Adjuvant Therapy For Hepatocellular Carcinoma Research Articles

Hepatocellular carcinoma from the view of gastroenterologist/hepatologist

Hepatocellular carcinoma (HCC) is one of the major complications of chronic liver disease, mostly of liver cirrhosis. Liver diseases from different causes differ in the risks of HCC development. Different mechanisms of carcinogenesis are involved in HCC development in different liver diseases as well. Generally, two main pathways are distinguished: the cause of liver disease itself (e.g. viral infections, accumulation of heavy metals etc.) and chronic liver inflammation and fibrogenesis, including mechanisms of oxidative stress. Rare cases of HCC in liver without underlying cirrhosis are likely the consequences of the mechanisms directly linked with particular etiological factor (e.g. protein X in chronic hepatitis B virus (HBV) infection). The key approach which can lead to significantly better results of any treatment used in HCC cases is HCC screening and surveillance. The appropriate method of HCC surveillance is abdominal ultrasonography in 6-month intervals. There is still one question to be solved: the correct definition of target population which should undergo this method of surveillance. Currently, the target population in the developed world is defined as all patients with liver cirrhosis. Unfortunately, the only method of primary prevention of HCC is available: universal HBV vaccination. Antiviral treatment of hepatitis B or C is considered as a method of secondary prevention. Adjuvant therapy of HCC after its primary therapy (antiviral therapy after HCC resection etc.) and other measures able to reduce HCC recurrence risk are usually mentioned as tertiary prevention approach. The BCLC staging system is the most common system used in Europe for the classification of HCC at the dia-gnosis. This classification combines the stage of HCC itself with other parameters, such as liver disease severity (Child - Pugh classification), portal hypertension etc. BCLC is a system which guides the physicians to optimal treatment options in every HCC stage. The only potentially curable approaches are surgical resection or liver transplantation. These options may be used in 1/3 of all HCC patients. Unfortunately, the vast majority of HCC patients can be treated only by palliative treatment options with transarterial chemoembolisation being the most common one.

Glutamic-Pyruvic Transaminase 1 Facilitates Alternative Fuels for Hepatocellular Carcinoma Growth-A Small Molecule Inhibitor, Berberine.

Metabolic reprogramming is an essential hallmark of cancer. Besides the “Warburg effect”, cancer cells also actively reprogram amino acid metabolism to satisfy high nutritional demands in a nutrient-poor environment. In the glucose–alanine cycle, exogenous alanine taken up by hepatocytes is converted to pyruvate via glutamic-pyruvic transaminases (GPTs). However, the precise role of the glucose–alanine cycle in hepatocellular carcinoma (HCC) remains elusive. The current study revealed that alanine, as an alternative energy source, induced the metabolic reprogramming of HCC cells via activation of the downstream glucose–alanine cycle and thus promoted HCC growth in nutrient-depleted conditions. Further overexpression and loss-of-function studies indicated that GPT1 was an essential regulator for alanine-supplemented HCC growth. Combining molecular docking and metabolomics analyses, our study further identified a naturally occurring alkaloid, berberine (BBR), as the GPT1 inhibitor in HCC. Mechanically, BBR-mediated metabolic reprogramming of alanine-supplemented HCC via GPT1 suppression attenuated adenosine triphosphate (ATP) production and thus suppressed HCC growth. In conclusion, our study suggests that GPT1-mediated alanine–glucose conversion may be a potential molecular target for HCC therapy. Further demonstration of BBR-mediated metabolic reprogramming of HCC would contribute to the development of this Chinese medicine-derived compound as an adjuvant therapy for HCC.

Sorafenib as an adjuvant therapy for hepatocellular carcinoma with microvascular invasion after radical resection: A prospective multicenter nonrandomized controlled study.

