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BACKGROUND: Our phase II trial (FABRIC study) failed to verify the efficacy of gemcitabine plus oxaliplatin (GEMOX) in patients with pancreatic ductal adenocarcinoma (PDAC) with a familial or personal history of pancreatic, breast, ovarian or prostate cancer, which suggested that a family and personal history may be insufficient to determine response to platinum-based chemotherapy. METHODS: This ancillary analysis aimed to investigate the prevalence of germline variants of homologous recombination repair (HRR)-related genes and clarify the association of germline variants with the efficacy of GEMOX and patient outcome in PDAC patients. Of 45 patients enrolled in FABRIC study, 27 patients were registered in this ancillary analysis. RESULTS: Of the identified variants in HRR-related genes, one variant was considered pathogenic and eight variants in six patients (22%) were variants of unknown significance (VUS). Objective response to GEMOX was achieved by 43% of the seven patients and tended to be higher than that of patients without such variants (25%). Pathogenic/VUS variant in HRR-related genes was an independent favorable factor for progression-free survival (hazard ratio, 0.322; P = 0.047) and overall survival (hazard ratio, 0.195; P = 0.023) in multivariable analysis. CONCLUSIONS: The prevalence of germline variants in PDAC patients was very low even among patients with a familial/personal history of pancreatic, breast, ovarian or prostate cancer. Patients with one or more germline variants in HRR-related genes classified as pathogenic or VUS may have the potential to obtain better response to GEMOX and have better outcomes.
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Carcinoma Ductal Pancreático , Neoplasias Pancreáticas , Neoplasias da Próstata , Carcinoma Ductal Pancreático/tratamento farmacológico , Carcinoma Ductal Pancreático/genética , Predisposição Genética para Doença , Células Germinativas , Mutação em Linhagem Germinativa , Humanos , Masculino , Oxaliplatina/uso terapêutico , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/patologia , Neoplasias PancreáticasRESUMO
BACKGROUND: Vacuolar ATPase (V-ATPase) is involved in cancer development. The use of proton pump inhibitors (PPIs) as V-ATPase inhibitors has been reported to enhance the effectiveness of chemotherapy in certain cancers. This study aimed to evaluate the effect of PPIs on chemotherapy for esophageal cancer. METHODS: To investigate the effects of PPIs on esophageal cancer cells, human KYSE50 and 70 cells were plated and 3 PPIs (lansoprazole, esomeprazole, vonoprazan) were added at various concentrations with 5-Fluorouracil (5-FU) to the corresponding cells for a cell viability assay. To investigate the effects of PPI treatment on patients undergoing 5-FU-based therapy in the clinical setting, we retrospectively analyzed the clinical outcomes and chemotherapy-related adverse events in 40 esophageal cancer patients who received 5-FU chemotherapy in our hospital between May 2013 and April 2017. RESULTS: In the viability assays, all PPIs significantly enhanced the cytotoxic effect of 5-FU on the two esophageal cancer cell lines. In the clinical study, PPI-treated patients showed better overall survival (OS) than patients managed without PPI treatment. A multivariate analysis revealed that PPI treatment was independently associated with OS (p = 0.009, HR, 0.33; 95% CI, 0.12-0.76). CONCLUSIONS: PPI treatment may safely enhance chemosensitivity in esophageal cancer patients.
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Signet-ring cell carcinoma (SRCC) is a unique subtype of gastric cancer that is impaired for cell-cell adhesion. The pathogenesis of SRCC remains unclear. Here, we show that expression of kinesin-associated protein 3 (KAP3), a cargo adaptor subunit of the kinesin superfamily protein 3 (KIF3), a motor protein, is specifically decreased in SRCC of the stomach. CRISPR/Cas9-mediated gene knockout experiments indicated that loss of KAP3 impairs the formation of circumferential actomyosin cables by inactivating RhoA, leading to the weakening of cell-cell adhesion. Furthermore, in KAP3 knockout cells, post-Golgi transport of laminin, a key component of the basement membrane, was inhibited, resulting in impaired basement membrane formation. Together, these findings uncover a potential role for KAP3 in the pathogenesis of SRCC of the stomach.
