Limited Generalizability of Retrospective Single-Center Cohort Study in Comparison to Multicenter Cohort Study on Prognosis of Hepatocellular Carcinoma.

Introduction: We aimed to evaluate the generalizability of retrospective single-center cohort studies on prognosis of hepatocellular carcinoma (HCC) by comparing overall survival (OS) after various treatments between a nationwide multicenter cohort and a single-center cohort of HCC patients. Methods: Patients newly diagnosed with HCC between January 2008 and December 2018 were analyzed using data from the Korean Primary Liver Cancer Registry (multicenter cohort, n=16,443), and the Asan Medical Center HCC registry (single-center cohort, n=15,655). The primary outcome, OS after initial treatment, was compared between the two cohorts for both the entire population and for subcohorts with Child-Pugh A liver function (n=2797 and n=5151, respectively) treated according to the Barcelona-Clinic-Liver-Cancer (BCLC) strategy, using Log rank test and Cox proportional hazard models. Results: Patients of BCLC stages 0 and A (59.3% vs 35.2%) and patients who received curative treatment (42.1% vs 32.1%) were more frequently observed in the single-center cohort (Ps<0.001). Multivariable analysis revealed significant differences between the two cohorts in OS according to type of treatment: the multicenter cohort was associated with higher risk of mortality among patients who received curative (adjusted hazard ratio [95% confidence interval], 1.48 [1.39-1.59]) and non-curative (1.22 [1.17-1.27]) treatments, whereas the risk was lower in patients treated with systemic therapy (0.83 [0.74-0.92]) and best supportive care (0.85 [0.79-0.91]). Subcohort analysis also demonstrated significantly different OS between the two cohorts, with a higher risk of mortality in multicenter cohort patients who received chemoembolization (1.72 [1.48-2.00]) and ablation (1.44 [1.08-1.92]). Conclusion: Comparisons of single-center and multicenter cohorts of HCC patients revealed significant differences in OS according to treatment modality after adjustment for prognostic variables. Therefore, the results of retrospective single-center cohort studies of HCC treatments may not be generalizable to real-world practice.

Clinical and Radiologic Predictors of Response to Atezolizumab-Bevacizumab in Advanced Hepatocellular Carcinoma.

Purpose: This study aimed to identify clinical and radiologic characteristics that could predict response to atezolizumab-bevacizumab combination therapy in patients with advanced hepatocellular carcinoma (HCC). Materials and Methods: This single-center retrospective study included 108 advanced HCC patients with intrahepatic lesions who were treated with atezolizumab-bevacizumab. Two radiologists independently analyzed Imaging characteristics of the index tumor on pretreatment computed tomography. Predictive factors associated with progressive disease (PD) at the best response based on Response Evaluation Criteria in Solid Tumors, Version 1.1 were evaluated using logistic regression analysis. Progression-free survival (PFS) was estimated by the Kaplan-Meier method and compared with the log-rank test. Results: Of 108 patients with a median PFS of 15 weeks, 40 (37.0%) had PD during treatment. Factors associated with PD included the presence of extrahepatic metastases (adjusted odds ratio [aOR], 4.13; 95% confidence interval [CI], 1.19-14.35; p=0.03), the infiltrative appearance of the tumor (aOR, 3.07; 95% CI, 1.05-8.93; p=0.04), and the absence of arterial phase hyperenhancement (APHE) (aOR, 6.34; 95% CI, 2.18-18.47; p<0.001). Patients with two or more of these factors had a PD of 66.7% and a median PFS of 8 weeks, indicating a significantly worse outcome compared to the patients with one or no of these factors. Conclusion: In patients with advanced HCC treated with atezolizumab-bevacizumab treatment, the absence of APHE, infiltrative appearance of the intrahepatic tumor, and presence of extrahepatic metastases were associated with poor response and survival. Evaluation of early response may be necessary in patients with these factors.

Extrahepatic Malignancies and Antiviral Drugs for Chronic Hepatitis B: A Nationwide Cohort Study.

