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1.
Scand J Immunol ; : e13397, 2024 Jul 30.
Artigo em Inglês | MEDLINE | ID: mdl-39080853

RESUMO

Graft-infiltrating lymphocytes (GILs) play an important role in promoting rejection after organ transplantation. We recently reported that GILs that accumulated up to 3 days post-transplantation did not promote rejection, whereas GILs present 3-5 days post-transplantation promoted rejection in a mouse heart transplantation model. However, the immunological behaviour of GILs in murine skin transplantation remains unclear. GILs were isolated on days 3, 5 or 7 post-transplantation from C57BL/6 (B6) allogeneic skin grafts transplanted onto BALB/c mice. BALB/c Rag2-/- γc-/- mice (BRGs) underwent B6 skin graft transplantation 10 weeks after adoptive transfer of day 3, 5, or 7 GILs. BRGs reconstituted with day 5 or 7 GILs completely rejected B6 grafts. However, when B6 grafts harvested from recipient BALB/c mice on day 5 or 7 were re-transplanted into BRGs, half of the re-transplanted day 5 grafts established long-term survival, although all re-transplanted day 7 grafts were rejected. BRGs reconstituted with day 3 GILs did not reject B6 grafts. Consistently, re-transplantation using day 3 skin grafts resulted in no rejection. Administration of anti-CD25 antibodies did not prevent the phenomenon observed for the day 3 skin grafts. Furthermore, BRGs reconstituted with splenocytes from naïve BALB/c mice immediately rejected the naïve B6 skin grafts and the re-transplanted day 3 B6 grafts, suggesting that day 3 GILs were unable to induce allograft rejection during the rejection process. In conclusion, the immunological role of GILs depends on the time since transplantation. Day 3 GILs had neither protective nor alloreactive effects in the skin transplant model.

2.
Hepatol Res ; 53(1): 18-25, 2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36002995

RESUMO

AIM: Human immunodeficiency virus (HIV)/hepatitis C virus (HCV) co-infection from blood products for hemophilia has been a social problem in Japan, and liver transplantation (LT) for these patients has been a challenging procedure. However, with the advent of the direct-acting antiviral agent for HCV and change in the policy for prioritization of deceased donor LT, the results of LT for patients co-infected with HCV/HIV may have improved. METHODS: This study was conducted to provide updated results of our nationwide survey of LT for patients co-infected with HCV/HIV, from January 1997 to December 2019. We collected data on 17 patients with HIV/HCV co-infection who underwent either deceased donor LT (n = 5) or living donor LT (n = 12). RESULTS: All the patients were men with hemophilia, and the median age was 41 (range, 23-61) years. The median CD4 count before LT was 258 (range, 63-751). Most patients had poor liver function before surgery with Child-Pugh grade C and a Model for End-stage Liver Disease score of 20 (range, 11-48). The right lobe was used for most grafts for living donor liver transplantation (n = 10). Overall survival was significantly better with a sustained viral response (SVR) than without an SVR, and a univariate analysis indicated that SVR after direct-acting antiviral or interferon/ribavirin showed the highest hazard ratio for patient survival after LT. A multivariate analysis was not possible because of the limited number of cases. CONCLUSION: SVR for HCV showed the highest impact on the outcome of LT for patients with hemophilia co-infected with HIV/HCV. SVR for HCV should be achieved before or after LT for patients with hemophilia co-infected with HIV/HCV for a better outcome.

3.
Nihon Shokakibyo Gakkai Zasshi ; 119(12): 1096-1102, 2022.
Artigo em Japonês | MEDLINE | ID: mdl-36504102

RESUMO

A 15-year-old female patient was diagnosed with a fulminant-type Wilson's disease. She had severe illness with a Model for End-Stage Liver Disease score of 25 and new Wilson Index score of 11. She underwent plasma exchanges, hemodiafiltration, and administration of fresh frozen plasma on consecutive days. Finally, she had recovered from severe illness and was discharged from the hospital. After 18 months of waiting time, she underwent deceased liver transplantation and returned to normal daily life. In Japan, the critical shortage of donated organs requires a long waiting time. Previous studies demonstrated that artificial liver support systems, including plasma exchange and hemodiafiltration, could be useful for a fulminant-type Wilson's disease. For such a disease, multidisciplinary bridging treatments are crucial for a successful liver transplantation.