e16685 Background: Hepatocellular carcinoma (HCC) with microvascular invasion (MVI) is established with poorer outcome and more frequent postoperative recurrence. Sorafenib is the first target drug that successfully prolongs the survival of advanced HCC, but it failed to prolong the survival of HCC after radical resection or ablation in the STORM study. After that, series studies revealed that sorafenib could improve the survival of HCC with MVI after surgery, while most studies with positive results were retrospective ones. Methods: A multicenter, prospective non-randomized, open-label study was performed in pts undergoing radical resection, postoperative pathology confirming HCC with MVI (BCLC A or B stage; T2 or part T3aN0M0). Pts in the treatment group (S group) started sorafenib within 4-6 postoperative weeks at the dose of 400mg per day at most 2 years, and the control group (C group) never received sorafenib. The primary endpoint is recurrence-free survival (RFS) rate at the 2nd postoperative year, and the secondary endpoints include postoperative median time to recurrence (TTR), 1-year postoperative RFS, pts’ overall survival (OS), and safety. This study was approved by Ethical Committee of Sun Yat-sen University Cancer Center, and registered at ClinicalTrials.gov with number NCT02867280. Results: Between 1 June 2015 and 31 August 2019, 154 eligible pts from 3 academic hospitals in China were enrolled (83 in C group and 53 in S group). Baseline demographics were balanced between the two groups. The 2-yr RFS rate was 56.1% in the S group vs. 55.7% in the C group, respectively ( P = 0.955), and the median RFS was 15.5 vs. 16.0 months ( P = 0.827).The recurrence rates at the 1st postoperative year were 38.6% vs. 34.0% ( P = 0.568), and the median TTR was the same as the RFS. There were 31 pts (54.4%) of the S group experienced treatment-related adverse events (AEs). The most common AE was hand-foot syndrome (HFS, 19/57, 10 pts ≥ grade-2). Other AEs included diarrhoea (15/57, 26.4%), alopecia (11/57, 19.3%), hypertension (5/57, 8.8%) and decreased platelet (3/57, 5.3%), and gastric ulcer with bleeding (1/57, 1.8%). Sorafenib was interrupted or discontinued in 7 pts due to AEs. Recruiting of this study was closed according to the results of the planned mid-term analysis, and all pts were followed on schedule to observe the other survival data. Conclusions: Postoperative sorafenib treatment with dose of 400mg once daily was well tolerated, but did not improve the RFS and TTR of Chinese HCC pts with MVI. Clinical trial information: NCT02867280 .

Effect of postoperative apatinib treatment after resection of hepatocellular carcinoma with portal vein invasion: A phase II study.

514 Background: Adjuvant therapy for hepatocellular carcinoma (HCC) is an unmet need. Apatinib, a VEGFR2 inhibitor, showed antitumor activity and tolerable toxicity for advanced HCC in a phase 2 study. We were aiming to explore the safety and efficacy of apatinib in adjuvant settings after resection of HCC with portal vein tumor thrombosis (PVTT). Methods: This is a single-center single-arm phase 2 study. The key inclusion criteria were: (1) pathologically confirmed HCC; (2) underwent liver resection with curative intention within 4-6 wk before recruitment; (3) PVTT assessed by preoperative imaging or intraoperative findings. Eligible pts received apatinib at 500 mg/day for a maximum of 12 mo until unacceptable toxicity or tumor recurrence. The primary outcome was recurrence-free survival (RFS) defined as the interval between surgery and the diagnosis of tumor recurrence or death from any causes whichever comes first. The secondary outcome is overall survival (OS) and treatment safety. Results: From Aug 17, 2017 to Dec 18, 2018, 49 pts were screened, and 30 pts were recruited. PVTT were classified as Vp1 (n = 7), Vp2 (n = 11), and Vp3 (n = 12) according to the LCSGJ classification. As the data cutoff on Aug 22, 2019, 4 pts are still on treatment. The median follow-up was 14.3 mo (IQR 12.3-19.3). Median duration of treatment was 4.8 mo (IQR 2.0–8.8). 20 recurrence and 2 death occurred including one death without recurrence. The mRFS was 7.6 mo (95% CI, 3.7-11.5), and the 1-year RFS rate was 36.1%. The mOS was not reached, and 1-year OS rate was 93.3% (standard error, 4.6%). Treatment-related adverse events occurred in 29 pts (96.7%). Grade 3 or 4 adverse events were reported in 14 pts (46.7%) (Table). Dose modification due to adverse events was recorded in 23 pts (76.7%). Conclusions: Apatinib is tolerant in most pts after resection for HCC with PVTT. A controlled study is warranted to prove its efficacy on tumor recurrence. Clinical trial information: NCT03261791. [Table: see text]

Efficacy and safety of Chinese patent medicine (Jinlong capsule) in the treatment of advanced hepatocellular carcinoma: a meta-analysis.