Background/Aims: Chronic hepatitis B (CHB) is related to an increased risk of extrahepatic malignancy (EHM), and antiviral treatment is associated with an incidence of EHM comparable to controls. We compared the risks of EHM and intrahepatic malignancy (IHM) between entecavir (ETV) and tenofovir disoproxil fumarate (TDF) treatment. Methods: Using data from the National Health Insurance Service of Korea, this nationwide cohort study included treatment-naïve CHB patients who initiated ETV (n=24,287) or TDF (n=29,199) therapy between 2012 and 2014. The primary outcome was the development of any primary EHM. Secondary outcomes included overall IHM development. E-value was calculated to assess the robustness of results to unmeasured confounders. Results: The median follow-up duration was 5.9 years, and all baseline characteristics were well balanced after propensity score matching. EHM incidence rate differed significantly between within versus beyond 3 years in both groups (P<0.1, Davies test). During the first 3 years, EHM risk was comparable in the propensity score-matched cohort (5.88 versus 5.84/1,000 person-years; subdistribution hazard ratio [SHR]=1.01, 95% confidence interval [CI]=0.88-1.17, P=0.84). After year 3, however, TDF was associated with a significantly lower EHM incidence compared to ETV (4.92 versus 6.91/1,000 person-years; SHR=0.70, 95% CI=0.60-0.81, P<0.01; E-value for SHR=2.21). Regarding IHM, the superiority of TDF over ETV was maintained both within (17.58 versus 20.19/1,000 person-years; SHR=0.88, 95% CI=0.81-0.95, P<0.01) and after year 3 (11.45 versus 16.20/1,000 person-years; SHR=0.68, 95% CI=0.62-0.75, P<0.01; E-value for SHR=2.30). Conclusions: TDF was associated with approximately 30% lower risks of both EHM and IHM than ETV in CHB patients after 3 years of antiviral therapy.

Extrahepatic malignancies in metabolic dysfunction-associated fatty liver disease: A nationwide cohort study.

BACKGROUND AND AIMS: Metabolic dysfunction-associated fatty liver disease (MAFLD) encompasses heterogeneous fatty liver diseases associated with metabolic disorders. We aimed to evaluate the association between MAFLD and extrahepatic malignancies based on MAFLD subtypes. METHODS: This nationwide cohort study included 9 298 497 patients who participated in a health-screening programme of the National Health Insurance Service of Korea in 2009. Patients were further classified into four subgroups: non-MAFLD, diabetes mellitus (DM)-MAFLD, overweight/obese-MAFLD and lean-MAFLD. The primary outcome was the development of any primary extrahepatic malignancy, while death, decompensated liver cirrhosis and liver transplantation were considered competing events. The secondary outcomes included all-cause and extrahepatic malignancy-related mortality. RESULTS: In total, 2 500 080 patients were diagnosed with MAFLD. During a median follow-up of 10.3 years, 447 880 patients (6.0%) with extrahepatic malignancies were identified. The DM-MAFLD (adjusted subdistribution hazard ratio [aSHR] = 1.13; 95% confidence interval [CI] = 1.11-1.14; p < .001) and the lean-MAFLD (aSHR = 1.12; 95% CI = 1.10-1.14; p < .001) groups were associated with higher risks of extrahepatic malignancy than the non-MAFLD group. However, the overweight/obese-MAFLD group exhibited a similar risk of extrahepatic malignancy compared to the non-MAFLD group (aSHR = 1.00; 95% CI = .99-1.00; p = .42). These findings were reproduced in several sensitivity analyses. The DM-MAFLD was an independent risk factor for all-cause mortality (adjusted hazard ratio [aHR] = 1.41; 95% CI = 1.40-1.43; p < .001) and extrahepatic malignancy-related mortality (aHR = 1.20; 95% CI = 1.17-1.23; p < .001). CONCLUSION: The diabetic or lean subtype of MAFLD was associated with a higher risk of extrahepatic malignancy than non-MAFLD. As MAFLD comprises a heterogeneous population, appropriate risk stratification and management based on the MAFLD subtypes are required.

Association between statin use and the prognosis of hepatocellular carcinoma after resection: a nationwide cohort study.

