Tenofovir versus entecavir on recurrence and mortality of hepatitis B virus-related hepatocellular carcinoma after curative therapy.

BACKGROUND: Tenofovir disoproxil fumarate (TDF) and entecavir (ETV) reduce the risk of hepatocellular carcinoma (HCC) in patients of hepatitis B. This study compared the difference between ETV and TDF on risk of HCC recurrence and mortality in patients with HBV-related HCC after curative intent treatment. METHODS: Patients with HBV-related HCC who received HCC treatment (surgery or radiofrequency ablation [RFA]) and underwent long-term ETV or TDF therapy were retrospectively included. Baseline characteristics including age, sex, antiviral therapy, liver reserve, HCC stages, pathology reports and treatment modality were obtained. The risk of tumor recurrence, all-cause mortality, HCC-related mortality, and liver function were compared. RESULTS: We identified 390 HBV-related HCC patients with curative intent treatment for HCC and treated with ETV (n = 328) or TDF (n = 62) between January 2011 and December 2020. The median age was 60 years, and 90.7% patients were males. After a median follow-up of 29 months, 186 patients developed recurrent HCC and 111 died. The baseline characteristics were comparable except more ALBI grade 3 patients in TDF group (76% vs. 48%, P < 0.001). Compared to ETV group, TDF users had lower all-cause mortality (adjusted hazard ratio [aHR]: 0.38, P = 0.003), and HCC-related mortality (aHR: 0.23, P = 0.005). Lower recurrence rate was noticed in TDF users after inverse probability of treatment weighting (IPTW). TDF users had improved ALBI grade and FIB-4 index compared with ETV groups. CONCLUSIONS: TDF therapy is associated with a reduced risk of HCC-related outcomes among patients with HBV-related HCC after curative intent treatment compared with ETV usage.

Metabolic Dysfunction-Associated Steatotic Liver Disease Facilitates Hepatitis B Surface Antigen Seroclearance and Seroconversion.

BACKGROUND & AIMS: Hepatitis B surface antigen (HBsAg) seroclearance is the goal of functional cure for hepatitis B virus (HBV) infection. However, the impact of metabolic dysfunction-associated steatotic liver disease (MASLD) on this favorable outcome remains unclear. METHODS: Patients with chronic hepatitis B (CHB) were consecutively recruited. MASLD was defined by the newly proposed disease criteria. Cumulative incidences and associated factors of HBsAg seroclearance/seroconversion were compared between the MASLD and non-MASLD groups. RESULTS: From 2006 to 2021, 4084 treatment-naive hepatitis B e antigen (HBeAg)-negative CHB patients were included. At baseline, CHB patients with concurrent MASLD (n = 887) had significantly lower levels of HBsAg and HBV DNA than the non-MASLD group (n = 3197). During a median follow-up of 5.0 years, MASLD was associated with a higher likelihood of HBsAg seroclearance (adjusted hazard ratio [aHR], 1.43; 95% confidence interval [CI], 1.10-1.85; P = .007), and the accumulation of individual metabolic dysfunctions additively facilitated HBsAg seroclearance. In addition, a higher rate of HBsAg seroconversion was observed in patients with MASLD versus those without MASLD (aHR, 1.37; 95% CI, 1.00-1.86; P = .049). In sensitivity analysis, patients with intermittent MASLD had an intermediate probability of HBsAg seroclearance. After balancing clinical and virologic profiles by inverse probability of treatment weighting (IPTW), MASLD was still associated with a higher HBsAg seroclearance rate (IPTW-adjusted HR, 1.41; 95% CI, 1.09-1.84; P = .010). CONCLUSIONS: In untreated HBeAg-negative CHB patients, concurrent MASLD is associated with higher rates of HBsAg seroclearance and seroconversion. Metabolic dysfunctions have additive effects on the functional cure of CHB.

High PIVKA-II level and ASAP score predict 1-year risk of hepatocellular carcinoma in non-cirrhotic chronic hepatitis B patients.

