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INTRODUCTION: Atezolizumab plus bevacizumab (AB) therapy was the effective immune checkpoint inhibitor (ICI) for unresectable hepatocellular carcinoma (u-HCC). However, immune-related adverse events (irAEs) are common in patients receiving ICI therapies. Our research aimed to explore the risk factors for irAE development, with attention to interleukin-7 (IL-7) risk alleles, lymphocyte counts, and autoantibodies. METHODS: Seventy-six patients receiving AB therapy for u-HCC were recruited. Single nucleotide polymorphism genotyping was done for the analysis of rs16906115 polymorphism near IL-7-expressing genes using 20 µL of stored buffy coat at baseline. The association between IL-7 risk alleles, lymphocyte counts, autoantibodies, and irAE development was investigated. RESULTS: irAEs were found in 14 (18%) patients. The incidence of irAEs did not differ significantly between the groups showing IL-7 AG/AA and the GG group (p = 0.72). The incidence in the group with a lymphocyte count of 1,130/µL or more at baseline was higher than in that with a value below 1,130/µL (p = 0.0093). The group showing IL-7 AG/AA or lymphocyte count >1,130/µL had a higher irAE prevalence rate than the others (p = 0.019). IL-7 AG/AA or lymphocyte count >1,130/µL and positivity for autoantibodies at baseline were the prognostic factors for irAE development. irAE incidence could be stratified using a combination of IL-7 AG/AA or lymphocyte counts ≥1,130/µL and positive autoantibodies (p = 0.016). CONCLUSION: Patients with IL-7 risk alleles, high lymphocyte counts, and autoantibodies at baseline may require careful monitoring for irAE development.
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AIM: Atezolizumab plus bevacizumab (AB) combination therapy is the first-line treatment for unresectable hepatocellular carcinoma (u-HCC). The management of immune-related adverse events (irAEs) is an important issue associated with achieving a good therapeutic response in patients receiving AB therapy. However, few studies have reported irAE development in patients receiving AB therapy. This study focused on the association between irAE development and autoantibodies at baseline in patients receiving AB therapy. METHODS: Sixty-one patients receiving AB therapy were enrolled. For autoantibodies, the following antibodies were tested before the start of AB therapy: antinuclear antibodies, rheumatoid factor (RF), anti-thyroglobulin antibodies, thyroid peroxidase antibodies, anti-thyroid stimulating hormone receptor antibodies, and acetylcholine receptor antibodies. A patient was considered to have pre-existing antibodies if any of the listed antibodies were present at baseline. RESULTS: Ten patients (16%) developed irAEs during the observation period. The irAEs included liver injury, hypothyroidism, adrenal insufficiency, adrenocorticotropic hormone deficiency, and rhabdomyolysis. Patients with irAE (n = 10) were more likely to be positive for any autoantibody (hazard ratio [HR] 3.7, p = 0.047) and RF at baseline (HR 5.4, p = 0.035) and to achieve complete response (HR 5.8, p = 0.027) than those without. The presence of autoantibodies at baseline was an independent factor associated with irAE development. CONCLUSION: In the real world, 16% of patients receiving AB therapy for u-HCC developed irAEs. Patients with autoantibodies at baseline are at high risk of developing irAEs and require cautious follow-up.
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AIM: The role of the zinc fingers and homeoboxes family (ZHX1-3), transcriptional repressors, through their subcellular localization in hepatocellular carcinoma (HCC), is not fully understood. The present study aimed to examine the differential nuclear and cytoplasmic expression of ZHXs in HCC tissues. METHODS: Immunohistochemistry was utilized to detect the expression of ZHXs in 54 liver tissues from HCC (n = 33), hepatitis C (n = 16), and the normal liver tissue surrounding hepatic metastasis of colorectal cancer (n = 5). Next-generation sequencing and digital polymerase chain reaction identified gene mutations associated with HCC. Kaplan-Meier curves were constructed to evaluate the relationship between ZHX expression and survival. The results were validated using data from The Cancer Genome Atlas. Univariate and multivariate Cox regression analyses were undertaken to identify independent prognostic factors. RESULTS: High nuclear expression of ZHX1 was associated with poor overall survival (OS), while high nuclear expression of ZHX2 correlated with higher recurrence. Conversely, patients with high cytoplasmic expression of ZHX3 had lower recurrence and better OS. Hepatitis B virus-associated HCC was related to high cytoplasmic expression of ZHX1, which was marginally related to telomerase reverse transcriptase (TERT) promoter mutation-negative HCC. In contrast, low nuclear expression of ZHX3 was associated with TERT promoter mutation-positive HCC and HCC patients over 70 years old. CONCLUSIONS: These results suggest that the expression and localization of different ZHXs may be related to HCC progression, potentially inferring genetic backgrounds such as TERT promoter mutation. Further studies on the relationship between HCC and ZHXs will enhance our understanding and control of HCC.
