http://radiology.rsna.org/lookup/suppl/doi:10.1148/radiol.13130150/-/DC1.

Background: It remains unknown whether antiviral treatment for HBeAg-negative chronic hepatitis B (CHB) patients having high viral loads without significant elevation of alanine aminotransferase (ALT) levels would reduce the risks of clinical events. Aim: To compare clinical outcomes of high viral load CHB patients untreated for normal or mildly elevated ALT vs those treated for ALT ≥ 2 upper limit of normal (ULN). Methods: This historical cohort study included 5414 HBeAg-negative CHB patients without cirrhosis at a tertiary hospital in Korea from 2000 to 2013. Inactive phase was defined as serum hepatitis B virus [HBV] DNA < 2000 IU/mL and persistently normal ALT (n = 3572). High viral load (HBV DNA ≥ 2000 IU/mL) patients were classified into three phases by ALT levels: Replicative (persistently normal ALT, n = 900);Mildly active (ALT 1-2ULN, n = 396); and Active (ALT ≥ 2ULN, n = 546) phases. All Active phase patients were treated with nucleos(t)ide analogues. Results:The mean age of the patients was 47 years without a significant difference among the groups. Compared with the treated Active phase group, the untreated Replicative phase group showed a significantly higher risk of hepatocellular carcinoma (HCC; HR 1.76; 95% CI 1.00 -3.10, P = 0.05) and death/transplantation (HR 2.14; 5% CI 1.09 -4.21, P = 0.03) by propensity score-matched analysis. The untreated mildly active phase patients had further increase in risk of HCC and death/ transplantation compared with the treated Active phase group by unadjusted, PSmatched, competing risks, and multivariable-adjusted analyses. Conclusions: Untreated high viral load HBeAg-negative CHB patients without significant ALT elevation had higher risks of clinical events than treated Active phase patients with elevated ALT. S U PP O RTI N G I N FO R M ATI O N Additional supporting information will be found online in the Supporting Information section at the end of the article. How to cite this article: Choi GH, Kim G-A, Choi J, Han S, Lim Y-S. High risk of clinical events in untreated HBeAg-negative chronic hepatitis B patients with high viral load and no significant ALT elevation. Aliment Pharmacol Ther. 2019;50: 215-226. https ://doi.

Background: Studies have shown a higher risk of hepatocellular carcinoma (HCC) with higher baseline serum hepatitis B virus (HBV) DNA levels in chronic hepatitis B (CHB) patients. However, the association between very high HBV DNA levels (>6 log 10 IU/mL) and HCC risk remains unclear, especially in middle-aged and old HBeAgpositive patients. Aim:To identify the association between broad-range HBV DNA levels and HCC risk. Methods:We conducted a historical cohort study in Korea involving 6949 non-cirrhotic, treatment-naïve CHB patients with alanine aminotransferase (ALT) <2× upper limit of normal for >1 year. HBV DNA was >6 log 10 IU/mL in 2029 (29.2%) patients.Follow-up was censored when the antiviral therapy was initiated. Results:The mean age of the patients was 45 years. During 8.0 years of median follow-up, 363 patients (5.2%) developed HCC. By multivariable Cox regression analysis, HCC risk was highest with baseline HBV DNA levels of 6-7 log 10 IU/mL (adjusted hazard ratio [aHR] 4.98; P < 0.001), and lowest with >8 log 10 IU/mL (aHR 0.90; P = 0.71) and ≤4 log 10 IU/mL (aHR 1.00; reference), which was independent of other predictive factors. The similar association between HBV DNA levels and HCC risk was consistently observed in all age subgroups (age <40, 40-49 and ≥ 50 years). Conclusions:HCC risk was highest with moderate serum HBV DNA levels of 6-7 log 10 IU/mL in CHB patients without significant ALT elevation. Extending treatment indication to CHB patients with moderate levels of HBV DNA may be considered to further prevent HCC, regardless of ALT levels.