Jinlong capsule (JLC), a type of herbal medicine, is considered to be a promising adjuvant therapy for hepatocellular carcinoma (HC). Although an analysis of the published literature has been performed, the exact effects and safety of JLC are yet to be systematically investigated. Therefore, a wide-ranging systematic search of electronic databases to draw conclusions was performed. Data from 29 trials, including 2488 patients with advanced HC, were analyzed. The results indicated that, compared with conventional treatment alone, the combination of conventional treatment and JLC markedly improved overall patient response (odds ratio (OR) 2.06 [95% confidence interval (CI) 1.71–2.49]; P<0.00001), disease control rate (DCR) (OR 2.17 [95% CI 1.74–2.71]; P<0.00001) and quality of life (QoL) (OR 2.71 [95% CI 2.05–3.58]; P<0.00001), and significantly prolonged 6- (P=0.01), 12- (P<0.00001), 24- (P=0.001) and 36-month (P<0.0001) overall survival (OS) rates. The immune function of patients was also significantly enhanced after combined conventional therapy and JLC treatment, indicated by clearly increased percentages of CD3+ (P<0.0001), CD4+ (P<0.00001) and natural killer (NK) cells (P=0.0003), and CD4+/CD8+ ratio (P<0.00001). The incidence of leukopenia (P<0.00001), hepatotoxicity (P=0.005), and myelosuppression (P=0.0007) was lower in HC patients injected with JLC, whereas other adverse events did not differ significantly between the two groups (P>0.05). In summary, results of this meta-analysis suggest that the combination of conventional treatment and JLC is more effective for the treatment of HC than conventional treatment alone.

Efficacy and Safety of Lenvatinib as an Adjuvant Therapy for Hepatocellular Carcinoma

Efficacy and Safety of Lenvatinib as an Adjuvant Therapy for Hepatocellular Carcinoma

Preoperative transcatheter arterial chemoembolization for surgical resection of huge hepatocellular carcinoma (≥ 10cm): a multicenter propensity matching analysis.

Surgical resection for hepatocellular carcinoma (HCC) is potentially curative, but long-term survival remains unsatisfactory. There is currently no effective neoadjuvant or adjuvant therapy for HCC. We sought to evaluate the impact of preoperative transcatheter arterial chemoembolization (TACE) on long-term prognosis after surgical resection of huge HCCs (≥ 10cm). Using a multicenter database, consecutive patients who underwent curative-intent resection for huge HCC without macrovascular invasion between 2004 and 2014 were identified. The association between preoperative TACE with perioperative outcomes, long-term overall survival (OS), and recurrence-free survival (RFS) was assessed before and after propensity score matching (PSM). Among the 377 enrolled patients, 88 patients (23.3%) received preoperative TACE. The incidence of perioperative mortality and morbidity was comparable among patients who did and did not undergo preoperative TACE (3.4% vs. 2.4%, p= 0.704, and 33.0% vs. 31.1%, p= 0.749, respectively). PSM analysis created 84 matched pairs of patients. In examining the entire cohort as well as the PSM cohort, median OS (overall cohort: 32.8 vs. 22.3months, p= 0.035, and PSM only: 32.8 vs. 18.1months, p= 0.023, respectively) and RFS (12.9 vs. 6.4months, p= 0.016, and 12.9 vs. 4.1months, p= 0.009, respectively) were better among patients who underwent preoperative TACE vs. patients who did not. After adjustment for other confounding factors on multivariable analyses, preoperative TACE remained independently associated with a favorable OS and RFS after the resection of huge HCC. Preoperative TACE did not increase perioperative morbidity or mortality, yet was associated with an improved OS and RFS after liver resection of huge HCC (≥ 10cm).

Controversies of hepatectomy and adjuvant therapy for hepatocellular carcinoma: moving forward

Controversies of hepatectomy and adjuvant therapy for hepatocellular carcinoma: moving forward

Systematic review: Renin-angiotensin system inhibitors in chemoprevention of hepatocellular carcinoma.

