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Liver transplantation is the definitive treatment for advanced liver cirrhosis with portal hypertension. In Japan, the scarcity of deceased donors leads to reliance on living donors, often resulting in smaller grafts. Managing portal venous pressure (PVP) is critical to prevent fatal posttransplant complications. This study explored the possibility of predicting intraoperative PVP. We analyzed 475 living donor liver transplant cases from 2006 to 2023, excluding those with acute liver failure or prior splenectomy or splenic artery embolization. Patients were divided into a training group (n=425) and a test group (n=50). We evaluated the correlation between preoperative factors and PVP at laparotomy, to predict PVP at laparotomy and closure. The predictive model was validated with the test group data. PVP at laparotomy could be predicted using correlated preoperative factors: prothrombin time ( p <0.001), predicted splenic volume ( p <0.001), and presence of a portosystemic shunt ( p =0.002), as follows: Predicted PVP at laparotomy (mmHg)=25.818 - 0.077×[prothrombin time (%)]+0.004×[predicted splenic volume (ml)] - 2.067×[1: with a portosystemic shunt] ( p <0.001; R=0.346). Additionally, PVP at closure could be predicted using correlated operative factors, including measured PVP at laparotomy, as follows: predicted PVP at closure (mmHg)=14.268+0.149×[measured PVP at laparotomy (mmHg)] - 0.040×[GV/SLV (%)] - 0.862×[1: splenectomy (if yes)] - 3.511×[1: splenic artery ligation without splenectomy (if yes)] ( p <0.001; R=0.339).This study demonstrated the feasibility of predicting intraoperative PVP using preoperative factors in liver transplant patients with decompensated cirrhosis. This predictive approach could refine surgical planning, potentially improving patient outcomes.
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PURPOSE: To evaluate the short term-outcomes of venous reconstruction using a round ligament-covered prosthetic vascular graft and assess its effectiveness in the prevention of prosthetic vascular graft migration in rightlobe living donor liver transplantation (LDLT). METHODS AND RESULTS: Thirty patients underwent reconstruction of the middle hepatic vein (MHV) tributaries during right lobe LDLT between January, 2021 and October, 2022. These patients were divided into the autologous vascular graft group (A group, n = 24) and the round ligament-covered prosthetic vascular graft group (RP group, n = 6). The computed tomography (CT) density ratio of the drainage area in the posterior segment of patent grafts was significantly higher in the RP group than in the A group (0.91 vs. 1.06, p = 0.0025). However, the patency rates of reconstructed MHV tributaries in the A and RP groups were 61% and 67%, respectively, with no significant difference between the groups (p = 0.72). Prosthetic vascular graft migration did not occur in the RP group. CONCLUSION: Venous reconstruction using round ligament-covered prosthetic vascular grafts is a feasible and simple method to prevent prosthetic vascular graft migration in right-lobe LDLT.
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Prótese Vascular , Veias Hepáticas , Transplante de Fígado , Doadores Vivos , Humanos , Transplante de Fígado/métodos , Veias Hepáticas/cirurgia , Veias Hepáticas/diagnóstico por imagem , Masculino , Feminino , Pessoa de Meia-Idade , Tomografia Computadorizada por Raios X , Adulto , Ligamentos/cirurgia , Ligamentos/transplante , Procedimentos de Cirurgia Plástica/métodos , Resultado do Tratamento , Implante de Prótese Vascular/métodos , Grau de Desobstrução Vascular , Procedimentos Cirúrgicos Vasculares/métodos , Migração de Corpo Estranho/prevenção & controle , Migração de Corpo Estranho/cirurgiaRESUMO
