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1.
Cancers (Basel) ; 13(16)2021 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-34439111

RESUMO

The aim of this study was to investigate the early tumor response and safety of atezolizumab plus bevacizumab for patients with unresectable hepatocellular carcinoma in real-world practice. Forty patients with Child-Pugh class A liver function and eastern cooperative oncology group performance status 0 or 1 were enrolled. The objective response rate (ORR) at six weeks after the start of treatment, changes in α-fetoprotein (AFP) and des-γ-carboxyprothrombin, incidence of adverse events (AEs), and changes in albumin-bilirubin (ALBI) score and serum ammonia level, were evaluated. Among 40 patients, 24 had histories of prior molecular targeted agents (MTAs). The ORR was 22.5% based on mRECIST. Multivariate analysis showed that an AFP ratio <1.0 at three weeks (odds ratio 39.2, 95% confidence interval CI 2.37-649.0, p = 0.0103) was the only significant factor for predicting early response. There was no significant difference in the frequency of AEs between patients receiving first-line treatments and others. Fatigue, proteinuria, and ascites were more frequent in patients who experienced prior treatment. No decrease in ALBI score or increase in serum ammonia level was observed. Our study demonstrated that AFP may be useful in assessing early response and that this treatment is safe, including in patients with prior MTA treatments.

2.
BMC Gastroenterol ; 21(1): 306, 2021 Jul 31.
Artigo em Inglês | MEDLINE | ID: mdl-34332532

RESUMO

BACKGROUND: We previously reported on the trends in the etiologies of hepatocellular carcinoma (HCC) diagnosed in patients between 1995 and 2009. The aims of our updated study were to evaluate the incidence, nonhepatitis B and nonhepatitis C viral (NBNC) etiologies, and clinical characteristics of HCCs occurring in patients between 1992 and 2018. METHODS: The study enrolled 2171 consecutive patients with HCC between 1992 and 2018. Their medical records were reviewed. The patients were divided into two groups, patients with early diagnoses from 1992 to 2009 and those with late diagnoses from 2010 to 2018. RESULTS: NBNC-HCC occurred in 514 patients (23.6%). The percentage of patients with HCC who had NBNC-HCC increased from 26.5% in 2009 to 46.3% in 2018. Patients with NBNC-HCC were older (median ages from 67 to 73 years). Type 2 diabetes mellitus (48.5-60.3%: P = 0.008), hypertension (48.5-57.4%: P = 0.047), and hyperlipidemia (39.2-53.8%: P = 0.001) increased significantly in recent years. The median FIB-4 index decreased (4.37-3.61: P = 0.026) and the median platelet count increased (15.1-17.9 × 104/µL: P = 0.013). Among the 514 patients with NBNC-HCC, 194 underwent hepatic resection for nonalcoholic steatohepatitis (NASH) (15%), alcoholic liver disease (ALD) (29%), and cryptogenic hepatitis (56%). Cirrhosis was detected in 72%, 39%, and 16% of patients with NASH, ALD, and cryptogenic hepatitis, respectively. The prevalence of cirrhosis in patients with NASH was significantly higher than the prevalence of cirrhosis in the other groups (P < 0.001). Overall, 70% of the non-malignant liver tissue of patients with NBNC-HCC was not involved with cirrhosis. On the other hand, the median FIB-4 index in patients with cryptogenic HCC was 2.56, which was a significantly lower value than those values in the other groups of patients. The FIB-4 index considered as one of useful screening of HCC. CONCLUSIONS: The prevalence of NBNC-HCC has increased rapidly even in a regional university hospital. Metabolic syndrome may be an important risk factor for HCC. HCC was also found in patients with non-cirrhotic livers. The FIB-4 index may be a useful screening method for HCC in patients with NBNC.


Assuntos
Carcinoma Hepatocelular , Diabetes Mellitus Tipo 2 , Neoplasias Hepáticas , Idoso , Carcinoma Hepatocelular/epidemiologia , Carcinoma Hepatocelular/etiologia , Humanos , Incidência , Cirrose Hepática/complicações , Cirrose Hepática/epidemiologia , Neoplasias Hepáticas/epidemiologia , Neoplasias Hepáticas/etiologia
3.
Intern Med ; 60(13): 2047-2053, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34193774

RESUMO

A 68-year-old man with hepatocellular carcinoma (HCC) visited his previous hospital due to abdominal pain and was diagnosed with ruptured HCC. Before visiting our hospital, he underwent HCC treatment at his previous hospital, but his tumors did not improve. Although he started treatment with sorafenib, the tumors rapidly grew. Subsequently, regorafenib was given, and the tumors shrank. After 22 months being treated with regorafenib, HCC reoccurred, with a new lung metastasis and a contrast-enhanced nodule on the peritoneal dissemination appearing. He underwent conversion surgery and survived for 4.5 years after his HCC was diagnosed.