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OBJECTIVES: In patients with unresectable malignant hilar biliary obstruction (UMHBO), drainage of ≥ 50% liver volume correlates with better clinical outcomes. Accurately measuring the liver volume to be drained by biliary stents is required. We aimed to develop a novel method for calculating the drained liver volume (DLV) using a 3D volume analyzer (3D volumetry), and assess the usefulness for drainage in patients with UMHBO. METHODS: Three-dimensional volumetry comprises the following steps: (1) manual tracing of bile duct using 3D imaging system; (2) 3D reconstruction of bile duct and liver parenchyma; and (3) calculating DLV according to the 3D distribution of bile ducts. Using 3D volumetry, we reviewed data of patients who underwent biliary drainage for UMHBO, calculated the DLV, and determined the association between DLV and biliary drainage outcome. RESULTS: There were 104 eligible cases. The mean DLV was 708 ± 393 ml (53% ± 21%). and 65 patients (63%) underwent drainage of ≥50% liver volume. The clinical success rate was significantly higher in patients with DLV ≥ 50% than in patients with DLV < 50% (89% vs. 28%, P < 0.001). The median time to recurrence of biliary obstruction (TRBO) and survival time were significantly longer in patients with DLV ≥ 50% than in patients with DLV < 50% (TRBO, 292 vs. 119 days, P = 0.03; survival, 285 vs. 65days, P = 0.004, log-rank test, respectively). CONCLUSIONS: Three-dimensional volumetry, a novel method to calculate DLV accurately according to bile duct distribution was useful for drainage in UMHBO patients.
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Neoplasias de los Conductos Biliares , Colestasis , Humanos , Neoplasias de los Conductos Biliares/complicaciones , Neoplasias de los Conductos Biliares/diagnóstico por imagen , Neoplasias de los Conductos Biliares/patología , Hígado/diagnóstico por imagen , Hígado/patología , Colestasis/diagnóstico por imagen , Colestasis/etiología , Colestasis/cirugía , Conductos Biliares/patología , Stents , Drenaje/métodos , Resultado del TratamientoRESUMEN
The advent of direct-acting antiviral (DAA) therapy has revolutionized hepatitis C virus (HCV) treatment, enabling most HCV-infected patients to achieve a sustained viral response (SVR) easily and safely in a short period. On the other hand, it is gradually being recognized that a significant proportion of patients are still at risk of developing de novo and recurrent hepatocellular carcinoma (HCC), even after HCV elimination, and therefore, elucidation of the risk of de novo and recurrent HCC, investigation of its molecular basis, and construction of accurate prediction models are emerging as new important clinical topics. In this review, we present recent advances regarding these issues.
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A 76-year-old woman with a suspected double extrahepatic bile duct was referred to our hospital. MRCP revealed that the left hepatic and posterior ducts combined to form the ventral bile duct and that the anterior duct formed the dorsal bile duct. ERCP demonstrated that the ventral bile duct was linked with the Wirsung duct. Amylase levels in the bile were unusually high. Based on these findings, we diagnosed a double extrahepatic bile duct with pancreaticobiliary maljunction and choledocholithiasis. Duplicate bile duct resection and bile duct jejunal anastomosis were performed considering the risk of biliary cancer due to pancreaticobiliary maljunction. The resected bile duct epithelium demonstrated no atypia or hyperplastic changes.