Background/Aims: The role of serum myokine levels in sarcopenia and the outcome of hepatocellular carcinoma (HCC) patients are not clear. This study investigated the serum levels of myostatin, follistatin, and interleukin-6 (IL-6) in HCC patients and their association with sarcopenia and survival.Methods: Using prospectively collected pretreatment samples from 238 HCC patients in a hospital from 2012 to 2015, the serum levels of 3 myokines were determined and compared to 50 samples from age and sex-matched healthy controls. Sarcopenia was evaluated using the psoas muscle index (PMI) measured at the third lumbar level in the computed tomography, and clinical data were collected until 2017.Results: The median levels of the 3 myokines for the male and female HCC patients were as follow: myostatin (3,979.3 and 2,976.3 pg/mL), follistatin (2,118.5 and 2,174.6 pg/mL), and IL-6 (2.5 and 2.7 pg/mL), respectively. Those in the HCC patients were all significantly higher than in the healthy controls. In the HCC patient, the median PMI was 4.43 (males) and 2.17 cm²/m² (females) with a sarcopenic prevalence of 56.4%. The serum levels of myostatin, IL-6 and follistatin in the HCC patients showed a positive, negative, and no correlation with PMI, respectively. The serum follistatin level was an independent factor for poor survival in HCC patients.Conclusions: The serum levels of myostatin, follistatin, and IL-6 and their correlation with sarcopenia and survival were presented in HCC patients for the first time. The role of the serum follistatin level as a poor prognostic biomarker warrants further study.

Purpose:To compare the time to progression (TTP) and overall survival (OS) in patients with advanced-stage hepatocellular carcinoma (HCC) who are undergoing sorafenib treatment combined with transarterial chemoembolization (TACE) versus sorafenib monotherapy. Materials andMethods:The retrospective analysis of the data was approved by the institutional review board, and the requirement to obtain informed consent was waived. Of 355 patients with advanced-stage HCC (Barcelona Clinic Liver Cancer stage C) who were undergoing sorafenib therapy for at least 5 weeks between April 2007 and July 2011, 164 (46.2%) underwent repeat TACE (or chemolipiodolization if indicated) along with sorafenib therapy (combined group); the remaining 191 patients (53.8%) received sorafenib alone (monotherapy group). The median patient age was 53 years (range, 22-84 years). The median age was 53 years (range, 26-84 years) for men and 56 years (range, 22-75 years) for women. Propensity score-based methods were used to minimize bias when evaluating TTP on the basis of modified Response Evaluation Criteria in Solid Tumors and OS. Statistical analysis was performed with the Kaplan-Meier method by using the log-rank test and Cox regression models. Results:In the combined and monotherapy groups, respectively, 64.6% and 49.2% of patients had vascular invasion, 87.8% and 91.1% had extrahepatic metastasis, and 54.3% and 47.1% had both. During follow-up (median duration, 5.5 months), the median TTP and OS in the combined group were longer than those in the monotherapy group (TTP: 2.5 months vs 2.1 months, respectively, P = .008; OS: 8.9 months vs 5.9 months, P = .009). At univariate and subsequent multivariate analyses, additional TACE was an independent predictor of favorable TTP and OS (adjusted hazard ratio: 0.74 and 0.57, respectively; P , .05 for both), consistent with the outcomes of inverse probability of treatment weighting. In the propensity scorematched cohort (96 pairs), the median TTP in the combined group was significantly longer than that in the monotherapy group (2.7 months vs 2.1 months, respectively; P = .011), but median OS was not (9.1 months vs 6.7 months, P = .21). Conclusion:In this retrospective study, TACE plus sorafenib was superior to sorafenib alone with respect to TTP in patients with advancedstage HCC, although it may or may not improve OS.q RSNA, 2013 Supplemental material: http://radiology.rsna.org/lookup /suppl/

