Progression from early to advanced stage of immune-related cholangitis.

AIM: We report a rare case of immune-related cholangitis in which the natural course could be demonstrated. CASE PRESENTATION: Eight courses of pembrolizumab maintenance therapy were given as first-line treatment for squamous cell lung cancer; however, the patient was subsequently hospitalized due to a rapid increase in hepatobiliary enzymes. On endoscopic ultrasound, the common bile duct was dilated to 11 mm, and the wall, throughout its length from the papilla, was thickened. Endoscopic retrograde cholangiopancreatography showed no obvious stenosis in the lower bile duct; however, a parapapillary diverticulum was found, and papillary incision and bile duct plastic stent insertion were carried out. However, the liver disorder did not improve and overt jaundice appeared subsequently; therefore, an immune-related cholangitis was suspected, and prednisolone (PSL) 35 mg/day was introduced from day 59 of admission. Following PSL initiation, a decrease in serum bilirubin level was observed; however, significant decrease was not observed in alkaline phosphatase. Given the history of recurrent infectious cholangitis, magnetic resonance cholangiopancreatography was carried out on day 70 of admission. The intrahepatic bile duct showed stenosis and dilated findings, which was considered to be a factor for repeated infectious cholangitis. CONCLUSION: No previous case reports have described the changes and progression in bile duct images in immune-related adverse events. Therefore, this case is noteworthy for considering the progression of immune-related cholangitis.

Clinical implication of immune checkpoint inhibitor on the chronic hepatitis B virus infection.

AIM: The risk of hepatitis B virus (HBV) reactivation with immune checkpoint inhibitors (ICIs) is an important issue that has not yet been fully investigated. ICI is also expected to have an antiviral effect on HBV due to its immune tolerance inhibitory effect. We herein investigated the risk of HBV reactivation and the antiviral effect of ICI administration. METHODS: This study included 892 patients on ICIs between September 2014 and May 2021 at our hospital. The frequency of HBV reactivation and antiviral effects were investigated. RESULTS: Among the 892 patients who underwent ICI, 27 were hepatitis B surface antigen (HBsAg) positive. HBV reactivation was evaluated in 24 cases, among which 4.1% (1/24) had HBV reactivation. Nucleic acid analog prophylaxis was not administered to patients with reactivation. In a study of 15 cases, the amount of HBsAg decreased from baseline; 2.18 ± 0.77 log to 48 weeks later; 1.61 ± 1.38 log (p = 0.17). Forty-eight weeks after the start of ICI, disappearance of HBsAg was observed in two out of 15 cases (13.3%), and one case each with and without nucleic acid analog. CONCLUSION: In rare cases, HBsAg-positive patients may be reactivated by ICI administration. On the other hand, when ICI is administered, it is expected to have an antiviral effect on HBV due to its immune tolerance inhibitory effect, and future drug development is expected.

Comparison of efficacy and safety of entecavir and switching from entecavir to tenofovir alafenamide fumarate in chronic hepatitis B: Long-term effects from a prospective study.

AIM: Both entecavir (ETV) and tenofovir alafenamide fumarate (TAF) are widely used to treat chronic hepatitis B (CHB) in Japan. However, it remains unclear whether the efficacy of TAF in decreasing the hepatitis B surface antigen (HBsAg) level, and its safety, are superior to those of ETV. This study aimed to report the long-term effects and safety of 96-week ETV and TAF treatment in patients with CHB. METHODS: A prospective comparative observational study was undertaken on the following two groups: patients with CHB who received continuous ETV (n = 32) and patients with CHB who were switched from ETV to TAF upon request (n = 48). The HBsAg, urinary ß2-microglobulin (ß2MG)/creatinine (Cr), urinary N-acetyl-ß-D-glucosaminidase (NAG)/Cr, and serum alanine aminotransferase (ALT) levels, estimated glomerular filtration rate (eGFR), and bone mineral density (lumbar spine and femur) at 96 weeks were compared. RESULTS: The two groups did not significantly differ with respect to mean age, male / female patient ratio, or rate of hepatitis B e antigen-positive status. The mean changes in serum HBsAg level and eGFR at 96 weeks were not significantly different between the two groups. The ß2MG/Cr and NAG/Cr levels at 96 weeks were similar between the two groups. Additionally, the bone mineral density of the lumbar spine and femur as well as the serum ALT did not significantly differ. CONCLUSIONS: When compared with patients who received continuous ETV, those who were introduced to TAF after ETV showed similar effects in terms of the decrease in HBsAg level and safety.