PURPOSE: To clarify the Japan criteria (JC), as proposed in 2019, in order to identify the most appropriate treatment methods for hepatocellular carcinoma (HCC) recurrence and assess the feasibility of pre-living donor liver transplantation (LDLT) downstaging within these criteria. METHODS: The subjects of this study were 169 LDLT patients with HCC recurrence. We performed univariate and multivariate analyses of the factors contributing to HCC recurrence after LDLT and clarified the post-transplant outcomes of pre-LDLT downstaging. RESULTS: Univariate and multivariate analysis identified beyond the JC (p = 0.0018) and a neutrophil-to-lymphocyte ratio > 2.01 (p = 0.029) as independent risk factors. Patients who met the JC had significantly higher recurrence-free and overall survival rates after LDLT (p < 0.0001) than those who did not (p = 0.0002). The post-transplant outcomes of patients within the JC after downstaging were significantly better than those of patients beyond the JC (p = 0.034) and equivalent to those within the JC without downstaging. CONCLUSION: Even for HCC recurrence, the JC could play an important role in deciding on the best treatment strategy, and downstaging within the JC had good post-transplant outcomes.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Transplante de Fígado , Humanos , Carcinoma Hepatocelular/cirurgia , Neoplasias Hepáticas/cirurgia , Transplante de Fígado/métodos , Japão , Resultado do Tratamento , Doadores Vivos , Recidiva Local de NeoplasiaRESUMO
Living-donor liver transplantation (LDLT) is an established treatment for patients with end-stage liver disease or acute liver failure, and outflow reconstruction is considered one of the most vital techniques in LDLT. To date, many strategies have been reported to prevent outflow obstruction, which can be refractory to liver dysfunction and can cause life-threatening graft loss or mortality. In addition, in this era of laparoscopic hepatectomy in donor surgery, especially LDLT using a left liver graft, it has been predicted that cutting the hepatic vein with automatic linear staplers will lead to more outflow-related problems than with conventional open hepatectomy because of the short neck of the anastomosis orifice. We herein review 10 cases of venoplasty performed with a novel venous cuff system using a donor's round ligament around the hepatic vein in LDLT with a left lobe graft, which makes anastomosis of the hepatic vein sterically easy for postoperative venous patency.
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Estudos de Viabilidade , Veias Hepáticas , Transplante de Fígado , Doadores Vivos , Veias Mesentéricas , Transplante de Fígado/métodos , Humanos , Veias Hepáticas/cirurgia , Veias Mesentéricas/cirurgia , Feminino , Masculino , Pessoa de Meia-Idade , Adulto , Anastomose Cirúrgica/métodos , Hepatectomia/métodos , Fígado/irrigação sanguínea , Fígado/cirurgia , Ligamentos Redondos/cirurgia , Procedimentos Cirúrgicos Vasculares/métodos , Laparoscopia/métodosRESUMO
The association between tumor microenvironment (TME) and cancer-associated fibroblasts (CAFs) in intrahepatic cholangiocarcinoma (ICC) progression is poorly understood. This study aimed to reveal whether specific microRNAs (miRNAs) in extracellular vesicles (EVs) derived from CAFs were involved in ICC progression. Conditioned medium (CM) and EVs in the CM of CAFs and normal fibroblasts (NFs) derived from ICC specimens were used to investigate the effects on tumor cell lines. miRNA microarray assay was used to examine the miRNAs of EVs derived from CAFs and NFs in ICC, and the effects of miR-493-5p on tumor cell lines were examined. Additionally, databases were used to identify miR-493-5p targets, and the relationship between prognosis of ICC patients and cocaine- and amphetamine-regulated transcript propeptide (CARTPT), one of the targets of miR-493-5p, expression in ICC tissues was retrospectively analyzed. Compared with NF-derived CM and EVs, CAF-derived CM and EVs promoted cell lines in proliferation, scratch, migration, and invasion assays. miRNA microarray analysis revealed that miR-493-5p was significantly increased in CAF-derived EVs compared to NF-derived EVs. Tumor cell lines transfected with miR-493-5p were promoted in proliferation and scratch assays. Immunohistochemical staining was performed on 76 ICC specimens; both overall and recurrence-free survival rates were significantly worse in the CARTPT-negative group. Univariate and multivariate analyses showed that low CARTPT expression was an independent poor prognostic factor for overall and recurrence-free survival. Overall, our data suggest that CAFs in the ICC TME suppress CARTPT in tumor cells and promote tumor cells via miR-493-5p in EVs.
