ARBs, thanks to the suppression of some cytokines such as vascular endothelial growth factor, hypoxia-inducible factor-1a, transforming growth factor-beta and tumor necrosis factor alpha. All or parts of these mechanisms were demonstrated in rodents developing fewer HCC and preneoplastic lesions after receiving such drugs. CONCLUSION: In humans, RAS inhibitors - alone or in combination - significantly suppressed the cumulative HCC recurrence, without prolonging patient survival, but some limitations intrinsic to these studies prompt further investigations.
Assuntos
Antagonistas de Receptores de Angiotensina/uso terapêutico , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Carcinoma Hepatocelular/terapia , Neoplasias Hepáticas/terapia , Recidiva Local de Neoplasia/prevenção & controle , Neovascularização Patológica/prevenção & controle , Antagonistas de Receptores de Angiotensina/farmacologia , Inibidores da Enzima Conversora de Angiotensina/farmacologia , Animais , Carcinoma Hepatocelular/irrigação sanguínea , Carcinoma Hepatocelular/mortalidade , Quimioterapia Adjuvante/métodos , Modelos Animais de Doenças , Quimioterapia Combinada/métodos , Hepatectomia , Humanos , Fígado/irrigação sanguínea , Fígado/efeitos dos fármacos , Fígado/cirurgia , Neoplasias Hepáticas/irrigação sanguínea , Neoplasias Hepáticas/mortalidade , Recidiva Local de Neoplasia/epidemiologia , Estudos Observacionais como Assunto , Ensaios Clínicos Controlados Aleatórios como Assunto , Sistema Renina-Angiotensina/efeitos dos fármacos , Resultado do TratamentoRESUMO
The collaboration of hepatopancreaticobiliary with transplant surgery expands technical options and opportunity for potentially curative resection in traditionally inoperable cases. We identified and describe three different types of ex vivo hepatic resections that include (1) explantation with formal hepatectomy, (2) explantation with re-implantation of the whole liver after vascular reconstruction, and (3) explantation with formal hepatectomy after future liver remnant volume augmentation.