Nonalcoholic fatty liver disease (NAFLD) may be a cause of hepatocellular carcinoma (HCC), but its high prevalence challenges current surveillance strategies. We aimed to evaluate HCC incidences in ...different risk stratifications for noncirrhotic NAFLD. Using Taiwan's National Health Insurance Research Database, we located 31,571 patients with NAFLD between the years 1998 and 2012. After excluding other causes of hepatitis, underlying cirrhosis or malignancy, 18,080 patients were recruited for final analysis. Cumulative incidences of HCC were analyzed after adjusting for competing mortality. With a median follow-up duration of 6.32 years in the study cohort, the 10-year cumulative incidence of HCC was 2.73% 95% confidence interval (CI): 1.69-3.76%. Hepatoprotectant was used as a surrogate marker for elevated serum alanine transaminase (ALT). After adjusting for age, gender, hypertension, hypercholesterolemia, diabetes mellitus, gout, statin use, metformin use and aspirin use, elevated ALT was independently associated with an increased HCC risk hazard ratio (HR) 6.80, 95% CI: 3.00-15.42; p < 0.001. Multivariate stratified analysis verified this association in all subgroups (HR> 1.0). Moreover, increased age (HR 1.08 per year, 95% CI: 1.05-1.11) and statin use (HR 0.29, 95% CI: 0.12-0.68) were also identified as independent risk factors. The 10-year cumulative HCC incidence was highest in older (age >55 years) patients with ALT elevation (12.41%, 95% CI: 5.99-18.83%), but lowest in younger patients without ALT elevation (0.36%, 95% CI: 0-1.08%). The incidence of HCC was relatively low in patients with clinically noncirrhotic NAFLD, however, HCC risk was significantly increased in older patients experiencing an elevated serum ALT.
MicroRNA-122 (miR-122), which accounts for 70% of the liver's total miRNAs, plays a pivotal role in the liver. However, its intrinsic physiological roles remain largely undetermined. We demonstrated ...that mice lacking the gene encoding miR-122a (Mir122a) are viable but develop temporally controlled steatohepatitis, fibrosis, and hepatocellular carcinoma (HCC). These mice exhibited a striking disparity in HCC incidence based on sex, with a male-to-female ratio of 3.9:1, which recapitulates the disease incidence in humans. Impaired expression of microsomal triglyceride transfer protein (MTTP) contributed to steatosis, which was reversed by in vivo restoration of Mttp expression. We found that hepatic fibrosis onset can be partially attributed to the action of a miR-122a target, the Klf6 transcript. In addition, Mir122a(-/-) livers exhibited disruptions in a range of pathways, many of which closely resemble the disruptions found in human HCC. Importantly, the reexpression of miR-122a reduced disease manifestation and tumor incidence in Mir122a(-/-) mice. This study demonstrates that mice with a targeted deletion of the Mir122a gene possess several key phenotypes of human liver diseases, which provides a rationale for the development of a unique therapy for the treatment of chronic liver disease and HCC.
The epithelial‐mesenchymal transition (EMT) is critical for induction of invasiveness and metastasis of human cancers. In this study we investigated the expression profiles of the EMT markers, the ...relationship between EMT markers and patient/tumor/viral factors, and the interplay between major EMT regulators in human hepatocellular carcinoma (HCC). Reduced E‐cadherin and nonmembranous β‐catenin expression, the hallmarks of EMT, were shown in 60.2% and 51.5% of primary HCC samples, respectively. Overexpression of Snail, Twist, or Slug, the major regulators of EMT, was identified in 56.9%, 43.1%, and 51.4% of primary HCCs, respectively. Statistical analysis determined that Snail and Twist, but not Slug, are major EMT inducers in HCC: overexpression of Snail and/or Twist correlated with down‐regulation of E‐cadherin, nonmembranous expression of β‐catenin, and a worse prognosis. In contrast, there were no such significant differences in samples that overexpressed Slug. Coexpression of Snail and Twist correlated with the worst prognosis of HCC. Hepatitis C‐associated HCC was significantly correlated with Twist overexpression. HCC cell lines with increased Snail and Twist expression (e.g., Mahlavu) exhibited a greater capacity for invasiveness/metastasis than cells with low endogenous Twist/Snail expression (e.g., Huh‐7). Overexpression of Snail or/and Twist in Huh‐7 induced EMT and invasiveness/metastasis, whereas knockdown of Twist or Snail in Mahlavu reversed EMT and inhibited invasiveness/metastasis. Twist and Snail were independently regulated, but exerted an additive inhibitory effect to suppress E‐cadherin transcription. Conclusion: Our study provides a comprehensive profile of EMT markers in HCC, and the independent and collaborative effects of Snail and Twist on HCC metastasis were confirmed through different assays. (HEPATOLOGY 2009.)