Protein induced by Vitamin K absence or antagonists-II (PIVKA-II) is a diagnostic marker of hepatocellular carcinoma (HCC). We aimed to investigate the predictive role of PIVKA-II and ASAP score for development of HCC in 1 year among untreated patients of chronic hepatitis B (CHB). We conducted this case-control study to include untreated CHB patients followed at the National Taiwan University Hospital and grouped into HCC and matched non-HCC groups. Their archived serum samples were assayed for PIVKA-II levels 1 year before HCC, at HCC or their last serum sample. A total of 69 HCC cases and 102 non-HCC controls were recruited. Baseline PIVKA-II level was significantly higher in the HCC group than in the control group and it could predict HCC development in 1 year with an area under the receiver operating characteristic curve of 0.76. Multivariable analysis adjusting age, sex, liver function and alpha-fetoprotein level showed that baseline PIVKA-II ≥31 mAU/mL (vs. <31 mAU/mL) increased 12.5-fold risk (95% CI: 4.9-31.7) of HCC in 1 year, and even in patients with normal alpha-fetoprotein levels. The ASAP score, a combination of age, sex, alpha-fetoprotein and PIVKA-II, increases the predictability for HCC in 1 year. We concluded that both high PIVKA-II level and ASAP score may predict HCC development in 1 year in untreated CHB patients, especially in patients with normal alpha-fetoprotein level.

Serial increase and high alpha-fetoprotein levels predict the development of hepatocellular carcinoma in 6 months.

AIM: Alpha-fetoprotein (AFP) checkup with abdominal ultrasonography for hepatocellular carcinoma (HCC) surveillance remains controversial. We evaluated a serial AFP-increase and high AFP levels in the prediction of HCC. METHODS: At-risk patients with chronic liver disease underwent HCC surveillance with trimonthly AFP measurement were included and categorized into HCC and non-HCC groups. Their AFP levels at 12, 9, and 6 months (-6M) before the outcome date were evaluated. Group-based trajectory analysis and multivariable regression analysis were performed to identify AFP trajectories as risk predictors for HCC. RESULTS: Overall, 2776 patients were included in the HCC (n = 326) and non-HCC (n = 2450) groups. Serial AFP levels were significantly higher in the HCC than the non-HCC groups. Trajectory analysis identified AFP-increase group (11%) increased 24-fold risks of HCC compared with the AFP-stable (89%) group. Compared with patients without the AFP-increase, a serial 3-month AFP-increase ≥10% elevated HCC risk by 12.1-fold (95% CI: 6.5-22.4) in 6 months, and the HCC risks increased 13-60 fold in patients with cirrhosis, hepatitis B, or C receiving antiviral therapy, or AFP levels <20 ng/ml. Combining serial AFP-increase ≥10% and AFP ≥20 ng/ml at -6M significantly increased 41.7-fold (95% CI: 13.8-126.2) HCC risks. In patients who underwent biannual AFP checkups, those with both 6-month AFP-increase ≥10% and AFP ≥20 ng/ml increased 22.1-fold (95% CI: 12.52-39.16) HCC risks in 6 months. Most HCCs were detected at an early stage. CONCLUSIONS: Serial 3-6-month AFP-increase of ≥10% previously and AFP level of ≥20 ng/ml significantly increased HCC risks in 6 months.

Pre-operative gamma-glutamyl transferase levels predict outcomes in hepatitis B-related hepatocellular carcinoma after curative resection.