BACKGROUNDNeoangiogenesis is one of the key pathogenetic mechanisms in hepatocellular carcinoma (HCC). Modulation of the renin-angiotensin system (RAS) by angiotensin-converting enzyme inhibitors (ACE-Is) and angiotensin receptor blockers (ARBs) seems to be a possible adjuvant therapy for HCC, due to the anti-angiogenic and anti-fibrogenic activity of these drugs.AIMTo elucidate the role of ARBs and ACE-Is in HCC.METHODSWe performed an electronic search of the literature using the most accessed online databases (PubMed, Cochrane library, Scopus and Web of Science), entering the query terms "angiotensin-converting enzyme inhibitors" OR "ACE inhibitors" OR "ACE-I" AND "hepatocarcinoma*" OR "hepatocellular carcinoma; moreover "angiotensin II type 1 receptor blockers" OR "ARBs" AND "hepatocarcinoma*" OR "hepatocellular carcinoma". Eligibility criteria were: (1) prospective or retrospective clinical studies; (2) epidemiological studies; and (3) experimental studies conducted in vivo or in vitro. s, conference papers, and reviews were excluded a priori. We limited our literature search to articles published in English, in peer-reviewed journals.RESULTSThirty-one studies were selected. Three interventional studies showed that ACE-Is had a significant protective effect on HCC recurrence only when used in combination with vitamin K or branched chain aminoacids, without a significant increase in overall survival. Of six retrospective observational studies, mainly focused on overall survival, only one demonstrated a prolonged survival in the ACE-Is group, whereas the two that also evaluated tumor recurrence showed conflicting results. All experimental studies displayed beneficial effects of RAS inhibitors on hepatocarcinogenesis. Numerous experimental studies, conducted either on animals and cell cultures, demonstrated the anti-angiogenetic and antifibrotic effect of ACE-Is and ARBs, thanks to the suppression of some cytokines such as vascular endothelial growth factor, hypoxia-inducible factor-1a, transforming growth factor-beta and tumor necrosis factor alpha. All or parts of these mechanisms were demonstrated in rodents developing fewer HCC and preneoplastic lesions after receiving such drugs.CONCLUSIONIn humans, RAS inhibitors - alone or in combination - significantly suppressed the cumulative HCC recurrence, without prolonging patient survival, but some limitations intrinsic to these studies prompt further investigations.

Research developments of adjuvant therapies for hepatocellular carcinoma after resection

Hepatocellular carcinoma (HCC) is a common malignancy with high rate of morbidity and mortality. Liver resection is the most effective curative treatment, yet subsequent recurrence and death are common, with 5-year overall survival rate remaining about 50% and 5-year postoperative recurrence reaching as high as 60%-70% reported by previous publications. Therefore, it is essential to identify the optimal adjuvant therapy for patients with unfavorable prognostic factors to decrease the postoperative recurrence or metastasis, thereby to deliver the promise of improved outcomes. However, there is no consensus about it and several treatment options were under investigation, including transcatheter arterial chemoembolization (TACE), radiotherapy, targeted therapy, and other treatments. Here, we review studies on the role of adjuvant therapies, to provide evidences for further research and clinical practice. Key words: Liver neoplasms/surgery; Liver neoplasms/interventional therapy; Liver neoplasms/radiotherapy; Liver neoplasms/targeted therapy; Research progress

Novel biomarkers GEP/ABCB5 regulate response to adjuvant transarterial chemoembolization after curative hepatectomy for hepatocellular carcinoma

BackgroundTransarterial chemoembolization (TACE) is the most commonly used adjuvant therapy for hepatocellular carcinoma (HCC) after curative resection. Responses to TACE are variable due to tumor and patient heterogeneity. We had previously demonstrated that expression of Granulin-epithelin precursor (GEP) and ATP-dependent binding cassette (ABC)B5 in liver cancer stem cells was associated with chemoresistance. The present study aimed to evaluate the association between GEP/ABCB5 expression and response to adjuvant TACE after curative resection for HCC. MethodsPatients received adjuvant TACE after curative resection for HCC and patients received curative resection alone were identified from a prospectively collected database. Clinical samples were retrieved for biomarker analysis. Patients were categorized into 3 risk groups according to their GEP/ABCB5 status for survival analysis: low (GEP−/ABCB5−), intermediate (either GEP+/ABCB5− or GEP−/ABCB5+) and high (GEP+/ABCB5+). Early recurrence (recurrence within 2 years after resection) and disease-free survival were analyzed. ResultsClinical samples from 44 patients who had followed-up for more than 2 years were retrieved for further biomarker analysis. Among them, 18 received adjuvant TACE and 26 received surgery alone. Patients with adjuvant TACE in the intermediate risk group was associated with significantly better overall survival and 2-year disease-free survival than those who had surgery alone (P = 0.036 and P = 0.011, respectively). Adjuvant TACE did not offer any significant differences in the early recurrence rate, 2-year disease-free survival and overall survival for patients in low and high risk groups. ConclusionsAdjuvant TACE can only provide survival benefits for patients in the intermediate risk group (either GEP+/ABCB5− or GEP−/ABCB5+). A larger clinical study is warranted to confirm its role in patient selection for adjuvant TACE.