Assuntos
Doença Hepática Terminal , Degeneração Hepatolenticular , Transplante de Fígado , Feminino , Humanos , Adolescente , Estado Terminal , Degeneração Hepatolenticular/cirurgia , Doadores Vivos , Índice de Gravidade de Doença
4.
Hepatol Res ; 51(2): 216-226, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-32949102

RESUMO

AIM: Acute liver failure (ALF) patients with coma need to be revived not only for spontaneous recovery but also as a bridge to liver transplantation. We developed a new high-volume plasma purification system using an on-line continuous hemodiafiltration (CHDF) system, and evaluated its safety and efficacy in a multicenter study. METHODS: A single arm interventional study using the new apparatus was undertaken in the six major liver centers in Japan. The primary end-point was the proportion of patients who regained consciousness within 10 days, which was compared with a historical control (47%). Nine ALF patients were enrolled and treated with the new machine. One patient was excluded because of the need for artificial respiration support according to the established protocol. RESULTS: Seven of eight (87.5%) patients regained consciousness during the on-line CHDF session, with five of those seven waking within 4 days. After waking, one patient spontaneously recovered, three received liver transplantation, two died of liver failure, and one died of another disease. The plasma ammonia levels significantly decreased after the start of on-line CHDF from 182.5 ± 64.8 µg/dL (mean ± SD) on day 0 to 87.0 ± 38.9 µg/dL on the last day of the session (P < 0.001). Similarly, the plasma glutamine level also significantly decreased from 2069 ± 1234 µmol/L to 628 ± 193 µmol/L. Although seven severe adverse events occurred during on-line-CHDF, no causal relationship with liver support was recognized. CONCLUSIONS: The newly developed on-line CHDF system showed high efficacy for regain of consciousness and excellent therapeutic safety for managing ALF.

5.
Hepatol Res ; 51(8): 909-914, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34132462

RESUMO

HIV/HCV co-infection from blood products for hemophilia has been a social problem in Japan. Liver transplantation (LT) is an important treatment option for hepatic failure and cirrhosis of the liver in co-infected patients, and appropriate indications for LT, especially organ form deceased donors, are required by society. The aim is to propose priority status for the waiting list for deceased donor (DD) LT in HIV/HCV co-infected patients in Japan based on medical and scientific considerations. Since 2009, we have been working on the subject in research projects under grants-in-aid for health and labour sciences research on AIDS measures provided by the Ministry of Health, Labour and Welfare (the Kanematsu project and Eguchi project). Our research showed that hepatic fibrosis is advanced in HIV/HCV co-infected Japanese patients, especially those with hemophilia who became infected from blood products at a faster rate than HCV mono-infected patients. In addition, those patients who developed portal hypertension had a poor prognosis at a young age. The results of our research contributed to increasing the priority score of those patients on the deceased donor liver transplantation (DDLT) waiting list in 2013 and to establishing a scoring system for DDLT corresponding to the Model for End-stage Liver disease (MELD) score in 2019. This paper introduces changes in priority and the current state of priority of the DDLT waiting list for HIV/HCV co-infected patients in Japan.

6.
Hepatol Res ; 50(6): 715-725, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32202371

RESUMO

This study aimed to determine the optimal psoas muscle mass index (PMI) cut-off values for diagnosis of skeletal muscle mass loss. METHODS: We evaluated PMI in two groups of normal controls: a medical check-up group and a liver donation candidate group. We analyzed two novel PMI cut-off values, one based on the mean - two standard deviations (2SD) and one based on the lower 5%. Skeletal muscle mass index (SMI) evaluations using computed tomography (sliceOmatic; TomoVision) and bioelectrical impedance analysis and PMI evaluation were undertaken simultaneously. We analyzed the correlation between our PMI cut-off values and the Japan Society of Hepatology-defined SMI cut-off values. The prevalence of skeletal muscle mass loss in patients with liver disease was assessed using the novel PMI cut-off values. RESULTS: In 504 normal controls aged ≤50 years, the PMI cut-off values based on mean -2SD and the lower 5% were set at 3.30 cm2 /m2 for men and 1.69 cm2 /m2 for women and 3.74 cm2 /m2 for men and 2.29 cm2 /m2 for women, respectively. The PMI cut-off values based on the lower 5% alone showed that skeletal muscle mass loss increased with age. Furthermore, they correlated well with Japan Society of Hepatology-defined SMI (sliceOmatic) cut-off values and showed a significantly higher prevalence of skeletal muscle mass loss in patients with liver cirrhosis than those without liver cirrhosis. CONCLUSIONS: We propose the following PMI cut-off values: 3.74 cm2 /m2 for male individuals and 2.29 cm2 /m2 for female individuals. These cut-off values can facilitate accurate diagnosis and management of sarcopenia in patients with chronic liver disease.