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Carcinoma de Células em Anel de Sinete , Neoplasias Gástricas , Proteínas Adaptadoras de Transdução de Sinal , Carcinoma de Células em Anel de Sinete/genética , Carcinoma de Células em Anel de Sinete/patologia , Proteínas do Citoesqueleto , Humanos , Cinesinas/genética , Laminina/genética , Neoplasias Gástricas/patologiaRESUMO
The human SOX2 gene was recently identified as a novel major oncogene, recurrently amplified and overexpressed in esophageal squamous cell carcinoma (ESCC). However, the role and molecular mechanism of SOX2 in the carcinogenesis of ESCC remain to be elucidated. The present study investigated the effect of SOX2 on ESCC cell survival and resistance to apoptosis under serum starvation conditions. An adenoviral vector-mediated expression system and RNA interference were used to study the effect of SOX2. The present results revealed that SOX2 promoted ESCC cell survival and enhanced resistance to apoptosis under serum starvation conditions, but not in culture conditions with serum. Mechanistically, SOX2 increased the expression levels of phosphorylated AKT and glycogen synthase kinase-3ß (GSK-3ß), a downstream factor of AKT, under serum starvation conditions, leading to the promotion of ESCC cell survival. Additionally, SOX2 activated AKT through the PTEN/PI3K/phosphoinositide-dependent protein kinase 1 and mammalian target of rapamycin complex 2 signaling pathways. Therefore, SOX2 may facilitate the survival of ESCC cells under poor nutrient conditions by activating the AKT/GSK-3ß signaling pathway.
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BACKGROUND: We recently reported the real-world changes in the etiologies of liver cirrhosis (LC) based on nationwide survey data and assessed the etiologies of LC with hepatocellular carcinoma (HCC). METHODS: Fifty-five participants from 68 institutions provided data on 23,637 patients with HCC-complicated LC. The changing trends in etiologies were assessed. We further analyzed the data from 29 hospitals that provided the annual number of newly identified HCC-complicated LC patients from 2008 to 2016 (N = 9362) without any missing years and assessed the transition in the real number of newly identified HCC-complicated LC cases. RESULTS: In the overall cohort, hepatitis C virus (HCV) infection (60.3%) and hepatitis B virus (HBV) infection (12.9%) were the leading and third-most common causes of HCC-complicated LC in Japan, respectively. HCV infection was found to be the leading cause throughout Japan. The rate of viral hepatitis-related HCC decreased from 85.3 to 64.4%. Among non-viral etiologies, notable increases were observed in nonalcoholic steatohepatitis (NASH)-related HCC (from 1.5 to 7.2%) and alcoholic liver disease (ALD)-related HCC (from 8.5 to 18.6%). Regarding the real number of newly diagnosed patients, the number of patients with viral hepatitis-related HCC decreased, while the number of patients with non-viral HCC, particularly NASH-related HCC, increased. CONCLUSIONS: Viral hepatitis has remained the main cause of HCC in Japan. However, the decrease in viral hepatitis-related HCC, particularly HCV-related HCC highly contributed to the etiological changes. In addition, the increased incidence of non-viral HCC, particularly NASH-related HCC, was involved in the changing etiologies of HCC-complicated LC in Japan.
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Carcinoma Hepatocelular/etiologia , Cirrose Hepática/etiologia , Idoso , Carcinoma Hepatocelular/epidemiologia , Feminino , Hepatite B/complicações , Hepatite B/epidemiologia , Hepatite C/complicações , Hepatite C/epidemiologia , Humanos , Incidência , Japão/epidemiologia , Cirrose Hepática/epidemiologia , Hepatopatias Alcoólicas/complicações , Neoplasias Hepáticas/complicações , Neoplasias Hepáticas/epidemiologia , Masculino , Pessoa de Meia-Idade , Inquéritos e QuestionáriosRESUMO
We explored the beneficial effects of GW7647, a peroxisome proliferator activated receptor α (PPARα) agonist, and metformin, an anti-diabetic drug on an advanced nonalcoholic steatohepatitis (NASH) model in rodents and investigated the possible mechanisms involved. Mice were fed control chow or a choline-deficient L-amino acid-defined diet containing 45% fat (HF-CDAA). The mice fed HF-CDAA diets for 16 weeks were divided into four groups: the no treatment (HF-CDAA), HF-CDAA containing 1000 mg/kg metformin, HF-CDAA containing 10 mg/kg GW7647, and HF-CDAA with both metformin and GW7647 groups. Metformin alone slightly deteriorated the aspartate and alanine aminotransferase (AST/ALT) values, whereas co-treatment with GW7647 and metformin greatly suppressed liver injury and fibrosis via activation of the AMP-activated protein kinase (AMPK) pathway. Further study revealed that co-treatment decreased the expression of inflammatory-, fibrogenesis-, and endoplasmic reticulum (ER) stress-related genes and increased the oxidized nicotinamide adenine dinucleotide (NAD)/reduced nicotinamide adenine dinucleotide (NADH) ratio, suggesting the superiority of co-treatment due to restoration of mitochondrial function. The additive benefits of a PPARα agonist and metformin in a HF-CDAA diet-induced advanced NASH model was firstly demonstrated, possibly through restoration of mitochondrial function and AMPK activation, which finally resulted in suppression of hepatic inflammation, ER stress, then, fibrosis.
