TRIM31 is upregulated in hepatocellular carcinoma and promotes disease progression by inducing ubiquitination of TSC1–TSC2 complex

Background: Lenvatinib has been recently approved as a first-line treatment option for patients with unresectable hepatocellular carcinoma (HCC) in Korea. We aimed to study the efficacy and safety of lenvatinib therapy in a real-world practice and to find prognostic factors related to survival and disease progression. Methods: A hospital-based retrospective study was conducted on 111 consecutive patients who had unresectable HCC and were treated with lenvatinib at Samsung Medical Center from October 2018 to March 2020. Efficacy was determined using the modified Response Evaluation Criteria in Solid Tumors (mRECIST) criteria in 111 patients who completed 1st tumor assessment. Safety was evaluated in 116 HCC patients including 5 patients who discontinued lenvatinib due to adverse events (AEs) before 1st tumor assessment using Common Terminology Criteria for AEs version 5.0. Results: A total of 111 patients with a median age of 59 years were analyzed during a median follow-up duration of 6.2 (4.4–9.0) months. The Kaplan-Meier estimate of overall survival was 10.5 months, and the median progression-free survival was 6.2 months. Based on mRECIST criteria, the objective response rate was 18.9% and disease control rate was 75.7%. AEs developed in 86/116 (74.1%) patients, and grade ≥3 AEs developed in 16/116 (13.8%) patients. Diarrhea, hand-foot skin rash, abdominal pain, hypertension, and anorexia were identified as the AEs with the highest frequencies of any grade. REFLECT eligibility criteria including tumor extent ≥50% liver occupation or inadequate bone marrow function and occurrence of anorexia were prognostic factors for survival, and occurrence of diarrhea was a favorable factor for disease progression. Conclusion: Lenvatinib therapy showed a favorable efficacy and safety in a real-world practice. The REFLECT eligibility criteria and specific AEs could be one of the prognostic markers.

Download Full-text

Genetic variants of programmed cell death 1 are associated with HBV infection and liver disease progression

Scientific Reports ◽

10.1038/s41598-021-87537-9 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Nghiem Xuan Hoan ◽

Pham Thi Minh Huyen ◽

Mai Thanh Binh ◽

Ngo Tat Trung ◽

Dao Phuong Giang ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Cell Death ◽

Liver Disease ◽

Programmed Cell Death ◽

Disease Progression ◽

Infection Risk ◽

Hbv Infection ◽

Liver Disease Progression ◽

Increased Risk ◽

Programmed Cell Death 1

AbstractThe inhibitory effects of programmed cell death 1/programmed cell death ligand 1 (PD-1/PD-L1) modulates T-cell depletion. T-cell depletion is one of the key mechanisms of hepatitis B virus (HBV) persistence, in particular liver disease progression and the development of hepatocellular carcinoma (HCC). This case–control study aimed to understand the significance of PD-1 polymorphisms (PD-1.5 and PD-1.9) association with HBV infection risk and HBV-induced liver disease progression. Genotyping of PD-1.5 and PD-1.9 variants was performed by direct Sanger sequencing in 682 HBV-infected patients including chronic hepatitis (CHB, n = 193), liver cirrhosis (LC, n = 183), hepatocellular carcinoma (HCC, n = 306) and 283 healthy controls (HC). To analyze the association of PD-1 variants with liver disease progression, a binary logistic regression, adjusted for age and gender, was performed using different genetic models. The PD-1.9 T allele and PD-1.9 TT genotype are significantly associated with increased risk of LC, HCC, and LC + HCC. The frequencies of PD-1.5 TT genotype and PD-1.5 T allele are significantly higher in HCC compared to LC patients. The haplotype CT (PD-1.5 C and PD-1.9 T) was significantly associated with increased risk of LC, HCC, and LC + HCC. In addition, the TC (PD-1.5 T and PD-1.9 C) haplotype was associated with the risk of HCC compared to non-HCC. The PD-1.5 CC, PD-1.9 TT, genotype, and the CC (PD-1.5 C and PD-1.9) haplotype are associated with unfavorable laboratory parameters in chronic hepatitis B patients. PD-1.5 and PD1.9 are useful prognostic predictors for HBV infection risk and liver disease progression.