7.
Hepatol Res ; 50(12): 1365-1374, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-32860719

RESUMO

AIM: Direct-acting antivirals for hepatitis C virus have reduced the decompensation risk. Immunosuppressants for transplantation raise the risk of occurrence of de novo malignancies. We assessed the probabilities of and risk factors for de novo hepatocellular carcinoma (HCC) development post-living donor liver transplantation (LDLT). METHODS: We retrospectively evaluated the data of developed HCC in a graft including metastatic HCC post-LDLT from 2779 adult cases collected from nine major liver transplantation centers in Japan. RESULTS: Of 2779 LDLT adult recipients, 34 (1.2%) developed HCCs in their grafts. Of 34, five HCCs appeared to be de novo because of a longer period to tumor detection (9.7 [6.4-15.4] years) and no HCC within the native liver of the two recipients. The donor origin of three of five de novo HCCs was confirmed using microsatellite analysis in resected tissue. Primary disease of all five was hepatitis C virus-related cirrhosis, of which two were treated with direct-acting antivirals. Four of five developed HCC de novo in the hepatitis B core antibody-positive grafts. De novo HCCs had favorable prognosis; four of five were cured with complete remission. However, recurrent HCC (n = 29) in the graft had a poorer outcome, especially in patients with neutrophil to lymphocyte ratio scores above 4 (median survival time, 262 [19-463] days). CONCLUSION: Analysis of the database from major liver transplantation institutes in Japan revealed that de novo HCCs determined by microsatellite analysis were rarely detected, but the majority were successfully treated. LDLT recipients with higher risks of de novo HCC, including those with hepatitis B core antibody-positive grafts, should be carefully followed by surveillance of the liver graft.

8.
Clin Transplant ; 33(6): e13584, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31074181

RESUMO

AIMS: This study examined the long-term quality of life (QOL) of living liver donors (LLDs) in Japan using both generic and LLD-specific instruments. METHODS: The sample comprised 374 LLDs from five university hospitals in Japan who underwent surgery more than a year previously. QOL was evaluated using the Short Form-36 health survey (SF-36) and LLD-QOL scale. RESULTS: SF-36 results indicated that the overall long-term QOL of LLDs was significantly better than the Japanese standard. When comparing by donor factors, LLDs whose recipients were children scored higher for "satisfaction" than those whose recipients were adults on the LLD-QOL scale. LLDs with complications had lower QOL for "scars" and "burden" on the LLD-QOL scale but no differences in SF-36 scores. LLDs with longer hospital stay had lower physical QOL on SF-36 and lower QOL for "scars" and "after-effects" on the LLD-QOL scale. LLDs whose recipients have died showed lower mental QOL on SF-36 and lower "satisfaction" and greater "lack of understanding of donor health" on the LLD-QOL scale. CONCLUSIONS: Our multicenter study clarified the long-term QOL of LLDs and suggested that donors' QOL was related to the donors' and recipients' ages, donor's complications and hospital stay length, and recipient's prognosis.


Assuntos
Nível de Saúde , Hepatectomia/reabilitação , Transplante de Fígado/psicologia , Doadores Vivos/psicologia , Qualidade de Vida , Coleta de Tecidos e Órgãos/psicologia , Adulto , Idoso , Feminino , Seguimentos , Hepatectomia/psicologia , Humanos , Japão , Masculino , Pessoa de Meia-Idade , Prognóstico , Fatores de Risco , Inquéritos e Questionários , Adulto Jovem
9.
Transpl Int ; 32(4): 356-368, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30556935

RESUMO

Expansion of the liver transplantation indication criteria for patients with hepatocellular carcinoma (HCC) has long been debated. Here we propose new, expanded living-donor liver transplantation (LDLT) criteria for HCC patients based on a retrospective data analysis of the Japanese nationwide survey. A total of 965 HCC patients undergoing LDLT were included, 301 (31%) of whom were beyond the Milan criteria. Here, we applied the Greenwood formula to investigate new criteria enabling the maximal enrollment of candidates while securing a 5-year recurrence rate (95% upper confidence limit) below 10% by examining various combinations of tumor numbers and serum alpha-fetoprotein values, and maintaining the maximal nodule diameter at 5 cm. Finally, new expanded criteria for LDLT candidates with HCC, the 5-5-500 rule (nodule size ≤5 cm in diameter, nodule number ≤5, and alfa-fetoprotein value ≤500 ng/ml), were established as a new regulation with a 95% confidence interval of a 5-year recurrence rate of 7.3% (5.2-9.3) and a 19% increase in the number of eligible patients. In addition, the 5-5-500 rule could identify patients at high risk of recurrence, among those within and beyond the Milan criteria. In conclusion, the new criteria - the 5-5-500 rule - might provide rational expansion for LDLT candidates with HCC.