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Neoplasias dos Ductos Biliares , Fibroblastos Associados a Câncer , Colangiocarcinoma , MicroRNAs , Humanos , Fibroblastos Associados a Câncer/metabolismo , Estudos Retrospectivos , MicroRNAs/genética , Proliferação de Células , Linhagem Celular Tumoral , Colangiocarcinoma/patologia , Neoplasias dos Ductos Biliares/patologia , Ductos Biliares Intra-Hepáticos/metabolismo , Microambiente Tumoral/genéticaRESUMO
PURPOSE: Transferrin receptor (TFR), a membrane protein that has a critical role in the transport of iron into cells, is known to be a ferroptosis-related marker. Although TFR is reported to be abundantly expressed in tumor cells, its relationship with ferroptosis inducers in hepatocellular carcinoma (HCC) remains unclear. METHODS: The authors performed immunohistochemical staining of TFR and divided 350 HCC patients into two groups according to its expression. They analyzed the association between TFR expression and prognosis or clinicopathologic factors. In addition, the regulation of malignant activity and its effect on the efficacy of ferroptosis inducers were investigated in vitro. RESULTS: For this study, 350 patients were divided into TFR-positive (n =180, 51.4%) and TFR-negative (n = 170, 48.6%) groups. The TFR-positive group had more hepatitis B surface antigen (HBs-Ag) (p = 0.0230), higher α-fetoprotein (AFP) levels (p = 0.0023), higher des-gamma-carboxyprothrombin (DCP) levels (p = 0.0327), a larger tumor size (p = 0.0090), greater proportions of Barcelona Clinic Liver Cancer (BCLC) stage B or C (p = 0.0005), poor differentiation (p < 0.0001), and microscopic intrahepatic metastasis (p = 0.0066). In the multivariate analyses, TFR expression was an independent prognostic factor in disease-free survival (p = 0.0315). In vitro, TFRC knockdown decreased cell motility. In addition, TFRC knockdown abolished artesunate (AS)-, lenvatinib-, and sorafenib-induced ferroptosis in HCC cell lines. The study demonstrated that simultaneous treatment of AS with multi-kinase inhibitor augmented the ferroptosis-inducing effects of AS in HCC cell lines. CONCLUSION: TFR expression is a poor prognostic factor in HCC, but its expression increases sensitivity to ferroptosis-inducing agents.
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Carcinoma Hepatocelular , Ferroptose , Neoplasias Hepáticas , Humanos , Carcinoma Hepatocelular/patologia , Neoplasias Hepáticas/patologia , Prognóstico , Receptores da Transferrina/análiseRESUMO
BACKGROUND: Signal regulatory protein alpha (SIRPα), expressed in the macrophage membrane, inhibits phagocytosis of tumor cells via CD47/SIRPα interaction, which acts as an immune checkpoint factor in cancers. This study aimed to clarify the clinical significance of SIRPα expression in hepatocellular carcinoma (HCC). METHODS: This study analyzed SIRPα expression using RNA sequencing data of 372 HCC tissues from The Cancer Genome Atlas (TCGA) and immunohistochemical staining of our 189 HCC patient cohort. The correlation between SIRPα expression and clinicopathologic factors, patient survival, and intratumor infiltration of immune cells was investigated. RESULTS: Overall survival (OS) was significantly poorer with high SIRPα expression than with low expression in both TCGA and our cohort. High SIRPα expression correlated with lower recurrence-free survival (RFS) in our cohort. High SIRPα expression was associated with higher rates of microvascular invasion and lower serum albumin levels and correlated with greater intratumor infiltration of CD68-positive macrophages and myeloid-derived suppressor cells (MDSCs). Multivariate analysis showed that SIRPα expression and high infiltration of CD8-positive T cells and MDSCs were predictive factors for both RFS and OS. Patients with high SIRPα expression and infiltration of CD8-positive T cells and MDSCs had significantly lower RFS and OS rates. In spatial transcriptomics sequencing, SIRPα expression was significantly correlated with CD163 expression. CONCLUSIONS: High SIRPα expression in HCC indicates poor prognosis, possibly by inhibiting macrophage phagocytosis of tumor cells, promoting MDSC infiltration and inducing antitumor immunity. Treatment alternatives using SIRPα blockage should be considered in HCC as inhibiting macrophage antitumor immunity and MDSCs.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Humanos , Carcinoma Hepatocelular/genética , Relevância Clínica , Neoplasias Hepáticas/genética , Fagocitose , Receptores Imunológicos/genética , Receptores Imunológicos/metabolismoRESUMO
This paper proposes a deep sound-field denoiser, a deep neural network (DNN) based denoising of optically measured sound-field images. Sound-field imaging using optical methods has gained considerable attention due to its ability to achieve high-spatial-resolution imaging of acoustic phenomena that conventional acoustic sensors cannot accomplish. However, the optically measured sound-field images are often heavily contaminated by noise because of the low sensitivity of optical interferometric measurements to airborne sound. Here, we propose a DNN-based sound-field denoising method. Time-varying sound-field image sequences are decomposed into harmonic complex-amplitude images by using a time-directional Fourier transform. The complex images are converted into two-channel images consisting of real and imaginary parts and denoised by a nonlinear-activation-free network. The network is trained on a sound-field dataset obtained from numerical acoustic simulations with randomized parameters. We compared the method with conventional ones, such as image filters, a spatiotemporal filter, and other DNN architectures, on numerical and experimental data. The experimental data were measured by parallel phase-shifting interferometry and holographic speckle interferometry. The proposed deep sound-field denoiser significantly outperformed the conventional methods on both the numerical and experimental data. Code is available on GitHub (https://github.com/nttcslab/deep-sound-field-denoiser).