Background: The majority of patients with hepatocellular carcinoma (HCC) following hepatic resection experience tumor recurrence. Statin use is associated with a reduced risk of HCC development; however, the association between statin use and the prognosis of HCC after resection remains unclear. We aimed to investigate the effect of statin use on the prognosis after hepatic resection among patients with HCC. Methods: A nationwide cohort study was performed with data from the National Health Insurance Service Database in Korea. Among 65,101 HCC patients who underwent hepatic resection between January 2002 and December 2017, we included 21,470 patients. For validation, a hospital-based cohort of 3366 patients with very early or early-stage HCC who received curative-intent hepatic resection between January 2010 and December 2018 was analyzed. Recurrence-free survival (RFS) and overall survival (OS) was compared between statin users and non-users. Findings: Among the nationwide cohort of 21,470 patients, 2399 (11.2%) used statins and 19,071 (88.8%) did not. Among the hospital cohort of 3366 patients, 363 (10.8%) used statins and 3003 (89.2%) did not. In the propensity score-matched nationwide cohort, statin users had better RFS (hazard ratio [HR], 0.60; 95% confidence interval [CI], 0.56-0.64; P < 0.001) and OS (HR, 0.49; 95% CI, 0.45-0.53; P < 0.001), with a duration-response relationship. In the propensity score-matched validation hospital cohort, statin treatment was significantly associated with better RFS (HR, 0.73; 95% CI, 0.59-0.90; P = 0.003) and OS (HR, 0.48; 95% CI, 0.32-0.72; P < 0.001). The beneficial effects of statins were more prominent in non-cirrhotics, tumors sized ≥3 cm, tumors with microscopic vascular invasion, or early HCC recurrence (<2 years after resection). Interpretation: Statin use was associated with a better prognosis in a population-based cohort of patients with HCC after hepatic resection, which was further validated in a large hospital-based cohort. Funding: Asan Institute for Life Sciences and Corporate Relations; Korean Association for the Study of the Liver.

Treated chronic hepatitis B is a good prognostic factor of diffuse large B-cell lymphoma.

BACKGROUND/AIMS: Chronic hepatitis B (CHB) is a risk factor for non-Hodgkin lymphoma (NHL). Our recent study suggested that antiviral treatment may reduce the incidence of NHL in CHB patients. This study compared the prognoses of hepatitis B virus (HBV)-associated diffuse large B-cell lymphoma (DLBCL) patients receiving antiviral treatment and HBV-unassociated DLBCL patients. METHODS: This study comprised 928 DLBCL patients who were treated with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) at two referral centers in Korea. All patients with CHB received antiviral treatment. Time-to-progression (TTP) and overall survival (OS) were the primary and secondary endpoints, respectively. RESULTS: Among the 928 patients in this study, 82 were hepatitis B surface antigen (HBsAg)-positive (the CHB group) and 846 were HBsAg-negative (the non-CHB group). The median follow-up time was 50.5 months (interquartile range [IQR]=25.6-69.7 months). Multivariable analyses showed longer TTP in the CHB group than the non-CHB group both before inverse probability of treatment weighting (IPTW; adjusted hazard ratio [aHR]=0.49, 95% confidence interval [CI]=0.29-0.82, p=0.007) and after IPTW (aHR=0.42, 95% CI=0.26-0.70, p<0.001). The CHB group also had a longer OS than the non-CHB group both before IPTW (HR=0.55, 95% CI=0.33-0.92, log-rank p=0.02) and after IPTW (HR=0.53, 95% CI=0.32-0.99, log-rank p=0.02). Although liver-related deaths did not occur in the non-CHB group, two deaths occurred in the CHB group due to hepatocellular carcinoma and acute liver failure, respectively. CONCLUSION: Our findings indicate that HBV-associated DLBCL patients receiving antiviral treatment have significantly longer TTP and OS after R-CHOP treatment than HBV-unassociated DLBCL patients.

Transarterial chemoembolization as an alternative to radioembolization is associated with earlier tumor recurrence than in radioembolization-eligible patients.