Assuntos
Carcinoma Hepatocelular/cirurgia , Neoplasias Hepáticas/cirurgia , Transplante de Fígado/métodos , Doadores Vivos , Adolescente , Adulto , Idoso , Carcinoma Hepatocelular/sangue , Carcinoma Hepatocelular/mortalidade , Criança , Feminino , Humanos , Neoplasias Hepáticas/sangue , Neoplasias Hepáticas/mortalidade , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia , Estudos Retrospectivos , Adulto Jovem , alfa-Fetoproteínas/análise
11.
Biol Pharm Bull ; 41(7): 1112-1118, 2018 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-29760306

RESUMO

Therapeutic drug monitoring for voriconazole, an antifungal agent, is essential for maximizing efficacy and preventing toxicity. The aim of this study was to elucidate the optimal maintenance dose of voriconazole in patients with severe liver cirrhosis (Child-Pugh class C) by reviewing the plasma trough concentrations obtained by therapeutic drug monitoring and daily doses of voriconazole. We retrospectively evaluated 6 patients with Child-Pugh class C cirrhosis who received oral voriconazole treatment and were liver transplant recipients or were awaiting liver transplantation. We compared their voriconazole trough concentrations and daily maintenance doses to those of patients who did not have liver cirrhosis (n=56). We found that plasma voriconazole trough concentrations in all patients with Child-Pugh class C were almost within therapeutic range, and the median plasma trough concentration at steady state was not significantly different from that of patients who did not have liver cirrhosis. In addition, the median daily maintenance dose of voriconazole was significantly lower (2.13 mg/kg/d) than that of the control patients (6.27 mg/kg/d), suggesting that trough voriconazole concentrations are elevated in Child-Pugh class C patients. Thus, we conclude that oral voriconazole maintenance doses in patients with Child-Pugh class C should be reduced to approximately one-third that of patients with normal liver function, with the follow-up dose adjusted by therapeutic drug monitoring.


Assuntos
Antifúngicos/administração & dosagem , Monitoramento de Medicamentos , Cirrose Hepática/fisiopatologia , Micoses/tratamento farmacológico , Voriconazol/administração & dosagem , Administração Oral , Antifúngicos/farmacocinética , Feminino , Humanos , Fígado/fisiopatologia , Cirrose Hepática/sangue , Cirrose Hepática/complicações , Masculino , Pessoa de Meia-Idade , Micoses/sangue , Micoses/complicações , Estudos Retrospectivos , Índice de Gravidade de Doença , Voriconazol/farmacocinética
12.
Surg Today ; 48(12): 1081-1088, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-29980846

RESUMO

BACKGROUND AND PURPOSE: We reported previously that hydrogen gas (H2) reduced hepatic ischemia and reperfusion injury (IRI) after prolonged cold storage (CS) of livers retrieved from heart-beating donors. The present study was designed to assess whether H2 reduced hepatic IRI during donation of a cardiac death (DCD) graft with subsequent CS. METHODS: Rat livers were harvested after 30-min cardiac arrest and stored for 4 h in University of Wisconsin solution. The graft was reperfused with oxygenated buffer, with or without H2 (H2 or NT groups, respectively), at 37° for 90 min on isolated perfused rat liver apparatus. RESULTS: In the NT group, liver enzyme leakage, apoptosis, necrosis, energy depletion, redox status, impaired microcirculation, and bile production were indicative of severe IRI, whereas in the H2 group these impairments were significantly suppressed. The phosphorylation of cytoplasmic MKK4 and JNK were enhanced in the NT group and suppressed in the H2 group. NFkB-p65 and c-Fos in the nucleus were unexpectedly unchanged by IRI regardless of H2 treatment, indicating the absence of inflammation in this model. CONCLUSION: H2 was observed to ameliorate IRI in the DCD liver by maintaining microcirculation, mitochondrial functions, and redox status, as well as suppressing the cytoplasmic MKK4-JNK-mediated cellular death pathway.