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Conductos Biliares Extrahepáticos , Procedimientos Quirúrgicos del Sistema Biliar , Mala Unión Pancreaticobiliar , Femenino , Humanos , Anciano , Mala Unión Pancreaticobiliar/cirugía , Conductos Biliares Extrahepáticos/diagnóstico por imagen , Conductos Biliares Extrahepáticos/cirugía , Conductos Pancreáticos/diagnóstico por imagen , Conductos Pancreáticos/cirugía , Conductos Biliares/diagnóstico por imagen , Conductos Biliares/cirugía , BilisRESUMEN
INTRODUCTION: Atezolizumab plus bevacizumab combination therapy (AB) was the first-line treatment for unresectable hepatocellular carcinoma (u-HCC). IFN-γ-induced protein 10 (IP-10/CXCL10) is a chemokine to inhibit HCC proliferation by promoting the migration of cytotoxic T cells. We focused on the relationship between plasma IP-10/CXCL10 levels and the initial therapeutic response in patients receiving AB therapy. METHODS: Forty-six patients receiving AB therapy were enrolled. Plasma IP-10/CXCL10 levels were measured at baseline, 3-7 days, 3 weeks, 6 weeks, and 8-12 weeks after the start of AB therapy. The initial therapeutic response was evaluated at 8-12 weeks. RESULTS: The baseline IP-10/CXCL10 levels of partial response (PR) group was higher than that of stable disease (SD) or progressive disease (PD) group. Patients with the baseline IP-10/CXCL10 of 84 pg/mL or higher were likely to present PR than patients below (71 vs. 35%, p = 0.031), but prediction of PD using the baseline IP-10/CXCL10 levels was difficult. In contrast, IP-10/CXCL10 ratio of the PR group was lower than that of the SD/PD group at 3, 6, and 8-12 weeks. Patients with the 3, 6, and 8-12 weeks IP-10/CXCL10 ratio of 1.3, 0.4, and 0.4 or lower were likely to present PR than patients with ≥1.3, 0.4, and 0.4 (88, 35, 35 vs. 30, 3.8, 0%, p < 0.001, 0.011, 0.002). In other hand, the 3, 6, and 8-12 weeks IP-10/CXCL10 ratio for PD group was higher than that for non-PD group. Patients with the 3, 6, and 8-12 weeks IP-10/CXCL10 ratio of 1.3, 1.7, and 1.9 or higher were likely to present PD than patients below (85, 62, 57 vs. 32, 23, 14%, p = 0.002, 0.034, 0.009). CONCLUSION: High baseline IP-10/CXCL10 levels may be associated with better outcome, and high IP-10/CXCL10 ratio after 3-12 weeks may be associated with worse outcome in u-HCC patients receiving AB therapy.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Humanos , Carcinoma Hepatocelular/tratamiento farmacológico , Carcinoma Hepatocelular/patología , Bevacizumab , Quimiocina CXCL10/metabolismo , Quimiocina CXCL10/uso terapéutico , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Hepáticas/patologíaRESUMEN
INTRODUCTION: Atezolizumab and bevacizumab (AB) therapy was the first-line treatment for unresectable hepatocellular carcinoma (u-HCC). However, the predictive marker of therapeutic response that can be easily used in clinical practice is still unknown. We prospectively investigated the utility of time-intensity curve (TIC) analysis using contrast-enhanced ultrasound (CEUS) as a predictive indicator of therapeutic response after the start of AB therapy. METHODS: Thirty-five patients who received AB therapy for u-HCC were included in this study. TIC analysis was performed in 28 patients who were able to undergo CEUS before and 3-7 days after administration. We analyzed prognostic factors related to the initial therapeutic response and long progression-free survival (PFS). RESULTS: The initial therapeutic response using dynamic computed tomography or Gd-EOB magnetic resonance imaging at 8-12 weeks after administration was partial response/stable disease/progressive disease (PD) in 14/12/9 cases (40/34/26%). Cases with PD (n = 9) had more cases without decreased blood flow in TIC analysis compared with cases with non-PD (100 vs. 18%, p = 0.001). Cases without decreased blood flow in TIC analysis (n = 10) had more cases with PD compared with cases with decreased blood flow (60 vs. 0%, p = 0.001). PFS in patients without decreased blood flow early after the administration was shorter than that in those with decreased blood flow (9.1 vs. 28 weeks, p = 0.0051). CONCLUSION: Early evaluation by TIC analysis using CEUS may be useful in predicting the therapeutic response in patients treated with AB therapy for u-HCC.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Humanos , Carcinoma Hepatocelular/diagnóstico por imagen , Carcinoma Hepatocelular/tratamiento farmacológico , Carcinoma Hepatocelular/patología , Bevacizumab , Neoplasias Hepáticas/diagnóstico por imagen , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Hepáticas/patología , Pueblos del Este de Asia , Medios de Contraste/uso terapéuticoRESUMEN
INTRODUCTION: Several studies have reported kidney injury caused by immune checkpoint inhibitors, and proteinuria caused by vascular endothelial growth factor inhibitors for unresectable hepatocellular carcinoma (u-HCC). We investigated the relationship between renal function and prognosis in patients with u-HCC receiving atezolizumab and bevacizumab (AB) and lenvatinib (LEN) therapy. METHODS: Fifty-one patients who received AB and 50 patients who received LEN therapy were included. We analyzed prognostic factors related to the overall survival (OS), and characteristics related to renal function. RESULTS: In patients with AB therapy, OS was shorter in patients with baseline proteinuria of 1+ or higher, as assessed by urine dipstick test, compared to those with -/± (p = 0.024). There were many cases with two or more drugs with a high risk of renal dysfunction (p = 0.019) in patients with 1+ or higher. Furthermore, OS was shorter in the group with estimated glomerular filtration rate (eGFR) grade deterioration without urinary protein-creatinine ratio (UPCR) of 2 g/g·Cre or higher than in the other groups (p = 0.027). In the group where eGFR worsened without an increase in UPCR, there were many cases with a daily salt intake of 10 g or more (p = 0.027), three or more drugs with a high risk of renal dysfunction (p = 0.021), and a history of arteriosclerosis (p = 0.021). On the other hand, in patients with LEN therapy, OS tends to be shorter in patients with proteinuria of ± or higher, compared to those without (p = 0.074). There were many cases with a daily salt intake of 10 g or more in patients with ± or higher (p = 0.002). CONCLUSION: In patients receiving AB and LEN therapy, baseline proteinuria was associated with OS. Renal function deterioration without proteinuria was associated with a poor prognosis in AB therapy. Excessive salt intake, preexisting atherosclerotic disease, and drug with a high risk of renal dysfunction were risk factors for renal deterioration.