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Butiratos/farmacologia , Metformina/farmacologia , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Hepatopatia Gordurosa não Alcoólica/etiologia , Compostos de Fenilureia/farmacologia , Alanina Transaminase/sangue , Aminoácidos/farmacologia , Animais , Anti-Inflamatórios não Esteroides/farmacologia , Antioxidantes/farmacologia , Aspartato Aminotransferases/sangue , Deficiência de Colina/complicações , Dieta/efeitos adversos , Modelos Animais de Doenças , Quimioterapia Combinada , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Fatores de Crescimento de Fibroblastos/metabolismo , Masculino , Metformina/efeitos adversos , Camundongos Endogâmicos C57BL , Hepatopatia Gordurosa não Alcoólica/patologia , PPAR alfa/agonistasRESUMO
BACKGROUND: A family/personal history of breast, ovarian, or pancreatic cancer is a useful predictive marker for response to platinum-based chemotherapy in treating patients with pancreatic cancer. These cancers, and prostate cancer, are known as BRCA-related malignancies. We evaluated the efficacy of gemcitabine plus oxaliplatin (GEMOX) in patients with metastatic pancreatic cancer with a family/personal history of these cancers. METHODS: Chemotherapy-naïve patients with metastatic pancreatic cancer with a family history of pancreatic/breast/ovarian/prostate cancer or a personal history of breast/ovarian/prostate cancer were included. Patients received fixed dose-rate gemcitabine (1000 mg/m2) and oxaliplatin (100 mg/m2) every 2 weeks. The primary endpoint was 1-year survival, and the threshold and expected values were set at 30 and 50%, respectively. The target sample size was determined to be 43, with a one-sided alpha value of 5% and power of 80%. A total of 45 patients were enrolled. RESULTS: Among the first 43 enrolled patients, the 1-year survival rate was 27.9% [90% confidence interval (CI) 17.0-41.3], which did not meet the primary endpoint. Median overall survival, progression-free survival, and response rates were 7.6 months (95% CI 6.0-10.7), 4.0 months (95% CI 2.0-4.6), and 26.7% (95% CI 14.6-41.9), respectively, in all registered patients. The GEMOX regimen was generally tolerated; the most common grade three or higher adverse events were hematological toxicities. CONCLUSION: GEMOX did not show the expected efficacy in patients with metastatic pancreatic cancer with a family or personal history of pancreatic/breast/ovarian/prostate cancer. Selection of GEMOX based on family/personal history is not recommended. TRIAL REGISTRATION NUMBER: UMIN000017894.
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Adenocarcinoma/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Desoxicitidina/análogos & derivados , Neoplasias Pancreáticas/tratamento farmacológico , Adenocarcinoma/mortalidade , Adenocarcinoma/patologia , Adulto , Idoso , Neoplasias da Mama , Desoxicitidina/uso terapêutico , Feminino , Humanos , Masculino , Anamnese , Pessoa de Meia-Idade , Compostos Organoplatínicos/uso terapêutico , Neoplasias Ovarianas , Neoplasias Pancreáticas/mortalidade , Neoplasias Pancreáticas/patologia , Intervalo Livre de Progressão , Neoplasias da Próstata , Taxa de Sobrevida , Resultado do TratamentoRESUMO
Recently, treatment options for hepatocellular carcinoma (HCC) have expanded due to the development of the tyrosine kinase inhibitor ramucirumab and immune checkpoint inhibitors. Transcatheter arterial chemoembolization is the standard therapy for intermediate-stage HCC; however, in cases with anatomical problems, normal approaches are not possible. In such rare cases, direct hepatic puncture may be considered as an effective therapy and an indispensable treatment. We report our novel method of direct hepatic artery puncture in this case report. In 2011 and 2017, we reported 2 cases in the journal of the Japan Society of Hepatology in Japanese. This therapy is difficult and is associated with a high risk of complications; however, we succeeded in both cases in a similar way. We believe this method may provide an alternative treatment when standard treatment is not possible or when urgent therapy is required. In case 1, direct hepatic artery puncture was performed under ultrasonographic guidance, and we were able to control the disease with percutaneous lipiodol chemotherapy. Case 2 was an emergency case of ruptured HCC. Direct hepatic puncture successfully stopped tumor bleeding; furthermore, tumor necrosis also occurred, as seen on the enhanced computed tomography image. Our new method requires advanced puncture techniques and is not the treatment of choice if there are other safe alternatives available. However, it can be considered as an option if there are no other viable, effective treatments.