Assuntos
Sobrevivência de Enxerto/efeitos dos fármacos , Hidrogênio/administração & dosagem , Transplante de Fígado , Fígado/metabolismo , Fígado/patologia , Traumatismo por Reperfusão/prevenção & controle , Animais , Morte Celular/genética , Temperatura Baixa/efeitos adversos , Citoplasma/metabolismo , Morte , Gases , Parada Cardíaca , Hidrogênio/farmacologia , Técnicas In Vitro , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Fígado/irrigação sanguínea , Fígado/enzimologia , Masculino , Microcirculação , Mitocôndrias Hepáticas/metabolismo , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Preservação de Órgãos/efeitos adversos , Preservação de Órgãos/métodos , Oxirredução , Fosforilação/efeitos dos fármacos , Ratos Sprague-Dawley , Reperfusão/métodos , Doadores de Tecidos , Isquemia Quente
13.
Nihon Shokakibyo Gakkai Zasshi ; 115(4): 385-393, 2018.
Artigo em Japonês | MEDLINE | ID: mdl-29643291

RESUMO

When injected, indocyanine green (ICG) immediately combines with lipoproteins to fluoresce. Here, we studied whether ICG fluorescence is effective for endoscopic marking in gastric cancer surgery using a photodynamic eye (PDE) camera and fluorescent endoscope. An ICG solution was endoscopically injected into the submucosal layer of the gastric tumor 3 days before surgery. We observed the lesions using both a PDE camera and a fluorescent endoscope during laparotomy and laparoscopy, respectively;we also observed the fluorescent luminance and fluorescent size of the resected lesions. We could intraoperatively detect the size of the resected lesions in eight patients with early gastric cancer and six patients with advanced gastric cancer. We believe that the use of ICG fluorescence in endoscopic marking requires additional information, such as the volume of the ICG solution and the timing of the ICG injection.


Assuntos
Verde de Indocianina , Neoplasias Gástricas/cirurgia , Carbono , Corantes , Estudos de Viabilidade , Humanos
14.
Hepatology ; 64(2): 632-43, 2016 08.
Artigo em Inglês | MEDLINE | ID: mdl-26773713

RESUMO

UNLABELLED: Potent immunosuppressive drugs have significantly improved early patient survival after liver transplantation (LT). However, long-term results remain unsatisfactory because of adverse events that are largely associated with lifelong immunosuppression. To solve this problem, different strategies have been undertaken to induce operational tolerance, for example, maintenance of normal graft function and histology without immunosuppressive therapy, but have achieved limited success. In this pilot study, we aimed to induce tolerance using a novel regulatory T-cell-based cell therapy in living donor LT. Adoptive transfer of an ex vivo-generated regulatory T-cell-enriched cell product was conducted in 10 consecutive adult patients early post-LT. Cells were generated using a 2-week coculture of recipient lymphocytes with irradiated donor cells in the presence of anti-CD80/86 monoclonal antibodies. Immunosuppressive agents were tapered from 6 months, reduced every 3 months, and completely discontinued by 18 months. After the culture, the generated cells displayed cell-number-dependent donor-specific inhibition in the mixed lymphocyte reaction. Infusion of these cells caused no significant adverse events. Currently, all patients are well with normal graft function and histology. Seven patients have completed successful weaning and cessation of immunosuppressive agents. At present, they have been drug free for 16-33 months; 4 patients have been drug free for more than 24 months. The other 3 recipients with autoimmune liver diseases developed mild rejection during weaning and then resumed conventional low-dose immunotherapy. CONCLUSIONS: A cell therapy using an ex vivo-generated regulatory T-cell-enriched cell product is safe and effective for drug minimization and operational tolerance induction in living donor liver recipients with nonimmunological liver diseases. (Hepatology 2016;64:632-643).