BackgroundCombined hepatocellular-cholangiocarcinoma (cHCC-CC) can present as a hypervascular or peripherally enhancing tumor in dynamic imaging. We evaluated the effect of transarterial chemoembolization (TACE) on prognosis according to post-operative recurrence imaging patterns.MethodsWe retrospectively analyzed 42 cHCC-CC and 59 hepatocellular carcinoma (HCC-control) patients at the Asan Medical Center. We classified recurrent cHCC-CC according to enhancement pattern (globally enhancing: GE cHCC-CC, peripherally enhancing: PE cHCC-CC) and evaluated tumor response, time-to-local progression (TTPlocal), and overall survival (OS).ResultsThe GE cHCC-CC group had a significantly higher best objective response rate (complete remission + partial response) than the PE cHCC-CC group (36% vs 0%, P = 0.005), and it was comparable to that of the HCC-control group (35.6%, P = 0.97). TTPlocal in the GE cHCC-CC group was significantly shorter than in the HCC-control group (6.6 vs 27.1 months, P < 0.001), and was not significantly different from that in the PE cHCC-CC group (5.3 months, P = 0.12). OS was 12.4 months, 52.8 months, and 67.5 months in the PE cHCC-CC, GE cHCC-CC, and HCC-control groups, respectively (Ps < 0.05). The adjusted hazard ratios (HRs) for TTPlocal and OS revealed an independent association with enhancement pattern of recurrent cHCC-CC (TTPlocal: HR 2.46; 95% CI 1.10–5.46; P = 0.03; OS: HR 5.97; 95% CI 2.38–14.96; P < 0.001).ConclusionsThe GE cHCC-CC group showed better response and prognosis after TACE than the PE cHCC-CC group, but poorer response and prognosis than the HCC-control group. Enhancement patterns at recurrence were crucially associated with tumor response and overall survival.

Background: This study investigated the association of 3 components of body composition (sarcopenia, intramuscular fat deposition and visceral adiposity) with the overall or recurrence-free survival of hepatocellular carcinoma (HCC) patients who underwent curative hepatic resection.Methods: One hundred sixty newly diagnosed and surgically treated HCC patients were retrospectively enrolled from 2003 to 2011. Three items of body composition were measured using the 3 rd lumbar level image of preoperative computed tomography (CT): psoas muscle index (PMI), psoas muscle attenuation (PMA), and visceral adipose tissue index (VATI). Sex-specific optimal cut-off for each item was determined from receiver-operating characteristic curves. Results:The HCC patients showed a median age of 55 years, 75% of male, 78% of hepatitis B surface antigen positivity, and 96% of Child-Pugh A. The sarcopenic group (PMI less than the sex-specific cutoff of 3.33 cm 2 /m 2 for men and 2.38 cm 2 /m 2 for women) had 17.5% of the patients with a lower PMA (more fat deposition) but similar VATI compared to the non-sarcopenic group. PMI showed a positive correlation with PMA (ρ=0.493, P<0.001), while there was no significant correlation between PMI and VATI, and between PMA and VATI. On the multivariate analysis, a high PMI and low VATI were independent factors affecting overall survival while PMA was not. Nevertheless, PMI and VATI were not independent factors for recurrence-free survival.Conclusions: In curatively resected HCC patients, sarcopenia and high visceral adiposity predict poor overall survival but not recurrence-free survival, while PMA did not predict overall survival.

Background & Aims As surrogate markers for autoimmune hepatitis (AIH), serum alanine aminotransferase (ALT) and immunoglobulin G (IgG) are convenient to measure under immunosuppression. However, the long‐term prognosis of patients who achieve complete biochemical remission (CBR) in comparison with patients who achieve only biochemical remission (BR) is uncertain. Methods A total of 291 patients (89.7% female) diagnosed with AIH were retrospectively reviewed. CBR was defined as normal ALT and IgG levels with immunosuppression, while BR was defined as normal ALT levels. CBR was further divided into early CBR (<1year) and late CBR (≥1year) by the timing of remission. Liver‐related adverse outcomes including liver‐related death, liver transplantation and hepatocellular carcinoma were evaluated. Results With immunosuppressive treatment, 222 (76.3%) patients achieved CBR (early CBR: 168 and late CBR: 54). BR was achieved in 55 (18.9%) patients and 14 (4.8%) patients remained non‐remission. With a median follow‐up duration of 6.6 years, the risk of liver‐related mortality was the lowest in patients with CBR, followed by patients with late CBR, BR and non‐response. The cumulative risk of liver‐related adverse outcomes was the highest in patients with non‐response (8.51/100 person‐years [PYs]), followed by BR (1.95/100 PYs), late CBR (1.89/100 PYs) and early CBR (0.75/100 PYs). By multivariable analysis, age, cirrhosis and treatment responses were independently associated with liver‐related adverse outcomes. Conclusions Patients with CBR within 1 year after treatment initiation had the lowest risk of liver‐related adverse outcomes. Patients with late CBR and those with only BR had a comparable risk of long‐term outcomes.