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BACKGROUND: To assess the recent real-world changes in the etiologies of liver cirrhosis (LC) in Japan, we conducted a nationwide survey in the annual meeting of the Japan Society of Hepatology (JSH). METHODS: We investigated the etiologies of LC patients accumulated from 68 participants in 79 institutions (N = 48,621). We next assessed changing trends in the etiologies of LC by analyzing cases in which the year of diagnosis was available (N = 45,834). We further evaluated the transition in the real number of newly identified LC patients by assessing data from 36 hospitals with complete datasets for 2008-2016 (N = 18,358). RESULTS: In the overall data, HCV infection (48.2%) was the leading cause of LC in Japan, and HBV infection (11.5%) was the third-most common cause. Regarding the transition in the etiologies of LC, the contribution of viral hepatitis-related LC dropped from 73.4 to 49.7%. Among the non-viral etiologies, alcoholic-related disease (ALD) and nonalcoholic steatohepatitis (NASH)-related LC showed a notable increase (from 13.7 to 24.9% and from 2.0 to 9.1%, respectively). Regarding the real numbers of newly diagnosed patients from 2008 to 2016, the numbers of patients with viral hepatitis-related LC decreased, while the numbers of patients with non-viral LC increased. CONCLUSIONS: HCV has remained the main cause of LC in Japan; however, the contribution of viral hepatitis as an etiology of LC is suggested to have been decreasing. In addition, non-viral LC, such as ALD-related LC and NASH-related LC, is suggested to have increased as etiologies of LC in Japan.
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Hepatite C/complicações , Cirrose Hepática/etiologia , Hepatopatias Alcoólicas/complicações , Hepatopatia Gordurosa não Alcoólica/complicações , Idoso , Feminino , Hepatite B/complicações , Hepatite B/epidemiologia , Hepatite C/epidemiologia , Humanos , Japão/epidemiologia , Cirrose Hepática/epidemiologia , Hepatopatias Alcoólicas/epidemiologia , Masculino , Pessoa de Meia-Idade , Hepatopatia Gordurosa não Alcoólica/epidemiologia , Inquéritos e QuestionáriosRESUMO
OBJECTIVE: This trial compared the efficacy and safety of transarterial chemoembolisation (TACE) plus sorafenib with TACE alone using a newly established TACE-specific endpoint and pre-treatment of sorafenib before initial TACE. DESIGN: Patients with unresectable hepatocellular carcinoma (HCC) were randomised to TACE plus sorafenib (n=80) or TACE alone (n=76). Patients in the combination group received sorafenib 400 mg once daily for 2-3 weeks before TACE, followed by 800 mg once daily during on-demand conventional TACE sessions until time to untreatable (unTACEable) progression (TTUP), defined as untreatable tumour progression, transient deterioration to Child-Pugh C or appearance of vascular invasion/extrahepatic spread. Co-primary endpoints were progression-free survival (PFS), which is not a conventional one but defined as TTUP, or time to any cause of death plus overall survival (OS). Multiplicity was adjusted by gatekeeping hierarchical testing. RESULTS: Median PFS was significantly longer in the TACE plus sorafenib than in the TACE alone group (25.2 vs 13.5 months; p=0.006). OS was not analysed because only 73.6% of OS events were reached. Median TTUP (26.7 vs 20.6 months; p=0.02) was also significantly longer in the TACE plus sorafenib group. OS at 1 year and 2 years in TACE plus sorafenib group and TACE alone group were 96.2% and 82.7% and 77.2% and 64.6%, respectively. There were no unexpected toxicities. CONCLUSION: TACE plus sorafenib significantly improved PFS over TACE alone in patients with unresectable HCC. Adverse events were consistent with those of previous TACE combination trials. TRIAL REGISTRATION NUMBER: NCT01217034.
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Antineoplásicos/uso terapêutico , Carcinoma Hepatocelular/terapia , Quimioembolização Terapêutica , Neoplasias Hepáticas/terapia , Sorafenibe/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/efeitos adversos , Quimioembolização Terapêutica/efeitos adversos , Terapia Combinada , Progressão da Doença , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Intervalo Livre de Progressão , Estudos Prospectivos , Sorafenibe/efeitos adversos , Taxa de SobrevidaRESUMO
BACKGROUND AND AIMS: Nonalcoholic fatty liver disease (NAFLD) is a hepatic manifestation of metabolic syndrome, and its progression is associated with aging-associated impairment in metabolic homeostasis. Recently, energy metabolism in adipose tissue has been the subject of renewed interest, because significant energy expenditure can be induced in cells derived from white adipose tissue progenitors, in addition to brown adipose tissue (BAT). Here we evaluated whether aging-associated change in various adipose tissue depots affects the progression of NAFLD. METHODS: Six-week-old male C57BL/6NCrSlc mice were fed control chow (C) or high-fat diet (60% fat; HF) for 12 or 24 weeks (12w/C, 12w/HF, 24w/C and 24w/HF groups, respectively) or switched from C to HF diet at 18 weeks of age (24w/C/HF group) and fed for a further 24 weeks. Some 24w/HF mice received a subcutaneous transplantation of adipose progenitors (106 cells/mouse) from young donor mice. Basal energy expenditure, glucose tolerance, and liver and adipose tissue histology were then evaluated. In addition, features of senescence and the capacity of adipose progenitors to "brown" were compared in mice of various ages. RESULTS: 12w/HF mice demonstrated compensation in the forms of hypertrophy of interscapular classical BAT and the appearance of subcutaneous beige adipocytes, consistent with improved metabolic homeostasis. In contrast, 24w/HF and 24w/C/HF mice developed obesity, glucose intolerance, and severe NAFLD, with accelerated senescence and loss of adipose progenitors in subcutaneous fat tissues. Recruitment of adipose progenitors ameliorated these findings in 24w/HF mice. CONCLUSION: Impaired metabolic compensation in adipose tissue resulted in the progression of NAFLD, which was associated with aging-related deterioration in adipose progenitors. A new approach targeting adipose tissue progenitors might represent a potential strategy for the prevention of NAFLD.
