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BACKGROUND AND AIMS: This study aimed to determine the safety and efficacy of atezolizumab + bevacizumab therapy in hepatocellular carcinoma patients receiving anti-platelet agents or anticoagulants. METHODS: Patients were divided into those using (IM out) and those not using (IM in) anti-platelet agents or anticoagulants, who violated the exclusion criteria of the IMbrave150 trial, and were retrospectively examined. RESULTS: The study included 185 patients (IM in: 157; IM out: 28). For first-line treatment, progression-free survival was 184 days for IM in and 266 days for IM out (p = .136). Overall survival was 603 days for IM in and not reached for IM out (p = .265), with no significant between-group difference. Similarly, there were no significant between-group differences in progression-free survival or overall survival for later-line treatment. Haemorrhagic adverse events of ≥grade 3 were observed in 11 IM in patients and 3 IM out patients. No significant factors associated with haemorrhagic adverse events of ≥grade 3 were identified in the multivariate analysis including IM out classification, whose p value was .547. Regarding thrombotic/embolic adverse events in the IM out group, one case of exacerbation of portal vein thrombosis was observed. No deaths were directly attributable to bleeding events or exacerbations of thrombosis. CONCLUSION: Atezolizumab + bevacizumab therapy shows similar safety and efficacy in patients receiving and those not receiving anti-platelet agents or anticoagulants; therefore, it can be considered for patients with hepatocellular carcinoma receiving anti-platelet agents or anticoagulants.
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Anticorpos Monoclonais Humanizados , Anticoagulantes , Bevacizumab , Carcinoma Hepatocelular , Neoplasias Hepáticas , Inibidores da Agregação Plaquetária , Humanos , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/mortalidade , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/mortalidade , Bevacizumab/uso terapêutico , Bevacizumab/efeitos adversos , Bevacizumab/administração & dosagem , Masculino , Feminino , Anticorpos Monoclonais Humanizados/uso terapêutico , Anticorpos Monoclonais Humanizados/efeitos adversos , Estudos Retrospectivos , Pessoa de Meia-Idade , Idoso , Inibidores da Agregação Plaquetária/uso terapêutico , Inibidores da Agregação Plaquetária/efeitos adversos , Anticoagulantes/uso terapêutico , Anticoagulantes/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Intervalo Livre de Progressão , Hemorragia/induzido quimicamente , AdultoRESUMO
A 67-year-old woman presented with a history of upper abdominal pain and weight loss. Physical examination revealed a lump in the right lower quadrant. She had undergone esophagogastroduodenoscopy at another hospital ten years ago, which showed a 15-mm elevated lesion in the duodenal bulb. The patient had not undergone further examinations or received treatment during the 10 years. Esophagogastroduodenoscopy conducted in our hospital revealed an enlarged tumor that was difficult to assess on the whole image. The tumor was diagnosed as a well-differentiated adenocarcinoma based on a biopsy specimen. Enhanced computed tomography revealed a hypervascular duodenal tumor with liver and lymph node metastases. The patient was treated with capecitabine plus oxaliplatin for the duodenal cancer. Lymph node metastases increased markedly after 2 courses of chemotherapy. The patient died 3 months after the initiation of chemotherapy. The natural history of sporadic non-ampullary duodenal epithelial tumors remains to be fully elucidated due to the low incidence rate. This case suggests that sporadic non-ampullary duodenal epithelial tumors have a biological potential for invasive malignancy.
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Adenocarcinoma , Neoplasias Duodenais , Feminino , Humanos , Idoso , Neoplasias Duodenais/tratamento farmacológico , Neoplasias Duodenais/cirurgia , Metástase Linfática , Fígado , DuodenoRESUMO
Immune checkpoint inhibitors (ICIs) cause various immune-related adverse events (irAEs). We encountered a patient in whom nivolumab was re-administered effectively and safely treat laryngeal cancer after nivolumab-induced cholangitis. A 60-year-old man with metastatic laryngeal squamous cell carcinoma received 3rd-line treatment with nivolumab. After the 8th cycle of chemotherapy, laboratory tests revealed grade 3 elevations of gamma-glutamyl transpeptidase and alkaline phosphatase. Computed tomography and endoscopic retrograde cholangiopancreatography showed diffuse hypertrophy, dilation of bile ducts, and intrahepatic bile ducts with irregular walls and mild stenosis. The histologic findings of a liver biopsy revealed portal inflammation and cholangitis, mainly composed of T cell infiltration. We diagnosed nivolumab-induced cholangitis and administered 30 mg of prednisolone (0.5 mg/kg) and ursodeoxycholic acid (600 mg) per day. Although we initiated 4th-line cytotoxic anticancer drug after the cholangitis improved, the laryngeal cancer progressed rapidly. Based on the improvement in hematologic parameters, radiologic imaging, and pathologic findings, we cautiously restarted nivolumab. During the 30 months after re-administration of nivolumab, the cholangitis did not recur and the disease was well-controlled.
