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BACKGROUND: Adenosine deaminase acting on RNA 1 (ADAR1) is an RNA-editing enzyme that significantly impacts cancer progression and various biological processes. The expression of ADAR1 mRNA has been examined in multiple cancer types using The Cancer Genome Atlas (TCGA) dataset, revealing distinct patterns in kidney chromophobe (KICH), kidney renal clear cell carcinoma (KIRC), kidney renal papillary cell carcinoma (KIRP), and liver hepatocellular carcinoma (LIHC) compared to normal controls. However, the reasons for these differential expressions remain unclear. METHODS: In this study, we performed RT-PCR and western blotting (WB) to validate ADAR1 expression patterns in clinical tissue samples. Survival analysis and immune microenvironment analysis (including immune score and stromal score) were conducted using TCGA data to determine the specific cell types associated with ADAR1, as well as the key genes in those cell types. The relationship between ADAR1 and specific cell types' key genes was verified by immunohistochemistry (IHC), using clinical liver and kidney cancer samples. RESULTS: Our validation analysis revealed that ADAR1 expression was downregulated in KICH, KIRC, and KIRP, while upregulated in LIHC compared to normal tissues. Notably, a significant correlation was found between ADAR1 mRNA expression and patient prognosis, particularly in KIRC, KIRP, and LIHC. Interestingly, we observed a positive correlation between ADAR1 expression and stromal scores in KIRC, whereas a negative correlation was observed in LIHC. Cell type analysis highlighted distinct relationships between ADAR1 expression and the two stromal cell types, blood endothelial cells (BECs) and lymphatic endothelial cells (LECs), and further determined the signature gene claudin-5 (CLDN5), in KIRC and LIHC. Moreover, ADAR1 was inversely related with CLDN5 in KIRC (n = 26) and LIHC (n = 30) samples, verified via IHC. CONCLUSIONS: ADAR1 plays contrasting roles in LIHC and KIRC, associated with the enrichment of BECs and LECs within tumors. This study sheds light on the significant roles of stromal cells within the complex tumor microenvironment (TME) and provides new insights for future research in tumor immunotherapy and precision medicine.
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Adenosina Desaminase , Carcinoma Hepatocelular , Carcinoma de Células Renais , Regulação Neoplásica da Expressão Gênica , Neoplasias Renais , Neoplasias Hepáticas , Proteínas de Ligação a RNA , Microambiente Tumoral , Adenosina Desaminase/genética , Adenosina Desaminase/metabolismo , Humanos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/metabolismo , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patologia , Carcinoma Hepatocelular/mortalidade , Neoplasias Renais/genética , Neoplasias Renais/patologia , Neoplasias Renais/metabolismo , Neoplasias Renais/mortalidade , Carcinoma de Células Renais/genética , Carcinoma de Células Renais/metabolismo , Carcinoma de Células Renais/patologia , Proteínas de Ligação a RNA/metabolismo , Proteínas de Ligação a RNA/genética , Prognóstico , Feminino , Masculino , Biomarcadores Tumorais/metabolismo , Biomarcadores Tumorais/genética , Pessoa de Meia-IdadeRESUMO
The tumor microenvironment is a complex network of cells, extracellular matrix, and signaling molecules that plays a critical role in tumor progression and metastasis. Lymphatic and blood vessels are major routes for solid tumor metastasis and essential parts of tumor drainage conduits. However, recent studies have shown that lymphatic endothelial cells (LECs) and blood endothelial cells (BECs) also play multifaceted roles in the tumor microenvironment beyond their structural functions, particularly in hepatocellular carcinoma (HCC). This comprehensive review summarizes the diverse roles played by LECs and BECs in HCC, including their involvement in angiogenesis, immune modulation, lymphangiogenesis, and metastasis. By providing a detailed account of the complex interplay between LECs, BECs, and tumor cells, this review aims to shed light on future research directions regarding the immune regulatory function of LECs and potential therapeutic targets for HCC.