Assuntos
Antineoplásicos , Carcinoma Hepatocelular , Neoplasias Hepáticas , Idoso , Antineoplásicos/uso terapêutico , Carcinoma Hepatocelular/tratamento farmacológico , Humanos , Neoplasias Hepáticas/tratamento farmacológico , Masculino , Compostos de Fenilureia/uso terapêutico , Piridinas , Sorafenibe/uso terapêutico
4.
Clin J Gastroenterol ; 14(5): 1517-1524, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34291386

RESUMO

The overall survival of patients with advanced hepatocellular carcinoma with tumor thrombosis of the main trunk or bilobar branches of the portal vein is extremely poor. Moreover, there is no standard treatment established for the condition. Herein, we present the case of a 65-year-old man who were treated the patient with hepatic arterial infusion chemotherapy, radiation therapy for tumor thrombosis, portal vein stent placement, lenvatinib administration, and renal venous shunt embolization. A complete response was observed according to mRECIST and the patient has been alive for 14 months since treatment initiation with no tumor recurrence.


Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , Trombose , Idoso , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/terapia , Humanos , Infusões Intra-Arteriais , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/terapia , Masculino , Recidiva Local de Neoplasia , Veia Porta , Trombose/etiologia , Trombose/terapia
5.
BMC Cancer ; 21(1): 668, 2021 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-34090354

RESUMO

BACKGROUND: Patients diagnosed with Barcelona Clinic Liver Cancer (BCLC) intermediate stage hepatocellular carcinoma (HCC) encompass a broad clinical population. Kinki criteria subclassifications have been proposed to better predict prognoses and determine appropriate treatment strategies for these patients. This study validated the prognostic significance within the Kinki criteria substages and analyzed the role of liver resection in patients with intermediate stage HCC. METHODS: Patients with intermediate stage HCC (n = 378) were retrospectively subclassified according to the Kinki criteria (B1, n = 123; B2, n = 225; and B3, n = 30). We analyzed the overall survival (OS) and treatment methods. RESULTS: The OS was significantly different between adjacent substages. Patients in substage B1 who underwent liver resection had a significantly better prognosis than those who did not, even after propensity score matching (PSM). Patients in substage B2 who underwent liver resection had a significantly better prognosis than those who did not; however, there was no difference after PSM. There was no difference in prognosis based on treatments among patients in substage B3. CONCLUSIONS: The Kinki criteria clearly stratify patients with intermediate stage HCC by prognosis. For substage B1 HCC patients, liver resection provides a better prognosis than other treatment modalities. In patients with substage B2 and B3, an alternative approach is required.


Assuntos
Carcinoma Hepatocelular/terapia , Quimioembolização Terapêutica/estatística & dados numéricos , Hepatectomia/estatística & dados numéricos , Neoplasias Hepáticas/terapia , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma Hepatocelular/diagnóstico , Carcinoma Hepatocelular/mortalidade , Carcinoma Hepatocelular/patologia , Quimioembolização Terapêutica/métodos , Cisplatino/administração & dosagem , Feminino , Seguimentos , Humanos , Óleo Iodado/administração & dosagem , Estimativa de Kaplan-Meier , Fígado/irrigação sanguínea , Fígado/efeitos dos fármacos , Fígado/patologia , Fígado/cirurgia , Neoplasias Hepáticas/diagnóstico , Neoplasias Hepáticas/mortalidade , Neoplasias Hepáticas/patologia , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Prognóstico , Estudos Retrospectivos , Medição de Risco/métodos , Sorafenibe/administração & dosagem , Resultado do Tratamento
6.
J Viral Hepat ; 28(9): 1304-1311, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34105859