Download Full-text

Inflammatory Mechanisms Underlying Nonalcoholic Steatohepatitis and the Transition to Hepatocellular Carcinoma

Cancers ◽

10.3390/cancers13040730 ◽

2021 ◽

Vol 13 (4) ◽

pp. 730

Author(s):

Moritz Peiseler ◽

Frank Tacke

Keyword(s):

Hepatocellular Carcinoma ◽

Liver Disease ◽

Disease Progression ◽

Immune Cells ◽

Nonalcoholic Steatohepatitis ◽

Adaptive Immune System ◽

Nonalcoholic Fatty Liver ◽

Inflammatory Processes ◽

New Treatment ◽

End Stage

Nonalcoholic fatty liver disease (NAFLD) is a rising chronic liver disease and comprises a spectrum from simple steatosis to nonalcoholic steatohepatitis (NASH) to end-stage cirrhosis and risk of hepatocellular carcinoma (HCC). The pathogenesis of NAFLD is multifactorial, but inflammation is considered the key element of disease progression. The liver harbors an abundance of resident immune cells, that in concert with recruited immune cells, orchestrate steatohepatitis. While inflammatory processes drive fibrosis and disease progression in NASH, fueling the ground for HCC development, immunity also exerts antitumor activities. Furthermore, immunotherapy is a promising new treatment of HCC, warranting a more detailed understanding of inflammatory mechanisms underlying the progression of NASH and transition to HCC. Novel methodologies such as single-cell sequencing, genetic fate mapping, and intravital microscopy have unraveled complex mechanisms behind immune-mediated liver injury. In this review, we highlight some of the emerging paradigms, including macrophage heterogeneity, contributions of nonclassical immune cells, the role of the adaptive immune system, interorgan crosstalk with adipose tissue and gut microbiota. Furthermore, we summarize recent advances in preclinical and clinical studies aimed at modulating the inflammatory cascade and discuss how these novel therapeutic avenues may help in preventing or combating NAFLD-associated HCC.

Download Full-text

An Imbalance in TAZ and YAP Expression in Hepatocellular Carcinoma Confers Cancer Stem Cell–like Behaviors Contributing to Disease Progression

Cancer Research ◽

10.1158/0008-5472.can-15-0291 ◽

2015 ◽

Vol 75 (22) ◽

pp. 4985-4997 ◽

Cited By ~ 62

Author(s):

Hiromitsu Hayashi ◽

Takaaki Higashi ◽

Naomi Yokoyama ◽

Takayoshi Kaida ◽

Keita Sakamoto ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Stem Cell ◽

Cancer Stem Cell ◽

Disease Progression

Download Full-text

Circulating tumor DNA profiling reveals clonal evolution and real-time disease progression in advanced hepatocellular carcinoma

International Journal of Cancer ◽

10.1002/ijc.30798 ◽

2017 ◽

Vol 141 (5) ◽

pp. 977-985 ◽

Cited By ~ 27

Author(s):

Zhi-Xiong Cai ◽

Geng Chen ◽

Yong-Yi Zeng ◽

Xiu-Qing Dong ◽

Min-Jie Lin ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Disease Progression ◽

Real Time ◽

Clonal Evolution ◽

Circulating Tumor Dna ◽

Dna Profiling ◽

Advanced Hepatocellular Carcinoma ◽

Tumor Dna

Download Full-text

Is disease progression a contraindication for the strategy of portal vein embolization followed by hepatectomy for hepatocellular carcinoma?

Surgery ◽

10.1016/j.surg.2018.10.023 ◽

2019 ◽

Vol 165 (4) ◽

pp. 696-702 ◽

Cited By ~ 2

Author(s):

Katsunori Imai ◽

Yo-ichi Yamashita ◽

Yosuke Nakao ◽

Norio Uemura ◽

Fumimasa Kitamura ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Portal Vein ◽

Disease Progression ◽

Portal Vein Embolization

Download Full-text

Area between the hepatic and heart curves of99mTc-galactosyl-human serum albumin scintigraphy represents liver function and disease progression for preoperative evaluation in hepatocellular carcinoma patients

Journal of Hepato-Biliary-Pancreatic Sciences ◽

10.1007/s00534-011-0486-2 ◽

2011 ◽

Vol 19 (6) ◽

pp. 667-673 ◽

Cited By ~ 7

Author(s):

Kohei Harada ◽

Toru Mizuguchi ◽

Yoshimi Katagiri ◽

Masaki Kawamoto ◽

Yukio Nakamura ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Human Serum Albumin ◽

Liver Function ◽

Serum Albumin ◽

Human Serum ◽

Disease Progression ◽

Preoperative Evaluation ◽

Galactosyl Human Serum Albumin

Download Full-text

Serum miR-375 Levels Are Closely Related to Disease Progression from HBV Infection to HBV-Related Hepatocellular Carcinoma

BioMed Research International ◽

10.1155/2020/5819385 ◽

2020 ◽

Vol 2020 ◽

pp. 1-9

Author(s):