BACKGROUND: Surgical resection is a curative therapy for early-stage hepatocellular carcinoma (HCC); however, HCC recurrence is not uncommon. Identifying outcome predictors helps to manage the disease. Gamma-glutamyl transferase (GGT) may predict the development of HCC, but its role to predict the outcomes after surgical resection of HCC was unclear. This study aimed to investigate pre-operative GGT levels for outcome prediction in patients with hepatitis B virus (HBV)-related HCC. METHODS: We conducted a retrospective cohort study to include patients with HBV-related HCC receiving surgical resection. Clinical information, HCC characteristics and usage of antiviral therapy were collected. A time-dependent Cox proportional hazard regression analysis were used to predict HCC recurrence and survival. RESULTS: A total of 699 consecutive patients with HBV-related HCC who received surgical resection with curative intent between 2004 and 2013 were included. After a median of 4.4 years, 266 (38%) patients had HCC recurrence. Pre-operative GGT positively correlated with cirrhosis, tumor burden and significantly increased in patients to develop HCC recurrence. Multivariable analysis demonstrated that pre-operative GGT ≥38 U/L increased 57% risk (hazard ratio [HR]: 1.57, 95% confidence interval [CI]: 1.20-2.06) of recurrent HCC after adjustment for confounding factors. Specifically, pre-operative GGT ≥38 U/L predicted early (<2 years) HCC recurrence (HR: 1.94, 95% CI: 1.30-2.89). Moreover, pre-operative GGT ≥38 U/L predicted all-cause mortality (HR: 1.73, 95% CI: 1.06-2.84) after surgery. CONCLUSION: Pre-operative GGT levels ≥38 U/L independently predict high risks of HCC recurrence and all-cause mortality in HBV-related HCC patients receiving surgical resection.

Distinct effects of hepatic steatosis and metabolic dysfunction on the risk of hepatocellular carcinoma in chronic hepatitis B.

OBJECTIVE: Chronic hepatitis B (CHB) and metabolic dysfunction-associated fatty liver disease (MAFLD) are the leading causes of hepatocellular carcinoma (HCC). We aim to explore the impact of concurrent MAFLD on the risk of HCC in CHB. METHODS: Patients with CHB were consecutively recruited from 2006 to 2021. MAFLD was defined by steatosis and either obesity, diabetes mellitus, or other metabolic abnormalities. The cumulative incidence of HCC and associated factors were compared between the MAFLD and non-MAFLD groups. RESULTS: 10,546 treatment-naïve CHB patients were included with a median follow-up of 5.1 years. CHB patients with MAFLD (n = 2212) had fewer hepatitis B e antigen (HBeAg)-positivity, lower HBV DNA levels, and Fibrosis-4 index compared with the non-MAFLD group (n = 8334). MAFLD was independently associated with a 58% reduced risk of HCC (adjusted hazard ratio [aHR] 0.42, 95% confidence interval [CI] 0.25-0.68, p < 0.001). Furthermore, steatosis and metabolic dysfunction had distinct effects on HCC. Steatosis was protective against HCC (aHR 0.45, 95% CI 0.30-0.67, p < 0.001), while a greater burden of metabolic dysfunction increased the risk (aHR 1.40 per dysfunction increase, 95% CI 1.19-1.66, p < 0.001). The protective effect of MAFLD was further confirmed in analysis with inverse probability of treatment weighting (IPTW), patients who had undergone antiviral therapy, those with probable MAFLD, and after multiple imputation for missing data. CONCLUSIONS: Concurrent hepatic steatosis is independently associated with a lower risk of HCC, whereas the increasing burden of metabolic dysfunction aggravates the risk of HCC in untreated CHB patients.

Diversity and composition of gut microbiota in healthy individuals and patients at different stages of hepatitis B virus-related liver disease.