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Despite N6-methyladenosine (m6A) is functionally important in various biological processes, its role and the underlying regulatory mechanism in the liver remain largely unexplored. In the present study, we showed that fat mass and obesity-associated protein (FTO, an m6A demethylase) was involved in mitochondrial function during hepatic ischemia-reperfusion injury (HIRI). We found that the expression of m6A demethylase FTO was decreased during HIRI. In contrast, the level of m6A methylated RNA was enhanced. Adeno-associated virus-mediated liver-specific overexpression of FTO (AAV8-TBG-FTO) ameliorated the HIRI, repressed the elevated level of m6A methylated RNA, and alleviated liver oxidative stress and mitochondrial fragmentation in vivo and in vitro. Moreover, dynamin-related protein 1 (Drp1) was a downstream target of FTO in the progression of HIRI. FTO contributed to the hepatic protective effect via demethylating the mRNA of Drp1 and impairing the Drp1-mediated mitochondrial fragmentation. Collectively, our findings demonstrated the functional importance of FTO-dependent hepatic m6A methylation during HIRI and provided valuable insights into the therapeutic mechanisms of FTO.
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Adenosina/análogos & derivados , Dioxigenase FTO Dependente de alfa-Cetoglutarato/metabolismo , Dinaminas/metabolismo , Fígado/irrigação sanguínea , Mitocôndrias Hepáticas/metabolismo , Traumatismo por Reperfusão/metabolismo , Adenosina/metabolismo , Animais , Fígado/metabolismo , Fígado/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Mitocôndrias Hepáticas/patologia , Traumatismo por Reperfusão/patologiaRESUMO
This study aimed to provide diagnostic clues for patients with elevated serum alpha-fetoprotein (AFP) in the absence of liver tumors and rectify some previously confused concepts about hepatoid carcinoma of the lung through a systematic review on hepatoid adenocarcinoma of the lung (HAL). A thorough search for original articles on HAL published prior to November 2020 was performed using the PubMed, EBSCOhost, Embase, WanFang Data, and China National Knowledge Infrastructure (CNKI) databases. Ninety-four patients from 88 studies met the eligibility criteria. HAL was rare and mainly occurred among male Asian smokers in their 60 s, presenting with cough, hemoptysis, chest pain, dyspnea and/or weight loss, as well as elevated serum AFP with a mass usually in the right upper lung lobe but no liver masses. Hepatoid differentiation regions, acinar or papillary structures in tumor tissues, and positive immunohistochemical expression of AFP, HepPar-1, and CK8/18 were crucial indicators for the diagnosis of HAL. Surgery-based strategies were recommended for stage I-III patients, while stage IV patients were mainly treated with chemotherapy-based strategy. The 1-, 3-, and 5-year overall survival rates were 40%, 35%, and 19%, respectively. The 1-year relapse-free survival rate was 58%. The postoperative monitoring of AFP contributed to the early detection of tumor recurrence, with a positive rate of 71.43%. In conclusion, patients with elevated serum AFP levels without any detectable hepatic lesions should be evaluated for the possibility of HAL.