Radiofrequency ablation for hepatocellular carcinoma: Clinical value of ultrasound-ultrasound overlay fusion for optimal ablation and local controllability.

AIM: To retrospectively investigate the potential benefit of ultrasound-ultrasound (US-US) overlay fusion guidance for local controllability of radiofrequency ablation (RFA) in the treatment of hepatocellular carcinoma (HCC). METHODS: Patients (n = 101) with 121 HCCs (mean ± SD, 1.8 ± 0.7 cm) who underwent RFA guided by US-US overlay fusion were included in the retrospective study. By overlaying pre/postoperative US, the tumor image could be projected onto the ablative hyperechoic zone. The ablative margin could thereby be evaluated three-dimensionally during the RFA procedure. As a control group, all 325 patients with 453 HCCs who underwent conventional RFA during the same study period were selected. RESULTS: The total number of RF needle insertions per tumor for ablation was significantly more in the US overlay fusion group (mean 1.9 vs. 1.2; P < 0.01). The technical success rates of ablation after a single session were 100% (101/101) and 96.6% (314/325) for the US overlay fusion group and the control group, respectively. For early assessment of RFA response, 5-mm safety margins were achieved in 89.3% (108/121) and 47.0% (213/453) of nodules in the US overlay fusion group and the control group, respectively (P < 0.01). During the follow-up period (median 19 months), the 2-year local tumor progression rates were 0.8% (1/121) and 6.0% (27/453) in the US overlay fusion group and the control group, respectively (P = 0.022, log-rank test). CONCLUSIONS: US-US overlay fusion guidance can be highly effective for safety margin achievement in RFA for HCC, providing a lower risk of local tumor progression.

Switching from entecavir to tenofovir alafenamide versus maintaining entecavir for chronic hepatitis B.

Tenofovir alafenamide (TAF) is a newly developed prodrug of tenofovir (TFV). We divided 48 chronic hepatitis B patients who had taken entecavir (ETV) for ≥2 years into two groups: the ETV continuation (n = 24) and the TAF switching (n = 24) groups, and compared the antiviral effects and safety until 48 weeks after the start of the study. There were no significant differences in the alterations in the serum levels of HBs antigen (HBsAg) level between the ETV continuation and the TAF switching groups at 24 or 48 weeks. We also examined the effect of baseline HBsAg level on the decrease of HBsAg during the treatment; in the TAF switching group, the decrease of HBsAg level at 48 weeks was more significant in patients with low baseline HBsAg (<800 IU/mL) than those with high baseline HBsAg ( >800 IU/mL) (change of HBsAg; - 0.029 vs - 0.132 for high and low baseline HBsAg, respectively, P = .007). Also, the effect on renal function was found to be comparable between the TAF switch group and the ETV continuation group. In this study, switching from ETV to TAF may represent higher efficacy for a decrease of HBsAg than a continuation of ETV among the patients with low baseline HBsAg level.

Chronic Fibro-Inflammatory Responses in Autoimmune Pancreatitis Depend on IFN-α and IL-33 Produced by Plasmacytoid Dendritic Cells.

In previous studies, we found that human IgG4-related autoimmune pancreatitis (AIP) and murine AIP are driven by activation of plasmacytoid dendritic cells (pDCs) producing IFN-α. In the present studies we examined additional roles of pDC-related mechanisms in AIP pathogenesis, particularly those responsible for induction of fibrosis. We found that in murine AIP (MRL/Mp mice treated with polyinosinic-polycytidylic acid) not only the pancreatic infiltration of immune cells but also the development of fibrosis were markedly reduced by the depletion of pDCs or blockade of type I IFN signaling; moreover, such treatment was accompanied by a marked reduction of pancreatic expression of IL-33. Conversely, polyinosinic-polycytidylic acid-induced inflamed pancreatic tissue in murine AIP exhibited increased expression of type I IFNs and IL-33 (and downstream IL-33 cytokines such as IL-13 and TGF-ß1). pDCs stimulated by type I IFN were the source of the IL-33 because purified populations of these cells isolated from the inflamed pancreas produced a large amount of IL-33 upon activation by TLR9 ligands, and such production was abrogated by the neutralization of type I IFN. The role of IL-33 in murine AIP pathogenesis was surprisingly important because blockade of IL-33 signaling by anti-ST2 Ab attenuated both pancreatic inflammation and accompanying fibrosis. Finally, whereas patients with both conventional pancreatitis and IgG4-related AIP exhibited increased numbers of acinar cells expressing IL-33, only the latter also exhibited pDCs producing this cytokine. These data thus suggest that pDCs producing IFN-α and IL-33 play a pivotal role in the chronic fibro-inflammatory responses underlying murine AIP and human IgG4-related AIP.