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INTRODUCTION: The proportion of gastroduodenal ulcers caused by drugs is increasing. However, the risk of gastroduodenal ulcer from drugs other than nonsteroidal anti-inflammatory drugs (NSAIDs) and low-dose aspirin is unclear. An association between immunosuppressive drugs and gastroduodenal ulcers has been suggested. We aimed to identify the immunosuppressive drugs and clinical characteristics associated with gastroduodenal ulcers in post-liver transplant patients. METHODS: The study investigated 119 patients who underwent esophagogastroduodenoscopy after liver transplantation, and 2 patients were excluded. Clinical characteristics, medications, and endoscopic images were retrospectively reviewed. RESULTS: Among 117 post-living donor liver transplant recipients, gastroduodenal ulcers were found in 10 (9.2%) patients. The ulcer group had endoscopic gastritis more frequently (40%) compared with the non-ulcer group (10%). Logistic regression analysis revealed gastritis, NSAID use, and mycophenolate mofetil were risk factors in the post-liver transplant patients. Among 103 patients not on NSAIDs, 8 (7.8%) had peptic ulcer. The most common ulcer site and ulcer shape were the gastric antrum and a circular shape, respectively. All patients in the ulcer group were taking mycophenolate mofetil, which was the only immunosuppressive drug that showed a significant difference between the two groups. Five out of 8 ulcer patients (63%) were taking gastric acid suppressants, and gastroduodenal ulcers in post-liver transplant recipients were suggested to be refractory. CONCLUSION: Patients treated with immunosuppressive drugs after liver transplantation can develop gastroduodenal ulcers, even with gastric acid suppressant medication. Mycophenolate mofetil may increase the risk of gastroduodenal ulcers compared with other immunosuppressive drugs.
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Gastrite , Transplante de Fígado , Úlcera Péptica , Humanos , Transplante de Fígado/efeitos adversos , Ácido Micofenólico/efeitos adversos , Estudos Retrospectivos , Doadores Vivos , Úlcera Péptica/tratamento farmacológico , Úlcera Péptica/epidemiologia , Úlcera Péptica/induzido quimicamente , Anti-Inflamatórios não Esteroides/efeitos adversos , Imunossupressores/efeitos adversos , Terapia de Imunossupressão , Gastrite/induzido quimicamenteRESUMO
AIMS: The fibroblast growth factor receptor 2 (FGFR2) fusion gene is frequently found as a genetic abnormality in the FGFR pathway in patients with intrahepatic cholangiocarcinoma (ICC). The FGFR fusion protein, produced from the FGFR fusion gene, is thought to cause tumor cell growth. To date, there have been few reports on the relationship between pathologic FGFR2 expression and prognosis in patients who have undergone hepatectomy for ICC, and on the relationship between FGFR2 and tumor-infiltrating lymphocytes (TILs). METHODS AND RESULTS: We enrolled 92 patients who underwent hepatectomy for ICC and performed immunohistochemical staining for FGFR2 and cluster of differentiation 8, and hematoxylin and eosin staining for evaluating TILSs. The relationships between the FGFR2 and clinicopathological characteristics and outcomes were analyzed, and patients were classified into positive (n = 18) and negative (n = 74) FGFR2 groups. The FGFR2-positive group contained more men (p < 0.0001) and had lower serum albumin (p = 0.0355) and higher carcinoembryonic antigen (p = 0.0099). Furthermore, multivariable analyses revealed that the FGFR2-positive group had worse disease-free survival (DFS) (p = 0.0002). Multivariate analysis showed that the independent prognostic factors for DFS were maximum tumor size (≥5 cm) (p = 0.0011), tumor localization (perihilar type) (p = 0.0180), and FGFR2 positivity (p = 0.0029). There was no significant difference in TILs count between the two groups. CONCLUSION: We showed that FGFR2 high expression was an independent prognostic factor for recurrence of resected ICC.