Weilu Zhang ◽

Ting Fu ◽

Zhenjun Guo ◽

Ye Zhang ◽

Lei Zhang ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Hepatitis B ◽

Disease Progression ◽

Cellular Proliferation ◽

Hbv Infection ◽

Cell Counting ◽

Specificity And Sensitivity ◽

And Migration ◽

Proliferation And Migration

Background. There is an urgent need to identify ideal serological biomarkers that not only are closely related to disease progression from hepatitis B virus (HBV) infection to hepatocellular carcinoma (HCC) but also have high specificity and sensitivity. We conducted this study to analyze whether miR-375 has a potential value in the early prediction of the progression from HBV-related hepatitis or cirrhosis to HCC. Methods. A total of 177 participants were enrolled. Receiver operating characteristic (ROC) curve was used to evaluate the predictive capability of selected miR-375 for HBV-HCC. We upregulated the miR-375 expression in HepG2, HepG2.2.15, and HepAD38 cells to determine its effect on cellular proliferation and migration, in vitro using Cell Counting Kit-8 (CCK-8) assays. Results. Serum miR-375 levels decreased in order from healthy controls to chronic hepatitis B (CHB) without cirrhosis, followed by cirrhosis, and finally, HBV-HCC patients. miR-375 levels were significantly lower in HBeAg-positive and HBV DNA-positive patients than negative (P<0.05) and significantly lower in patients with elevated alpha-fetoprotein (AFP) and carcinoembryonic antigen (CEA) than normal levels (P<0.05). miR-375 might be a biomarker for HBV-HCC, with a high area under the curve (AUC) of 0.838 (95% confidence interval (CI) 0.780 to 0.897; sensitivity: 73.9%; specificity: 93.0%). The AUC (0.768 vs. 0.584) and sensitivity (93.8% vs. 75.0%) for miR-375 were higher than those for AFP. The overexpression of miR-375 noticeably inhibited proliferation and migration in HepG2, HepG2.2.15, and HepAD38, especially in HepG2.2.15 and HepAD38, which are stably infected with HBV. Conclusions. Serum miR-375 levels are closely related to disease progression from HBV-related hepatitis or cirrhosis to HCC.

Download Full-text

Baseline and Early Predictors of Good Patient Candidates for Second-Line after Sorafenib Treatment in Unresectable Hepatocellular Carcinoma

Cancers ◽

10.3390/cancers11091256 ◽

2019 ◽

Vol 11 (9) ◽

pp. 1256 ◽

Cited By ~ 5

Author(s):

Hitomi Takada ◽

Masayuki Kurosaki ◽

Kaoru Tsuchiya ◽

Yasuyuki Komiyama ◽

Jun Itakura ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Liver Function ◽

Disease Progression ◽

Kinase Inhibitors ◽

Tumor Burden ◽

Second Line ◽

Inclusion Criteria ◽

Sorafenib Treatment ◽

Unresectable Hepatocellular Carcinoma ◽

Early Predictors

Background: Recent advances in the development of tyrosine kinase inhibitors (TKIs) have enabled patients with unresectable hepatocellular carcinoma (HCC) to receive multiple TKIs in sequence. The aim of this study was to identify predictors of good candidates for second-line treatment after disease progression during sorafenib treatment. Methods: This is a retrospective cohort study of 190 consecutive HCC patients who were treated with sorafenib in our hospital. Three criteria of good candidates for second-line TKI at the time of disease progression during sorafenib treatment were defined as follows: criterion 1 was the same as the inclusion criteria of the regorafenib for patients with hepatocellular carcinoma who progressed on sorafenib treatment (RESORCE) study, criterion 2 was the inclusion criteria of the RESORCE study plus Child–Pugh score 5, and criterion 3 was the inclusion criteria of the RESORCE study plus albumin–bilirubin (ALBI) grade 1. Factors at baseline and at week 4 during sorafenib treatment were used to predict patients fulfilling each of these three criteria. Results: The distribution of patients was 29%, 13%, and 6% in criteria 1, 2, and 3, respectively. Significant factors for meeting criterion 1 was the combination of baseline albumin >3.7 g/dL (odds ratio (OR) 2.7) plus degree of decrease in albumin (Δalbumin) at week 4 <0.2 g/dL (OR 2.6), or the combination of baseline ALBI score <−2.33 (OR 2.5) and ΔALBI at week 4 <0.255 (OR 4.9). For criterion 2, the value of baseline albumin and ALBI score was identical to criterion 1; however, Δalbumin (<0.1 g/dL) and ΔALBI score (<0.19) became stricter. For criterion 3, the value of baseline albumin (>3.8 g/dL) and ALBI (<−2.55) became stricter, as did Δalbumin (<0.1 g/dL) and ΔALBI (<0.085). Furthermore, tumor burden (>11) was selected as an additional predictor (OR 5.4). Conclusion: Predictors to satisfy the RESORCE study inclusion criteria were as follows: preserved liver function at baseline, as reflected by albumin or ALBI score, and small deterioration of liver function early during sorafenib therapy, as reflected by Δalbumin or ΔALBI at week 4. Liver function at baseline and degree of change in liver function during sorafenib treatment need to be stricter for better outcomes of liver function with disease progression.

Download Full-text