RESUMO

While the preS1 region of the large hepatitis B surface protein plays an essential role in hepatitis B virus (HBV) infection, the effect of preS1 on liver fibrosis and hepatocarcinogenesis in chronic hepatitis B (CHB) patients is not well known. In this study, we measured serum preS1 levels by chemiluminescent immunoassay technology in 690 CHB patients and evaluated the correlation between serum preS1 levels and HBV, liver function markers and liver inflammation, fibrosis assessed by histological findings. Predictive factors for hepatocellular carcinoma (HCC) development in patients who had no previous history of HCC at the time of preS1 level measurement were also analysed. Median hepatitis B surface antigen (HBsAg) and preS1 levels were 3.08 log IU/mL and 98 ng/mL, respectively. PreS1 values were significantly correlated with serum HBsAg (p <0.001), hepatitis B core-related antigen (HBcrAg) (p <0.001) and HBV DNA levels (p <0.01). PreS1 values were also significantly correlated with serum alanine aminotransferase levels (p <0.001) and were significantly higher in patients who had higher grading of liver inflammatory activity (p <0.05). HBsAg level was correlated, but preS1/HBsAg ratio reflected liver fibrosis staging more directly than HBsAg alone. Multivariate analysis identified age ≥53 years (hazard ratio [HR], 18.360 for <53 years; p = 0.021) and preS1/HBsAg ratio ≥0.12 (HR, 6.205 for <0.12; p = 0.040) as significant and independent factors for HCC development in CHB patients. The preS1/HBsAg ratio directly reflects liver fibrosis, and the ratio might be a predictive marker for HCC development in CHB patients.


Assuntos
Carcinoma Hepatocelular , Hepatite B Crônica , Neoplasias Hepáticas , Carcinoma Hepatocelular/diagnóstico , Carcinoma Hepatocelular/epidemiologia , DNA Viral , Antígenos de Superfície da Hepatite B , Vírus da Hepatite B/genética , Hepatite B Crônica/complicações , Humanos , Cirrose Hepática/diagnóstico , Neoplasias Hepáticas/diagnóstico , Pessoa de Meia-Idade
7.
Cancers (Basel) ; 13(9)2021 May 07.
Artigo em Inglês | MEDLINE | ID: mdl-34067075

RESUMO

Few studies exist on the relationship between post-progression survival (PPS) and skeletal muscle volume in hepatocellular carcinoma (HCC) patients receiving sorafenib. This study aimed to analyze the effects of muscle volume on clinical outcomes. We retrospectively enrolled 356 HCC patients. Various clinical parameters, including skeletal muscle index, were analyzed as predictors of overall survival (OS), progression-free survival (PFS), and PPS. Patients with high muscle volume showed longer survival or PPS than those with low muscle volume (median survival time: 12.8 vs. 9.5 months, p = 0.005; median PPS: 8.2 vs. 6.3 months, p = 0.015); however, no differences in PFS were found. Multivariate analysis indicated that muscle volume was an independent predictor of PPS and OS. Skeletal muscle volume was a PPS predictor in HCC patients receiving sorafenib. Therefore, survival can be prolonged by the upregulation of skeletal muscle volume, especially in HCC patients with skeletal muscle depletion.

8.
Medicine (Baltimore) ; 100(26): e26436, 2021 Jul 02.
Artigo em Inglês | MEDLINE | ID: mdl-34190166

RESUMO

ABSTRACT: Bariatric surgery has been reported to improve non-alcoholic steatohepatitis (NASH), which is a frequent comorbidity in morbidly obese patients. We performed a retrospective cohort study to estimate the therapeutic effect of sleeve gastrectomy (SG), the most common bariatric surgery in Japan, on obese patients with NASH by comparing the findings of paired liver biopsies.Eleven patients who underwent laparoscopic SG for the treatment of morbid obesity, defined as body mass index (BMI) > 35 kg/m2, from March 2015 to June 2019 at Hiroshima University Hospital, Japan, were enrolled. All patients were diagnosed with NASH by liver biopsy before or during SG and were re-examined with a second liver biopsy 1 year after SG. The clinical and histological characteristics were retrospectively analyzed.One year after SG, body weight and BMI were significantly reduced, with median reductions in body weight and BMI of-22 kg and -7.9 kg/m2, respectively. Body fat was also significantly reduced at a median of 13.7%. Liver-related enzymes were also significantly improved. On re-examination by paired liver biopsy, liver steatosis improved in 9 of the 11 patients (81.8%), ruling out of the pathological diagnosis of NASH. However, fibrosis stage did not significantly improve 1 year after SG. The non-alcoholic fatty liver disease activity score was significantly reduced in 10 of 11 patients (90.9%).Pathological improvement or remission of NASH could be achieved in most morbidly obese Japanese patients 1 year after SG.