Gankyrin Contributes to Tumorigenesis and Chemoresistance in Sporadic Colorectal Cancer.

BACKGROUND: Although Gankyrin is overexpressed in many malignancies, the role of Gankyrin for tumorigenesis and chemoresistance remains to be elucidated in sporadic colorectal cancer (CRC). AIMS: We investigate whether Gankyrin affects Adenomatous polyposis coli (Apc) inactivation-induced tumorigenesis and therapeutic response to anti-angiogenic agents. METHODS: Epithelial cell-specific APC and/or Gankyrin-deficient mice were used. The patients with metastatic CRC (n = 53) who were enrolled in this study underwent resection of primary cancer followed by systemic chemotherapy containing bevacizumab. We determined whether gene expression in CRC tissues before chemotherapy is associated with radiological responses. RESULTS: Deletion of Gankyrin in epithelial cell reduced the expression of c-Myc, a critical mediator of the APC signaling pathway, and interleukin-6. Gankyrin deficiency decreased the expression of Bmi1, a downstream molecule of c-Myc, and the activity of V-Akt murine thymoma viral oncogene homolog and extracellular signal-regulated protein kinase, leading to reduced Apc inactivation-induced tumorigenesis. Of 53 patients, 38 (72%) had increased Gankyrin expression in tumor cells. The enhanced Gankyrin expression in tumor cells was associated with unfavorable progression-free survival (log-rank test p = 0.026). CONCLUSION: Gankyrin in epithelial cell contributes to the development of sporadic CRC and the expression could serve as a biomarker to predict therapeutic response in patients with metastatic CRC.

Ultrasound-ultrasound image overlay fusion improves real-time control of radiofrequency ablation margin in the treatment of hepatocellular carcinoma.

OBJECTIVES: To assess the clinical feasibility of US-US image overlay fusion with evaluation of the ablative margin in radiofrequency ablation (RFA) for hepatocellular carcinoma (HCC). METHODS: Fifty-three patients with 68 HCCs measuring 0.9-4.0 cm who underwent RFA guided by US-US overlay image fusion were included in this retrospective study. By an overlay of pre-/postoperative US, the tumor image could be projected onto the ablative hyperechoic zone. Therefore, the ablative margin three-dimensionally could be shown during the RFA procedure. US-US image overlay was compared to dynamic CT a few days after RFA for assessment of early treatment response. Accuracy of graded response was calculated, and the performance of US-US image overlay fusion was compared with that of CT using a Kappa agreement test. RESULTS: Technically effective ablation was achieved in a single session, and 59 HCCs (86.8 %) succeeded in obtaining a 5-mm margin on CT. The response with US-US image overlay correctly predicted early CT evaluation with an accuracy of 92.6 % (63/68) (k = 0.67; 95 % CI: 0.39-0.95). CONCLUSION: US-US image overlay fusion can be proposed as a feasible guidance in RFA with a safety margin and predicts early response of treatment assessment with high accuracy. KEY POINTS: • US-US image overlay fusion visualizes the ablative margin during RFA procedure. • Visualizing the margin during the procedure can prompt immediate complementary treatment. • US image fusion correlates with the results of early evaluation CT.

Gankyrin induces STAT3 activation in tumor microenvironment and sorafenib resistance in hepatocellular carcinoma.