Effect of Huaier granule on recurrence after curative resection of HCC: a multicentre, randomised clinical trial

ObjectiveThere is little evidence that adjuvant therapy after radical surgical resection of hepatocellular carcinoma (HCC) improves recurrence-free survival (RFS) or overall survival (OS). We conducted a multicentre, randomised, controlled, phase...

Efficacy of cytokine-induced killer cell infusion as an adjuvant immunotherapy for hepatocellular carcinoma: a systematic review and meta-analysis.

This study was designed to evaluate the efficacy and safety of cytokine-induced killer (CIK) cell-based immunotherapy as an adjuvant therapy for hepatocellular carcinoma (HCC). Published studies were identified by searching Medline, Cochrane, EMBASE, and Google Scholar databases with the keywords: cytokine-induced killer cell, hepatocellular carcinoma, and immunotherapy. The outcomes of interest were overall survival, progression-free survival, and disease-free survival. Eight randomized controlled trials (RCTs), six prospective studies, and three retrospective studies were included. The overall analysis revealed that patients in the CIK cell-treatment group had a higher survival rate (pooled hazard ratio (HR) =0.594, 95% confidence interval [CI] =0.501–0.703, P<0.001). Patients treated with CIK cells in non-RCTs had a higher progression-free survival rate (pooled HR =0.613, 95% CI =0.510–0.738, P<0.001). However, CIK cell-treated patients in RCTs had progression-free survival rates similar to those of the control group (pooled HR =0.700, 95% CI =0.452–1.084, P=0.110). The comparison between pooled results of RCTs and non-RCTs regarding the progression-free survival rate did not reach statistical significance. Patients in the CIK cell-treatment group had lower rates of relapse in RCTs (pooled HR =0.635, 95% CI =0.514–0.784, P<0.001). Similar results were found when non-RCT and RCTs were pooled (pooled HR =0.623, 95% CI =0.516–0.752, P<0.001). Adjuvant CIK cell-based immunotherapy is a promising therapeutic approach that can improve overall survival and reduce recurrence in patients with HCC.

Autologous transplantation of cytokine-induced killer cells as an adjuvant therapy for hepatocellular carcinoma in Asia: an update meta-analysis and systematic review

BackgroundHigh recurrence rate after curative treatment is the major problem for hepatocellular carcinoma (HCC). Cytokine-induced killer cells (CIKs) therapy was extensively studied among HCC patients. However, the value of CIKs therapy was controversial. A meta-analysis was performed to investigate the efficacy of adjuvant CIKs after invasive treatments among HCC patients.MethodsWe searched online for literatures studying sequential CIKs therapy for HCC patients. Recurrence-free survival (RFS), progress-free survival (PFS) and overall survival (OS) were set as the main endpoints. Both overall and subgroup analysis were accomplished.ResultsA total of 12 clinical trials with 1,387 patients were included. The pooled analysis showed a significant improvement of RFS, PFS and OS in CIK group (HR 0.56, 95% CI 0.47-0.67, p<0.00001 for RFS; HR 0.53, 95% CI 0.40-0.69, p<0.00001 for PFS; HR 0.59, 95% CI 0.46-0.77, p<0.0001 for OS). The proportion of CD4+ T cells increased significantly, while CD8+ T cells decreased significantly after CIKs therapy (WMD 4.07, 95% CI 2.58-5.56, p<0.00001; WMD -2.84, 95% CI -4.67 to -1.01, p=0.002, respectively). No significant differences of adverse events between CIK and non-CIK group existed.ConclusionsConventionally invasive therapies combined with CIKs therapy could improve the prognosis of HCC patients, especially for RFS and PFS, with mild side effects. Optimizing patient selection shall be the direction in future studies.