Assuntos
Cirurgia Bariátrica/métodos , Gastrectomia/métodos , Testes de Função Hepática/métodos , Fígado/patologia , Hepatopatia Gordurosa não Alcoólica , Obesidade Mórbida , Biópsia/métodos , Índice de Massa Corporal , Feminino , Humanos , Japão/epidemiologia , Laparoscopia/métodos , Cirrose Hepática/etiologia , Cirrose Hepática/patologia , Masculino , Pessoa de Meia-Idade , Hepatopatia Gordurosa não Alcoólica/sangue , Hepatopatia Gordurosa não Alcoólica/etiologia , Hepatopatia Gordurosa não Alcoólica/patologia , Obesidade Mórbida/complicações , Obesidade Mórbida/diagnóstico , Obesidade Mórbida/epidemiologia , Obesidade Mórbida/cirurgia , Indução de Remissão , Tempo
9.
J Exp Clin Cancer Res ; 40(1): 215, 2021 Jun 26.
Artigo em Inglês | MEDLINE | ID: mdl-34174931

RESUMO

BACKGROUND: There has been a recent surge in interest in predicting biological effects associated with genomic alterations in order to implement personalized cancer treatment strategies. However, no reports have yet evaluated the utility of profiling blood-based circulating tumor DNA (ctDNA) in hepatocellular carcinoma (HCC) patients treated with lenvatinib (LEN). METHOD: We retrospectively performed ctDNA next-generation sequencing (NGS) analysis in 24 patients with advanced HCC at baseline and 4 weeks after initiation of LEN. Association of the changes in variant allele frequencies (VAFs) during treatment and clinical outcome were evaluated. RESULTS: In total, 131 single nucleotide variants, 17 indels, and 23 copy number variations were detected as somatic alterations in 28, 6, and 12 genes, respectively in 23 of 24 patients. The most frequently altered genes were TP53 (54%), CTNNB1 (42%), TERT (42%), ATM (25%), and ARID1A (13%). The reduction in the mean frequency of variants (VAFmean) following 4 weeks of LEN treatment was associated with longer progression-free survival. The specificity and sensitivity of the reduction of VAFmean for predicting partial response were 0.67 and 1.0, respectively, which were higher than those of serum α-fetoprotein level (0.10 and 0.93, respectively). No association between the mutation status at baseline and the effectiveness of LEN was observed. CONCLUSION: Our study demonstrated that somatic alterations could be detected in the majority of advanced HCC patients by ctDNA profiling and that ctDNA-kinetics during LEN treatment was a useful marker of disease progression. These results suggest that ctDNA profiling is a promising method that provides valuable information in clinical practice.

10.
Liver Cancer ; 10(2): 151-160, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33977091

RESUMO

Background: Overall survival of patients with advanced hepatocellular carcinoma (HCC) with Vp4 (tumor thrombosis of the main trunk or bilobar of the portal vein) is extremely poor. Purpose: The purpose of this study is to clarify the prognosis of hepatic arterial infusion chemotherapy (HAIC) combined with radiation therapy (RT) for advanced HCC with Vp4 and to analyze the factors that contribute to the prognosis. Methods: In this retrospective cohort study, 51 HCC patients who were treated with HAIC and RT for portal vein tumor thrombosis and met the following criteria were enrolled: (i) with Vp4; (ii) Child-Pugh score of 5-7; (iii) Eastern Cooperative Oncology Group performance status of 0 or 1; (iv) no history of systemic therapy; and (v) from September 2004 to April 2019. Results: Median overall survival and median progression-free survival were 12.1 and 4.2 months, respectively. Multivariate analysis showed >50% of relative tumor volume in the liver (HR, 3.027; p = 0.008) and extrahepatic spread with (HR, 3.773; p = 0.040) as significant and independent factors of OS. The total overall response rate (ORR) was 19.6%; ORR in main tumor was 13.7%; and ORR in Vp4 was 51.0%. None of the patients who received HAIC combined with RT for advanced HCC with Vp4 developed hepatic failure. This combination therapy of HAIC with RT was safe and well tolerated in all cases. Conclusion: Combination therapies of HAIC and RT might be good therapy for advanced HCC with Vp4.

11.
Biochem Biophys Res Commun ; 559: 78-83, 2021 06 25.
Artigo em Inglês | MEDLINE | ID: mdl-33932902

RESUMO

Combination therapy with glecaprevir and pibrentasvir (PIB) has high efficacy for patients with hepatitis C virus (HCV) infection except among those who experienced NS5A-P32 deletion (del) mutation during prior DAA treatment failure. However, some patients fail to achieve SVR through combination treatment even in the absence of NS5A-P32del. We analyzed emergence of NS5A resistance-associated substitutions (RASs) against PIB using HCV-infected mice. Male human hepatocyte transplanted mice were infected with genotype 1b wild-type HCV. Mice were treated with PIB, resulting in a transient decrease in serum HCV RNA levels but followed by relapse during the treatment. Direct sequence analysis showed emergences of various mutations in the NS5A region, including L31V/P32del, L31F/P32del/Y93H, NS5A-P29del/Y85C, and NS5A-F37Y. PIB was less effective in mice with NS5A-F37Y mutations compared to mice with wild-type HCV. NS5A-F37Y showed 5.4-fold resistance to PIB relative to wild-type based on analysis using HCV subgenomic replicon systems. The present in vivo and in vitro studies identified NS5A-F37Y as a novel RAS against PIB and showed the possibility of emergence of various NS5A RASs including P29del, P32del and F37Y following PIB treatment. These mutations might emerge and lead to failure to respond to DAA therapies including PIB-based regimens in chronic hepatitis C patients.