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Antineoplásicos , Colangite , Antineoplásicos/efeitos adversos , Colangite/induzido quimicamente , Colangite/tratamento farmacológico , Humanos , Inibidores de Checkpoint Imunológico , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/tratamento farmacológico , Nivolumabe/efeitos adversosRESUMO
Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer. HCC cells consume large amounts of glutamine to survive, but can adapt to glutamine depletion in the presence of an exogenous asparagine. L-asparaginase (ASNase) converts glutamine and asparagine to glutamate and aspartate, respectively, and has been used to treat leukemia. Here we examined the effects of ASNase treatment on HCC cells and explored the potential impact of combining ASNase with the tyrosine kinase inhibitor lenvatinib (Len) for HCC treatment. Cell viability and death of HCC cell lines treated with either Len or ASNase alone or with Len and ASNase combined were determined. We assessed mRNA and protein expression levels of glutamine synthetase (GS) and asparagine synthetase (ASNS) by real-time quantitative PCR and immunoblotting. The antitumor effect of the combination therapy relative to Len or ASNase monotherapy was also evaluated in a xenograft tumor mouse model. ASNase treatment inhibited growth of SNU387 and SNU398 HCC cells, which have low GS and high ASNS expression levels, respectively, but did not clearly inhibit growth of the other cell lines. Len plus ASNase combination therapy synergistically inhibited proliferation and induced oxidative stress leading to cell death of some HCC cells lines. However, cell death of Huh7 cells, which express ASCT2, an important glutamine transporter for cancer cells, was not affected by the combination treatment. In a xenograft model, Len combined with ASNase significantly attenuated tumor development relative to mice treated with Len or ASNase alone. ASNase-mediated targeting of two amino acids, glutamine and asparagine, which are indispensable for HCC survival, induces oxidative stress and can be a novel cancer treatment option that exerts a synergistic effect when used in combination with Len.
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Combination treatment with tyrosine kinase inhibitors (TKIs) and immunotherapies has shown efficacy in the treatment of multiple cancers, but the immunomodulatory effect of TKIs on the tumor cell phenotype remains unknown in hepatocellular carcinoma (HCC). Given that human lymphocyte antigen class I (HLA-I) is essential for tumor antigen presentation and subsequent antitumor immunity, we examined the effects of regorafenib, as well as other TKIs (sorafenib, lenvatinib and cabozantinib) on HLA-I expression in HCC cell lines. Regorafenib increased cell surface HLA-I and ß2-microglobulin protein expression in the presence of interferon γ (IFNγ). The expressions of various genes associated with the HLA-I antigen processing pathway and its transcriptional regulators were also upregulated by regorafenib. Furthermore, we found that regorafenib had an activating effect on signal transducers and activators of transcription 1 (STAT1), and that regorafenib-induced HLA-I expression was dependent on the augmented IFNγ/STAT1 signaling pathway. Trametinib, an inhibitor of the extracellular signal-regulated kinase (ERK) kinase MEK, also activated IFNγ/STAT1 signaling and increased HLA-I expression, whereas the phosphatidylinositol 3-kinase (PI3K) inhibitor buparlisib did not. Given that regorafenib directly inhibits Raf/MEK/ERK signaling, the downregulation of the MEK/ERK pathway appears to be one of the mechanisms by which regorafenib promotes STAT1 activation. Sorafenib, lenvatinib, and cabozantinib also showed the same effects as regorafenib, while regorafenib had most potent effects on HLA-I expression, possibly dependent on its stronger inhibitory activity against the MEK/ERK pathway. These results support the clinical combination of TKIs with immunotherapy for the treatment of HCC.
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In patients with nonalcoholic fatty liver disease (NAFLD), liver fibrosis is the predictive factor for liver-related events and prognosis. This retrospective study aimed to evaluate longitudinal changes in the FIB-4 index and to determine a strategy for diagnosing and following patients with NAFLD using this index. We analyzed the FIB-4 index at baseline and after 1 and 5 years in 272 consecutive patients with biopsy-proven NAFLD. Of these, 52 patients underwent serial biopsies. The change in the FIB-4 index was correlated with changes in the fibrosis stage among these patients (p = 0.048). The median FIB-4 index was 1.64 at baseline, 1.45 at 1 year, and 1.74 at 5 years. The negative predictive value for advanced fibrosis at a low cutoff point was 90.4/90.1 at baseline/1 year. Its specificity at a high cutoff point increased from 65.0% at baseline to 82.3% at 1 year. Multivariate analysis identified the FIB-4 index at 1 year as a predictive factor for a FIB-4 index > 2.67 at 5 years. A FIB-4 index < 1.30 was acceptable for excluding advanced fibrosis at baseline. In contrast, to evaluate and predict advanced liver fibrosis with the FIB-4 index at a high cutoff point, we should use the index at 1 year after appropriate therapy.