Background & Aims Treatment for hepatitis B virus infection reduces the risk of hepatocellular carcinoma (HCC). However, the long-term protective effects for subgroups of patients with chronic ...hepatitis B are unclear. Methods We conducted a retrospective nationwide cohort study using data from Taiwan's National Health Insurance Research Database (from January 1, 1997, through December 31, 2010). Cumulative incidences were calculated and multivariable analyses were carried out after adjusting for competing mortality. Propensity scores were used to match 21,595 patients with chronic hepatitis B who received nucleoside analogue therapy for at least 90 days (treated cohort) with 21,595 untreated patients with chronic hepatitis B (controls), who received hepatoprotectants for at least 90 days. Data were collected from the treated cohort for a mean period of 3.46 years and from controls for 5.24 years. Results The treated cohort had a significantly lower 7-year incidence of HCC (7.32%; 95% confidence interval CI, 6.77%−7.87%) than controls (22.7%; 95% CI, 22.1%−23.3%; P < .001). After adjusting for competing mortality and other confounders, nucleos(t)ide analogue treatment was associated with a reduced risk of HCC, with an adjusted hazard ratio of 0.37 (95% CI, 0.34–0.39; P < .001). Sensitivity analyses confirmed the association between nucleos(t)ide analogue treatment and reduced risk of HCC. Age, sex, cirrhosis, and diabetes mellitus modified this association. Conclusions Based on a retrospective, nationwide study in Taiwan, nucleoside analogue therapy use is associated with reduced risk of HCC in patients with chronic hepatitis B virus infection.
Background and Aims
PreS mutants of HBV have been reported to be associated with HCC. We conducted a longitudinal study of the role of HBV preS mutations in the development of HCC, particularly in ...patients with chronic hepatitis B (CHB) having low HBV DNA or alanine aminotransferase (ALT) levels, and investigated the effects of secretion‐defective preS2 deletion mutant (preS2ΔMT) on hepatocyte damage in vitro and liver fibrosis in vivo.
Approach and Results
Association of preS mutations with HCC in 343 patients with CHB was evaluated by a retrospective case–control follow‐up study. Effects of preS2ΔMT on HBsAg retention, endoplasmic reticulum (ER) stress, calcium accumulation, mitochondrial dysfunction, and liver fibrosis were examined. Multivariate analysis revealed a significant association of preS mutations with HCC (HR, 3.210; 95% CI, 1.072‐9.613; P = 0.037) including cases with low HBV DNA or ALT levels (HR, 2.790; 95% CI, 1.133‐6.873; P = 0.026). Antiviral therapy reduced HCC risk, including cases with preS mutations. PreS2ΔMT expression promoted HBsAg retention in the ER and unfolded protein response (UPR). Transmission electron microscopic examination, MitoTracker staining, real‐time ATP assay, and calcium staining of preS2ΔMT‐expressing cells revealed aberrant ER and mitochondrial ultrastructure, reduction of mitochondrial membrane potential and ATP production, and calcium overload. Serum HBV secretion levels were ~100‐fold lower in preS2ΔMT‐infected humanized Fah–/–/ Rag2–/–/Il2rg–/– triple knockout mice than in wild‐type HBV‐infected mice. PreS2ΔMT‐infected mice displayed up‐regulation of UPR and caspase‐3 and enhanced liver fibrosis.