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Carcinoma Hepatocelular , Enfermedades Renales , Neoplasias Hepáticas , Humanos , Carcinoma Hepatocelular/tratamiento farmacológico , Bevacizumab/efectos adversos , Cloruro de Sodio Dietético , Factor A de Crecimiento Endotelial Vascular , Neoplasias Hepáticas/tratamiento farmacológico , Pronóstico , Riñón/fisiologíaRESUMEN
BACKGROUND: The damping ratio (DR) and the loss modulus (Gâ³) obtained by 3D MR elastography complex modulus analysis has been reported recently to reflect early intrahepatic inflammation, and is expected to be a noninvasive biomarker of inflammation in nonalcoholic fatty liver disease (NAFLD). However, the role of the DR and the Gâ³ in Japanese NAFLD patients remains unclear. METHODS: We enrolled 39 Japanese patients with NAFLD who underwent liver biopsy and 3D MR elastography within 1 month and analyzed the association between DR, Gâ³, and histological activity. RESULTS: Regarding DR, no evident correlation was observed between the DR and histological activity (p = 0.14) when patients with all fibrosis stages were included. However, when patients were restricted up to stage F2 fibrosis, the association of the DR and inflammation became significant, the DR increasing with the degree of activity (p = 0.02). Among the constituents of fibrosis activity, ballooning correlated with the DR (p < 0.01) while lobular inflammation did not. Regarding Gâ³, it was correlated with histological activity (p < 0.01), ballooning (p < 0.01), and lobular inflammation (p < 0.01) in patients with all fibrosis stages and in patients up to F2 fibrosis (p = 0.03 for activity and p = 0.04 for ballooning). The best cutoff value of DR for hepatitis activity in patients within the F2 stage was 0.094 (area under the receiver operating characteristic curve 0.775, 95% CI: 0.529-1.000) and Gâ³ was 0.402 (area under the receiver operating characteristic curve 0.825, 95% CI: 0.628-1.000). CONCLUSIONS: The DR and Gâ³ reflected the histological activity in Japanese patients with NAFLD during the early stage, indicating these values for noninvasive diagnosis of inflammation in Japanese patients with NAFLD.
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BACKGROUND: Recently, with the advent of sofosbuvir/velpatasvir therapy, sustained virological response (SVR) can now be achieved even in patients with decompensated cirrhosis (dLC). However, the prognosis after SVR does not always improve in dLC, and appropriate indicators enabling prediction of prognosis is desired. PATIENTS AND METHODS: Serum IP-10/CXCL10 levels were measured in 47 patients (15 chronic hepatitis [CH], 17 compensated cirrhosis [cLC], and 15 dLC) receiving direct acting antiviral (DAA) therapy, and their changes during the therapy were examined. RESULTS: All the patients achieved SVR. In patients with CH, the average IP-10 level was 367, 102, and 68 pg/ml respectively at baseline, at the end of therapy and at 12 weeks after SVR (SVR12), and was decreased upon DAA therapy (P < 0.001). In patients with cLC, IP-10 was respectively 215, 91, and 77 pg/ml, and was decreased upon DAA therapy (P < 0.001) while it was 283, 131, and 182 pg/ml in patients with dLC and there was no evident decrease (P = 0.55). When patients with dLC were further classified depending on the difference in Child-Pugh (CP) score improvement at SVR12, a significant decrease in IP-10 was observed after treatment in those with improvement (P = 0.023) while a significant increase was observed in those without improvement (P = 0.016). CONCLUSION: While serum IP-10 level was decreased in patients with CH/cLC and dLC with post-SVR-CP improvement following SVR, it was increased in patients with dLC without post-SVR CP improvement. The result indicates that IP-10 dynamics may be useful for predicting liver function after DAA therapy.