Assuntos
Antivirais/farmacologia , Benzimidazóis/farmacologia , Farmacorresistência Viral , Hepacivirus/efeitos dos fármacos , Hepatite C/tratamento farmacológico , Pirrolidinas/farmacologia , Animais , Antivirais/uso terapêutico , Benzimidazóis/uso terapêutico , Hepacivirus/genética , Hepatite C/virologia , Hepatócitos/virologia , Humanos , Masculino , Camundongos , Camundongos SCID , Mutação/efeitos dos fármacos , Pirrolidinas/uso terapêutico
12.
Oncology ; 99(8): 507-517, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33946070

RESUMO

INTRODUCTION: We evaluated the efficacy and safety of lenvatinib-transcatheter arterial chemoembolization (LEN-TACE) sequential therapy for patients (n = 88) with intermediate-stage hepatocellular carcinoma (HCC). METHODS: Eighty-eight patients who obtained tumor control by LEN treatment were analyzed; 30 received LEN followed by TACE (LEN-TACE sequential therapy), and 58 received LEN monotherapy. Propensity score matching was performed, and the outcomes of 19 patients in the LEN-TACE group and 19 patients in the LEN-alone group were compared. Objective response rate (ORR), progression-free survival (PFS), overall survival (OS), incidence of adverse events (AEs), and change in albumin-bilirubin (ALBI) score were evaluated. RESULTS: After matching, baseline characteristics were similar between the groups. The ORR was 63.2% with LEN-TACE group and 63.2% with the LEN-alone group. Multivariate analysis showed that addition of TACE during LEN treatment (hazard ratio [HR] 0.264, 95% confidence interval [CI] 0.087-0.802, p = 0.019) and Child-Pugh score 5 (HR 0.223, 95% CI 0.070-0.704, p = 0.011) were the significant factors for PFS. Median PFS was 11.6 months with LEN-TACE and 10.1 months with LEN-alone. The survival rate of the LEN-TACE group was significantly higher than that of the LEN-alone group (median survival time; not reached vs. 16.9 months, p = 0.007). The incidence of common LEN-associated AEs was similar between groups. Although elevated aspartate aminotransferase/alanine aminotransferase and fever were more frequent with LEN-TACE group, these events were manageable. CONCLUSION: For patients with intermediate-stage HCC, LEN-TACE sequential therapy may provide a deep response and favorable prognosis.


Assuntos
Carcinoma Hepatocelular/terapia , Quimioembolização Terapêutica/métodos , Neoplasias Hepáticas/terapia , Compostos de Fenilureia/administração & dosagem , Quinolinas/administração & dosagem , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Carcinoma Hepatocelular/patologia , Quimioembolização Terapêutica/efeitos adversos , Estudos de Coortes , Feminino , Humanos , Neoplasias Hepáticas/patologia , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Compostos de Fenilureia/efeitos adversos , Intervalo Livre de Progressão , Pontuação de Propensão , Quinolinas/efeitos adversos , Estudos Retrospectivos , Taxa de Sobrevida
13.
Oncology ; 99(8): 491-498, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34000725

RESUMO

INTRODUCTION: This study compared clinical outcomes of 2nd- and 3rd-line regorafenib in patients with unresectable hepatocellular carcinoma. METHODS: In this retrospective cohort study, 48 patients were treated with regorafenib for unresectable hepatocellular carcinoma. Thirty-five and 13 patients were initiated on 2nd- and 3rd-line therapy, respectively. We assessed the responses to and safety of the therapy. RESULTS: There were no statistically significant differences in clinical characteristics at the start of 2nd- or 3rd-line regorafenib therapy. The overall response rate of 2nd- and 3rd-line regorafenib was 20 and 8%, respectively. The disease control rate was 57 and 54%, respectively. Median overall survival (mOS) from the start of 2nd-line regorafenib was 17.5 months. mOS from the start of 3rd-line regorafenib was not obtained. Median progression-free survival of 2nd- and 3rd-line regorafenib was 4.9 and 2.3 months, respectively. mOS from 1st-line therapy with tyrosine kinase inhibitor plus sorafenib-regorafenib-lenvatinib was 29.5 months; that with lenvatinib-sorafenib-regorafenib was not obtained. Patients on 3rd-line therapy tended to have better Child-Pugh scores and tumor factors at the start of 1st-line therapy than other patients. CONCLUSION: Patients on 2nd- and 3rd-line regorafenib showed favorable responses. Good Child-Pugh scores and tumor factors may be associated with a better response rate and OS.