BACKGROUND: Hepatitis B virus (HBV) causes chronic hepatitis B (CHB), liver cirrhosis, and hepatocellular carcinoma. The evolution of human gut microbiota during the progression of HBV-related liver diseases remains unclear. Therefore, we prospectively enrolled patients with HBV-related liver diseases and healthy individuals. Through 16S ribosomal RNA amplicon sequencing, we characterized the gut microbiota of the participants and predicted the functions of microbial communities. RESULTS: We analyzed the gut microbiota of 56 healthy controls and 106 patients with HBV-related liver disease [14 with resolved HBV infection, 58 with CHB, and 34 with advanced liver disease (15 with liver cirrhosis and 19 with hepatocellular carcinoma)]. Patients with HBV-related liver disease exhibited a higher degree of bacterial richness (all P < 0.05) than did healthy controls. Beta diversity analyses revealed a distinct clustering pattern between healthy controls and patients with HBV-related liver disease (all P < 0.05). The composition of bacteria (from the phylum level to the genus level) varied across the stages of liver disease. Linear discriminant analysis effect size revealed multiple taxa that differ significantly in abundance between healthy controls and patients with HBV-related liver disease; however, fewer differences were observed among patients with resolved HBV infection, those with CHB, and those with advanced liver disease. The ratio of Firmicutes to Bacteroidetes was increased in all three patient groups compared with the ratio in healthy controls (all P < 0.001). The analysis of the sequencing data by using PICRUSt2 revealed the changes in microbial functions with disease progression. CONCLUSIONS: The diversity and composition of gut microbiota appear to vary significantly between healthy controls and patients at different stages of HBV-related liver disease. The understanding of gut microbiota may provide novel therapeutic options in these patients.

Optimizing Survival Benefit by Surgical Resection by the Seven-Eleven Criteria in Barcelona Clinic Liver Cancer Stage A/B Hepatocellular Carcinoma beyond the Milan Criteria.

Introduction: Optimal treatment of hepatocellular carcinoma (HCC) beyond the Milan criteria is in debate. We aimed to identify candidates for surgical resection (SR) in Barcelona Clinic Liver Cancer (BCLC)-A/B HCC beyond the Milan criteria with survival benefit. Methods: Patients with BCLC-A/B HCC beyond the Milan criteria at the National Taiwan University Hospital during 2005 and 2019 were screened, and those who received transarterial chemoembolization (TACE) or SR were consecutively included. The tumor burden was classified by the seven-eleven criteria into low (≤7), intermediate (7-11), or high (>11). Multivariable Cox proportional hazard regression analysis was used for outcome prediction. Results: Overall, 474 patients who received SR (n = 247) and TACE (n = 227) were enrolled. Patients who underwent SR were significantly younger with better liver reserve. There were 76 (31%) and 129 (57%) deaths in the SR and TACE groups after a median follow-up of 3.9 and 2.1 years, respectively. The seven-eleven criteria could distinguish median overall survival (OS) among low (n = 149), intermediate (n = 203), and high (n = 122) tumor burden groups (7.7 vs. 6.9 vs. 2.8 years, respectively, p < 0.001). Patients receiving SR had a significantly higher median OS compared with TACE in those with intermediate (8.2 vs. 2.6 years, p < 0.001) and high (5.6 vs. 1.5 years, p = 0.001) tumor burden. After adjustment for age, sex, and liver reserve, SR was predictive for better OS in intermediate (adjusted hazard ratio [aHR]: 0.45, 95% confidence interval [CI]: 0.27-0.75) and high tumor burden groups (aHR: 0.54, 95% CI: 0.32-0.92). The survival benefit of SR especially confines to patients within 3 tumors. Conclusions: In patients with BCLC-A/B HCC beyond the Milan criteria with tumor burden beyond the up-to-7 criteria but within 3 tumors, SR has better OS than TACE and should be considered in resectable patients.

Evaluating correlates of protection for mix-match vaccine against COVID-19 VOCs with potential of evading immunity.