Most hepatocellular carcinomas (HCC) develop as a result of chronic liver inflammation. We have shown that the oncoprotein gankyrin is critical for inflammation-induced tumorigenesis in the colon. Although the in vitro function of gankyrin is well known, its role in vivo remains to be elucidated. We investigated the effect of gankyrin in the tumor microenvironment of mice with liver parenchymal cell-specific gankyrin ablation (Alb-Cre;gankyrinf/f ) and gankyrin deletion both in liver parenchymal and non-parenchymal cells (Mx1-Cre;gankyrinf/f ). Gankyrin upregulates vascular endothelial growth factor expression in tumor cells. Gankyrin binds to Src homology 2 domain-containing protein tyrosine phosphatase-1 (SHP-1), mainly expressed in liver non-parenchymal cells, resulting in phosphorylation and activation of signal transducer and activator of transcription 3 (STAT3). Gankyrin deficiency in non-parenchymal cells, but not in parenchymal cells, reduced STAT3 activity, interleukin (IL)-6 production, and cancer stem cell marker (Bmi1 and epithelial cell adhesion molecule [EpCAM]) expression, leading to attenuated tumorigenic potential. Chronic inflammation enhances gankyrin expression in the human liver. Gankyrin expression in the tumor microenvironment is negatively correlated with progression-free survival in patients undergoing sorafenib treatment for HCC. Thus, gankyrin appears to play a critical oncogenic function in tumor microenvironment and may be a potential target for developing therapeutic and preventive strategies against HCC.

Influence of Liver Inflammation on Liver Stiffness Measurement in Patients with Autoimmune Hepatitis Evaluation by Combinational Elastography.

OBJECTIVE: In order to evaluate the influence of liver inflammation on liver stiffness measurement (LSM) by the simultaneous use of shear wave and strain imaging (combinational elastography), shear wave and strain imaging were compared before and after initial therapy for autoimmune hepatitis (AIH). METHODS: Nine AIH patients initially treated with steroid were enrolled. Transient elastography and real-time tissue elastography were performed just before and 1 month after the start of initial steroid treatment. Blood samples, LSM, and the liver fibrosis index (LFI) were compared. RESULTS: Aspartate aminotransferase (p = 0.002) and alanine aminotransferase (ALT) (p = 0.015) were significantly decreased after initial treatment. The LSM was 15.5 ± 9.6 kPa at baseline, decreasing to 7.2 ± 2.3 kPa after initial treatment p = 0.034). The LFI was 1.67 ± 0.67 at baseline and 1.61 ± 0.66 after initial treatment; no significant change in LFI was recognized (p = 0.842). Between ΔALT and ΔLSM, a significant regression equation could be calculated as follows: ΔALT = -0.55 + 0.654 × ΔLSM. CONCLUSIONS: Combinational elastography was useful in evaluating not only the degree of liver fibrosis, but also the degree of liver inflammation in AIH.

Outcome of Combination Therapy with Sofosbuvir and Ledipasvir for Chronic Type C Liver Disease.

INTRODUCTION: Recently, the treatment of chronic hepatitis C has markedly advanced. A phase III clinical study of combination therapy with sofosbuvir (SOF) and ledipasvir (LDV) was conducted in Japan, and the additive therapeutic effects were reported. In this study, we report the results of treatment in our hospital. METHODS: Of 147 patients with chronic type C liver disease who had consulted our hospital since September 2015 and received SOF/LDV therapy, in 91 subjects a sustained virological response of 12 weeks (SVR12) could be evaluated. RESULTS: In all 91 patients, end treatment response was achieved. Subsequently, recrudescence was noted in 1 before the completion of treatment (week 12); an SVR12 was achieved in 90 patients (99%). The following adverse reactions were observed in 3 patients (3.3%): bradycardia, paroxysmal atrial fibrillation, and heart failure with QT prolongation, which were associated with heart disease. CONCLUSION: A favorable SVR was achieved by SOF/LDV therapy even in elderly patients, those with liver cirrhosis, or those having undergone radical treatment of liver cancer. Furthermore, a high tolerance was demonstrated, but adverse reactions associated with the heart may appear in patients with heart disease as an underlying disease; strict management during treatment is necessary.

Prophylactic Suturing Closure Is Recommended after Endoscopic Treatment of Colorectal Tumors in Patients with Antiplatelet/Anticoagulant Therapy.