Conclusions
PreS mutations were significantly associated with HCC development in patients with CHB, including those with low HBV DNA or ALT levels. Antiviral therapy reduced HCC occurrence in patients with CHB, including those with preS mutations. Intracellular accumulation of mutated HBsAg induced or promoted ER stress, calcium overload, mitochondrial dysfunction, impaired energy metabolism, liver fibrosis, and HCC.
Objective
To investigate the evolution and clinical significance of vasoconstriction on magnetic resonance angiography (MRA) in patients with reversible cerebral vasoconstriction syndromes (RCVS).
...Methods
Patients with RCVS were recruited and followed up with MRA examinations until normalization of vasoconstriction or for 6 months. The vasoconstriction severity of the major cerebral arterial segments (M1, M2, A1, A2, P1, P2, and basilar artery) was scored on a 5‐point scale: 0 (0–<10%), 1 (10–<25%), 2 (25–<50%), 3 (50–<75%), and 4 (≥75%). Subjects with at least 1 segment with a vasoconstriction score ≥2 were eligible for the study. Initial mean scores of single or combined arterial segments were used to predict ischemic complications.
Results
Seventy‐seven patients with RCVS (8 men/69 women; average age 47.7 ± 11.6 years) finished the study with a total of 225 MRAs performed. The mean number of arterial segments involved was 5.3 ± 3.0 in the initial MRA. Vasoconstriction scores reached their maximum 16.3 ± 10.2 days after headache onset, close to the average timing of headache resolution (16.7 ± 8.6 days). Vasoconstriction evolved in a parallel trend among different arterial segments. Seven (9.1%) patients developed posterior reversible encephalopathy syndromes (PRES). Six (7.8%) patients had ischemic stroke. A logistic regression model demonstrated that the M1–P2 combined score was associated with highest risk of PRES (odds ratio OR, 11.6, p = 0.005) and ischemic stroke (OR, 3.4; p = 0.026).
Interpretation
MRA evaluation in patients with RCVS is valid. Vasoconstriction was pervasive and outlasted headache resolution. Vasoconstrictions in M1 and P2 are important determinants for PRES and ischemic stroke. ANN NEUROL 2010;67:648–656
Background/Aims Hepatitis B virus (HBV) levels correlate with the development of hepatocellular carcinoma (HCC), but the role of viral load in HCC recurrence after tumor resection remains unclear. ...Herein we aimed to investigate the role of viral load in HCC recurrence following tumor resection. Methods From 1990 to 2002, 193 HBV-related HCC patients who underwent tumor resection in Taipei Veterans General Hospital were enrolled. Serum HBV DNA level and mutations were analyzed for association with early and late recurrence, together with other clinical variables. Results During a follow-up of 58.2 ± 44 months, 134 patients had HCC recurrence. Multivariate analysis showed that multinodularity (Hazard ratio HR, 95% confidence interval CI; 2.232, 1.021–4.878), macroscopic venous invasion (4.693, 1.645–13.391), AFP >20 ng/ml (3.891, 1.795–8.475), and cut margin ⩽1 cm (3.333, 1.487–7.470) were correlated with early recurrence (within two years of operation) of HCC. In addition, multivariate analysis determined that Ishak hepatic inflammatory activity >6 (4.658, 1.970–11.017), multinodularity (3.266, 1.417–7.526), ICG-15 >10% (2.487, 1.095–5.650) and HBV DNA level >106 copies/ml (2.548, 1.040–6.240) were significantly associated with late recurrence (>two years after resection). Patients with high viral loads tended to have higher Ishak inflammatory (7.00 ± 3.07 vs. 5.33 ± 2.96, p = 0.001) and fibrosis scores (4.17 ± 2.01 vs. 3.20 ± 2.41, p = 0.007) than those with lower loads. Conclusions Tumor factors were associated with early HCC recurrence while high viral loads and hepatic inflammatory activity were associated with late recurrence. Pre- and post-operative antiviral and anti-inflammatory therapies may be crucial in reducing late recurrence.