BACKGROUND: In the face of rapid emerging variants of concern (VOCs) with potential of evading immunity from Beta to Omicron and uneven distribution of different vaccine brands, a mix-match strategy has been considered to enhance immunity. However, whether increasing immunogenicity using such a mix-match can lead to high clinical efficacy, particularly when facing Omicron pandemic, still remains elusive without using the traditional phase 3 trial. The aim of this study is to demonstrate how to evaluate correlates of protection (CoP) of the mix-match vaccination. METHODS: Data on neutralizing antibody (NtAb) titers and clinical efficacy against Wuhan or D614G strains of homologous ChAdOx1 nCov-19 or mRNA-1273 and heterologous vaccination were extracted from previous studies for demonstration. The reductions in NtAb titers of homologous vaccination against Beta, Delta, and Omicron variants were obtained from literatures. A Bayesian inversion method was used to derive CoP from homologous to mix-match vaccine. Findings The predicted efficacy of ChAdOx1 nCov-19 and mRNA-1273 for Wuhan or D614G strains was 93 % (89 %-97 %). Given 8 âˆ¼ 11-fold, 2 âˆ¼ 5.5-fold, and 32.5 âˆ¼ 36-fold reduction of NtAb for Beta, Delta, and Omicron variants compared with D614G, the corresponding predictive efficacy of the mix-match ranged from 75.63 % to 73.87 %, 84.87 % to 81.25 %, and 0.067 % to 0.059 %, respectively. Interpretations While ChAdOx1 nCov-19 and mRNA-1273 used for demonstrating how to timely evaluate CoP for the mix-match vaccine still provides clinical efficacy against Beta and Delta VOCs but it appears ineffective for Omicron variants, which highlights the urgent need for next generation vaccine against Omicron variant.

Assessing efficacy of antiviral therapy for COVID-19 patients: A case study on remdesivir with bayesian synthesis design and multistate analysis.

BACKGROUND/PURPOSE: A synthesis design and multistate analysis is required for assessing the clinical efficacy of antiviral therapy on dynamics of multistate disease progression and in reducing the mortality and enhancing the recovery of patients with COVID-19. A case study on remdesivir was illustrated for the clinical application of such a novel design and analysis. METHODS: A Bayesian synthesis design was applied to integrating the empirical evidence on the one-arm compassion study and the two-arm ACTT-1 trial for COVID-19 patients treated with remdesivir. A multistate model was developed to model the dynamics of hospitalized COVID-19 patients from three transient states of low, medium-, and high-risk until the two outcomes of recovery and death. The outcome measures for clinical efficacy comprised high-risk state, death, and discharge. RESULTS: The efficacy of remdesivir in reducing the risk of death and enhancing the odds of recovery were estimated as 31% (95% CI, 18-44%) and 10% (95% CI, 1-18%), respectively. Remdesivir therapy for patients with low-risk state showed the efficacy in reducing subsequent progression to high-risk state and death by 26% (relative rate (RR), 0.74; 95% CI, 0.55-0.93) and 62% (RR, 0.38; 95% CI, 0.29-0.48), respectively. Less but still statistically significant efficacy in mortality reduction was noted for the medium- and high-risk patients. Remdesivir treated patients had a significantly shorter period of hospitalization (9.9 days) compared with standard care group (12.9 days). CONCLUSION: The clinical efficacy of remdesvir therapy in reducing mortality and accelerating discharge has been proved by the Bayesian synthesis design and multistate analysis.

Effectiveness of non-pharmaceutical interventions and vaccine for containing the spread of COVID-19: Three illustrations before and after vaccination periods.

BACKGROUND: There are few studies demonstrating how the effectiveness of various extents of non-pharmaceutical interventions (NPIs) before and after vaccination periods. The study aimed to demonstrate such an effectiveness in the alteration of the epidemic curves from theory to practice. METHODS: The empirical data on the daily reported COVID-19 cases were extracted from open source. A computer simulation design in conjunction with the susceptible-exposed-infected-recovered (SEIR) type model was applied to evaluating confinement measures in Italy with adjustment for underreported cases; isolation and quarantine in Taiwan; and NPIs and vaccination in Israel. RESULTS: In Italy scenario, the extents of confinement measures were 34% before the end of March and then scaled up to 70% after then. Both figures were reduced to 22-69% after adjusting for underreported cases. Approximately 44% of confinement measures were implemented in the second surge of pandemic in Italy. Fitting the observational data on Taiwan assuming the initial outbreak similar to Wuhan, China, 44% of isolation and quarantine were estimated before March 23rd, 2020. Isolation and quarantine were scaled up to 90% and at least 60% to contain community-acquired outbreaks from March 24th, 2020 onwards. Given 15% monthly vaccination rate from December 2020 in Israel, the effectiveness estimates of reducing the infected toll were 36%, 56%, and 85% for NPIs alone, vaccination alone, and both combined, respectively. CONCLUSION: We demonstrated how various NPIs stamp out and delay the epidemic curve of COVID-19. The optimal implementation of these NPIs has to be planned before wide vaccine uptake worldwide.