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AIM: The hemoglobin, albumin, lymphocyte, and platelet (HALP) score reflects the immune system and the nutritional status of patients, and prognosis in various cancers. However, the HALP score in hepatocellular carcinoma has not been reported. METHODS: Data were analyzed retrospectively from Child-Pugh A patients undergoing hepatic resection for single hepatocellular carcinoma ≤5 cm. For cross-validation, patients were divided into the training (332 patients) and validation cohort (210 patients). In the training cohort, we divided patients into two groups by appropriate cut-off value of the HALP score, and univariable and multivariable analyses were conducted for disease-free and overall survival (OS) between two groups. In the validation cohort, we examined OS by Kaplan-Meier analysis in the same cut-off value of the HALP score in the training cohort. RESULTS: The HALP-low group was significantly older (p = 0.0003), had fewer hepatitis B surface antigen-positive patients (p = 0.0369), higher prothrombin time (p = 0.0141), lower fibrosis-4 index (p = 0.0206), bigger maximum tumor size (p = 0.0196), and less histological liver fibrosis (p = 0.0077). Multivariate analysis showed that the independent prognostic factors for disease-free survival were fibrosis-4 index ≥2.67 (p = 0.0008), simple nodular type with extranodular growth or confluent multinodular type (p = 0.0221), and intrahepatic metastasis (p = 0.0233), and that for OS were fibrosis-4 index ≥2.67 (p = 0.0020), HALP ≤45.6 (p = 0.0228), and poor differentiation (p = 0.0305). In the validation cohort, Kaplan-Meier analysis revealed the trend toward significantly impaired OS (p = 0.0220) in the HALP-low group. CONCLUSION: We showed that a low HALP score is the independent prognostic factor for Child-Pugh A patients undergoing curative hepatic resection for single and small hepatocellular carcinoma.
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AIM: Although the survival rate after living-donor liver transplantation (LDLT) is improving, sepsis still limits the prognosis. Immune dysfunction and sarcopenia are often observed in LDLT patients, and increase susceptibility to infection. Brain-derived neurotrophic factor (BDNF) is a myokine produced by immune cells and skeletal muscle. We aimed to determine whether serum BDNF could be a feasible biomarker for sepsis of LDLT patients. METHODS: We measured serum samples from 124 patients who underwent LDLT and 9 healthy volunteers for BDNF. We examined its correlation with incidence rate of sepsis. To clarify the source of BDNF, we examined its expression in lymphocytes, skeletal muscle cells, and hepatocytes. RESULTS: Patients who experienced sepsis showed worse short-term survival. Preoperative serum BDNF was lower in LDLT patients compared with healthy volunteers, and was also lower in Child-Pugh C compared with Child-Pugh A or B. Serum BDNF was inversely correlated with Model for End-Stage Liver Disease and controlling nutritional status (CONUT) scores, but had a weak positive correlation with skeletal muscle mass index (SMI). Multivariate analysis revealed that serum BDNF was independently associated with sepsis. Preoperative serum BDNF was a better predictor of sepsis in LDLT patients than CONUT score or SMI. Serum BDNF was positively correlated with lymphocyte counts, especially T cells. In vitro, T cells and skeletal muscle cells produced BDNF. CONCLUSIONS: Preoperative serum BDNF could be a predictive biomarker for sepsis after LDLT, by reflecting the systemic condition including hepatic function, nutritional status, and immune status.
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AIM: We aimed to evaluate the association between the intraoperative indocyanine green (ICG) fluorescence imaging (FI) pattern, preoperative magnetic resonance imaging (MRI) findings using gadolinium ethoxybenzyl diethylenetriaminepentaacetic acid (Gd-EOB-DTPA), preoperative diffusion-weighted imaging (DWI) of MRI, and histological differentiation of hepatocellular carcinoma (HCC). METHODS: We retrospectively reviewed the data for 80 tumors of 64 patients. Intraoperative ICG FI patterns were classified into cancerous or rim-positive type. We evaluated the signal intensity ratio of the tumor and the surrounding liver tissue in the portal phase (SIRPP) and intensity in the hepatobiliary phase (HBP) of Gd-EOB-DTPA-enhanced MRI, the apparent diffusion coefficient (ADC) in the DWI of MRI, and clinicopathologic factors. RESULTS: In the rim-positive group, the rate of poorly differentiated HCC and hypointensity type in HBP were significantly higher, and SIRPP and ADC were significantly lower than the rim-negative group. In the cancerous group, the rate of well or moderately differentiated HCC and hyperintensity type in HBP, SIRPP, and ADC were significantly higher than the noncancerous group. Multivariate analysis identified low SIRPP, low ADC, and hypointensity type in HBP as the significant predictive factors for rim-positive HCC and high SIRPP, high ADC, and hyperintensity type in HBP as the significant predictive factors for cancerous HCC. The positive rate of programmed cell death 1-ligand 1 and vessels that encapsulate tumor clusters status of the rim-positive HCC and HCC with low SIRPP were significantly higher than the control group. CONCLUSIONS: The intraoperative ICG FI pattern of HCC closely correlated with histological differentiation, preoperative SIRPP and intensity type in the Gd-EOB-DTPA MRI, and preoperative ADC in the DWI of MRI.