Assuntos
Carcinoma Hepatocelular/tratamento farmacológico , Neoplasias Hepáticas/tratamento farmacológico , Compostos de Fenilureia/administração & dosagem , Piridinas/administração & dosagem , Administração Oral , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Carcinoma Hepatocelular/patologia , Estudos de Coortes , Feminino , Humanos , Neoplasias Hepáticas/patologia , Masculino , Pessoa de Meia-Idade , Compostos de Fenilureia/efeitos adversos , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/efeitos adversos , Piridinas/efeitos adversos , Quinolinas/administração & dosagem , Quinolinas/efeitos adversos , Estudos Retrospectivos , Sorafenibe/administração & dosagem , Sorafenibe/efeitos adversos , Taxa de Sobrevida , Resultado do Tratamento
14.
Oncology ; 99(5): 327-335, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33677453

RESUMO

INTRODUCTION: The clinical outcome of ramucirumab in multi-molecular targeted agent (MTA) sequential therapy for unresectable hepatocellular carcinoma (u-HCC) was assessed in comparison with that of prior tyrosine kinase inhibitor (TKI) therapy. METHODS: Sixteen patients who received ramucirumab as part of multi-MTA sequential therapy for u-HCC were enrolled in a retrospective, cohort study. Ramucirumab was started as 2nd line in 7 patients, 3rd line in 5 patients, and 4th line in 4 patients. RESULTS: The overall response rate was 6.3%, the disease control rate (DCR) was 50.0%, median progression-free survival was 2.0 months (evaluated by mRECIST), median overall survival (OS) with ramucirumab was 7.9 months, and the median OS from 1st-line therapy was 28.1 months. One month after the start of ramucirumab, α-fetoprotein (AFP) decreased in 6 of 12 cases (50.0%), and the DCR in AFP-decreased cases was 83.3%. The DCR of ramucirumab was 66.7% in cases in which disease control was obtained by prior TKI therapy, whereas it was 0.0% in the cases in which disease control was not obtained by prior TKI therapy. Examining the adverse events, no new safety concerns were confirmed. CONCLUSION: The AFP response to ramucirumab and the treatment response to prior TKI therapy are associated with treatment response to ramucirumab.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma Hepatocelular/mortalidade , Neoplasias Hepáticas/mortalidade , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais Humanizados/administração & dosagem , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/patologia , Feminino , Seguimentos , Humanos , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/patologia , Masculino , Pessoa de Meia-Idade , Compostos de Fenilureia/administração & dosagem , Prognóstico , Piridinas/administração & dosagem , Quinolinas/administração & dosagem , Estudos Retrospectivos , Sorafenibe/administração & dosagem , Taxa de Sobrevida
15.
IDCases ; 23: e01059, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33552903

RESUMO

Background: Multi-virus real-time polymerase chain reaction (PCR) system is able to simultaneously detect 163 viruses using a multiplex Taqman real-time PCR system. We present a case of acute liver failure (ALF) of unknown etiology diagnosed with echovirus 30 infection via multi-virus real-time PCR. Case presentation: A previously healthy 66-year-old man had a persistent fever and developed ALF of unclear etiology. Although viral infection was suspected, serological screening showed no evidence of acute viral infections such as hepatitis A, B, C and E, Epstein-Barr virus, herpes simplex virus, and varicella zoster virus. Multi-virus real-time PCR revealed the presence of enterovirus and echovirus 30 genomes, and reverse transcription-PCR using enterovirus-specific primers confirmed the presence of enterovirus genome in serum samples at the time of admission. Anti-echovirus antibody titers showed an increase in paired sera. In spite of multimodality treatment, the patient died due to multiple organ failure. Histological analysis in autopsy revealed extensive coagulative necrosis of the hepatocytes and immunohistochemical analysis showed the expression of enterovirus antigens in necrotic hepatocytes. Conclusions: We present here a case of echovirus 30 associated with ALF. Multi-virus real-time PCR is useful for detection of virus for patients with ALF of unknown etiology suspected of harboring a viral infection.