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AIM: The prevalence of nonalcoholic fatty liver disease (NAFLD) is increasing worldwide. The aim of this study was to determine the recent prevalence and clinical characteristics of NAFLD in Japan. METHODS: This study initially included 410 061 retrospectively enrolled adults from the medical health checkup registry for metabolic syndrome, chronic kidney disease, and fatty liver in Japan (MIRACLE-J; UMIN-CTR no. UMIN000049419), who were evaluated between 2014 and 2018 at 13 health centers in Japan. Individuals consuming >20 g of alcohol/day or with chronic liver disease were excluded. Fatty liver was diagnosed by ultrasonography. The probability of NAFLD with advanced fibrosis was estimated based on the fibrosis-4 index and NAFLD fibrosis score. RESULTS: A total of 71 254 participants were included in the final analysis. The overall prevalence of NAFLD was 25.8%. There was a significant, twofold difference in NAFLD prevalence between men (37.4%) and women (18.1%). Nonalcoholic fatty liver disease prevalence increased linearly with body mass index, triglycerides, and low-density lipoprotein cholesterol regardless of threshold values, even in the absence of obesity. Among patients with NAFLD, 14% had diabetes mellitus, 31% had hypertension, and 48% had dyslipidemia. The estimated prevalence of NAFLD with advanced fibrosis was 1.7% and 1.0% according to the fibrosis-4 index and NAFLD fibrosis score, respectively. CONCLUSIONS: The prevalence of NAFLD was approximately one-quarter of the general population in Japan. There was a linear relationship between NAFLD prevalence and various metabolic parameters, even in nonobese participants. The prevalence of NAFLD with advanced fibrosis was estimated to be 1%-2%.
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BACKGROUND AND AIM: Recently, pemafibrate and a low-carbohydrate diet (LCD) have each been reported to improve fatty liver disease. However, it is unclear whether their combination improves fatty liver disease and is equally effective in obese and non-obese patients. METHODS: In 38 metabolic-associated fatty liver disease (MAFLD) patients, classified by baseline body mass index (BMI), changes in laboratory values, magnetic resonance elastography (MRE), and magnetic resonance imaging-proton density fat fraction (MRI-PDFF) were studied after 1 year of combined pemafibrate plus mild LCD. RESULTS: The combination treatment resulted in weight loss (P = 0.002), improvement in hepatobiliary enzymes (γ-glutamyl transferase, P = 0.027; aspartate aminotransferase, P < 0.001; alanine transaminase [ALT], P < 0.001), and improvement in liver fibrosis markers (FIB-4 index, P = 0.032; 7 s domain of type IV collagen, P = 0.002; M2BPGi, P < 0.001). Vibration-controlled transient elastography improved from 8.8 to 6.9 kPa (P < 0.001) and MRE improved from 3.1 to 2.8 kPa (P = 0.017) in the liver stiffness. MRI-PDFF improved from 16.6% to 12.3% in liver steatosis (P = 0.007). In patients with a BMI of 25 or higher, improvements of ALT (r = 0.659, P < 0.001) and MRI-PDFF (r = 0.784, P < 0.001) were significantly correlated with weight loss. However, in patients with a BMI below 25, the improvements of ALT or PDFF were not accompanied by weight loss. CONCLUSIONS: Combined treatment with pemafibrate and a low-carbohydrate diet resulted in weight loss and improvements in ALT, MRE, and MRI-PDFF in MAFLD patients. Although such improvements were associated with weight loss in obese patients, the improvements were observed irrespective of weight loss in non-obese patients, indicating this combination can be effective both in obese and non-obese MAFLD patients.