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BACKGROUND: The hemoglobin-albumin-lymphocyte-platelet (HALP) score is a combination index that assesses nutritional status and systemic inflammatory response and is reported to predict prognosis in several cancer types. However, researches about the usefulness of the HALP score in intrahepatic cholangiocarcinoma (ICC) are limited. METHODS: This was a single-center, retrospective study of 95 patients who underwent surgical resection for ICC between 1998 and 2018. We divided patients into two groups by calculating the cutoff value of the HALP score and examined clinicopathological characteristics, prognosis, and sarcopenia. Tumor-infiltrating lymphocytes (TILs), CD8 + TILs, and FOXP3 + TILs were evaluated by immunohistochemical staining of resected tumors. RESULTS: Of 95 patients, 22 were HALP-low. The HALP-low group had significantly lower hemoglobin (p = 0.0007), lower albumin (p = 0.0013), higher platelet counts (p < 0.0001), fewer lymphocytes (p < 0.0001), higher CA19-9 levels (p = 0.0431), and more lymph node metastasis (p = 0.0013). Multivariate analysis revealed that the independent prognostic factors for disease-free survival were maximum tumor size (≥ 5.0 cm) (p = 0.0033), microvascular invasion (p = 0.0108), and HALP score (≤ 25.2) (p = 0.0349), and that factors for overall survival were lymph node metastasis (p = 0.0020) and HALP score (≤ 25.2) (p = 0.0014). The HALP-low group contained significantly more patients with sarcopenia (p = 0.0015). Immunohistochemistry showed that counts of CD8 + TILs were significantly lower in the HALP-low group (p = 0.0075). CONCLUSIONS: We demonstrated that low HALP score is an independent prognostic factor for ICC patients undergoing curative hepatic resection and is associated with sarcopenia and the immune microenvironment.
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Neoplasias dos Ductos Biliares , Colangiocarcinoma , Sarcopenia , Humanos , Prognóstico , Estudos Retrospectivos , Metástase Linfática/patologia , Sarcopenia/cirurgia , Sarcopenia/patologia , Albuminas , Linfócitos/patologia , Ductos Biliares Intra-Hepáticos/patologia , Neoplasias dos Ductos Biliares/cirurgia , Neoplasias dos Ductos Biliares/patologia , Hemoglobinas/análise , Microambiente TumoralRESUMO
The tyrosine kinase inhibitor lenvatinib is used to treat advanced hepatocellular carcinoma (HCC). Ferroptosis is a type of cell death characterized by the iron-dependent accumulation of lethal lipid reactive oxygen species (ROS). Nuclear factor erythroid-derived 2-like 2 (Nrf2) protects HCC cells against ferroptosis. However, the mechanism of lenvatinib-induced cytotoxicity and the relationships between lenvatinib resistance and Nrf2 are unclear. Thus, we investigated the relationship between lenvatinib and ferroptosis and clarified the involvement of Nrf2 in lenvatinib-induced cytotoxicity. Cell viability, lipid ROS levels, and protein expression were measured using Hep3B and HuH7 cells treated with lenvatinib or erastin. We examined these variables after silencing fibroblast growth factor receptor-4 (FGFR4) or Nrf2 and overexpressing-Nrf2. We immunohistochemically evaluated FGFR4 expression in recurrent lesions after resection and clarified the relationship between FGFR4 expression and lenvatinib efficacy. Lenvatinib suppressed system Xc - (xCT) and glutathione peroxidase 4 (GPX4) expression. Inhibition of the cystine import activity of xCT and GPX4 resulted in the accumulation of lipid ROS. Silencing-FGFR4 suppressed xCT and GPX4 expression and increased lipid ROS levels. Nrf2-silenced HCC cells displayed sensitivity to lenvatinib and high lipid ROS levels. In contrast, Nrf2-overexpressing HCC cells displayed resistance to lenvatinib and low lipid ROS levels. The efficacy of lenvatinib was significantly lower in recurrent HCC lesions with low-FGFR4 expression than in those with high-FGFR4 expression. Patients with FGFR4-positive HCC displayed significantly longer progression-free survival than those with FGFR4-negative HCC. Lenvatinib induced ferroptosis by inhibiting FGFR4. Nrf2 is involved in the sensitivity of HCC to lenvatinib.