Introduction: Although transarterial radioembolization (TARE) using yttrium-90 (90Y) is a treatment option for large hepatocellular carcinoma (HCC), a fraction of patients are ineligible for TARE due to high lung shunt fraction (LSF). Methods: We evaluated if treatment with transarterial chemoembolization (TACE), owing to TARE ineligibility was associated with early HCC progression. Consecutive patients with HCC who were initially TARE candidates were included. Patients with vascular invasion or metastasis were excluded. Primary endpoints were time-to-progression (TTP) and overall survival (OS). The secondary endpoint was objective response rate. Results: In total, 175 patients were included: 144 underwent TARE (TARE-eligible group) and 31 underwent TACE due to high LSF (TARE-ineligible group). This latter group had larger tumors (13.8 cm vs. 7.8 cm, P<0.001) and higher MoRAL scores (1,385.8 vs. 413.3, P=0.002) than the TARE-eligible group. After balancing baseline characteristics with an inverse probability of treatment weighting (IPTW), the TARE-ineligible group showed shorter TTP [adjusted hazard ratio (aHR)=2.16, 95% confidence interval (CI)=1.14-4.07, P=0.02] and OS (aHR=1.80, 95% CI=0.85-3.80, P=0.12), although the latter was not statistically significant. The TARE-ineligible group had a significantly lower objective response rate than the TARE-eligible group (9.7% vs. 56.9%, P<0.001). Conclusion: TARE-ineligible patients had larger tumors and higher MoRAL scores than TARE-eligible patients. Treatment with TACE, owing to high LSF, was associated with a shorter TTP even after balancing tumor size and MoRAL scores.

Association of Chronic Hepatitis B Infection and Antiviral Treatment With the Development of the Extrahepatic Malignancies: A Nationwide Cohort Study.

PURPOSE: Epidemiologic studies suggest that chronic hepatitis B (CHB) is a risk factor for various primary extrahepatic malignancies. Our aim was to evaluate the associations of CHB and nucleos(t)ide analog (NA) treatment with the risk of the development of extrahepatic malignancies. PATIENTS AND METHODS: We conducted an 18-month landmark analysis using nationwide claims data from the National Health Insurance Service of South Korea. Patients newly diagnosed with CHB in 2012-2014 (n = 90,944) and matched-controls (n = 685,436) were included. Patients with CHB were further classified as the NA-treated (CHB+/NA+, n = 6,539) or the NA-untreated (CHB+/NA-, n = 84,405) group. Inverse probability of treatment weighting analysis was applied to balance the treatment groups. Time-varying Cox analysis was performed to evaluate time-varying effect of NA treatment. The primary outcome was the development of any primary extrahepatic malignancy. Development of intrahepatic malignancy and death were considered as competing events. RESULTS: During the study period (median = 47.4 months), 30,413 patients (3.9%) developed any extrahepatic malignancy. The CHB+/NA- group had a higher overall risk of extrahepatic malignancy than the CHB+/NA+ group (adjusted subdistribution hazard ratio [aSHR] = 1.28; 95% CI, 1.12 to 1.45; P < .001) or controls (aSHR = 1.22; 95% CI, 1.18 to 1.26; P < .001). There was no difference in the risk of extrahepatic malignancy between the CHB+/NA+ group and the controls (CHB+/NA+ v control: aSHR = 0.96; 95% CI, 0.84 to 1.08; P = .48). In time-varying Cox analysis, the CHB+/NA- patients were associated with a higher risk of extrahepatic malignancy than the CHB+/NA+ patients (aSHR = 1.37; 95% CI, 1.23 to 1.52; P < .001). CONCLUSION: Patients with CHB have an elevated risk of developing primary extrahepatic malignancy. Long-term NA treatment was associated with a lower risk of extrahepatic malignancy development among patients with CHB.

Effectiveness of Transarterial Chemoembolization-First Treatment for Advanced Hepatocellular Carcinoma: A Propensity Score Matching Analysis.