Purpose To construct a nomogram with the albumin-bilirubin (ALBI) grade to assess the long-term outcomes of patients with early-stage hepatocellular carcinoma (HCC) after radiofrequency ablation ...(RFA). Materials and Methods This retrospective study was approved by the institutional review board, and informed consent was waived. We studied 622 treatment-naïve patients with HCC according to the Milan criteria who subsequently underwent RFA from 2002 to 2013. Baseline characteristics were collected to identify the risk factors for determination of poor overall survival after RFA. The multivariate Cox proportional hazards model based on significant prognostic factors of overall survival was used to construct the nomogram. Results After a median follow-up time of 35.7 months, 190 patients had died. The cumulative 5- and 10-year overall survival rates were 63.1% and 48.7%, respectively. Stratified according to ALBI grade, the cumulative 5- and 10-year survival rates were 80.0% and 67.9% for patients with grade 1, respectively, and 48.6% and 35.1% for those with grades 2-3, respectively (P < .001). Multivariate analysis results showed that patient age older than 65 years, a prothrombin time international normalized ratio greater than 1.1, α-fetoprotein level greater than 20 ng/mL, multiple tumors, and ALBI grade 2 or 3 were associated with overall mortality. A nomogram was developed on the basis of these five variables. Internal validation with 200 bootstrapped sample sets had a good concordance index of 0.770 (95% confidence interval: 0.633, 0.876). Conclusion This simple nomogram based on the ALBI grade offers personalized long-term survival data for patients with early-stage HCC who undergo RFA.
RSNA, 2017 Online supplemental material is available for this article.
Summary
Background
There is still controversy about whether tenofovir disoproxil fumarate (TDF) and entecavir (ETV) have different effects on the outcomes of patients with hepatitis B virus ...(HBV)‐related hepatocellular carcinoma (HCC).
Aims
The aim of this study was to compare the prognoses between ETV and TDF treatment among patients with HBV‐related HCC after hepatectomy.
Methods
An analysis was done on data from the Taiwan Cancer Registry, which was linked to Taiwan National Health Insurance Research Database, for the years 2011–2016. We identified 7107 patients with HBV‐related HCC after curative hepatectomy, and 25.3% of them used ETV or TDF after surgery. After propensity score overlap weighting, 1797 patients treated with ETV (n = 1365) or TDF (n = 432) were included for analyses. Cox proportional hazards models were used to compare the efficacy of ETV and TDF for recurrence and overall survival (OS).
Results
After hepatectomy, the recurrence rate per 100 person‐years was 14.87 for the ETV group and 9.25 for the TDF group. The risk of recurrence was similar in the TDF group and the ETV group (HR 95% CI: 0.91 0.69–1.19; p = 0.479), as was the risk of all‐cause mortality (HR 95% CI: 0.67 0.42–1.07; p = 0.091). When considering early recurrence (<2 years) and late recurrence (≧2 years), the TDF and ETV groups showed no significant differences. Subgroup analyses and sensitivity analyses demonstrated consistent results.
Conclusion
Both TDF and ETV showed similar health benefits in terms of recurrence and OS in patients with HBV‐related HCC patients after hepatectomy.
The long‐term outcomes were not different statistically between HCC patients who received entecavir and tenofovir after hepatectomy.
We investigated the outcomes of patients with ruptured hepatocellular carcinoma (HCC) and identified the optimal treatment modality for such patients. We retrospectively enrolled 91 patients with ...treatment-naive HCC and tumor rupture at diagnosis, including 38 patients who underwent surgical resection (SR) alone, 28 patients who were treated with transarterial chemoembolization (TACE) only, 20 patients who had a sequential combination therapy of TACE and SR, and 5 patients who received best supportive care. After a median follow-up of 13.1 months, 54 patients died. The cumulative 5 years overall survival (OS) rates were 55.1% and 0% in the SR group and non-SR group, respectively (p < 0.001). Non-SR therapy was associated with poorer OS according to a multivariate analysis with a hazard ratio of 6.649 (95% confidence interval 3.581-12.344, p < 0.001). Moreover, whether patients received TACE or not did not impact the OS in both the SR group and the non-SR group. In conclusion, for patients with HCC and tumor rupture at the time of diagnosis, SR could lead to better prognoses than non-surgery treatment modalities. Moreover, a sequential combination of TACE and SR had similar clinical outcomes when compared to SR alone.
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