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1.
Prediagnostic alterations in circulating bile acid profiles in the development of hepatocellular carcinoma.
Stepien, M, Lopez-Nogueroles, M, Lahoz, A, Kühn, T, Perlemuter, G, Voican, C, Ciocan, D, Boutron-Ruault, MC, Jansen, E, Viallon, V, et al
International journal of cancer. 2022;(8):1255-1268
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Abstract
Bile acids (BAs) play different roles in cancer development. Some are carcinogenic and BA signaling is also involved in various metabolic, inflammatory and immune-related processes. The liver is the primary site of BA synthesis. Liver dysfunction and microbiome compositional changes, such as during hepatocellular carcinoma (HCC) development, may modulate BA metabolism increasing concentration of carcinogenic BAs. Observations from prospective cohorts are sparse. We conducted a study (233 HCC case-control pairs) nested within a large observational prospective cohort with blood samples taken at recruitment when healthy with follow-up over time for later cancer development. A targeted metabolomics method was used to quantify 17 BAs (primary/secondary/tertiary; conjugated/unconjugated) in prediagnostic plasma. Odd ratios (OR) for HCC risk associations were calculated by multivariable conditional logistic regression models. Positive HCC risk associations were observed for the molar sum of all BAs (ORdoubling = 2.30, 95% confidence intervals [CI]: 1.76-3.00), and choline- and taurine-conjugated BAs. Relative concentrations of BAs showed positive HCC risk associations for glycoholic acid and most taurine-conjugated BAs. We observe an association between increased HCC risk and higher levels of major circulating BAs, from several years prior to tumor diagnosis and after multivariable adjustment for confounders and liver functionality. Increase in BA concentration is accompanied by a shift in BA profile toward higher proportions of taurine-conjugated BAs, indicating early alterations of BA metabolism with HCC development. Future studies are needed to assess BA profiles for improved stratification of patients at high HCC risk and to determine whether supplementation with certain BAs may ameliorate liver dysfunction.
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Camrelizumab Combined with FOLFOX4 Regimen as First-Line Therapy for Advanced Hepatocellular Carcinomas: A Sub-Cohort of a Multicenter Phase Ib/II Study.
Li, H, Qin, S, Liu, Y, Chen, Z, Ren, Z, Xiong, J, Meng, Z, Zhang, X, Wang, L, Zhang, X, et al
Drug design, development and therapy. 2021;:1873-1882
Abstract
BACKGROUND Immune checkpoint inhibitors and chemotherapy can synergistically increase efficacy in a variety of malignancies. We conducted this phase Ib/II study to assess the safety and efficacy of anti-PD-1 antibody camrelizumab in combination with FOLFOX4 for treatment-naive advanced hepatocellular carcinoma (aHCC). METHODS This open-label, multicenter phase Ib/II study (NCT03092895) enrolled patients with aHCC and without prior systemic treatment for treatment with camrelizumab (3 mg/kg) and FOLFOX4 every two weeks. First, six patients were enrolled, followed by an additional 28 patients after dose-limiting toxicity cases were determined to be <33% of patients. The primary endpoint was tolerability and safety of treatment. RESULTS A total of 34 aHCC patients were enrolled and received study treatment. No dose-limiting toxicity were observed in the first six patients enrolled. Twenty-nine (85.3%) of the total 34 patients had grade ≥3 treatment-related adverse events (TRAEs), with the most common ones being decreased neutrophil count (55.9%) and decreased white blood cell count (38.2%). No TRAEs-related deaths occurred. The objective response and disease control rate were 29.4% (95% CI, 15.1-47.5) and 79.4% (95% CI, 62.1-91.3), respectively. The median duration of response, progression-free survival, and overall survival was 6.9 months (range, 3.3-11.5), 7.4 months (95% CI, 3.9-9.2), and 11.7 months (95% CI, 8.2-22.0), respectively. CONCLUSION Camrelizumab combined with FOLFOX4 for first-line treatment of patients with aHCC showed good safety and tolerability, with promising preliminary antitumor activity.
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Effect of sodium cantharidinate/vitamin B6 injection on survival, liver function, immune function, and quality of life in patients with hepatocellular carcinoma: Protocol for a meta-analysis.