Long-term effectiveness of population-wide multifaceted interventions for hepatocellular carcinoma in Taiwan.

BACKGROUND & AIMS: Taiwan has launched a series of population-wide interventions to prevent hepatocellular carcinoma (HCC) related to hepatitis B and C virus infection since 1984. We took this opportunity to investigate the impact of each intervention on the incidence and case-fatality rate of HCC, and assessed their relative contributions to the overall reduction in mortality during this period. METHODS: Population-based registry data on HCC mortality and incidence from individuals aged 0 to 84 years between 1979 and 2016 were collected before (Period 1) and after universal hepatitis B vaccination from 1984 (Period 2), universal health care from 1995 (Period 3), and viral hepatitis therapy from 2003 (Period 4). A Bayesian Poisson regression model was used for mortality decomposition analysis to estimate the respective contributions of these interventions to the reduction in age-specific incidence and case-fatality rates. RESULTS: Mortality declined substantially in children, young- and middle-aged groups, but only slightly decreased in the elderly group. The declining trends in mortality were in part explained by incidence reduction and in part by a remarkable decline in case-fatality rate attributed to universal health care. Hepatitis B vaccination led to a 35.9% (26.8% to 44.4%) reduction in incidence for individuals aged 30 years or below, whereas antiviral therapy reduced the incidence of HCC by 14.9% (11.8% to 17.9%) and 15.4% (14.1% to 16.6%) for individuals aged 30-49 years and 50-69 years, respectively. CONCLUSIONS: Vaccination and antiviral therapy were effective in reducing HCC incidence and mortality for the young and middle-aged groups, while the case-fatality rate was improved by universal health care for all age groups. LAY SUMMARY: Since 1984, a series of population-wide interventions have been launched in Taiwan to prevent viral hepatitis-related hepatocellular carcinoma, including a universal hepatitis B vaccination program (from 1984), universal health care (from 1995), and a national viral hepatitis therapy program (from 2004). Vaccination and antiviral therapy were effective in reducing HCC incidence and mortality for the young and middle-aged groups, while the case-fatality rate was improved by universal health care for all age groups.

Clinical manifestations and outcomes of patients with scirrhous hepatocellular carcinoma.

BACKGROUND: The scirrhous hepatocellular carcinoma (HCC) is a rare subtype characterized by prominent fibrous stroma separating nests of tumor cells histologically. The clinical characteristics of scirrhous HCC have not been clearly elucidated due to limited literatures. We aimed to investigate the clinical manifestations and outcomes of patients with scirrhous HCC. METHODS: A total of 4012 patients with histologically proven HCC from the Cancer Registry Database (2004-2016) of the National Taiwan University Hospital (NTUH) were enrolled; whereas, 30 patients with scirrhous HCC were identified from the pathology database of NTUH. We matched 120 patients with non-scirrhous HCC through propensity score according to sex, age, Barcelona Clinic Liver Cancer stage and initial treatment modality for comparison. RESULTS: No significant difference in baseline characteristics and presentations was observed between the patients with scirrhous and non-scirrhous HCC except baseline alpha-fetoprotein level. The overall survival was comparable in these two groups. For the patients undergoing curative therapy, the risk of recurrence in the patients with scirrhous HCC was significantly higher within 24 months after curative therapy (hazard ratio [HR], 2.88, 95% confidence interval [CI], 1.43-5.80, p value, 0.003) as compared with those with non-scirrhous HCC. The overall recurrence rate was comparable in these two groups. CONCLUSIONS: Using propensity score matching, the risk of recurrence in the patients with scirrhous HCC was significantly higher in the first 2 years after curative therapy as compared to those with non-scirrhous HCC. An individualized post-curative treatment monitoring strategy should be considered for the patients with scirrhous HCC.