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BACKGROUND: Acute kidney injury (AKI) after surgery appears to increase the risk of death in patients with liver cancer. In recent years, machine learning algorithms have been shown to offer higher discriminative efficiency than classical statistical analysis. AIM: To develop prediction models for AKI after liver cancer resection using machine learning techniques. METHODS: We screened a total of 2450 patients who had undergone primary hepatocellular carcinoma resection at Changzheng Hospital, Shanghai City, China, from January 1, 2015 to August 31, 2020. The AKI definition used was consistent with the Kidney Disease: Improving Global Outcomes. We included in our analysis preoperative data such as demographic characteristics, laboratory findings, comorbidities, and medication, as well as perioperative data such as duration of surgery. Computerized algorithms used for model development included logistic regression (LR), support vector machine (SVM), random forest (RF), extreme gradient boosting (XGboost), and decision tree (DT). Feature importance was also ranked according to its contribution to model development. RESULTS: AKI events occurred in 296 patients (12.1%) within 7 d after surgery. Among the original models based on machine learning techniques, the RF algorithm had optimal discrimination with an area under the curve value of 0.92, compared to 0.87 for XGBoost, 0.90 for DT, 0.90 for SVM, and 0.85 for LR. The RF algorithm also had the highest concordance-index (0.86) and the lowest Brier score (0.076). The variable that contributed the most in the RF algorithm was age, followed by cholesterol, and surgery time. CONCLUSION: Machine learning algorithms are highly effective in discriminating patients at high risk of developing AKI. The successful application of machine learning models may help guide clinical decisions and help improve the long-term prognosis of patients.
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Angiomiolipoma/diagnóstico , Neoplasias Hepáticas/diagnóstico , Angiomiolipoma/patologia , Biomarcadores/metabolismo , Diagnóstico Diferencial , Erros de Diagnóstico , Humanos , Imuno-Histoquímica , Fígado/diagnóstico por imagem , Neoplasias Hepáticas/patologia , Tomografia Computadorizada por Raios XAssuntos
Carcinoma Hepatocelular/patologia , Carcinoma Neuroendócrino/patologia , Neoplasias Hepáticas/patologia , Recidiva Local de Neoplasia , Neoplasias Complexas Mistas/patologia , Neoplasias Primárias Múltiplas/patologia , Biomarcadores Tumorais/sangue , Carcinoma Hepatocelular/sangue , Carcinoma Hepatocelular/cirurgia , Carcinoma Neuroendócrino/sangue , Carcinoma Neuroendócrino/cirurgia , Humanos , Neoplasias Hepáticas/sangue , Neoplasias Hepáticas/cirurgia , Recidiva Local de Neoplasia/patologia , Neoplasias Complexas Mistas/sangue , Neoplasias Complexas Mistas/cirurgia , Neoplasias Primárias Múltiplas/sangue , Neoplasias Primárias Múltiplas/cirurgia , Prognóstico , Taxa de SobrevidaRESUMO
BACKGROUND: With a novel finding of significantly lower incidence of acute rejection (AR) in patients with hepatocellular carcinoma (HCC) after liver transplantation, compared with those with benign end-stage liver disease (BESLD), in a large national cohort, we analyzed the correlations among the perioperative immuno-inflammation status, postoperative AR, and prognosis in HCC and BESLD patients with same etiology of hepatitis B virus (HBV), who underwent liver transplantation. METHODS: Patients who underwent liver transplantation due to HBV-related HCC or BESLD and experienced AR between September 2008 and April 2017 were analyzed retrospectively and followed up until April 2018. HCC patients with AR were matched with those without AR according to tumor stage and immunosuppressant concentration, at a 1:3 ratio. Preoperative immuno-inflammation status and prognosis of patients in both groups were compared. RESULTS: The overall incidences of AR in patients with HCC and BESLD were 8.60% and 10.61%, respectively. The postoperative 28-day incidence of AR was significantly lower in HCC compared with BESLD patients (3.23% vs 7.08%, p = 0.031). Compared with BESLD patients, the rejection activity index and perioperative CD4/CD8 ratio were significantly lower (p = 0.047 and p < 0.001, respectively), while platelet/lymphocyte ratio was significantly higher in HCC patients (p = 0.041). Later tumor stage in HCC patients was associated with higher systemic immuno-inflammation index, neutrophil/lymphocyte ratio, monocyte/lymphocyte ratio, platelet/lymphocyte ratio, aspartate aminotransferase/lymphocyte ratio, C-reactive protein/albumin ratio and fibrinogen level, and lower CD4/CD8 ratio before transplantation. In HCC patients with AR, the percentage of regulatory T cells (CD4+/CD25+) and the level of IL-10 significantly decreased (p = 0.0023, < 0.0001, respectively), while Th1/Th2 ratio, levels of IFN-γ and IL-2 markedly increased before transplantation (p = 0.0018, 0.0059, 0.0416, respectively). Preoperative monocyte/lymphocyte ratio was an independent risk factor for overall and recurrence-free survival after liver transplantation in HCC patients (p = 0.025, < 0.001, respectively). The 1-, 3-, and 5-year survival rates were 76%, 71% and 53% in the AR group, and 67%, 37% and 25% in the non-AR group (p = 0.042). CONCLUSION: Preoperative tumor-related immunosuppression may persist after liver transplantation in HCC patients, and reduce the incidence of AR. AR after liver transplantation may indicate a better prognosis in HCC patients.