Zhu, M, Liu, X, Zhou, C, Li, J
Medicine. 2020;(34):e21952
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Abstract
BACKGROUND Sodium cantharidinate/vitamin B6 (SC/VB6) injection, a famous insect-derived traditional Chinese medicine preparation, has been widely applied as a promising adjunctive drug for hepatocellular carcinoma (HCC). However, its exact clinical efficacy and safety is still not well investigated. In this study, we aimed to summarize the efficacy of SC/VB6 injection on survival, liver function, immune function, and quality of life (QoL) in patients with HCC through the meta-analysis. METHODS All available randomized controlled trials (RCTs) and high-quality prospective cohort studies that investigated the efficacy and safety of SC/VB6 for patients with HCC were searched from ten electronic databases including PubMed, Google Scholar, Cochrane Library, Excerpt Medica Database (Embase), Medline, Web of Science (WOS), Chinese Biomedical Literature Database (CBM), China National Knowledge Infrastructure (CNKI), China Scientific Journal Database (CSJ), and Wanfang Database. Papers in Chinese or English published from January 2000 to July 2020 will be included without any restrictions.Study selection and data extraction will be performed independently by 2 researchers. The clinical outcomes including overall survival (OS), QoL, liver function, immune function, and adverse events, were systematically evaluated. Review Manager 5.3 and Stata 14.0 were used for data analysis, and the quality of the clinical trials was also evaluated. RESULTS The results of this study will be published in a peer-reviewed journal, and provide a helpful evidence for clinicians to formulate the best postoperative adjuvant treatment strategy for HCC patients. CONCLUSION Our study will draw an objective conclusion of the efficacy of SC/VB6 on survival, liver function, immune function, and QoL in patients with HCC. INPLASY REGISTRATION NUMBER INPLASY202070121.
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Retinoids in health and disease: A role for hepatic stellate cells in affecting retinoid levels.
Haaker, MW, Vaandrager, AB, Helms, JB
Biochimica et biophysica acta. Molecular and cell biology of lipids. 2020;(6):158674
Abstract
Vitamin A (retinol) is important for normal growth, vision and reproduction. It has a role in the immune response and the development of metabolic syndrome. Most of the retinol present in the body is stored as retinyl esters within lipid droplets in hepatic stellate cells (HSCs). In case of liver damage, HSCs release large amounts of stored retinol, which is partially converted to retinoic acid (RA). This surge of RA can mediate the immune response and enhance the regeneration of the liver. If the damage persists activated HSCs change into myofibroblast-like cells producing extracellular matrix, which increases the chance of tumorigenesis to occur. RA has been shown to decrease proliferation and metastasis of hepatocellular carcinoma. The levels of RA and RA signaling are influenced by the possibility to esterify retinol towards retinyl esters. This suggests a complex regulation between different retinoids, with an important regulatory role for HSCs.
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Tyrosine Kinase Inhibitors and Hepatocellular Carcinoma.
da Fonseca, LG, Reig, M, Bruix, J
Clinics in liver disease. 2020;(4):719-737
Abstract
Sorafenib was the first tyrosine kinase inhibitor (TKI) that showed success in extending survival in patients with advanced hepatocellular carcinoma (HCC). In recent years, additional TKIs have been shown to improve survival and expanded the armamentarium for treating this malignancy. The current landscape includes other classes of drugs, such as immune checkpoint inhibitors and monoclonal antibodies. The challenge is now placed on how to best select, combine, and sequence drugs with the goal of improving efficacy and minimizing toxicities to deliver better outcomes for HCC patients.
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Stellate Cells in the Tumor Microenvironment.
Roife, D, Sarcar, B, Fleming, JB
Advances in experimental medicine and biology. 2020;:67-84
Abstract
As tumor microenvironments share many of the same qualities as chronic wounds, attention is turning to the wound-repair cells that support the growth of cancerous cells. Stellate cells are star-shaped cells that were first discovered in the perisinusoidal spaces in the liver and have been found to support wound healing by the secretion of growth factors and extracellular matrix. They have since been also found to serve a similar function in the pancreas. In both organs, the wound-healing process may become dysregulated and lead to pathological fibrosis (also known as cirrhosis in the liver). In recent years there has been increasing attention paid to the role of these cells in tumor formation and progression. They may be a factor in initiating the first steps of carcinogenesis such as with liver cirrhosis and hepatocellular carcinoma and also contribute to continued tumor growth, invasion, metastasis, evasion of the immune system, and resistance to chemotherapy, in cancers of both the liver and pancreas. In this chapter we aim to review the structure and function of hepatic and pancreatic stellate cells and their contributions to the tumor microenvironment in their respective cancers and also discuss potential new targets for cancer therapy based on our new understanding of these vital components of the tumor stroma.
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Molecular therapies for HCC: Looking outside the box.
Faivre, S, Rimassa, L, Finn, RS
Journal of hepatology. 2020;(2):342-352
Abstract
Over the past decade, sorafenib has been the only systemic agent with proven clinical efficacy for patients with unresectable hepatocellular carcinoma (HCC). Recently, lenvatinib was shown to be non-inferior to sorafenib, while regorafenib, cabozantinib, and ramucirumab were shown to be superior to placebo in patients failing sorafenib. In addition, trials of immune checkpoint inhibitors reported encouraging efficacy signals. However, apart from alpha-fetoprotein, which is used to select patients for ramucirumab, no biomarkers are available to identify patients that may respond to a specific treatment. Different synergisms have been postulated based on the potential interplay between antiangiogenic drugs and immunotherapy, with several clinical trials currently testing this hypothesis. Indeed, encouraging preliminary results of phase I studies of bevacizumab plus atezolizumab and lenvatinib plus pembrolizumab have led to the design of ongoing phase III trials, including both antiangiogenics and immune checkpoint inhibitors in the front-line setting. Other important phase II studies have tested molecular therapies directed against different novel targets, such as transforming growth factor-beta, MET (hepatocyte growth factor receptor), and fibroblast growth factor receptor 4. These studies integrated translational research with the aim of better defining the biological tumour profile and identifying tumour and blood biomarkers that select patients who may really benefit from a specific molecular therapy. Importantly, good safety profiles make these drugs suitable for future combinations. In this review, we discuss the most recent data on novel combination strategies and targets, as well as looking ahead to the future role of molecular therapies in the treatment of patients with advanced HCC.