16.
J Viral Hepat ; 28(2): 400-409, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33197288

RESUMO

Although glucocorticoids have been used for immunosuppression of patients with primary hepatitis B virus (HBV) infection-induced severe hepatitis, the treatment is associated with a high frequency of adverse events. We conducted a pilot study for evaluating the efficacy and safety of abatacept, a cytotoxic T lymphocyte antigen-4 immunoglobulin (CTLA4), for acute hepatitis B. Five patients with severe acute hepatitis B (prothrombin activity ≤ 60%) were treated for immunosuppression by abatacept. Four patients received abatacept concurrently with methylprednisolone, and another patient was treated with abatacept alone. Rapid decrease in serum alanine aminotransferase levels, increase in prothrombin activity and improvement of general condition were obtained in four out of five patients. The patient with the most severe hepatitis underwent liver transplantation due to exacerbation of hepatitis in spite of treatment with both abatacept and methylprednisolone. None of the patients developed significant adverse events associated with the use of abatacept. Hepatitis B surface antigen (HBsAg) became negative in all five patients. The effect of abatacept and methylprednisolone for severe hepatitis B was compared using a mouse model. Rapid reduction in mouse serum HBV DNA and human albumin levels and elevation of serum interferon-gamma and granzyme A levels were observed in HBV-infected human hepatocyte-transplanted immunodeficient mice that were administered human peripheral blood mononuclear cells. These hepatocyte injuries were inhibited to a greater extent by abatacept compared to methylprednisolone. Abatacept might be an effective therapy alternative to methylprednisolone to reduce acute massive liver damage for patients with severe acute hepatitis caused by HBV infection.

17.
Clin J Gastroenterol ; 14(1): 283-287, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33200345

RESUMO

Immune checkpoint inhibitor (ICI) therapy has potent anti-cancer effects but is associated with immune-related adverse events (irAEs). We present a case who developed secondary sclerosing cholangitis following treatment with nivolumab for non-small cell lung cancer who did not respond to immunosuppressive treatments and died of liver failure. A 75 year-old male with lung cancer who had been treated with nivolumab for non-small cell lung cancer developed Grade 3 liver injury with significant elevation of hepatobiliary enzymes. Magnetic resonance cholangiopancreatography (MRCP) revealed diffuse dilatation of the common bile duct and multifocal stenosis with prestenotic dilatation from the perihilar to intrahepatic bile duct, consistent with sclerosing cholangitis. Histological findings represented an infiltration of mainly CD8-positive T cells around the bile ducts in the liver. Despite treatments with ursodeoxycholic acid, prednisolone, and mycophenolate mofetil, the sclerosing cholangitis did not improve, and the patient died due to liver failure and aggravation of lung cancer. These findings suggest that immune checkpoint inhibitors may lead to resistance to immunosuppressive treatment as well as pose a risk of life-threatening sclerosing cholangitis.


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Colangite Esclerosante , Neoplasias Pulmonares , Idoso , Ductos Biliares Intra-Hepáticos , Colangite Esclerosante/induzido quimicamente , Colangite Esclerosante/tratamento farmacológico , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Masculino , Nivolumabe/efeitos adversos
18.
Intern Med ; 60(6): 829-837, 2021 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-33087674

RESUMO

Objective Lusutrombopag is a thrombopoietin receptor agonist that improves thrombocytopenia in patients with chronic liver disease scheduled to undergo invasive procedures. However, information on the efficacy of repeated lusutrombopag treatment and factors associated with the treatment is scarce. We analyzed the efficacy of repeated lusutrombopag treatment and the factors associated with a response to lusutrombopag. Methods Thirty-nine patients with chronic liver disease who received lusutrombopag treatment before undergoing invasive procedures were enrolled in this retrospective study. Of the 39 patients, 10 received lusutrombopag treatment multiple times for a total of 53 regimens of lusutrombopag treatment. Changes in platelet counts, the effects of repeated lusutrombopag treatment, and factors associated with response to lusutrombopag were analyzed. Results The median platelet count increased significantly from 4.5×104/µL before lusutrombopag treatment to 7.2×104/µL before the invasive procedure (p<0.01), and patients undergoing 49 of the 53 (92%) treatment regimens succeeded in undergoing invasive procedures without needing platelet transfusions. In patients who received lusutrombopag treatment repeatedly, the median platelet count significantly increased following the second administration of lusutrombopag, and the effects of lusutrombopag were similar between the first and second administration. A multivariate analysis identified the absence of diabetes mellitus (odds ratio, 5.56 for presence; p=0.04) as a significant and independent predictor of a response to lusutrombopag. Conclusion Lusutrombopag treatment significantly increased platelet counts in patients with chronic liver disease, making it possible to receive invasive procedures. The treatment produced identical effects when it was repeated. The efficacy of lusutrombopag might be decreased in patients with diabetes mellitus.