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AIMS: The liver function of patients with hepatitis C virus (HCV) infection who obtained sustained virologic response (SVR) has been known to improve after HCV eradication. However, a predictor of liver function after SVR has not been definitively identified. The aim of this retrospective study was to identify a predictor of deteriorated liver function and Fibrosis-4 (FIB-4) index after SVR was achieved by direct-acting antiviral (DAA) treatment. METHODS: This study retrospectively enrolled 248 patients who obtained SVR by DAA treatment. None of the patients developed hepatocellular carcinoma during this study. Liver function was assessed at the end of treatment (EOT) and at 24, 48, 72, and 96 weeks after EOT. RESULTS: At 96 weeks after EOT, the serum aspartate aminotransferase and alanine aminotransferase levels were significantly decreased from those at EOT. The platelet count was significantly increased from 14.9 × 104 /µL at EOT to 17.1 × 104 /µL at 96 weeks after EOT. Ten patients showed an increased FIB-4 (>1.00) index. Multivariate analysis with 171 patients who underwent endoscopic assessment revealed that the presence of varices was an independent predictor of deterioration in the FIB-4 index (odds ratio, 5.56; P = 0.041). CONCLUSION: Most of the study patients who obtained SVR showed improved liver function after EOT. Patients without increasing platelet counts after SVR due to DAA therapy should be evaluated for complications induced by portal hypertension.
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BACKGROUND: We reported a cross-sectional study on causes of liver injury in Japanese type 2 diabetes mellitus (T2D) patients (JG 2013). We assessed overall and cause-specific mortality risk during follow-up of patients enrolled in JG 2013. METHODS: This was a longitudinal, multicenter cohort study. Of the 5642 Japanese T2D patients who visited T2D clinics of nine hospitals in the original study, 3,999 patients were followed up for an average of 4.5 years. Expected deaths in T2D patients were estimated using age-specific mortality rates in the general population (GP) of Japan. Standardized mortality ratios (SMRs) were calculated to compare mortality between T2D patients and GP. RESULTS: All-cancer mortality was significantly higher in T2D patients than in the GP [SMR 1.58, 95% confidence interval (CI) 1.33-1.87]. Among malignancies, hepatocellular carcinoma (HCC) conferred the highest mortality risk in T2D patients (SMR 3.57, 95% CI 2.41-5.10). HCC-associated mortality risk in T2D patients remained significantly high (SMR 2.56, 95% CI 1.64-3.97) after adjusting for high positivity rates of hepatitis B surface antigen (1.7%) and anti-hepatitis C virus (5.3%). In T2D patients with platelet counts < 200 × 103/µl, SMR of HCC increased from 3.57 to 6.58 (95% CI 4.34-9.58). T2D patients with platelet count > 200 × 103/µl showed no increase in mortality risk (SMR 0.68) of HCC. CONCLUSIONS: HCC-associated mortality risk was the highest among all cancers in Japanese T2D patients. Regular follow-up may be important for T2D patients with platelet counts < 200 × 103/µl for early detection of HCC.