NIACE score refines the overall survival of hepatocellular carcinoma by Barcelona clinic liver cancer staging.

BACKGROUND AND AIM: The NIACE score provides prognostic values for hepatocellular carcinoma (HCC) in European studies. We aim to evaluate the prognostic value of the NIACE score in Asian patients. METHODS: Patients with HCC were retrospectively enrolled from a tertiary medical center in Taiwan during 2009-2014, and their clinical information were collected. The NIACE score was calculated according to the Nodular numbers, tumor Infiltration, Alpha-fetoprotein level, Child-Pugh score, and Eastern Cooperative Oncology Group score. The prognostic values of NIACE score for overall survival according to individual treatment and the Barcelona clinic liver cancer (BCLC) staging were analyzed. RESULTS: A total of 468 patients were included with a median follow-up of 30 months. A greater NIACE score correlated with lower median survival and higher BCLC staging. Regardless of treatment modalities, NIACE scores (0, 1-1.5, 2.5-3, and 4-7) significantly predicted survival between groups (log-rank P < 0.001). Specifically, NIACE score (0, 1-1.5, 2.5-3, and 4-7) significantly predicted survival in patients receiving transarterial chemoembolization (log-rank P < 0.001). NIACE score 1, 2.5, and 4 further distinguished overall survival in BCLC A, B, and C patients, respectively (all log-rank P < 0.01). After adjustment of the confounders and the BCLC staging, NIACE score of 2.5-3 and 4-7 (vs 0) had a significantly increased risk of mortality with a hazard ratio of 4.04 (95% confidence interval: 2.14-7.64, P < 0.001) and 7.45 (95% confidence interval: 3.22-17.23, P < 0.001), respectively. CONCLUSIONS: The NIACE score helps refine differential prognosis among BCLC A, B, and C subgroups of Asian patients with HCC, especially in those receiving transarterial chemoembolization.

Clinical Manifestations and Outcomes of Patients with Sarcomatoid Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) is the fifth most common cancer and the second leading cause of cancer-related deaths worldwide. Sarcomatoid HCC is a rare histological subtype of HCC with largely unclear clinical manifestations and outcomes. We evaluated the clinical manifestations and outcomes of patients with sarcomatoid HCC. We identified 5,047 patients with histologically proven HCC from the Cancer Registry Database (1996-2016) of National Taiwan University Hospital. Among them, 40 patients with sarcomatoid HCC were identified from the pathology database of National Taiwan University Hospital. We included 160 patients with nonsarcomatoid HCC through propensity score matching according to sex, age, and Barcelona Clinic Liver Cancer stage. The majority of these patients with sarcomatoid HCC were men (75%); their median age was 58 years. Only 47.5% of the patients with sarcomatoid HCC presented with typical image patterns of HCC. The pathological grading of sarcomatoid HCC was more advanced compared with that of nonsarcomatoid HCC (42.5% vs. 23.8% in grade III and IV, P < 0.0001). The sarcomatoid group had significantly shorter median recurrence-free (13.3 vs. 84.2 months, log-rank P < 0.0001) and overall (8.3 vs. 69.3 months, log-rank P < 0.0001) survival than did the nonsarcomatoid group. The results of the multivariable Cox proportional hazard model revealed histological sarcomatoid subtype as an independent factor for all-cause mortality (hazard ratio [HR], 6.47; 95% confidence interval [CI], 3.12-13.43; P < 0.0001) and tumor recurrence (HR, 4.08; 95% CI, 1.72-9.66; P = 0.001). Conclusion: Compared with nonsarcomatoid HCC, sarcomatoid HCC was associated with more advanced histological grades and atypical image patterns. Histological sarcomatoid subtype is an independent predictor of tumor recurrence after curative treatment and all-cause mortality in patients with HCC.

An unusual case of primary hepatic lymphoma with dramatic but unsustained response to bendamustine plus rituximab and literature review.