The prophylactic closure of mucosal defects after endoscopic resection is known to prevent postoperative bleeding in colorectal lesions. However, closure of large mucosal defects is difficult with conventional clips only, and several closure techniques have been previously described; use of an Endoloop, 8-ring loop, or loop clip and a small incision around the mucosal defect. Given that the prophylactic closure requires much cost and time, the application should be limited to high-risk cases. Medication of antithrombotics or antiplatelet agents would be one of the reasonable indications for prophylactic closure of mucosal defects after endoscopic resection of colorectal tumors.

Clinical Significance of Bmi1 Expression in Inflammatory Bowel Disease.

BACKGROUND: Although the stem cell marker Bmi1 is overexpressed in many malignancies, its role in inflammation-associated cancer is unclear. Colitis-associated cancer (CAC) is caused by chronic intestinal inflammation and often results from refractory inflammatory bowel disease (IBD). METHODS: To assess the involvement of Bmi1 in the development of CAC, we analyzed the gene expression of colon tissues collected from 111 patients with IBD and CAC. RESULTS: In the colonic mucosa of patients with ulcerative colitis, the expression of Bmi1 correlated significantly with the expression of inflammatory cytokines such as IL-6, IL-17, IL-23, and tumor necrosis factor α (TNF-α). In the colonic mucosa of patients with Crohn's disease, the expression of Bmi1 correlated significantly with the expression of TNF-α and IL-23. The expression of Bmi1 was enhanced in the colonic mucosae of refractory IBD, suggesting that Bmi1 expression might be related to increased cancer risk. In addition, patients with high Bmi1 expression showed significantly lower response rates upon subsequent anti-TNF-α therapy as compared to patients with low Bmi1 expression. In human CAC specimens, the expression of Bmi1 was upregulated in nontumor tissues as well as tumors. CONCLUSIONS: Bmi1 expression is related to a refractory clinical course of IBD and upregulated in refractory IBD and CAC. Measurement of Bmi1 expression is a promising approach for the advanced treatment and personalized management of IBD patients.

Malignant Transformation of Hepatocellular Adenoma.

The patient was a 20-year-old male in whom a hepatic hypervascular mass accompanied by intratumoral hemorrhage was detected on examination for epigastric pain. Based on the enlargement of the mass and diagnostic imaging, hepatocellular adenoma (HCA) was suspected and hepatectomy was performed. The lesion was diagnosed as malignant transformation of ß-catenin-activated HCA. There are only few reports of cases with malignant transformation of HCA in Japan; it is necessary to accumulate cases to investigate it.

Contrast-Enhanced Tissue Harmonic Imaging versus Phase Inversion Harmonic Sonographic Imaging for the Delineation of Hepatocellular Carcinomas.

OBJECTIVE: To compare contrast tissue harmonic imaging (THI) with low mechanical index (MI) and conventional contrast harmonic imaging (CHI) with respect to lesion visibility of hepatocellular carcinoma (HCC). METHODS: One hundred and twenty-five patients (84 men and 41 women, age range 39-94 years, mean age 74 years) with 100 naïve HCCs and 30 lesions after radiofrequency ablation (RFA) for HCC were evaluated. One hundred and four patients had liver cirrhosis of Child-Pugh class A, and the remaining 21 had Child-Pugh class B cirrhosis. The lesion conspicuity and intratumoral echogenicity during the postvascular phase were compared using conventional CHI and contrast THI with low MI. RESULTS: The MI values ranged from 0.20 to 0.30 on conventional CHI and from 0.30 to 0.35 on contrast THI. Regarding HCC lesion conspicuity, contrast THI with low MI was clearer in 79 lesions (60.8%), equal in 34 lesions (26.2%), and less clear in 17 lesions (13.1%) when compared with conventional CHI. The lesion conspicuity with contrast THI was significantly better than that with conventional CHI (p < 0.01). All of the postablative lesions were well delineated in patients who received RFA. CONCLUSION: Low-MI contrast THI was superior to conventional CHI with respect to lesion visibility of HCCs and might offer good imaging for the guiding of RFA.

Computer-Aided Diagnosis Based on Convolutional Neural Network System for Colorectal Polyp Classification: Preliminary Experience.