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Objective Although most patients who obtain a sustained virological response (SVR) show an improved liver function, some show decreased platelet counts after the eradication of hepatitis C virus (HCV). The aim of this retrospective study was to clarify the association of the liver and spleen volumes with the platelet count after SVR achieved by direct-acting antiviral (DAA) treatment. Methods This study enrolled 36 consecutive patients treated by DAAs who obtained an SVR between September 2014 and December 2018. The liver and spleen volumes were derived from computed tomography scans obtained at pretreatment, SVR, and 48 weeks after SVR. No patient developed hepatocellular carcinoma during this study. Results Compared with pretreatment, the median aspartate aminotransferase, alanine aminotransferase, albumin serum levels, and platelet counts were significantly improved at SVR and 48 weeks after SVR. The liver/spleen volumes per body weight had decreased significantly from 22.5/4.2 mL/kg at baseline to 21.1/3.6 mL/kg at 48 weeks after SVR. The change in the liver volume was associated with the change in the platelet count, and the change in the spleen volume was negatively associated with the change in the serum albumin level. A multivariate analysis identified the change in the liver volume (≥95%, odds ratio 76.9, p=0.005) as the factor associated with improvement in the platelet count at 48 weeks after SVR. The patients with an increased liver volume at 48 weeks after SVR showed an increased platelet count. Conclusion Both the liver and spleen volume decreased significantly after the eradication of HCV. The patients with a re-increased liver volume showed a rapid increase in the platelet count.
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Antivirais/uso terapêutico , Hepatite C/tratamento farmacológico , Cirrose Hepática/patologia , Tamanho do Órgão/fisiologia , Contagem de Plaquetas/estatística & dados numéricos , Baço/patologia , Idoso , Idoso de 80 Anos ou mais , Feminino , Hepacivirus , Hepatite C/complicações , Humanos , Cirrose Hepática/etiologia , Testes de Função Hepática , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Resposta Viral SustentadaRESUMO
BACKGROUND & AIMS: PNPLA3 rs738409 has been associated with increased risks of fibrosis in patients with non-alcoholic fatty liver disease (NAFLD). Recently, carriage of the rs6834314 G allele, which is in high linkage with rs72613567 of 17-beta-hydroxysteroid dehydrogenase 13 (HSD17B13), was reported to be associated with a reduced risk of liver injury in NAFLD patients. We estimated the impact of these genetic variants on hepatic fibrosis in Japanese patients with NAFLD. METHODS: We analysed the associations of these genetic variants with liver histology in 290 Japanese patients with biopsy-proven NAFLD diagnosed during 2002-2019. During follow-up, 14 patients (4.8%) developed hepatocellular carcinoma. RESULTS: Prevalences of the PNPLA3 rs738409 genotypes were 0.17 for CC, 0.41 for CG, 0.42 for GG, and those for HSD17B13 rs6834314 were 0.54 for AA, 0.39 for AG and 0.07 for GG. There was no significant interaction between the PNPLA3 and HSD17B13 genotypes. Prevalences of advanced fibrosis according to PNPLA3/HSD17B13 genotypes were 0.16 for CC,CG/AG,GG, 0.20 for CC,CG/AA, 0.30 for GG/AG,GG and 0.37 for GG/AA. Multivariate analysis identified PNPLA3 GG as a predictor of advanced fibrosis (stage 3/4) in carriers of HSD17B13 AA (odds ratio 2.4, P = .041), but not HSD17B13 AG/GG (P = .776). The HSD17B13 genotype G was significantly associated with lower prevalences of severe inflammation and ballooning and tended to be associated with a higher prevalence of advanced steatosis. CONCLUSIONS: In Japanese patients with NAFLD, carriage of the HSD17B13 rs6834314 G allele attenuated the effect of the PNPLA3 rs738409 GG genotype on advanced hepatic fibrosis.