OBJECTIVES: Primary hepatic lymphoma is an uncommon cause of hepatic space-occupying lesions. METHODS: We describe the case of a 73-year-old man with primary hepatic lymphoma, who presented with a low-grade fever and lower limb weakness which had progressed in the past 2 months. RESULTS: Abdominal ultrasound and computed tomography showed multiple small hepatic tumors. Echo-guided biopsy of the hepatic tumor demonstrated primary hepatic diffuse large B cell lymphoma. Moreover, bone marrow was uninvolved, but the bone marrow smear disclosed hemophagocytosis, which is uncommon in diffuse large B cell lymphoma. Chemotherapy with bendamustine and rituximab treatment was initiated with a dramatic response: hepatic tumors markedly shrank in size shown by follow-up computed tomography and the patient returned to his normal life. Nevertheless, the response was sustained for only 8 months. Finally, the disease resisted further chemotherapy and this patient died of a severe Klebsiella pneumoniae infection. CONCLUSION: Chemotherapy with bendamustine and rituximab has shown a dramatic, but not durable, response in the present case with old age and multiple comorbidities.

Cholelithiasis and Nephrolithiasis in HIV-Positive Patients in the Era of Combination Antiretroviral Therapy.

OBJECTIVES: This study aimed to describe the epidemiology and risk factors of cholelithiasis and nephrolithiasis among HIV-positive patients in the era of combination antiretroviral therapy. METHODS: We retrospectively reviewed the medical records of HIV-positive patients who underwent routine abdominal sonography for chronic viral hepatitis, fatty liver, or elevated aminotransferases between January 2004 and January 2015. Therapeutic drug monitoring of plasma concentrations of atazanavir was performed and genetic polymorphisms, including UDP-glucuronosyltransferase (UGT) 1A1*28 and multidrug resistance gene 1 (MDR1) G2677T/A, were determined in a subgroup of patients who received ritonavir-boosted or unboosted atazanavir-containing combination antiretroviral therapy. Information on demographics, clinical characteristics, and laboratory testing were collected and analyzed. RESULTS: During the 11-year study period, 910 patients who underwent routine abdominal sonography were included for analysis. The patients were mostly male (96.9%) with a mean age of 42.2 years and mean body-mass index of 22.9 kg/m2 and 85.8% being on antiretroviral therapy. The anchor antiretroviral agents included non-nucleoside reverse-transcriptase inhibitors (49.3%), unboosted atazanavir (34.4%), ritonavir-boosted lopinavir (20.4%), and ritonavir-boosted atazanavir (5.5%). The overall prevalence of cholelithiasis and nephrolithiasis was 12.5% and 8.2%, respectively. Among 680 antiretroviral-experienced patients with both baseline and follow-up sonography, the crude incidence of cholelithiasis and nephrolithiasis was 4.3% and 3.7%, respectively. In multivariate analysis, the independent factors associated with incident cholelithiasis were exposure to ritonavir-boosted atazanavir for >2 years (adjusted odds ratio [AOR], 6.29; 95% confidence interval [CI], 1.12-35.16) and older age (AOR, 1.04; 95% CI, 1.00-1.09). The positive association between duration of exposure to ritonavir-boosted atazanavir and incident cholelithiasis was also found (AOR, per 1-year exposure, 1.49; 95% CI, 1.05-2.10). The associated factors with incident nephrolithiasis were hyperlipidemia (AOR, 3.97; 95% CI, 1.32-11.93), hepatitis B or C coinfection (AOR, 3.41; 95% CI, 1.09-10.62), and exposure to abacavir (AOR, 12.01; 95% CI, 1.54-93.54). Of 180 patients who underwent therapeutic drug monitoring of plasma atazanavir concentrations and pharmacogenetic investigations, we found that the atazanavir concentrations and UGT 1A1*28 and MDR1 G2677T/A polymorphisms were not statistically significantly associated with incident cholelithiasis and nephrolithiasis. CONCLUSIONS: In HIV-positive patients in the era of combination antiretroviral therapy, a high prevalence of cholelithiasis and nephrolithiasis was observed, and exposure to ritonavir-boosted atazanavir for >2 years was associated with incident cholelithiasis.