BACKGROUND AND AIM: Computer-aided diagnosis (CAD) is becoming a next-generation tool for the diagnosis of human disease. CAD for colon polyps has been suggested as a particularly useful tool for trainee colonoscopists, as the use of a CAD system avoids the complications associated with endoscopic resections. In addition to conventional CAD, a convolutional neural network (CNN) system utilizing artificial intelligence (AI) has been developing rapidly over the past 5 years. We attempted to generate a unique CNN-CAD system with an AI function that studied endoscopic images extracted from movies obtained with colonoscopes used in routine examinations. Here, we report our preliminary results of this novel CNN-CAD system for the diagnosis of colon polyps. METHODS: A total of 1,200 images from cases of colonoscopy performed between January 2010 and December 2016 at Kindai University Hospital were used. These images were extracted from the video of actual endoscopic examinations. Additional video images from 10 cases of unlearned processes were retrospectively assessed in a pilot study. They were simply diagnosed as either an adenomatous or nonadenomatous polyp. RESULTS: The number of images used by AI to learn to distinguish adenomatous from nonadenomatous was 1,200:600. These images were extracted from the videos of actual endoscopic examinations. The size of each image was adjusted to 256 × 256 pixels. A 10-hold cross-validation was carried out. The accuracy of the 10-hold cross-validation is 0.751, where the accuracy is the ratio of the number of correct answers over the number of all the answers produced by the CNN. The decisions by the CNN were correct in 7 of 10 cases. CONCLUSION: A CNN-CAD system using routine colonoscopy might be useful for the rapid diagnosis of colorectal polyp classification. Further prospective studies in an in vivo setting are required to confirm the effectiveness of a CNN-CAD system in routine colonoscopy.

Magnifying Narrow Band Imaging (NBI) for the Diagnosis of Localized Colorectal Lesions Using the Japan NBI Expert Team (JNET) Classification.

OBJECTIVE: The Japan NBI Expert Team (JNET) proposed a new narrow band imaging (NBI) classification system for colorectal tumors in June 2014. In this classification system, types 1, 2A, 2B, and 3 correspond to hyperplastic polyps (HPs) including sessile serrated polyps (SSPs), low-grade dysplasia (LGD), high-grade dysplasia (HGD) to shallow submucosal invasive (SM-s) carcinomas, and deep submucosal invasive (SM-d) carcinomas, respectively. METHODS: To validate this system, we performed a retrospective image evaluation study, in which 199 colorectal tumors previously assessed by NBI magnifying endoscopy were classified by 3 blinded experienced colonoscopists using the JNET system. The results were compared with the final pathological diagnoses to determine the JNET classification's accuracy. The interobserver agreement was calculated, and the intraobserver agreement was assessed after 6 months. RESULTS: The final pathological diagnoses identified 14 HPs/SSPs, 127 LGDs, 22 HGDs, 19 SM-s carcinomas, and 17 SM-d carcinomas. The respective sensitivities, specificities, positive predictive value, negative predictive value, and accuracies were as follows: Type 1, 85.7, 99.5, 92.3, 98.9, and 98.5%; Type 2A, 96.0, 81.9, 90.3, 92.1, and 90.9%; Type 2B, 75.6%, 90.5, 67.3, 93.4, and 87.4%; and Type 3, 29.4%, 100, 100, 93.8, and 94.0%. The interobserver agreement and the intraobserver agreement were moderate (κ value: 0.52) and excellent (κ value: 0.88), respectively. Lesions presenting as Type 2B during NBI comprised a range of colorectal tumors, including HGDs, SM-s, and SM-d. CONCLUSIONS: The JNET classification was useful for the diagnosis of HPs/SSPs, LGDs, and SM-d, but not SM-s lesions. For low-confidence cases, magnified chromoendoscopy is recommended to ensure correct diagnoses.

Hepatocarcinogenesis Is Associated with Serum Albumin Levels after Sustained Virological Responses with Interferon-Based Therapy in Patients with Hepatitis C.