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Hígado , Enfermedad del Hígado Graso no Alcohólico , Humanos , Hígado/diagnóstico por imagen , Hígado/patología , Enfermedad del Hígado Graso no Alcohólico/diagnóstico por imagen , Enfermedad del Hígado Graso no Alcohólico/tratamiento farmacológico , Enfermedad del Hígado Graso no Alcohólico/complicaciones , Butiratos , Obesidad/complicaciones , Obesidad/tratamiento farmacológico , Obesidad/patología , Imagen por Resonancia Magnética/métodos , Pérdida de PesoRESUMEN
One concern associated with pancreatic diseases is the poor prognosis of pancreatic cancer. Even with advances in diagnostic modalities, risk stratification of premalignant lesions and differentiation of pancreatic cysts are challenging. Pancreatic lesions of concern include intraductal papillary mucinous neoplasms, mucinous cystic neoplasms, serous cystadenomas, pseudocysts, and retention cysts, as well as cystic degeneration of solid tumors such as solid pseudopapillary neoplasms and pancreatic neuroendocrine neoplasms. Pancreatic juice obtained during endoscopic retrograde cholangiopancreatography has previously been used for the detection of KRAS mutation. Recently, duodenal fluid, which can be obtained during the relatively minimally invasive procedures of endoscopic ultrasound (EUS) and esophagogastroduodenoscopy, and cyst fluid collected by EUS-guided fine-needle aspiration (FNA) were used for molecular biological analysis. Furthermore, advanced analytic methods with high sensitivity were used for the detection of single and multiple markers. Early detection of malignant pancreatic tumors and risk stratification of premalignant tumors can be performed using duodenal fluid samples with a single marker with high sensitivity. Technological advances in simultaneous detection of multiple markers allow for the differentiation of cystic pancreatic tumors. One thing to note is that the clinical guidelines do not recommend pancreatic cyst fluid and pancreatic juice (PJ) sampling by EUS-FNA and endoscopic retrograde cholangiopancreatography, respectively, in actual clinical practice, but state that they be performed at experienced facilities, and duodenal fluid sampling is not mentioned in the guidelines. With improved specimen handling and the combination of markers, molecular markers in PJ samples may be used in clinical practice in the near future.
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Quiste Pancreático , Neoplasias Pancreáticas , Humanos , Jugo Pancreático , Neoplasias Pancreáticas/patología , Quiste Pancreático/patología , Biopsia con Aguja Fina , Mutación , Biopsia por Aspiración con Aguja Fina Guiada por Ultrasonido EndoscópicoRESUMEN
Routinely available clinical samples of all stages of pancreatic cancer are used in the present study to elucidate its molecular mechanisms and identify novel therapeutic targets. We evaluated the use of next-generation sequencing (NGS) of endoscopically obtained pancreatic cancer tissues. We enrolled 147 patients who underwent endoscopic ultrasound-guided fine-needle aspiration or endoscopic biopsy. The quantity and quality of the extracted DNA was assessed. Tissue samples were used for NGS of 78 cancer-related genes, from which gene alterations and microsatellite instability (MSI) were extracted. NGS was successful in 141 out of 147 (96%) cases. Gene alterations were detected in 134 out of 141 (91%) samples, among which eight out of 10 samples with a DNA concentration below the detection limit had some type of gene alteration. Targetable genes were detected in 28 (19.9%) cases. MSI and germline mutations in homologous recombination repair associated genes were detected in 5% and 3% of cases, respectively. Cox regression analysis revealed that metastasis (P < .005; hazard ratio [HR], 3.30) was associated with poor prognosis in all pancreatic cancer patients. In addition, fewer than three mutations (P = .03; HR, 2.48) and serum carcinoembryonic antigen levels >5 ng/mL (P < .005; HR, 3.94) were associated with worse prognosis in cases without and with metastasis, respectively. Targeted sequencing of all stages of pancreatic cancer using available samples from real clinical practice could be used to determine the relationship between gene alterations and prognosis to help determine treatment choices.