Assuntos
Terapia Baseada em Transplante de Células e Tecidos , Transplante de Fígado , Linfócitos T Reguladores , Tolerância ao Transplante , Adulto , Feminino , Humanos , Doadores Vivos , Masculino , Pessoa de Meia-Idade , Projetos Piloto
15.
World J Surg Oncol ; 15(1): 156, 2017 Aug 22.
Artigo em Inglês | MEDLINE | ID: mdl-28830473

RESUMO

BACKGROUND: Because hepatectomy is not recommended in patients with stage B hepatocellular carcinoma (HCC) of the Barcelona Clinic Liver Cancer (BCLC) staging, we evaluated the survival outcomes of hepatectomy for stage B in the BCLC system. METHODS: Data were collected from 297 consecutive adult stage B patients who underwent curative hepatectomy for HCC between 1996 and 2014 in Hokkaido University Hospital. Overall survival (OS), disease-free survival (DFS), and risk factors were analyzed using the Kaplan-Meier method. Independent prognostic factors were evaluated using a Cox proportional hazards regression model. AP-factor (alpha-fetoprotein [AFP] × protein induced by vitamin K absence or antagonism factor II [PIVKA-II]) was categorized according to the serum concentrations of AFP and PIVKA-II: AP1 (AFP < 200 ng/ml and PIVKA-II < 100 mAU/ml), AP2 (AFP × PIVKA-II < 105), and AP3 (AFP × PIVKA-II ≥ 105). RESULTS: There were 130 deaths among our 297 stage B patients (43.8%). The causes of death in these cases were HCC recurrence (n = 106; 81.5%), liver failure (n = 7; 5.4%), and other causes (n = 17; 16.1%). The operative mortality rate was 0.34% (1/297). The 5-year OS and DFS rates for the stage B cases were 54.3 and 21.9%, respectively. By multivariate analysis, tumor number and AP-factor were risk factors for both survival and recurrence that were tumor related and could be evaluated preoperatively. The study patients with stage B HCC were classified into three groups by tumor number (B1, 1; B23, 2 or 3; B4over: ≥4) and into three groups stratified by AP-factor (AP1, AP2, and AP3). The 5-year OS rates of B1, B23, and B4over were 63.6, 52.3, and 29.0%. The 5-year OS rates of AP1, AP2, and AP3 were 67.6, 65.2, and 39.1%. Stratified by the 5-year OS rate, stage B HCC patients were classified into three subgroups (A-C).The 5-year OS rates of groups A (B1 or B23 and AP-1 or AP-2), B (B1 or B23 and AP-3, or B4over and AP-1 or AP-2), and C (B4over and AP-3) were 69.5, 43.7, and 21.3%. CONCLUSION: Stage B HCC patients with a tumor number ≤ 3 and/or AP-factor < 1 × 105 show acceptable 5-year OS rates and could be treated by hepatectomy.


Assuntos
Carcinoma Hepatocelular/cirurgia , Hepatectomia , Neoplasias Hepáticas/cirurgia , Recidiva Local de Neoplasia/mortalidade , Seleção de Pacientes , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/sangue , Carcinoma Hepatocelular/classificação , Carcinoma Hepatocelular/mortalidade , Carcinoma Hepatocelular/patologia , Intervalo Livre de Doença , Feminino , Seguimentos , Humanos , Estimativa de Kaplan-Meier , Neoplasias Hepáticas/classificação , Neoplasias Hepáticas/mortalidade , Neoplasias Hepáticas/patologia , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Recidiva Local de Neoplasia/sangue , Recidiva Local de Neoplasia/patologia , Estadiamento de Neoplasias , Prognóstico , Modelos de Riscos Proporcionais , Precursores de Proteínas/sangue , Protrombina , Fatores de Risco , Taxa de Sobrevida , Resultado do Tratamento , Adulto Jovem , alfa-Fetoproteínas/análise
16.
Artif Organs ; 40(12): 1128-1136, 2016 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-27140066

RESUMO

Hydrogen gas reduces ischemia and reperfusion injury (IRI) in the liver and other organs. However, the precise mechanism remains elusive. We investigated whether hydrogen gas ameliorated hepatic I/R injury after cold preservation. Rat liver was subjected to 48-h cold storage in University of Wisconsin solution. The graft was reperfused with oxygenated buffer with or without hydrogen at 37° for 90 min on an isolated perfusion apparatus, comprising the H2 (+) and H2 (-) groups, respectively. In the control group (CT), grafts were reperfused immediately without preservation. Graft function, injury, and circulatory status were assessed throughout the perfusion. Tissue samples at the end of perfusion were collected to determine histopathology, oxidative stress, and apoptosis. In the H2 (-) group, IRI was indicated by a higher aspartate aminotransferase (AST), alanine aminotransferase (ALT) leakage, portal resistance, 8-hydroxy-2-deoxyguanosine-positive cell rate, apoptotic index, and endothelial endothelin-1 expression, together with reduced bile production, oxygen consumption, and GSH/GSSG ratio (vs. CT). In the H2 (+) group, these harmful changes were significantly suppressed [vs. H2 (-)]. Hydrogen gas reduced hepatic reperfusion injury after prolonged cold preservation via the maintenance of portal flow, by protecting mitochondrial function during the early phase of reperfusion, and via the suppression of oxidative stress and inflammatory cascades thereafter.