OBJECTIVE: It is a generally accepted fact that eradication of hepatitis virus C inhibits the subsequent development of hepatocellular carcinoma (HCC). On the contrary, a significant population of patients developed HCC despite sustained virological responses (SVRs) to interferon (IFN) therapy. METHODS: A total of 415 patients with chronic hepatitis C, who were treated at our hospital between 2004 and 2014, were enrolled for this study. We examined the risk factors for HCC development after IFN therapy. RESULTS: After analyzing various clinical parameters, it was concluded that a serum albumin (ALB) level <4.0 g/dL and the presence or absence of SVR achievement were risk factors for the development of HCC. When analyzing pre- and posttreatment factors, only a serum ALB level <4.0 g/dL was considered a significant risk factor. The presence or absence of liver fibrosis progression was not identified as a risk factor. CONCLUSIONS: In patients with a serum ALB level <4.0 g/dL before IFN therapy, hepatic carcinogenesis after SVR achievement need to be considered. Furthermore, the serum ALB level may be more useful than the degree of fibrosis for the prediction of HCC after SVR in chronic hepatitis C.

Hepatocellular Carcinoma after Achievement of Sustained Viral Response with Daclatasvir and Asunaprevir in Patients with Chronic Hepatitis C Virus Infection.

BACKGROUND: Interferon-based antiviral therapies against hepatitis C virus (HCV) infection have been shown to reduce the incidence of hepatocellular carcinoma (HCC) in patients with sustained viral response (SVR). Recently, direct-acting antivirals (DAAs) have been proven to be much more effective in achieving SVR than interferon-based therapies. However, whether DAAs can efficiently prevent the occurrence of HCC after SVR remains controversial. To clarify this issue, we analyzed the clinical features of patients in whom HCC developed after achievement of SVR with DAAs for chronic HCV infection. SUMMARY: Among patients who achieved SVR with daclatasvir and asunaprevir (n = 100), HCC developed in 17 patients (HCC group; n = 17) and did not develop in 83 patients (non-HCC group; n = 83) during a mean observation period of 15 months. A multivariate Cox proportional hazards analysis identified past history of HCC and male sex as significant risk factors for the emergence of HCC after DAAs. Sixteen cases with HCC after DAAs were in the very early or early stage (16/17, 94.1%), and one case was in the advanced stage (1/17, 5.9%) with portal venous tumor thrombus. Radiofrequency ablation and/or transarterial chemoembolization were performed in most cases as curative therapy (16/17, 94.1%). Key Messages: SVR by DAAs did not completely prevent the occurrence of HCC. However, even if HCC did develop after SVR, curative anticancer therapy was applicable in most cases.

Unique Characteristics Associated with Sustained Liver Damage in Chronic Hepatitis C Patients Treated with Direct Acting Antivirals.

BACKGROUND AND AIMS: Direct-acting antivirals (DAAs) dramatically improve the sustained virological response (SVR) of chronic hepatitis C (CHC) patients. However, continuous liver damage after SVR may be a risk of hepatocellular carcinoma (HCC). We clarified pretreatment characteristics related to sustained liver damage after SVR. METHODS: A total of 286 CHC patients were treated with an interferon-free DAA regimen. Among them, 250 patients achieved SVR for 12 weeks after the end of treatment (SVR12); these individuals were classified based on α-fetoprotein (AFP) and alanine transaminase (ALT) levels posttreatment. Baseline characteristics significantly associated with AFP >5 ng/mL and ALT level ≥20 IU/L after SVR were clarified using multivariate analyses. RESULTS: Among the pretreatment factors examined, serum AFP values and the presence of fatty liver (FL) were significantly associated with abnormal AFP (p < 0.0001) and ALT levels 12 weeks after SVR12 (SVR24; p = 0.0109). For 126 patients who showed an increase in baseline AFP level, FL, fibrosis-4 (FIB-4) index, and albumin levels before treatment were related to abnormal AFP at SVR24 (p = 0.0005, 0.0232, and 0.0400 for FL, FIB-4 index, and albumin, respectively). Similarly, for 150 patients with abnormal baseline ALT levels, FL was associated with an ALT level ≥ 30 IU/L after SVR (p = 0.0430). CONCLUSIONS: High FIB-4 index, low albumin level, and FL before DAA treatment were associated with a risk of sustained liver damage with AFP and ALT elevation after SVR; patients with these factors should be carefully monitored for emergence of HCC.