Peretinoin as an adjuvant therapy for hepatocellular carcinoma

ABSTRACTIntroduction: The current curative treatment modalities for hepatocellular carcinoma (HCC) are unfortunately fraught with high rates of HCC recurrence. Hence there is a need to prevent or reduce HCC recurrence after initial curative therapy. Peretinoin is a synthetic oral retinoid showing significant reduction in the incidence of recurrent or new HCC in patients who had received curative HCC therapy.Areas covered: Peretinoin is analysed against the background of molecular pathogenesis of the different causes of HCC. Publications related to peretinoin since 1996 are reviewed, covering clinical characteristics, safety and tolerance profile as well as the current status of clinical development.Expert commentary: Early phase studies are promising but we need to await the results of the ongoing phase III study of peretinoin in hepatitis C related HCC. Long term impact of peretinoin may be diminished by the foreseeable near eradication of hepatitis C by the direct acting antivirals.

New Natural Pigment Fraction Isolated from Saw Palmetto: Potential for Adjuvant Therapy of Hepatocellular Carcinoma.

For the first time, we discovered a small proportion of aqueous fraction from Saw Palmetto apart from the fatty acid-rich fraction exhibited pharmacological activity. Therefore, this study aims to explore the anti-tumor potential of red pigmented aqueous fraction of Saw Palmetto, NYG on human hepatocellular carcinoma and its possible targets. Subcutaneous xenograft and orthotopic implantation models of HCC were used to evaluate the tumor inhibitory effect of NYG. Human hepatocellular carcinoma (HCC) cell lines and human umbilical vein endothelial cells (HUVEC) were used as in vitro model. The mRNA expression was conducted by qPCR. Protein expression was monitored by immunoblotting and immunohistochemistry. Cell migration and blood vessel formation were determined by chamber assay and tube formation assay, respectively. Significant tumor inhibition of NYG in dose-dependent manner was observed on subcutaneous xenograft and orthotopic HCC model. NYG has no direct action on cell viability or VEGF secretion of HCC cells. However, NYG reduced in vitro migration and vessel formation activities of HUVEC cells, as well as in vivo intratumoral neovascularization. NYG attenuated extracellular signal-regulated kinases (ERK) activation in endothelial cells, which may be associated with the suppression of migration and tube formation of HUVEC. NYG suppressed tumor expansion of HCC via inhibiting neovascularization, and may be potential adjuvant treatment for HCC.

Improvement of the cytotoxic T lymphocyte response against hepatocellular carcinoma by transduction of cancer cells with an adeno-associated virus carrying the interferon-γ gene.

Dendritic cell (DC)-based antigen-targeted immunotherapy may offer effective adjuvant therapy for hepatocellular carcinoma (HCC), in which cytotoxic T lymphocytes (CTLs) are key. However, in a number of cases, the activity of CTLs is completely inhibited due to the downregulated expression of major human leukocyte antigen (HLA) class I molecules by HCC cells. The aim of the present study was to overcome this issue. Hep3B cells were transduced by HCC‑specific recombinant adeno‑associated virus (rAAV) carrying human α‑fetoprotein promoter (AFPp) and the interferon‑γ (IFN‑γ) gene (rAAV/AFPp‑IFN‑γ). rAAV carrying the cytomegalovirus promoter (CMVp) and human α‑fetoprotein (AFP) gene (rAAV/CMVp‑AFP) was used to transduce professional antigen‑presenting DCs for the purpose of stimulating a CTL response. It was observed that transduction of DCs with rAAV/CMVp‑AFP resulted in: (i) AFP and interleukin‑12 expression; (ii) high expression levels of cluster of differentiation (CD)80, CD83, CD86, CD40, HLA‑death receptor and CD1a; (iii) T cell populations with marked IFN‑γ expression; (iv) a high percentage of CD69+/CD8+ T cells; and (v) the activity of CTLs against HLA‑A2‑expressing Hep3B cells. The transduction of Hep3B cells with rAAV/AFPp‑IFN‑γ resulted in: (i) IFN‑γ expression; (ii) upregulated expression of HLA‑A2; and (iii) an improved CTL response against HLA‑A2‑deficient Hep3B cells. rAAV/CMVp‑AFP‑transduced DCs elicited an AFP‑specific and HLA‑class I‑restricted CTL response against Hep3B cells. In conclusion, it was shown that the transduction of Hep3B with rAAV/AFPp-IFN-γ upregulated the expression of HLA-A2 and improved the sensitivity to CTL response.