Assuntos
Hidrogênio/farmacologia , Fígado/fisiologia , Preservação de Órgãos/métodos , Perfusão/métodos , Substâncias Protetoras/farmacologia , Traumatismo por Reperfusão/prevenção & controle , Adenosina/farmacologia , Alopurinol/farmacologia , Animais , Apoptose/efeitos dos fármacos , Temperatura Baixa , Desenho de Equipamento , Glutationa/farmacologia , Insulina/farmacologia , Fígado/efeitos dos fármacos , Fígado/patologia , Testes de Função Hepática , Masculino , Preservação de Órgãos/instrumentação , Soluções para Preservação de Órgãos/farmacologia , Estresse Oxidativo , Consumo de Oxigênio , Perfusão/instrumentação , Rafinose/farmacologia , Ratos , Ratos Sprague-Dawley
17.
Hepatol Res ; 45(10): E21-31, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-25382703

RESUMO

AIM: To evaluate the oncological implications of multiplication of α-fetoprotein (AFP) and protein induced by vitamin K absence or antagonists-II (PIVKA-II) in patients with hepatocellular carcinoma (HCC). METHODS: Data were prospectively collected from 516 consecutive patients who underwent a curative primary hepatectomy for HCC between 1998 and 2010. The AP-factor (AFP × PIVKA-II) was evaluated in relation to 2-year survival outcomes by receiver-operator curve analysis to determine the cut-off values. Patient survival, recurrence-free survival and risk factors were analyzed in accordance with the preoperative AP-factor. RESULTS: The AP-factor was categorized into three groups depending on the serum concentrations of AFP and PIVKA-II as follows: AP1 (n = 206; AFP < 200 ng/mL and PIVKA-II < 100 mAU/mL), AP2 (n = 152; AFP × PIVKA-II < 10(5) ) and AP3 (n = 158; AFP × PIVKA-II ≥ 10(5) ). The AP-factor was found to be significantly related to pathological factors such as differentiation, portal vein invasion, hepatic vein invasion and intrahepatic metastasis. Multivariate analysis was performed to identify the risk factors for survival and recurrence. Albumin, AP-factor and pathological factors including portal vein invasion, hepatic vein invasion and intrahepatic metastasis are independent risk factors for survival. Tumor number, AP-factor, and a non-cancerous liver were determinants of recurrence. CONCLUSION: The AP-factor is closely related to differentiation and microscopic vascular invasion, and was selected by multivariate analysis as an independent factor for survival and recurrence, in HCC. Patients hopeful of obtaining good outcomes after a hepatectomy could be selected by the AP-factor evaluation.

18.
Surg Today ; 45(6): 663-71, 2015 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-24894564

RESUMO

In living-donor liver transplantation with a left lobe graft, which can reduce the burden on the donor compared to right lobe graft, the main problem is small-for-size (SFS) syndrome. SFS syndrome is a multifactorial disease that includes aspects related to the graft size, graft quality, recipient factors and even technical issues. The main pathophysiology of SFS syndrome is the sinusoidal microcirculatory disturbance induced by shear stress, which is caused by excessive portal inflow into the smaller graft. The donor age, the presence of steatosis of the graft and a poor recipient status are all risk factors for SFS syndrome. To resolve SFS syndrome, portal inflow modulation, splenectomy, splenic artery modulation and outflow modulation have been developed. It is important to establish strict criteria for managing SFS syndrome. Using pharmacological interventions and/or therapeutic approaches that promote liver regeneration could increase the adequate outcomes in SFS liver transplantation. Left lobe liver transplantation could be adopted in Western countries to help resolve the organ shortage.


