• Direct-acting antiviral
• Hepatitis C virus
• Hepatocellular carcinoma
• Liver resection
• Sustained virological response

• adjuvant therapy
• hepatocellular carcinoma
• mTOR inhibitors
• metformin

• hepatitis B virus
• hepatocellular carcinoma
• postoperative
• predictor
• preoperative

The development of multidrug resistance in cancer chemotherapy is a major obstacle to the effective treatment of human malignant tumors. Several epidemiological studies have demonstrated that inflammation is closely related to cancer and plays a key role in the development of both solid and liquid tumors. Therefore, targeting inflammation and the molecules involved in the inflammatory process may be a good strategy for treating drug-resistant tumors. In this review, we discuss the molecular mechanisms underlying inflammation in regulating anticancer drug resistance by modulating drug action and drug-mediated cell death pathways. Inflammation alters the effectiveness of drugs through modulation of the expression of multidrug efflux transporters (e.g., ABCG2, ABCB1, and ABCC1) and drug-metabolizing enzymes (e.g., CYP1A2 and CYP3A4). In addition, inflammation can protect cancer cells from drug-mediated cell death by regulating DNA damage repair, downstream adaptive response (e.g., apoptosis, autophagy, and oncogenic bypass signaling), and tumor microenvironment. Intriguingly, manipulating inflammation may affect drug resistance through various molecular mechanisms validated by in vitro/in vivo models. In this review, we aim to summarize the underlying molecular mechanisms that inflammation participates in cancer drug resistance and discuss the potential clinical strategies targeting inflammation to overcome drug resistance.

Hepatocellular carcinoma (HCC) is a highly heterogeneous, invasive, and conventional chemotherapy-insensitive tumor with unique biological characteristics. The main methods for the radical treatment of HCC are surgical resection or liver transplantation. However, recurrence rates are as high as 50% and 70% at 3 and 5 years after liver resection, respectively, and even in Milan-eligible recipients, the recurrence rate is approximately 20% at 5 years after liver transplantation. Therefore, reducing the postoperative recurrence rate is key to improving the overall outcome of liver cancer. This review discusses the risk factors for recurrence in patients with HCC radical surgical resection and adjuvant treatment options that may reduce the risk of recurrence and improve overall survival, including local adjuvant therapy (e.g., transcatheter arterial chemoembolization), adjuvant systemic therapy (e.g., molecular targeted agents and immunotherapy), and other adjuvant therapies (e.g., antiviral and herbal therapy). Finally, potential research directions that may change the paradigm of adjuvant therapy for HCC are analyzed.

• Adjuvant therapy
• Liver cancer
• Immunotherapy
• Chemotherapy
• Targeted therapy

The long-term prognosis of hepatocellular carcinoma (HCC) treated at a very-early-stage (the Barcelona Clinical Liver Cancer (BCLC) classification stage 0) was unclear, especially in terms of background liver disease.

This single-center, retrospective study included 302 patients with BCLC stage 0 HCC treated with radiofrequency ablation (RFA) and followed for at least six months. We examined the impact of background liver disease on overall survival and recurrence.

The median age was 72 (range; 36–91) years; the median tumor diameter was 15 (range; 8–20) mm. The etiologies of background liver disease were hepatitis B virus infection (HBV) in 24 cases, hepatitis C virus infection (HCV) in 195 cases, and non-viral (NBNC) in 83 cases. Among the patients with HCV, 63 had achieved sustained virological response (SVR) by antiviral therapy (HCV SVR) before developing HCC (n = 37) or after HCC treatment (n = 26), and 132 had active HCV infection (HCV non-SVR). The median overall survival was 85 (95% CI; 72–98) months, and the median recurrence-free survival was 26 (95% CI; 20–30) months. Active infection with hepatitis C virus negatively contributed to overall survival (HR 2.91, 95% CI 1.31–3.60, p = 0.003) and recurrence-free survival (HR 1.47, 95% CI 1.06–2.05, p = 0.011).

The prognosis of RFA treatment for very early-stage HCC was favorable. Achieving SVR in hepatitis C was important for further prognosis improvement.