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Immunostimulatory monoclonal antibodies for hepatocellular carcinoma therapy. Trends and perspectives.
Mazzolini, GD, Malvicini, M
Medicina. 2018;(1):29-32
Abstract
Hepatocellular carcinoma (HCC) is the second cause of cancer-related death in the world and is the main cause of death in cirrhotic patients. Unfortunately, the incidence of HCC has grown significantly in the last decade. Curative treatments such as surgery, liver transplantation or percutaneous ablation can only be applied in less than 30% of cases. The multikinase inhibitor sorafenib is the first line therapy for advanced HCC. Regorafenib is the standard of care for second-line patients. However, novel and more specific potent therapeutic approaches for advanced HCC are still needed. The liver constitutes a unique immunological microenvironment, although anti-tumor immunity seems to be feasible with the use of checkpoint inhibitors such as nivolumab. Efficacy may be further increased by combining checkpoint inhibitors or by applying loco-regional treatments. The success of immune checkpoint blockade has renewed interest in immunotherapy in HCC.
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New chemical treatment options in second-line hepatocellular carcinoma: what to do when sorafenib fails?
Woo, HY, Yoo, SY, Heo, J
Expert opinion on pharmacotherapy. 2017;(1):35-44
Abstract
There have been no therapies available for patients who experience disease progression after sorafenib treatment. Regorafenib inhibits multiple kinases involved in tumor proliferation and neoangiogenesis, which has produced a survival benefit in hepatocellular carcinoma (HCC) after sorafenib failure. Other active candidate agents are c-Met inhibitors and immune checkpoint inhibitors. Areas covered: This paper presents an updated summary of the preclinical and clinical experience with regorafenib, c-Met inhibitors (tivantinib, cabozantinib and tepotinib), and a checkpoint inhibitor (nivolumab, pembrolizumab) in HCC. The reported data were obtained from abstracts of international conferences and journal articles published up to August 2016 and found in a PubMed search. Expert opinion: Based on favorable data from preclinical and clinical trials, regorafenib, c-Met inhibitor, and checkpoint inhibitors are promising agents for HCC after sorafenib failure. However, further efforts to maximize the survival benefit and minimize adverse events of these drugs in the treatment of HCC are still necessary. Additionally, searching for predictors of good responders could allow these new drugs to be applied in personalized treatments of HCC.
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Effect of a Perioperative Nutritional Supplementation with Oral Impact® in Patients undergoing Hepatic Surgery for Liver Cancer: A Prospective, Placebo-Controlled, Randomized, Double-Blind Study.
Seguin, P, Locher, C, Boudjema, K, Hamon, C, Mouchel, C, Malledant, Y, Bellissant, E
Nutrition and cancer. 2016;(3):464-72
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Abstract
Perioperative nutrition with supplements containing L-arginine, ω3-polyunsaturated fatty acids, and nucleotides could boost liver function recovery, immune response, and resistance to infection after hepatic resection. We conducted a placebo-controlled, randomized, double-blind study to assess the effect of a perioperative nutritional supplementation with Oral Impact® in patients undergoing hepatic surgery for liver cancer. Treatment was given three times daily for 7 days before and 3 days after surgery. Primary outcome was factor V, 3 days after surgery. Thirty-five patients (placebo: 17; Oral Impact: 18) were included. Five patients (placebo: three; Oral Impact: two) were not operated and five (placebo: two; Oral Impact: three) did not undergo hepatic resection. Factor V (mean ± SD) was 70 ± 27% and 79 ± 25% (P = 0.409) 3 days after surgery and 90 ± 30% and 106 ± 16% (P = 0.066) 5 days after surgery, in placebo and Oral Impact groups, respectively. There were no significant differences between groups on other outcomes assessing liver function recovery (bile production, γ-glutamyl transferase, α-fetoprotein), immune response (CD3, CD4, CD8 cells, CD4/CD8 ratio, natural killer cells, B lymphocytes), number of infections, and tolerance. A 10-day perioperative nutritional supplementation with Oral Impact does not improve hepatic function, immune response, and resistance to infection in patients undergoing hepatic surgery for liver cancer.