Assuntos
Transplante de Fígado/efeitos adversos , Transplante de Fígado/métodos , Fígado/anatomia & histologia , Fígado/cirurgia , Doadores Vivos , Rejeição de Enxerto/prevenção & controle , Sobrevivência de Enxerto , Humanos , Circulação Hepática , Regeneração Hepática/fisiologia , Tamanho do Órgão , Veia Porta/cirurgia , Fatores de Risco , Artéria Esplênica/cirurgia , Síndrome , Resultado do Tratamento
19.
Surg Today ; 45(7): 892-903, 2015 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-25362520

RESUMO

BACKGROUND AND PURPOSE: Hydrogen sulfide (H2S) ameliorates hepatic ischemia and reperfusion injury (IRI), but the precise mechanism remains elusive. We investigated whether sodium hydrogen sulfide (NaHS), a soluble derivative of H2S, would ameliorate hepatic IRI, and if so, via what mechanism. METHODS: Mice were subjected to partial warm ischemia for 75 min followed by reperfusion. Either NaHS or saline was administered intravenously 10 min before reperfusion. The liver and serum were collected 3, 6, and 24 h after reperfusion. RESULTS: In the NaHS(-) group, severe IRI was apparent by the ALT leakage, tissue injury score, apoptosis, lipid peroxidation, and inflammation (higher plasma TNF-α, IL-6, IL-1ß, IFN-γ, IL-23, IL-17, and CD40L), whereas IRI was significantly ameliorated in the NaHS(+) group. These effects could be explained by the augmented nuclear translocation of Nrf2, and the resulting up-regulation of HO-1 and thioredoxin-1. Phosphorylation of the PDK-1/Akt/mTOR/p70S6k axis, which is known to mediate pro-survival and anti-apoptotic signals, was significantly augmented in the NaHS(+) group, with a higher rate of PCNA-positive cells thereafter. CONCLUSION: NaHS ameliorated hepatic IRI by direct and indirect anti-oxidant activities by augmenting pro-survival, anti-apoptotic, and anti-inflammatory signals via mechanisms involving Nrf-2, and by accelerating hepatic regeneration via mechanisms involving Akt-p70S6k.


Assuntos
Citocinas/metabolismo , Fígado/irrigação sanguínea , Substâncias Protetoras/uso terapêutico , Traumatismo por Reperfusão/prevenção & controle , Reperfusão/efeitos adversos , Sulfetos/uso terapêutico , Isquemia Quente/efeitos adversos , Animais , Apoptose/efeitos dos fármacos , Biomarcadores/metabolismo , Western Blotting , Imuno-Histoquímica , Fígado/efeitos dos fármacos , Fígado/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Estresse Oxidativo/efeitos dos fármacos , Substâncias Protetoras/farmacologia , Traumatismo por Reperfusão/etiologia , Traumatismo por Reperfusão/metabolismo , Sulfetos/farmacologia
20.
Transplant Proc ; 56(8): 1890-1895, 2024 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-39217028

RESUMO

To resolve the critical donor shortage worldwide, enlarging the potential donor pool to include expanded criteria donors is necessary. Despite numerous attempts to establish new preservation solutions, no dramatic innovation has occurred since University of Wisconsin (UW) solution displaced Euro Collins' solution; UW solution remains the global gold standard. We previously developed a heavy water (D2O)-containing organ storage solution, Dsol, which is effective for livers subjected to extended cold storage (CS), and reported its effectiveness. Dsol is a modified UW solution; however, the substances or conditions that exhibit a synergistic or additive effect with D2O are unclear. Here we made UWD solution by removing hydroxyethyl starch (HES) from and adding 30%-D2O to UW solution, and compared the effects of these solutions. After 48 hours of CS, the livers were reperfused at 37 °C on an isolated perfused rat liver apparatus, and their perfusion kinetics, functions, and injuries were compared. In the UW group, portal vein resistance significantly increased and the oxygen consumption rate and bile production decreased; in contrast, these changes were suppressed in the UWD group. Organ expansion and liver damage progressed in both groups. These results confirmed that the removal of HES from and addition of D2O to the UW solution reduced CS-induced cellular function impairments and microcirculatory disorders. However, to reduce injury during reperfusion after CS, it is necessary to provide conditions that inhibit injury progression after reperfusion.


Assuntos
Adenosina , Alopurinol , Fígado , Soluções para Preservação de Órgãos , Preservação de Órgãos , Rafinose , Animais , Soluções para Preservação de Órgãos/farmacologia , Fígado/efeitos dos fármacos , Ratos , Preservação de Órgãos/métodos , Rafinose/farmacologia , Alopurinol/farmacologia , Adenosina/farmacologia , Masculino , Insulina , Glutationa/farmacologia , Ratos Sprague-Dawley , Óxido de Deutério/farmacologia , Transplante de Fígado
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