• Adult
• Aged
• Aged, 80 and over
• Carcinoma, Hepatocellular/diagnosis
• Carcinoma, Hepatocellular/epidemiology
• Carcinoma, Hepatocellular/therapy
• Carcinoma, Hepatocellular/virology
• Comorbidity
• Female
• Hepatitis B/epidemiology
• Hepatitis C/epidemiology
• Humans
• Liver Neoplasms/diagnosis
• Liver Neoplasms/epidemiology
• Liver Neoplasms/therapy
• Liver Neoplasms/virology
• Male
• Middle Aged
• Prognosis
• Radiofrequency Ablation

• Japan Agency for Medical Research and Development

The genomic characteristics of hepatocellular carcinoma (HCC) after a sustained virological response (SVR) and its differences according to whether an SVR was achieved by treatment with direct‐acting antivirals (DAA) or interferon (IFN) are still not fully understood.

Sixty‐nine surgically resected HCCs from patients with hepatitis C virus infection were analyzed by gene expression profiling and whole‐exome sequencing.

Among the 69 HCC patients, 34 HCCs in which an SVR was not achieved at the time of surgery were classified as HCV‐positive, and 35 HCCs in which an SVR was achieved at the time of surgery were classified as HCV‐SVR. According to the HCV treatment, 35 HCV‐SVR HCCs were classified into two groups: eight tumors with DAA (HCV‐SVR‐DAA) and 24 tumors with interferon (HCV‐SVR‐IFN). The frequency of samples with ARID2 mutations was significantly lower in HCV‐SVR than in HCV‐positive tumors (p = 0.048). In contrast, the frequency of samples with PREX2 mutations was significantly higher in HCV‐SVR samples than in HCV‐positive samples (p = 0.048). Among the patients with HCV‐SVR, the frequency of samples with TP53 mutations was significantly higher in HCV‐SVR‐DAA tumors than in HCV‐SVR‐IFN tumors (p = 0.030). TP53 inactivation scores in HCV‐SVR‐DAA tumors were found to be significantly enhanced in comparison to HCV‐SVR‐IFN tumors (p = 0.022). In addition, chromosomal instability and PI3K/AKT/mTOR pathway signatures were enhanced in HCV‐SVR‐DAA tumors. HCV‐SVR‐DAA was significantly associated with portal vein invasion (p = 0.003) in comparison to HCV‐SVR‐IFN.

Our dataset potentially serves as a fundamental resource for the genomic characteristics of HCV‐SVR‐DAA tumors. Our comprehensive genetic profiling by WES revealed significant differences in the mutation rate of several driver genes between HCV‐positive tumors and HCV‐SVR tumors. Furthermore, it was revealed that the frequency of samples with mutations in TP53 was significantly higher in HCV‐SVR‐DAA tumors than in HCV‐SVR‐IFN tumors.

• direct-acting antiviral agent
• hepatitis C virus
• hepatocellular carcinoma
• interferon
• sustained virological response

• antiviral agents
• carcinoma
• hepatitis C
• hepatocellular
• immunotherapy

• 19K09152 Japan Society for the Promotion of Science
• H30-Kansei-Shitei-003 Ministry of Health, Labour and Welfare of Japan

• direct acting antiviral agents
• hepatitis virus infection status
• hepatocellular carcinoma
• prognosis

• Biliary Tract Neoplasms/diagnosis
• Biliary Tract Neoplasms/epidemiology
• Biliary Tract Neoplasms/etiology
• Biliary Tract Neoplasms/surgery
• Biliary Tract Surgical Procedures/methods
• Digestive System Diseases/diagnosis
• Digestive System Diseases/epidemiology
• Digestive System Diseases/etiology
• Digestive System Diseases/surgery
• Humans

• P30 CA008748 NCI NIH HHS

• hepatectomy
• hepatitis C virus
• hepatocellular carcinoma
• regression of liver fibrosis
• sustained virologic response

• Consensus
• DAA
• HCV
• Hepatitis C
• TASL
• Taiwan

• Adolescent
• Antiviral Agents/therapeutic use
• Carcinoma, Hepatocellular/drug therapy
• Carcinoma, Hepatocellular/therapy
• Child
• Coinfection/drug therapy
• Consensus
• Female
• Hepacivirus
• Hepatitis C/complications
• Hepatitis C/drug therapy
• Hepatitis C/epidemiology
• Hepatitis C, Chronic/drug therapy
• Humans
• Liver Neoplasms/drug therapy
• Liver Neoplasms/epidemiology
• Pregnancy
• Taiwan/epidemiology