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Carcinoma Hepatocelular , Doença Hepática Terminal/cirurgia , Rejeição de Enxerto , Neoplasias Hepáticas , Transplante de Fígado , Carcinoma Hepatocelular/imunologia , Carcinoma Hepatocelular/patologia , Carcinoma Hepatocelular/cirurgia , China/epidemiologia , Feminino , Rejeição de Enxerto/epidemiologia , Rejeição de Enxerto/etiologia , Humanos , Hospedeiro Imunocomprometido , Incidência , Neoplasias Hepáticas/imunologia , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/cirurgia , Transplante de Fígado/efeitos adversos , Transplante de Fígado/métodos , Masculino , Pessoa de Meia-Idade , Monitorização Imunológica/métodos , Monitorização Imunológica/estatística & dados numéricos , Estadiamento de Neoplasias , Avaliação de Processos e Resultados em Cuidados de Saúde , Prognóstico , Análise de SobrevidaAssuntos
Carcinoma Hepatocelular/mortalidade , Carcinoma Hepatocelular/cirurgia , Neoplasias Hepáticas/mortalidade , Neoplasias Hepáticas/cirurgia , Transplante de Fígado/normas , Guias de Prática Clínica como Assunto , Carcinoma Hepatocelular/parasitologia , China , Feminino , Rejeição de Enxerto , Sobrevivência de Enxerto , Humanos , Neoplasias Hepáticas/patologia , Transplante de Fígado/mortalidade , Masculino , Seleção de Pacientes , Prognóstico , Medição de Risco , Análise de SobrevidaRESUMO
BACKGROUND: Hepatic epithelioid angiomyolipoma (HEAML) is a rare liver disease and is easily misdiagnosed. Enhanced recognition of HEAML is beneficial to the differential diagnosis of rare liver diseases. CASE SUMMARY: We presented two cases of HEAML in Changzheng Hospital, Naval Medical University, and then collected and analyzed all reports about HEAML recorded in PubMed, MEDLINE, China Science Periodical Database, and VIP database from January 2000 to March 2018. A total of 409 cases of HEAML in 97 reports were collected, with a ratio of men to women of 1:4.84 and an age range from 12 years to 80 years (median 44 years). Among the patients with clinical symptoms mentioned, 61.93% (205/331) were asymptomatic, 34.74% (115/331) showed upper or right upper quadrant abdomen discomfort, while a few of them showed abdominal mass, gastrointestinal symptoms, low fever, or weight loss. The misdiagnosis rate of HEAML was as high as 40.34% (165/409) due to its nonspecific imaging findings. Most of the tumors were solitary and round in morphology, with clear boundaries. Ultrasound scan indicated low echo with internal nonuniformity and rich blood supply in most cases. Computer tomography/magnetic resonance imaging enhanced scan showed varied characteristics. The ratio of fast wash-in and fast wash-out, fast wash-in and slow wash-out, and delayed enhancement was roughly 4:5:1. A definite diagnosis of HEAML depended on the pathological findings of the epithelioid cells in lesions and the expression of human melanoma black 45, smooth muscle actin, melanoma antigen, and actin by immunohistochemical staining. HEAML had a relatively low malignant rate of 3.91%. However, surgical resection was the main treatment for HEAML, due to the difficulty diagnosing before operation. CONCLUSION: HEAML is a rare and easily misdiagnosed disease, and it should be diagnosed carefully, taking into account clinical course, imaging, pathological ,and immunohistochemical findings.