BACKGROUND: Still in real-world practice, advanced hepatocellular carcinoma (HCC) patients are treated with transarterial chemoembolization (TACE). This study compared the therapeutic effectiveness of initial TACE treatment and initial sorafenib treatment in advanced HCC patients. PATIENT AND METHODS: Advanced HCC patients initially treated with sorafenib or TACE were included in this study. Treatment crossover due to an unfavorable response to initial treatment was allowed. Propensity score (PS) matching was applied for balancing baseline characteristics. The primary outcome was overall survival (OS) and the secondary outcomes included tumor response. RESULTS: A total of 554 patients were included in this study: 85 were initially treated with sorafenib (the sorafenib-first group) and 469 with TACE (the TACE-first group). In the entire cohort, the TACE-first group was associated with lower risk of death [adjusted hazard ratio (HR)=0.75, P=0.04]. In the PS-matched cohort (85 patients per group), the TACE-first group showed longer OS than the sorafenib-first group in both univariable (HR=0.68, P=0.02) and multivariable analyses (adjusted HR=0.58, P=0.002). Specifically, within both the entire and the PS-matched cohorts, the TACE-first group showed longer OS in subgroups with major portal vein tumor thrombosis (HR=0.72, P=0.048; HR=0.52, P=0.003) or infiltrative HCC (HR=0.42, P<0.001; HR=0.30, P=0.004, respectively). The objective response rate was higher in the TACE-first group (29.3% vs 14.7%, P=0.03) within the PS-matched cohort. CONCLUSION: For advanced HCC, initial TACE leads to longer OS with a more favorable tumor response than initial sorafenib treatment. Intrahepatic tumor control with initial locoregional therapy may be a potent strategy for advanced HCC.

Radiomics-based neural network predicts recurrence patterns in glioblastoma using dynamic susceptibility contrast-enhanced MRI.

Glioblastoma remains the most devastating brain tumor despite optimal treatment, because of the high rate of recurrence. Distant recurrence has distinct genomic alterations compared to local recurrence, which requires different treatment planning both in clinical practice and trials. To date, perfusion-weighted MRI has revealed that perfusional characteristics of tumor are associated with prognosis. However, not much research has focused on recurrence patterns in glioblastoma: namely, local and distant recurrence. Here, we propose two different neural network models to predict the recurrence patterns in glioblastoma that utilizes high-dimensional radiomic profiles based on perfusion MRI: area under the curve (AUC) (95% confidence interval), 0.969 (0.903-1.000) for local recurrence; 0.864 (0.726-0.976) for distant recurrence for each patient in the validation set. This creates an opportunity to provide personalized medicine in contrast to studies investigating only group differences. Moreover, interpretable deep learning identified that salient radiomic features for each recurrence pattern are related to perfusional intratumoral heterogeneity. We also demonstrated that the combined salient radiomic features, or "radiomic risk score", increased risk of recurrence/progression (hazard ratio, 1.61; p = 0.03) in multivariate Cox regression on progression-free survival.

Prognostic impact of concurrent nonalcoholic fatty liver disease in patients with chronic hepatitis B-related hepatocellular carcinoma.

BACKGROUND AND AIM: As the prevalence of nonalcoholic fatty liver disease (NAFLD) is increasing globally, patients with both NAFLD and chronic hepatitis B (CHB)-related hepatocellular carcinoma (HCC) is also frequently found. This study aimed to investigate the clinical impact of concurrent NAFLD on the prognosis of patients with CHB-related HCC. METHODS: Patients with CHB-related HCC who underwent surgical resection were consecutively selected from August 2009 to December 2013. The association between histologically proven concurrent NAFLD and clinical outcomes were analyzed. Propensity score (PS) matching was adapted to adjust for baseline characteristics. We also investigated the presence of nonalcoholic steatohepatitis (NASH) among patients with NAFLD and its association with clinical outcomes. RESULTS: Among 338 CHB-related HCC patients selected, 196 patients (58.0%) were diagnosed with concurrent NAFLD. The median follow-up duration was 74.9 months. The patients with NAFLD tended to have better recurrence-free survival (RFS; log-rank, P = 0.16) and had significantly better overall survival (OS; log-rank, P = 0.004) than those without NAFLD. However, the survival benefit of the concurrent NAFLD was not significant in a multivariable Cox analysis (adjusted hazard ratio, 0.94; 95% confidence interval, 0.51-1.73, P = 0.84) or an analysis after PS matching (log-rank, P = 0.57). Regarding the presence or absence of NASH, no differences in the RFS (log-rank, P = 0.61) and OS (log-rank, P = 0.26) were found. CONCLUSIONS: Concurrent NAFLD was not associated with both RFS and OS in patients with CHB-related HCC after adjusting for baseline characteristics. Moreover, NAFLD patients with NASH did not have significantly different clinical outcomes compared with NAFLD patients without NASH.