A randomized controlled trial on patients with or without adjuvant autologous cytokine-induced killer cells after curative resection for hepatocellular carcinoma

ABSTRACTBackground & Aims: There is no generally accepted adjuvant therapy for hepatocellular carcinoma (HCC) after curative resection. Autologous cytokine-induced killer (CIK) cells therapy has been reported to improve outcomes of patients with HCC, but its role as an adjuvant therapy remains unclear. This study aimed to evaluate the efficacy and safety of CIK as an adjuvant therapy for HCC after curative resection. Methods: This is a single center, phase 3, open label, randomized controlled trial (RCT). Two hundred patients who were initially diagnosed with HCC of Barcelona Clinic Liver Cancer (BCLC) stage A or B, and underwent curative hepatectomy were randomly assigned to receive four cycles of CIK treatment (the CIK group, n = 100) or no treatment (the control group, n = 100). The primary outcome was time to recurrence. The secondary outcomes included disease-free survival (DFS), overall survival (OS) and adverse events. Results: All patients in the CIK group finished the treatment by protocol. The median time to recurrence (TTR) was 13.6 (IQR 6.5–25.2) mo in the CIK group and 7.8 (IQR 2.7–17.0) mo in the control group (p = 0.01). There were no significant differences between the groups in DFS and OS. All adverse events were grade 1 or 2. There were no significant differences in incidence between the two groups.Conclusions: Four cycles of CIK therapy were safe and effective to prolong the median TTR in patients with HCC after curative resection, but the treatment did not improve the DFS and OS.

Luteoloside Suppresses Proliferation and Metastasis of Hepatocellular Carcinoma Cells by Inhibition of NLRP3 Inflammasome

The inflammasome is a multi-protein complex which when activated regulates caspase-1 activation and IL-1β secretion. Inflammasome activation is mediated by NLR proteins that respond to stimuli. Among NLRs, NLRP3 senses the widest array of stimuli. NLRP3 inflammasome plays an important role in the development of many cancer types. However, Whether NLRP3 inflammasome plays an important role in the process of hepatocellular carcinoma (HCC) is still unknown. Here, the anticancer effect of luteoloside, a naturally occurring flavonoid isolated from the medicinal plant Gentiana macrophylla, against HCC cells and the underlying mechanisms were investigated. Luteoloside significantly inhibited the proliferation of HCC cells in vitro and in vivo. Live-cell imaging and transwell assays showed that the migration and invasive capacities of HCC cells, which were treated with luteoloside, were significantly inhibited compared with the control cells. The inhibitory effect of luteoloside on metastasis was also observed in vivo in male BALB/c-nu/nu mouse lung metastasis model. Further studies showed that luteoloside could significantly reduce the intracellular reactive oxygen species (ROS) accumulation. The decreased levels of ROS induced by luteoloside was accompanied by decrease in expression of NLRP3 inflammasome resulting in decrease in proteolytic cleavage of caspase-1. Inactivation of caspase-1 by luteoloside resulted in inhibition of IL-1β. Thus, luteoloside exerts its inhibitory effect on proliferation, invasion and metastasis of HCC cells through inhibition of NLRP3 inflammasome. Our results indicate that luteoloside can be a potential therapeutic agent not only as an adjuvant therapy for HCC, but also, in the control and prevention of metastatic HCC.

Adjuvant systemic drug therapy and recurrence of hepatocellular carcinoma following curative resection

Postoperative recurrence of hepatocellular carcinoma (HCC) has a negative impact on long-term survival. According to available evidence, many systemic untargeted agents are ineffective as adjuvant therapy to prevent the recurrence of HCC following curative resection. Interferon α has potential effectiveness as adjuvant therapy for HCC in the presence of underlying conditions such as HBV or HCV infection. Oral polyprenoic acid has also proven its effectiveness according to a prospective study; however, no other studies have reported polyprenoicacid (acyclic retinoid) to be effective. Sorafenib is the only systemic molecular targeted agent that has proven effectiveness as adjuvant therapy according to a pilot study. To date, 11 randomized clinical trials are underway with different agents as adjuvant systemic drug therapy to prevent the recurrence of HCC following curative resection according to Clinicaltrial.gov. Adjuvant systemic drugs may be the most promising of all adjuvant modalities in the near future since HCC may be a systemic disease rather than a local disease.