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Carcinoma de Células Escamosas/cirurgia , Hepatectomia/efeitos adversos , Neoplasias Hepáticas/cirurgia , Inoculação de Neoplasia , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma de Células Escamosas/diagnóstico por imagem , Carcinoma de Células Escamosas/patologia , Quimioterapia Adjuvante , Desoxicitidina/administração & dosagem , Desoxicitidina/análogos & derivados , Progressão da Doença , Evolução Fatal , Humanos , Neoplasias Hepáticas/diagnóstico por imagem , Neoplasias Hepáticas/patologia , Masculino , Oxaliplatina/administração & dosagem , Resultado do Tratamento , GencitabinaRESUMO
OBJECTIVE: To establish a non-invasive model for the assessment of portal venous pressure (PVP) based on the magnetic resonance (MR) parameters. METHODS: In this prospective study, contrast-enhanced magnetic resonance imaging (MRI) scan was performed in 109 patients indicated for upper abdominal surgeries after their written consents were obtained, and intraoperative PVP measurements were completed in 92 patients. Altogether 17 patients were excluded for not undergoing surgery or unsuccessful catheterization. A linear model was constructed for estimating PVP levels in 56 patients and further validation was conducted in the other 36 patients. RESULTS: The PVP levels were significantly correlated with MR parameters, including splenic volume (SV), splenic venous diameter (SVD), liver/splenic volume ratio, portal venous diameter, hepatic diameter, portal venous cross-sectional area, ascites, varices and arterial portal shunts. A linear model was established as follows: PVP (mmHg) = 2.529 + 1.572 × SVD (mm) + 0.231 × SV/body mass index (× 10(4) cm(5) /kg) + 3.44 × aspartate aminotransferase-to-platelet ratio index. This model showed excellent accuracy in the detection of portal hypertension, with the area under the receiver operating characteristic curve (AUROC) of 0.945 (95% CI 0.867-1.000), with the sensitivity and specificity of 91.7% and 93.7%, respectively. The agreement analysis revealed that the predictive value using this formula closely reflected the patients' actual PVP level. Moreover, the validation confirmed the accuracy of this model for the assessment of portal hypertension [AUROC 0.935 (95% CI 0.856-1.000)]. CONCLUSIONS: The MRI-based formula has great potential for detecting portal hypertension. As a non-invasive measurement, it may be clinically accepted for the replacement of invasive modalities after further refinement.