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Carcinoma Hepatocelular/epidemiologia , Diabetes Mellitus Tipo 2/epidemiologia , Antígenos de Superfície da Hepatite B/sangue , Neoplasias Hepáticas/epidemiologia , Idoso , Carcinoma Hepatocelular/mortalidade , Estudos de Coortes , Estudos Transversais , Diabetes Mellitus Tipo 2/mortalidade , Feminino , Seguimentos , Humanos , Japão/epidemiologia , Neoplasias Hepáticas/mortalidade , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Estudos ProspectivosRESUMO
AIM: Nonalcoholic fatty liver disease (NAFLD), including nonalcoholic steatohepatitis (NASH), is known to be associated with type 2 diabetes mellitus (T2DM) in high rate. The improvement in hepatic function due to sodium-glucose co-transporter 2 (SGLT2) inhibitors has been reported in T2DM patients with and without NAFLD. However, only a few studies have attempted to evaluate the role of SGLT2 inhibitors in T2DM patients with biopsy-proven NASH, and no detailed prospective studies including the individual hepatic fibrosis stage have been reported. Therefore, we investigated the effect of canagliflozin on hepatic function in T2DM patients with biopsy-confirmed NASH. METHODS: T2DM patients with NASH (hepatic fibrosis stage 1-3 confirmed via liver biopsy, n=10) were enrolled and received canagliflozin (100 mg) once a day for 12 weeks. The primary end point was change in serum alanine aminotransferase (ALT) levels from baseline to week 12. Secondary end points were liver function/fibrosis markers, metabolic parameters, and safety. RESULTS: The change in ALT from baseline to week 12 was -23.9 U/L (95% CI -48.1 to 0.3, P=0.0526). Significant improvements in several hepatic function/fibrosis markers, such as aspartate aminotransferase, fibrosis-4 index, and FM-fibro index, and metabolic parameters including hemoglobin A1c and body weight were found. No serious or liver-related adverse events were reported. Regarding individual patients, different trends in ALT-lowering effects between stage 1 and stage 2/3 subjects were observed; the degree of ALT-lowering effect tended to be greater in the stage 1 group than in the stage 2/3 group. CONCLUSION: Our results suggest that canagliflozin is effective and well-tolerated in patients with T2DM and NASH. Canagliflozin may be useful for the treatment of T2DM patients with NASH, especially those in early stages of NASH.
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PURPOSE: Resminostat is an oral inhibitor of class I, IIB, and IV histone deacetylases. This phase I/II study compared the safety and efficacy of resminostat plus sorafenib versus sorafenib monotherapy as first-line therapy for advanced hepatocellular carcinoma (HCC). EXPERIMENTAL DESIGN: In phase I, resminostat (400 mg or 600 mg/day on days 1 to 5 every 14 days) was administered with sorafenib (800 mg/day for 14 days) to determine the recommended dose for phase II. In phase II, patients were randomized (1:1) to sorafenib monotherapy or resminostat plus sorafenib. The primary endpoint was time-to-progression (TTP). RESULTS: Nine patients (3: 400 mg, 6: 600 mg) were enrolled in phase I, and the recommended dose of resminostat was determined to be 400 mg/day. Then 170 patients were enrolled in phase II. Median TTP/overall survival (OS) were 2.8/14.1 months with monotherapy versus 2.8/11.8 months with combination therapy (Hazard Ratio [HR]: 0.984, p = 0.925/HR: 1.046, p = 0.824). The overall incidence of adverse events was similar in both groups (98.8% versus 100.0%). However, thrombocytopenia ≥ Grade 3 was significantly more frequent in the combination therapy group (34.5% versus 2.4%, p < 0.001). Subgroup analysis revealed that median TTP/OS was 1.5/6.9 months for monotherapy versus 2.8/13.1 months for combination therapy (HR: 0.795, p = 0.392/HR: 0.567, p = 0.065) among patients with a normal-to-high baseline platelet count (≥ 150 × 103/mm3). CONCLUSIONS: In patients with advanced HCC, first-line therapy with resminostat at the recommended dose plus sorafenib showed no significant efficacy advantage over sorafenib monotherapy.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Povo Asiático , Carcinoma Hepatocelular/tratamento farmacológico , Inibidores de Histona Desacetilases/uso terapêutico , Ácidos Hidroxâmicos/administração & dosagem , Ácidos Hidroxâmicos/uso terapêutico , Neoplasias Hepáticas/tratamento farmacológico , Sorafenibe/uso terapêutico , Sulfonamidas/administração & dosagem , Sulfonamidas/uso terapêutico , Administração Oral , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Carcinoma Hepatocelular/patologia , Feminino , Inibidores de Histona Desacetilases/administração & dosagem , Humanos , Ácidos Hidroxâmicos/efeitos adversos , Estimativa de Kaplan-Meier , Neoplasias Hepáticas/patologia , Masculino , Estadiamento de Neoplasias , Sorafenibe/efeitos adversos , Sulfonamidas/efeitos adversos , Resultado do TratamentoRESUMO
The aberrant expression or alteration of microRNAs (miRNAs/miRs) contributes to the development and progression of cancer. In the present study, the functions of miR-96-5p in hepatocellular carcinoma (HCC) were investigated. It was identified that miR-96-5p expression was significantly upregulated in primary HCC tumors compared with their non-tumorous counterparts. A copy number gain was frequently observed at chromosomal region 7q32.2 in which the MIR96 locus is located, suggesting that gene amplification may be one of the mechanisms by which miR-96-5p expression is increased in HCC. Transfection of miR-96-5p mimic into HCC cells decreased the expression of CASP9, which encodes caspase-9, the essential initiator caspase in the mitochondrial apoptotic pathway, at the mRNA and protein levels. A putative binding site for miR-96-5p was identified in the CASP9 3'-untranslated region, and the results of a luciferase assay indicated that CASP9 is a potential direct target of miR-96-5p. The miR-96-5p mimic increased resistance to doxorubicin- and ultraviolet-induced apoptosis through the decrease in caspase-9 expression in HCC cells. Transfection of miR-96-5p inhibitor enhanced the cytotoxic effect of doxorubicin by increasing caspase-9 expression in the HCC cells, suggesting a synergistic effect between the miR-96-5p inhibitor and doxorubicin. In conclusion, the results of the present study suggest that miR-96-5p, which is frequently upregulated in HCC, inhibits apoptosis by targeting CASP9. Therefore, miR-96-5p may be a potential therapeutic target for HCC.