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Secuenciación de Nucleótidos de Alto Rendimiento , Neoplasias Pancreáticas/genética , Adulto , Anciano , Anciano de 80 o más Años , Biomarcadores de Tumor/genética , Biopsia por Aspiración con Aguja Fina Guiada por Ultrasonido Endoscópico , Femenino , Humanos , Masculino , Inestabilidad de Microsatélites , Persona de Mediana Edad , Mutación , Neoplasias Pancreáticas/mortalidad , Neoplasias Pancreáticas/patología , Pronóstico , Tasa de SupervivenciaRESUMEN
BACKGROUND AND AIMS: A retrospective study was to analyze the association of plasma renin activity (PRA) with overall survival and liver disease-related events in decompensated liver cirrhosis with ascites treated by tolvaptan. METHODS: We included 196 patients with decompensated cirrhosis treated with tolvaptan and for whom hepatic ascites had remained uncontrolled by conventional diuretics. Factors associated with prognosis and appearance of liver disease-related events were investigated, including vasopressin, sympathetic nervous system hormones (adrenaline, noradrenaline, and dopamine), and the renin-angiotensin system (PRA and aldosterone) at the beginning of tolvaptan treatment. RESULTS: Age, history of hepatocellular carcinoma (HCC), and PRA were identified as independent factors for prognosis after tolvaptan treatment. The median survival time in patients with PRA ≥9.5 ng/mL/h at the beginning of tolvaptan treatment was significantly shorter than in patients with PRA <9.5 ng/mL/h (193 vs. 893 days, p < 0.001). PRA and a history of HCC were independent factors for the occurrence of liver disease-related events. The median event-free period in patients with PRA ≥3.2 ng/mL/h was significantly shorter than that of patients with PRA <3.2 ng/mL/h (89 vs. 222 days, p < 0.001). CONCLUSIONS: PRA is an independent predictor of prognosis and appearance of liver disease-related events in patients with decompensated cirrhosis who have started tolvaptan treatment.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Ascitis/tratamiento farmacológico , Ascitis/etiología , Carcinoma Hepatocelular/complicaciones , Carcinoma Hepatocelular/tratamiento farmacológico , Humanos , Cirrosis Hepática/complicaciones , Cirrosis Hepática/tratamiento farmacológico , Neoplasias Hepáticas/complicaciones , Neoplasias Hepáticas/tratamiento farmacológico , Pronóstico , Renina , Estudios Retrospectivos , Tolvaptán/uso terapéuticoRESUMEN
Almost all patients achieved sustained virological response (SVR) by direct-acting antivirals (DAA) therapy, but it is not clear as to what extent DAA therapy affects changes in liver fibrosis after achieving SVR. In this study, we investigated the changes of liver stiffness by magnetic resonance elastogaraphy (MRE) during DAA therapy. A total of 308 patients were enrolled in the study. Liver stiffness was measured twice before and after DAA treatment using MRE and time-course change of liver stiffness was investigated. The median (interquartile range) values for liver stiffness were 4.2 (3.2-6.1) kPa at baseline and 3.3 (2.6-4.8) kPa at SVR, demonstrating a significant improvement (p < .01). A total of 44% of patients had no improvement in liver stiffness despite achieving SVR. In patients with advanced fibrosis (lower level of albumin [Alb] or histological fibrosis stage F4), it was difficult to improve liver stiffness. Except for Alb, there were no blood tests associated with nonimprovement in liver stiffness, making these cases difficult to predict. In conclusion, despite obtaining SVR, improvement in liver stiffness could not be obtained in some cases, especially in patients with advanced fibrosis. In these patients, liver stiffness must be followed even if SVR is obtained.
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Antivirales/uso terapéutico , Diagnóstico por Imagen de Elasticidad/métodos , Hepatitis C Crónica/tratamiento farmacológico , Hígado/patología , Anciano , Femenino , Hepacivirus/efectos de los fármacos , Hepatitis C Crónica/diagnóstico por imagen , Hepatitis C Crónica/virología , Humanos , Hígado/diagnóstico por imagen , Cirrosis Hepática/diagnóstico por imagen , Cirrosis Hepática/patología , Masculino , Persona de Mediana Edad , Respuesta Virológica Sostenida , Resultado del TratamientoRESUMEN
BACKGROUND: The genetic changes underlying carcinogenesis in patients with risk factors of gallbladder carcinoma (GBC) remains controversial, especially in patients with pancreaticobiliary maljunction (PBM). This study aimed to clarify the association between risk factors of GBC and genetic changes using next-generation sequencing (NGS). METHODS: We retrospectively analyzed resected tissues of 64 patients who were diagnosed with GBC (n = 26), PBM [with GBC (n = 8), without GBC (n = 20)], and chronic cholecystitis, used as a control group (n = 10). DNA was extracted from tumors and their surrounding tissues, which were precisely separated by laser-capture microdissection. Gene alterations of 50 cancer-related genes were detected by NGS and compared with clinical information, including PBM status. RESULTS: The most frequent gene alterations in GBC tissues occurred in TP53 (50%), followed by EGFR (20.6%), RB1 (17.6%), and ERBB2 (17.6%). Gene alterations that were targetable by molecular targeted drugs were detected in 20 cases (58.8%). Statistical analysis of gene alterations and risk factors revealed that TP53 alteration rate was higher in GBC patients with PBM than those without PBM (p = 0.038), and the TP53 mutation rates in the epithelium of control patients, epithelium of PBM patients without GBC, peritumoral mucosa of GBC patients with PBM, and tumor tissue of GBC patients with PBM were 10, 10, 38, and 75%, respectively (p < 0.01). CONCLUSIONS: TP53 alteration more than KRAS mutation was revealed to underlie carcinogenesis in patients with PBM.