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Carcinoma Hepatocelular , Ferroptose , Fator 4 de Crescimento de Fibroblastos , Neoplasias Hepáticas , Compostos de Fenilureia , Quinolinas , Carcinoma Hepatocelular/patologia , Fator 4 de Crescimento de Fibroblastos/antagonistas & inibidores , Humanos , Lipídeos , Neoplasias Hepáticas/patologia , Fator 2 Relacionado a NF-E2/metabolismo , Compostos de Fenilureia/farmacologia , Quinolinas/farmacologia , Espécies Reativas de Oxigênio/metabolismoRESUMO
AIM: Recently, new diagnostic criteria for acute-on-chronic liver failure (ACLF) were established in Japan. However, there is little evidence regarding the feasibility of classifying patients undergoing living-donor liver transplantation (LDLT). The aim was to re-evaluate the impact of these new diagnostic criteria on ACLF and the severity classification of patients undergoing LDLT. METHODS: We collected data of 82 recipients who underwent LDLT for liver failure between 1997 and 2020 and reviewed it retrospectively. RESULTS: Of the 82 patients with liver failure, 31 (37.8%) were diagnosed with ACLF; Grade 0 (n = 6), Grade 1 (n = 7), Grade 2 (n = 9), and Grade 3 (n = 9). There was no substantial difference in overall survival (OS) and the occurrence of postoperative complications between liver failure patients with and without ACLF. The OS after LDLT was significantly different among the four groups of ACLF patients (P = .036). Interestingly, ACLF Grade 3 patients had substantially lower OS compared to other ACLF groups even after LDLT (P = .006; 5-year OS rates, 33.3% vs. 85.9%). CONCLUSION: Proper use of the new diagnostic criteria for ACLF in Japan demonstrated that the presence and severity of ACLF, especially the presence of multiple organ failures, leads to morbidity and mortality even in an LDLT setting. Considering that the patients with ACLF Grade 3 do not have the favorable outcomes of LDLT, deceased-donor liver transplantation usage, or LDLT before reaching the severity of Grade 3 may be suitable for further research.
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Insuficiência Hepática Crônica Agudizada , Transplante de Fígado , Insuficiência Hepática Crônica Agudizada/etiologia , Insuficiência Hepática Crônica Agudizada/cirurgia , Humanos , Japão/epidemiologia , Doadores Vivos , Estudos Retrospectivos , Resultado do TratamentoRESUMO
The recipient muscle status is closely associated with postoperative poor survival in recipients of living donor liver transplantation (LDLT). However, it is uncertain whether LDLT donor muscle quality and quantity affect graft quality. Hence, we analyzed the correlation between donor muscle status and graft function. We measured the skeletal muscle mass index (SMI) and intramuscular adipose tissue content (IMAC) of 380 LDLT donors. We examined the correlation between donor SMI or IMAC and graft mortality, the occurrence rates of small-for-size graft (SFSG) syndrome, and 6-month graft survival rates. The donor SMI had no effect on the occurrence of SFSG syndrome and graft survival, while a high IMAC in both male and female donors was significantly correlated with the rate of SFSG syndrome [high vs low: (male donors) 15.8% vs. 2.5%, p = 0.0003; (female donors) 12.8% vs. 3.1%, p = 0.0234] and 6-month graft survival rates [(male donors) 87.7% vs 95.9%, p = 0.02; (female donors) 83.0% vs. 99.0%, p < 0.0001]. Multivariate analysis revealed that a high donor IMAC (HR; 5.42, CI; 2.13-13.8, p = 0.0004) was an independent risk factor for 6-month graft survival, and the donor IMAC is useful for donor selection for high-risk recipients.