Assuntos
Carcinoma Hepatocelular/genética , Caspase 9/genética , Neoplasias Hepáticas/genética , MicroRNAs/genética , Apoptose/efeitos dos fármacos , Apoptose/efeitos da radiação , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/patologia , Movimento Celular/efeitos dos fármacos , Movimento Celular/genética , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/genética , Doxorrubicina/administração & dosagem , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos da radiação , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos da radiação , Células Hep G2 , Humanos , Neoplasias Hepáticas/patologia , MicroRNAs/antagonistas & inibidores , Transfecção , Raios UltravioletaRESUMO
OBJECTIVE: To evaluate prospectively the efficacy and safety of sorafenib, which has been the first-line treatment for advanced hepatocellular carcinoma (HCC), in Japanese HCC patients (pts) with not only Child-Pugh (C-P) A class but also C-P B class. METHODS: Sorafenib was administered orally at the dose of 400 mg twice daily for pts with HCC and liver function of C-P score of 5-8. Administration was continued until the detection of disease progression or appearance of unacceptable toxicity. The primary endpoint was time to progression (TTP), and toxicity and the secondary endpoints included objective response, overall survival (OS). RESULTS: Forty C-P A pts and 12 C-P B pts were enrolled. The median TTP in the C-P A pts and C-P B pts was 3.3 months and 3.2 months, respectively. Among the pts with C-P A, complete response, partial response, and stable disease were achieved for 2.5%, 7.5% and 47.5%. Among the pts with C-P B, there were no treatment responses, 66.7% of pts had stable disease. The median OS in the C-P A pts and C-P B pts was 13.4 months and 7.4 months, respectively. With regard to toxicities, fewer C-P A pts experienced Grade 3/4 toxicities than C-P B pts (77.5% vs. 91.6%). There were no treatment-related deaths in either group of patients. CONCLUSIONS: This study shows sorafenib has similar effectiveness in the recent post-approval studies and is well-tolerated in Japanese pts with HCC and Child Pugh A class. Sorafenib should be used with great care for Child Pugh class B pts.
Assuntos
Povo Asiático , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/patologia , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/patologia , Niacinamida/análogos & derivados , Compostos de Fenilureia/uso terapêutico , Idoso , Progressão da Doença , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Niacinamida/efeitos adversos , Niacinamida/uso terapêutico , Compostos de Fenilureia/efeitos adversos , Sorafenibe , Análise de Sobrevida , Fatores de Tempo , Resultado do TratamentoRESUMO
BACKGROUND: Hepatic fibrosis is an independent risk factor for mortality and liver-related events in patients with nonalcoholic fatty liver disease (NAFLD). PNPLA3 rs738409 has been associated with fibrosis in viral and non-viral hepatitis. TLL1 rs17047200 also has been associated with developing hepatocellular carcinoma probably via hepatic fibrogenesis. We estimated the impact of these genetic polymorphisms on hepatic fibrosis in Japanese patients with NAFLD. METHODS: We analyzed the association between these genetic variants and the backgrounds of 817 individuals who received health checkups (health check cohort) from 2012 to 2014. Then, we investigated the relationship between genetic variants and liver histology in 258 consecutive patients with biopsy-proven NAFLD in Japan (NAFLD cohort) from 2012 to 2017 (UMIN000027399). RESULTS: The prevalence of PNPLA3 CG/GG in the NAFLD cohort was higher than that in the health check cohort (p < 0.001). The prevalence of patients with advanced fibrosis (stages 3-4) was higher for PNPLA3 genotype CG/GG than CC (p = 0.048) and for TLL1 genotype AT/TT than AA (p = 0.044). The high-risk group which had at least two risk alleles of these variants was more likely to have advanced fibrosis (p = 0.004). Multivariate analysis identified body mass index [odds ratio (OR) 1.123, serum AST (OR 1.037, p = 0.004], serum albumin (OR 0.247, p = 0.032), and genetic high risk (OR 2.632, p = 0.026) as predictors of advanced fibrosis. CONCLUSIONS: In Japanese patients with NAFLD, individuals with risk alleles of PNPLA3 and TLL1 may have a risk of advanced fibrosis.