Is Combination Antiviral Therapy Mandatory for Maintenance Therapy in Fully Suppressed Multidrug-Resistant Hepatitis B Patients?

AIM: The efficacy of tenofovir disoproxil fumarate (TDF) monotherapy as maintenance therapy in multidrug-resistant (MDR) hepatitis B virus (HBV) patients after complete virologic suppression (CVS) has not been well evaluated. We evaluated the efficacy of maintenance TDF monotherapy compared with conventional TDF plus entecavir combination therapy after CVS of MDR HBV. METHODS: In this single-center retrospective study, patients with MDR HBV who were previously treated with entecavir plus TDF combination therapy and achieved CVS were included. Patients were either maintained on entecavir plus TDF combination therapy or switched to TDF monotherapy after CVS. The primary endpoint was the virologic breakthrough, and secondary outcomes were liver cirrhosis (LC) or hepatocellular carcinoma (HCC) development. To overcome immortal time bias, time-varying Cox proportional hazard regression analysis was performed. RESULTS: A total of 201 patients were included, and 153 patients were maintained on entecavir plus TDF combination therapy (combination group); 48 patients were converted from combination therapy to TDF monotherapy (single group) after CVS. Five patients experienced a virologic breakthrough, one patient in the single group owing to poor transient compliance and four patients in the combination group (P = 0.51). One new case of LC developed in the single group; five cases of LC developed in the combination group (P = 0.35). No new HCC development occurred in the single group, while seven cases of HCC developments were noted in the combination group. However, these results were not statistically significant (P = 0.54). CONCLUSIONS: For patients with suppressed HBV DNA, the efficacy of TDF monotherapy as maintenance therapy is comparable to that of entecavir plus TDF combination therapy.

Inflammation of temporomandibular joint increases neural activity in rat vestibular nucleus.

To determine whether the vestibular nuclei are affected by inflammation of temporomandibular joint (TMJ) region, we studied vestibular nucleus neural activity using two experimental groups: (1) normal saline 0.1cm(3) injection at right TMJ region, (2) 10% formalin 0.1cm(3) injection at right TMJ region. Neural activity after 24 hours was assessed by immunohistochemical staining with free-floating section at the level of interaural -1.30 mm to -2.00 mm for c-Fos. In inflammation group, formalin injection produced a bilateral increase in c-Fos at vestibular nucleus with ipsilesional side higher activity. In control group, expression of c-Fos protein was also observed in the vestibular nucleus (VN), especially MVN. But stain intensity of Fos-positive neurons was much weaker and mean number of c-Fos positive cells was fewer than inflammation group. This result suggests that there is a close neural connection between TMJ and vestibular nucleus, especially in case of inflammation.

Accuracy of diffusion tensor magnetic resonance imaging tractography assessed using intraoperative subcortical stimulation mapping and magnetic source imaging.

OBJECT: Resecting brain tumors involves the risk of damaging the descending motor pathway. Diffusion tensor (DT)-imaged fiber tracking is a noninvasive magnetic resonance (MR) technique that can delineate the subcortical course of the motor pathway. The goal of this study was to use intraoperative subcortical stimulation mapping of the motor tract and magnetic source imaging to validate the utility of DT-imaged fiber tracking as a tool for presurgical planning. METHODS: Diffusion tensor-imaged fiber tracks of the motor tract were generated preoperatively in nine patients with gliomas. A mask of the resultant fiber tracks was overlaid on high-resolution T1- and T2-weighted anatomical MR images and used for stereotactic surgical navigation. Magnetic source imaging was performed in seven of the patients to identify functional somatosensory cortices. During resection, subcortical stimulation mapping of the motor pathway was performed within the white matter using a bipolar electrode. RESULTS: A total of 16 subcortical motor stimulations were stereotactically identified in nine patients. The mean distance between the stimulation sites and the DT-imaged fiber tracks was 8.7 +/- 3.1 mm (+/- standard deviation). The measured distance between subcortical stimulation sites and DT-imaged fiber tracks combines tracking technique errors and all errors encountered with stereotactic navigation. CONCLUSIONS: Fiber tracks delineated using DT imaging can be used to identify the motor tract in deep white matter and define a safety margin around the tract.