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Hipertensão Portal/diagnóstico por imagem , Modelos Cardiovasculares , Veia Porta/diagnóstico por imagem , Adulto , Idoso , Meios de Contraste , Feminino , Humanos , Hipertensão Portal/patologia , Hipertensão Portal/fisiopatologia , Imageamento por Ressonância Magnética/métodos , Masculino , Pessoa de Meia-Idade , Variações Dependentes do Observador , Pressão na Veia Porta , Veia Porta/patologia , Veia Porta/fisiopatologia , Valor Preditivo dos Testes , Estudos Prospectivos , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Baço/patologia , Veia Esplênica/diagnóstico por imagem , Veia Esplênica/patologiaRESUMO
BACKGROUND: Several studies have investigated the effect of intraoperative blood loss (IBL) on recurrence of tumors. However, the independent effect of IBL on oncological outcome after liver transplantation (LT) for hepatocellular carcinoma (HCC) is unclear. METHODS: A total of 479 patients who underwent LT for HCC from January 2001 to December 2012 at our institution were enrolled in this retrospective study. Kaplan-Meier and Cox regression methods were used to assess the recurrence rate, as well as its risk factors. Stratified analysis was performed to further examine the effect of IBL on HCC recurrence according to different characteristics of tumors. We also investigated the independent risk factors for excessive IBL using logistic regression analysis. RESULTS: The median follow-up was 28 months (range, 1-131 months). Kaplan-Meier analysis with the log-rank test according to IBL at per liter intervals showed that IBL > 4 L was significantly associated with a higher recurrence rate (P < 0.001). Multivariate analysis identified that IBL > 4 L (P < 0.001; hazard ratio [HR] = 2.32, 95 % confidence interval [CI] = 1.60-3.36) was an independent risk factor for post-LT HCC recurrence, as well as age < 60 years, exceeding Milan criteria, α-fetoprotein levels > 400 ng/mL, and micro- and macrovascular invasion. IBL > 4 L (P < 0.001; HR = 2.45, 95 % CI = 1.64-3.66) was also independently associated with early (within 1 year) recurrence after LT. Furthermore, a significant correlation between IBL > 4 L and vascular invasion (P = 0.019) was found. IBL > 4 L was independently associated with HCC recurrence for patients with vascular invasion, but not for patients without vascular invasion. Finally, we found that the presence of ascites, model for end-stage liver disease score, and operation time were independent risk factors for IBL > 4 L. CONCLUSIONS: Excessive IBL is an independent predictor of HCC recurrence after LT, especially in patients with vascular invasion.
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Perda Sanguínea Cirúrgica/estatística & dados numéricos , Carcinoma Hepatocelular/cirurgia , Neoplasias Hepáticas/cirurgia , Transplante de Fígado/efeitos adversos , Recidiva Local de Neoplasia/etiologia , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Carcinoma Hepatocelular/patologia , Feminino , Humanos , Estimativa de Kaplan-Meier , Neoplasias Hepáticas/patologia , Masculino , Pessoa de Meia-Idade , Invasividade Neoplásica , Modelos de Riscos Proporcionais , Estudos Retrospectivos , Fatores de Risco , alfa-Fetoproteínas/análiseRESUMO
The aim of this study was to validate a criteria-specific long-term survival prediction model (MHCAT) in a large cohort of hepatocellular carcinoma (HCC) patients after liver transplantation (LT) in China. Independent risk factors in MHCAT were retrospectively analysed for HCC patients recorded in the China Liver Transplant Registry. Survival predictions for each patient were calculated using MHCAT scores and the Metroticket formula separately, and the prediction efficacy of MHCAT and Metroticket was compared using the area under ROC curve (c-statistic). A total of 1371 LTs for HCC were analysed in the study, with a median follow-up of 22.2 months (IQR 6.1-72.4 months). The proportions meeting the Milan, UCSF, Fudan and Hangzhou criteria were 34.4%, 39.7%, 44.2% and 51.9%, respectively. The c-statistics for MHCAT predictions of 3- and 5-year survival rates of HCC recipients were 0.712-0.727 and 0.726-0.741, respectively. Among these patients, 1298 LTs for HCC were ultimately selected for the comparison analysis for prediction efficacy. The c-statistic of MHCAT for predictions of 3-year survival with reference to the Milan, UCSF and Fudan criteria was significantly increased compared with that for Metroticket (p < 0.05). In conclusion, MHCAT can effectively predict long-term survival for HCC recipients after LT.