Asunto(s)
Neoplasias de la Vesícula Biliar/genética , Genes p53/genética , Mutación , Mala Unión Pancreaticobiliar/genética , Adulto , Anciano , Estudios de Casos y Controles , Colecistitis/genética , Femenino , Perfilación de la Expresión Génica , Genes de Retinoblastoma , Genes erbB-1 , Genes erbB-2 , Genes ras , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Masculino , Persona de Mediana Edad , Acumulación de Mutaciones , Estudios Retrospectivos , Factores de RiesgoRESUMEN
Nonalcoholic fatty liver disease (NAFLD) has become a serious public health issue not only in Western countries but also in Japan. Within the wide spectrum of NAFLD, nonalcoholic steatohepatitis (NASH) is a progressive form of disease that often develops into liver cirrhosis and increases the risk of hepatocellular carcinoma (HCC). While a definite diagnosis of NASH requires liver biopsy to confirm the presence of hepatocyte ballooning, hepatic fibrosis is the most important prognostic factor in NAFLD. With so many NAFLD patients, it is essential to have an effective screening method for NAFLD with hepatic fibrosis. As HCC with non-viral liver disease has increased markedly in Japan, effective screening and surveillance of HCC are also urgently needed. The most common death etiology in NAFLD patients is cardiovascular disease event. Gastroenterologists must, therefore, pay close attention to CVD when examining NAFLD patients. In the updated guidelines, we propose screening and follow-up methods for hepatic fibrosis, HCC, and CVD in NAFLD patients. Several drug trials are ongoing for NAFLD/NASH therapy, however, there is currently no specific drug therapy for NAFLD/NASH. In addition to vitamin E and thiazolidinedione derivatives, recent trials have focused on sodium glucose co-transporter 2 (SGLT2) inhibitors and glucagon-like peptide-1 (GLP-1) analogues, and effective therapies are expected to be developed. These practical guidelines for NAFLD/NASH were established by the Japanese Society of Gastroenterology in conjunction with the Japan Society of Hepatology. Clinical evidence reported internationally between 1983 and October 2018 was collected, and each clinical and background question was evaluated using the Grades of Recommendation Assessment, Development and Evaluation (GRADE) system. This English summary pro- vides the core essentials of these clinical practice guidelines, which include the definition and concept, screening systems for hepatic fibrosis, HCC and CVD, and current therapies for NAFLD/NASH in Japan.
RESUMEN
The first edition of the clinical practice guidelines for liver cirrhosis was published in 2010, and the second edition was published in 2015 by the Japanese Society of Gastroenterology (JSGE). The revised third edition was recently published in 2020. This version has become a joint guideline by the JSGE and the Japanese Society of Hepatology (JSH). In addition to the clinical questions (CQs), background questions (BQs) are new items for basic clinical knowledge, and future research questions (FRQs) are newly added clinically important items. Concerning the clinical treatment of liver cirrhosis, new findings have been reported over the past 5 years since the second edition. In this revision, we decided to match the international standards as much as possible by referring to the latest international guidelines. Newly developed agents for various complications have also made great progress. In comparison with the latest global guidelines, such as the European Association for the Study of the Liver (EASL) and American Association for the Study of Liver Diseases (AASLD), we are introducing data based on the evidence for clinical practice in Japan. The flowchart for nutrition therapy was reviewed to be useful for daily medical care by referring to overseas guidelines. We also explain several clinically important items that have recently received focus and were not mentioned in the last editions. This digest version describes the issues related to the management of liver cirrhosis and several complications in clinical practice. The content begins with a diagnostic algorithm, the revised flowchart for nutritional therapy, and refracted ascites, which are of great importance to patients with cirrhosis. In addition to the updated antiviral therapy for hepatitis B and C liver cirrhosis, the latest treatments for non-viral cirrhosis, such as alcoholic steatohepatitis/non-alcoholic steatohepatitis (ASH/NASH) and autoimmune-related cirrhosis, are also described. It also covers the latest evidence regarding the diagnosis and treatment of liver cirrhosis complications, namely gastrointestinal bleeding, ascites, hepatorenal syndrome and acute kidney injury, hepatic encephalopathy, portal thrombus, sarcopenia, muscle cramp, thrombocytopenia, pruritus, hepatopulmonary syndrome, portopulmonary hypertension, and vitamin D deficiency, including BQ, CQ and FRQ. Finally, this guideline covers prognosis prediction and liver transplantation, especially focusing on several new findings since the last version. Since this revision is a joint guideline by both societies, the same content is published simultaneously in the official English journal of JSGE and JSH.