Assuntos
Hepatopatias , Trombocitopenia , Doença Crônica , Cinamatos , Humanos , Hepatopatias/complicações , Hepatopatias/tratamento farmacológico , Receptores de Trombopoetina , Estudos Retrospectivos , Tiazóis , Trombocitopenia/tratamento farmacológico
19.
J Gastroenterol Hepatol ; 36(6): 1685-1693, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33326154

RESUMO

BACKGROUND AND AIM: The aim of this study was to identify the factors that contribute to the maintenance of relative dose intensity (RDI) of lenvatinib in hepatocellular carcinoma (HCC) patients. METHODS: Thirty-two patients with advanced HCC treated with lenvatinib were enrolled. We evaluated the relationship between maintenance of RDI and various clinical data, parameters obtained by body composition measurements with bioelectrical impedance analysis (BIA) and grip strength at the start of lenvatinib treatment. RESULTS: Multivariate analysis showed that only the extracellular water to total body water ratio (ECW/TBW) ≤ 0.400 at initiation of treatment was associated with RDI ≥ 50% (odds ratio, 6.94; 95% confidence interval [CI], 1.00-48.00; P = 0.049). When the RDI was compared between ECW/TBW ≤ 0.400 group and ECW/TBW > 0.400 group, the RDI was significantly higher in the ECW/TBW ≤ 0.400 group at each of 0-4W, 4-6W, and 6-8W points. The P value at each point was 0.003, 0.003, and 0.005, respectively. On the other hand, multivariate analysis showed that only the ECW/TBW ≤ 0.400 at initiation of treatment was associated with the extension of duration until reduction or withdrawal of lenvatinib (hazard ratio, 4.86; 95% CI, 1.52-15.50; P = 0.007). CONCLUSION: The extracellular water to total body water ratio, a parameter of body composition measurement by BIA, was significantly associated with the maintenance of RDI and the duration until reduction or withdrawal of lenvatinib in HCC patients. In addition to standard predictors such as Child-Pugh score and modified albumin-bilirubin grade that have been used to date, ECW/TBW might be a new predictor of RDI in HCC patients treated with lenvatinib.

20.
Mol Med Rep ; 23(1)2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33179077

RESUMO

Non­alcoholic steatohepatitis (NASH) may progress via liver fibrosis along with hepatic stellate cell (HSC) activation. A single nucleotide polymorphism (SNP; rs58542926) located in transmembrane 6 superfamily 2 (TM6SF2) has been reported to be significantly associated with fibrosis in patients with NASH, but the precise mechanism is still unknown. The present study aimed to explore the role of TM6SF2 in HSC activation in vitro. Plasmids producing TM6SF2 wild-type (WT) and mutant type (MT) containing E167K amino acid substitution were constructed, and the activation of LX­2 cells was analyzed by overexpressing or knocking down TM6SF2 under transforming growth factor ß1 (TGFß) treatment. Intracellular α­smooth muscle actin (αSMA) expression in LX­2 cells was significantly repressed by TM6SF2­WT overexpression and increased by TM6SF2 knockdown. Following treatment with TGFß, αSMA expression was restored in TM6SF2­WT overexpressed LX­2 cells and was enhanced in TM6SF2 knocked­down LX­2 cells. Comparing αSMA expression under TM6SF2­WT or ­MT overexpression, expression of αSMA in TM6SF2­MT overexpressed cells was higher than that in TM6SF2­WT cells and was further enhanced by TGFß treatment. The present study demonstrated that intracellular αSMA expression in HCS was negatively regulated by TM6SF2 while the E167K substitution released this negative regulation and led to enhanced HSC activation by TGFß. These results suggest that the SNP in TM6SF2 may relate to sensitivity of HSC activation.


Assuntos
Actinas/genética , Células Estreladas do Fígado/citologia , Proteínas de Membrana/genética , Hepatopatia Gordurosa não Alcoólica/genética , Polimorfismo de Nucleotídeo Único , Linhagem Celular , Regulação da Expressão Gênica/efeitos dos fármacos , Técnicas de Silenciamento de Genes , Células Estreladas do Fígado/efeitos dos fármacos , Células Estreladas do Fígado/metabolismo , Humanos , Modelos Biológicos , Fator de Crescimento Transformador beta/farmacologia
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