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Carcinoma Hepatocelular/mortalidade , Carcinoma Hepatocelular/cirurgia , Neoplasias Hepáticas/mortalidade , Neoplasias Hepáticas/cirurgia , Transplante de Fígado , Intervalo Livre de Doença , Feminino , Humanos , Fígado/patologia , Masculino , Pessoa de Meia-Idade , Modelos Teóricos , Prognóstico , Curva ROC , Estudos Retrospectivos , Taxa de Sobrevida , Resultado do TratamentoRESUMO
AIM: To establish a model to predict long-term survival of hepatocellular carcinoma (HCC) patients after liver transplantation (MHCAT). METHODS: Two hundred and twenty-three patients with HCC were followed for at least six years to identify independent risk factors for long-term survival after liver transplantation (LT). The criteria for HCC liver transplantation included the Milan, University of California San Francisco, Hangzhou and Shanghai Fudan criteria. The Cox regression model was used to build MHCAT specifying these criteria. A survival analysis was carried out for patients with high or low risk. RESULTS: The one-, three- and five-year cumulative survival of HCC patients after LT was 78.9%, 53.2% and 46.4%, respectively. Of the HCC patients, the proportion meeting the Hangzhou and Fudan criteria was significantly higher than the proportion meeting the Milan criteria (64.6% vs 39.5%, 52.0% vs 39.5%, P < 0.05). Moreover, the proportion meeting the Hangzhou criteria was also significantly higher than the proportion meeting other criteria (P < 0.01). Pre-operative alfa-fetoprotein level, intraoperative blood loss and retransplantation were common significant predictors of long-term survival in HCC patients with reference to the Milan, University of California San Francisco and Fudan criteria, whereas in MHCAT based on the Hangzhou criteria, total bilirubin, intraoperative blood loss and retransplantation were independent predictors. The c-statistic for MHCAT was 0.773-0.824, with no statistical difference among these four criteria. According to the MHCAT scoring system, patients with low risk showed a higher five-year survival than those with high risk (P < 0.001). CONCLUSION: MHCAT can effectively predict long-term survival for HCC patients, but needs to be verified by multi-center retrospective or randomized controlled trials.
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Carcinoma Hepatocelular/cirurgia , Técnicas de Apoio para a Decisão , Neoplasias Hepáticas/cirurgia , Transplante de Fígado , Adulto , Perda Sanguínea Cirúrgica , Carcinoma Hepatocelular/sangue , Carcinoma Hepatocelular/mortalidade , Carcinoma Hepatocelular/patologia , Feminino , Humanos , Estimativa de Kaplan-Meier , Neoplasias Hepáticas/sangue , Neoplasias Hepáticas/mortalidade , Neoplasias Hepáticas/patologia , Transplante de Fígado/efeitos adversos , Transplante de Fígado/mortalidade , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Modelos de Riscos Proporcionais , Sistema de Registros , Reoperação , Medição de Risco , Fatores de Risco , Fatores de Tempo , Resultado do Tratamento , alfa-Fetoproteínas/metabolismoRESUMO
Endarterectomy and bypass surgery to treat renal artery stenosis are increasingly shunned these days due to high risks of complications during and after the surgery. Striving to find a sound alternative solution, we pioneered the construction of a tissue engineered renovascular graft that could immediately restore the normal blood flow to kidneys and sustain renal functions without suffering restenosis after the surgery. A highly porous scaffold was first constructed by electrospinning polycaprolactone, poliglecaprone, gelatin and elastin, giving the vast majority of non-woven fibers in the scaffold a diameter below 1200 nm. To recapitulate the anatomical and functional signatures of renal arteries, a bi-layer vasculature comprising a smooth muscle layer topped by an endothelial layer was built on the scaffold. The vasculature witnessed a sustained proliferation for up to 10 days in vitro and robustly secreted prostacyclin and endothelin-1, evidencing that the vasculature was functionally comparable to native renal arteries. After 30 days as a renovascular graft in mice, the luminal diameter of the graft remained clear without a restenosis and an increased confluence of the endothelial layer was observed. The tensile test confirmed that the renovascular graft was mechanically superior to native renal arteries and retained this advantage within 30 days in vivo. Also, this renovascular graft sustained renal functions as evidenced by normal levels of serum creatinine, urine creatinine and serum urea nitrogen and the lack of edema in the kidney cortex. These results demonstrate that this renovascular graft holds a great therapeutic promise for renal artery stenosis.