Assuntos
Lipase/genética , Cirrose Hepática/epidemiologia , Proteínas de Membrana/genética , Hepatopatia Gordurosa não Alcoólica/epidemiologia , Hepatopatia Gordurosa não Alcoólica/genética , Polimorfismo de Nucleotídeo Único , Metaloproteases Semelhantes a Toloide/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Aspartato Aminotransferases/sangue , Índice de Massa Corporal , Estudos de Coortes , Feminino , Genótipo , Humanos , Japão/epidemiologia , Cirrose Hepática/etiologia , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Hepatopatia Gordurosa não Alcoólica/complicações , Hepatopatia Gordurosa não Alcoólica/patologia , Prevalência , Albumina Sérica , Estatísticas não Paramétricas , Adulto JovemRESUMO
AIM: Type 2 diabetes mellitus (T2DM) is a major complication of patients with non-alcoholic fatty liver disease (NAFLD). The aim of this retrospective study is to determine the risk factors for development of T2DM in patients with biopsy-proven NAFLD. METHODS: One hundred and sixty two consecutive patients with biopsy-proven NAFLD who received a 75-g oral glucose tolerance test were enrolled as the total cohort. Among them, we analyzed 89 patients without T2DM diagnosed by oral glucose tolerance test to estimate the cumulative rate for development of T2DM as the follow-up cohort. RESULTS: Of 162 patients, the glucose tolerance pattern were DM in 45 patients (27.8%), impaired glucose tolerance in 68 (42.0%), and normal glucose tolerance in 49 (30.2%). Patients with NAFL tended to be more likely to have normal glucose tolerance than those with non-alcoholic steatohepatitis (NASH). The serum levels of pre- and post-load insulin were significantly higher in the NASH group. Of 89 patients without T2DM, 13 patients newly developed T2DM during a follow-up period of 5.2 years. The cumulative rate of T2DM incidence was 8.8% at the end of the 5th year and 23.4% at the end of the 10th year. Multivariate analysis identified homeostasis model of assessment - insulin resistance (≥3.85, hazard ratio 40.1, P = 0.033) as an independent risk factor for development of T2DM. CONCLUSIONS: Patients with NASH have an underlying potential of glucose intolerance. In NAFLD patients, insulin resistance is the most important risk factor for the incidence of T2DM. Appropriate therapy against insulin resistance could be needed for patients with NAFLD to prevent development of T2DM.
RESUMO
AIM: To investigate daclatasvir (DCV) and asunaprevir (ASV) efficacy in hepatitis C (HCV) patients, with respect to resistance-associated substitutions (RASs). METHODS: A total of 392 HCV-infected patients from multiple centers were included in this study. We evaluated their clinical courses and sustained virologic responses (SVR) according to pretreatment factors (gender, age, history of interferon-based regimens, platelet counts, level of viremia, pretreatment NA5A:L31, and Y93 substitutions). We also analyzed the pretreatment and post-treatment major RASs of NS3:D168, NS5A:L31 and Y93 substitutions using a direct-sequencing method in 17 patients who were unable to achieve SVR at 12 wk after treatment completion (SVR12). RESULTS: The overall SVR12 rate was 88.3%. Thirty-one patients discontinued treatment before 24 wk because of adverse events, 23 of whom achieved SVR12. There were no significant differences in SVR12 rates with respect to gender, age, history of interferon-based regimens, and platelet counts. The SVR12 rate in patients with viral loads of ≥ 6.0 log IU/mL was significantly lower than those with viral loads of < 6.0 log IU/mL (P < 0.001). The SVR12 rate in patients with Y93 substitution-positive was significantly lower than those with Y93 substitution-negative (P < 0.001). The L31 substitution-positive group showed a lower SVR12 rate than the L31 substitution-negative group, but the difference was not statistically significant. Seventeen patients who did not achieve SVR12 and had available pretreatment and post-treatment sera had additional RASs in NS3:D168, NS5:L31, and Y93 substitution at treatment failure. CONCLUSION: Combination of DCV and ASV is associated with a high SVR rate. Baseline RASs should be thoroughly assessed to avoid additional RASs after treatment failure.