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Transplante de Fígado , Masculino , Humanos , Feminino , Doadores Vivos , Estudos Retrospectivos , Músculo Esquelético , Fatores de Risco , Sobrevivência de Enxerto , Resultado do TratamentoRESUMO
AIM: Liver transplantation (LT) is the only curative therapy for decompensated liver cirrhosis. For recipients of living donor LT (LDLT), restoration of liver function after transplantation is highly dependent on liver regenerative capacity, which requires large amounts of intracellular energy. Mitochondrial metabolism provides a stable supply of adenosine 5'-triphosphate (ATP) for liver regeneration. Mitophagy is a selective process in which damaged, non-functional mitochondria are degraded and replaced with new functional mitochondria. We investigated the relationship between expression of Syntaxin17 (STX17), a key protein in mitophagy regulation, in donor livers and graft survival. METHODS: We examined STX17 expression in grafts from 143 LDLT donors who underwent right lobe resection and investigated the relationship between STX17 expression and graft function. We investigated the correlations among STX17 expression, mitochondrial membrane potential and cell proliferation, using a STX17-knockdown hepatocyte cell line. RESULTS: Recipients transplanted with low STX17-expression grafts had significantly lower graft survival rates than recipients transplanted with high STX17-expression grafts (88.9% vs. 100%, p < 0.01). Multivariate analysis showed that low STX17 expression (HR: 10.7, CI: 1.29-88.0, p < 0.05) and the absence of splenectomy (HR: 6.27, CI: 1.59-24.8, p < 0.01) were independent predictive factors for small-for-size graft syndrome, which is the severe complication in LDLT. In the vitro experiments, the percentage of depolarized damaged mitochondria was increased in the STX17-knockdown hepatocyte cell line, suggesting decreased mitophagy and ATP synthesis. Cell proliferation was significantly decreased in the STX17-knockdown hepatocyte cell line. CONCLUSION: STX17 contributes to mitophagy and maintenance of mitochondrial function in hepatocytes and may be a predictor of graft dysfunction in LDLT patients.
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BACKGROUND: Early recurrence (ER) of hepatocellular carcinoma (HCC) (within 1 year after resection) is known to be a poor prognostic factor. The aim was to identify the risk factors associated with ER after HCC resection. METHODS: Data were analyzed retrospectively from patients who underwent primary resection for HCC from two hospitals. For cross-validation, HCC resection cases were divided into the training and testing cohort. The clinicopathological factors between the ER and non-ER groups and factors for predicting ER and prognosis after HCC resection were compared. RESULTS: Out of 173 patients in the training dataset, 33 patients had ER and the ER group showed larger tumor size, more intrahepatic metastasis (IM), and a higher ratio of serum des-gamma-carboxy prothrombin (DCP) to tumor volume (TV) (DCP/TV) than the non-ER group. Out of 203 patients in the testing dataset, 30 patients had ER and the ER group demonstrated larger tumor size, more IM, and higher serum alpha-fetoprotein, AFP/TV, DCP/TV, AFP/tumor maximum diameter (TMD), and DCP/TMD than the non-ER group. The patients were divided into high and low DCP/TV groups and high serum DCP/TV was associated with unfavorable overall survival in the training and testing dataset. Multivariate analysis confirmed that high serum DCP/TV and IM were independently associated with ER. CONCLUSION: Preoperative high serum DCP/TV may be useful for stratifying patients at risk of early HCC recurrence after curative resection.
RESUMO
BACKGROUND: There is little evidence concerning survival after surgery in patients with hepatocellular carcinoma who have received lenvatinib treatment. The aim of this study was to evaluate whether post-lenvatinib surgical treatment in patients with hepatocellular carcinoma improves overall survival. METHODS: The cohort of this retrospective study comprised 55 patients with hepatocellular carcinoma who had undergone lenvatinib treatment. We classified them into two groups according to post-lenvatinib surgical treatment status and compared clinicopathologic factors and prognosis between the two groups with the aim of identifying predictors of overall survival. RESULTS: The median duration of lenvatinib administration was 5.8 months (range, 0.4-24.0 months). Twelve of the 55 patients underwent surgery after receiving lenvatinib. There was no significant difference in assessed clinicopathological factors between patients who did and did not undergo surgery after being treated with lenvatinib. Multivariate analysis revealed that older age was associated with a significantly worse overall survival (hazard ratio: 2.332; 95% confidence interval 1.062-5.168; P = 0.0369) and that surgery after treatment with lenvatinib achieved better overall survival than other forms of treatment (hazard ratio: 0.121; 95% confidence interval 0.016-0.901; P = 0.0393). CONCLUSIONS: Surgical treatment after lenvatinib administration may be a useful therapeutic option for select patients with hepatocellular carcinoma.