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Neoplasias Hepáticas , Hepatopatia Gordurosa não Alcoólica , Humanos , Japão/epidemiologia , Lipase/genética , Fígado/patologia , Cirrose Hepática/genética , Cirrose Hepática/patologia , Neoplasias Hepáticas/patologia , Proteínas de Membrana/genética , Hepatopatia Gordurosa não Alcoólica/epidemiologia , Hepatopatia Gordurosa não Alcoólica/genética , Hepatopatia Gordurosa não Alcoólica/patologia , Polimorfismo de Nucleotídeo ÚnicoRESUMO
Sodium-glucose cotransporter-2 inhibitors (SGLT2I) have been reported to have renal-protective effects in patients with type 2 diabetes (T2DM). This a retrospective study aimed to evaluate the effect of SGLT2I on renal function in patients with nonalcoholic fatty liver disease (NAFLD) and T2DM. We analyzed 69 consecutive patients with a biopsy-proven NAFLD and T2DM with an estimated glomerular filtration rate (eGFR) >60 mL/min. Of these 69 patients, 22 received SGLT2I and 47 were treated without SGLT2I. Liver function and eGFR were analyzed at baseline and after three years. Body mass index, liver function and HbA1c improved significantly in both groups. In the total population, the median eGFR declined from 80.7 mL/min at the baseline to 74.9 mL/min at the end of follow-up. The median eGFR at the baseline/end of follow-up was 81.2/80.4 mL/min in patients treated with SGLT2I and 80.2/70.8 mL/min in patients treated without SGLT2I. Multivariate analysis identified an increased FIB-4 index with an odds ratio (OR) of 4.721, (p = 0.045) and SGLT2I treatment (OR 0.263, p = 0.033) as predictive factors for decreased eGFR. SGLT2I treatment has a protective effect on the renal function for NAFLD with T2DM. A long-term, randomized, controlled trial is warranted to confirm the renal protective effect of SGLT2I in NAFLD patients with T2DM.
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Non-alcoholic fatty liver disease (NAFLD) is associated with chronic kidney disease (CKD). The aim of this retrospective study was to determine the risk factors for progression of CKD in patients with biopsy-proven NAFLD including patatin-like phospholipase domain containing 3 (PNPLA3) polymorphism. A total of 344 patients with biopsy-proven NAFLD were enrolled consecutively in this study. Multivariate analysis identified males (odds ratio (OR) 5.46), age (per 1 year, OR 1.07), and FIB-4 index (≥1.30, OR 3.85) as factors associated with CKD. Of the 154 patients with a baseline estimated glomerular filtration rate (eGFR) ≥60 mL/min, 30 had a deterioration in CKD stage and 15 developed CKD after 3 years. Multivariate analysis identified diabetes mellitus (OR 2.44) as a risk factor for deterioration in CKD stage, while diabetes mellitus (OR 21.54) and baseline eGFR (per 1 mL/min OR 0.88) were risk factors for development of CKD. PNPLA3 did not affect the change in eGFR. In NAFLD patients, a high FIB-4 index was associated with CKD to increases in the index linked to reductions in eGFR. In order to prevent development of CKD, an appropriate therapy focusing on renal function is needed for NAFLD patients, especially those with diabetes.
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Diabetes Mellitus Tipo 2/patologia , Hepatopatia Gordurosa não Alcoólica/patologia , Insuficiência Renal Crônica/patologia , Índice de Gravidade de Doença , Adulto , Idoso , Idoso de 80 Anos ou mais , Diabetes Mellitus Tipo 2/complicações , Feminino , Taxa de Filtração Glomerular , Humanos , Japão/epidemiologia , Lipase/genética , Fígado/metabolismo , Fígado/patologia , Masculino , Proteínas de Membrana/genética , Pessoa de Meia-Idade , Análise Multivariada , Hepatopatia Gordurosa não Alcoólica/etiologia , Razão de Chances , Insuficiência Renal Crônica/epidemiologia , Insuficiência Renal Crônica/etiologia , Estudos Retrospectivos , Fatores de Risco , Adulto JovemRESUMO
BACKGROUND: Sarcopenia is diagnosed with the skeletal muscle index (SMI) or the sarcopenia index (SI). We previously reported that the ratio of skeletal muscle mass to body fat mass (SF ratio) was a novel index of sarcopenia in patients with non-alcoholic fatty liver disease (NAFLD). The aim of this retrospective study was to evaluate sarcopenia with these indices in patients with NAFLD. METHODS: One hundred and fifty-six consecutive patients with biopsy-proven NAFLD and alanine aminotransferase (ALT) >40 IU/L were enrolled. Liver function and body composition were evaluated in 121 patients after 12 months. We evaluated the relationship between histological findings, changes in liver function, and the SMI, SI, and SF ratio. RESULTS: Of the 156 patients enrolled, 13.5% and 26.3% were diagnosed with sarcopenia with the SMI and SI. In patients with hepatic fibrosis stage <2, the SI and the SF ratio were significantly greater than in patients with fibrosis stage ≥2. There was no difference in SMI between groups. In the cohort assessed at baseline and 12 months later, transaminase activity and SMI decreased significantly, and the SF ratio increased over time. A multivariate analysis revealed the presence of the PNPLA3 G allele and an increase in SF ratio (odds ratio, 7.406) as predictive factors of ALT reduction >30% from baseline. CONCLUSIONS: Due to the high prevalence of obesity, we should consider both skeletal muscle mass and body fat mass in the diagnosis and treatment of NAFLD. The SF ratio could be a useful index in sarcopenic NAFLD.