Liver cancer international最新文献

Few types of cancers have witnessed such a dramatic change of the treatment paradigm in the last year as hepatocellular carcinoma (HCC). 2020 has been a milestone year, establishing atezolizumab plus bevacizumab as the new standard of care for first-line treatment of unresectable HCC, based on the results of the phase III IMbrave150 trial.^{1, 2} The success of the combination of an anti-programmed death-ligand 1 (PD-L1) monoclonal antibody (mAb) and an antiangiogenic agent is the result of a strong preclinical rationale, which has been widely studied in HCC, paving the way for its widespread clinical application. The positive results of the IMbrave150 study are just the tip of the iceberg, with several immunotherapy combinations currently under investigation in phase I-III studies. Immune checkpoint inhibitors (ICIs) used as monotherapy have led to disappointing results in HCC, both in first line, with nivolumab failing to demonstrate any survival advantage over sorafenib in the CheckMate 459 trial,³ and in second line, with pembrolizumab not confirming the promising results of the previous phase II trial in the KEYNOTE-240 trial.⁴ For this reason, combining ICIs with other drug classes could overcome innate tumour resistance and eventually increase the number of patients benefitting from immunotherapy. The novel treatment strategies under the spotlight include PD-1/PD-L1 mAbs plus antivascular endothelial growth factor (VEGF) mAb, PD-1/PD-L1 mAbs plus multikinase inhibitors (MKIs) and ICI combinations (PD-1/PD-L1 mAbs plus cytotoxic T lymphocyte antigen [CTLA]-4 mAbs). In preclinical studies, these combinations have shown to enhance the efficacy of the single agents, thus suggesting a potential synergistic effect.

The use of anti-VEGF agents rests on the principle that HCC is a richly vascularized cancer, and several proangiogenic factors play a central role in tumour growth and distant spread. In addition, preclinical research unravelled a whole world of immunomodulatory effects of the VEGF pathway, thus suggesting the possible use of bevacizumab in combination with immunotherapy. Indeed, VEGF receptors and the downstream effectors induce an immunosuppressive microenvironment by acting on innate and adaptive immune response. VEGF pathway can enhance the action of immature dendritic cells, myeloid-derived suppressor cells (MDSCs) and tumour-associated macrophages, while at the same time increasing the percentage and the action of regulatory T cells (T-regs) in the tumour microenvironment.⁵ In preclinical models, the use of bevacizumab has shown to revert these VEGF-induced immunosuppressive mechanisms, and, when bevacizumab is combined with an ICI, antitumor immune response induced by PD-1 blockade seems to be enhanced, even in ICI-resistant HCC models, thanks to an immunostimulatory T cell reprogramming.⁶ Based on a sim

Aflatoxins are produced by Aspergillus flavus and Aspergillus parasiticus and are toxic carcinogens. These ‘fungal molds’ grow on corn, groundnuts, cereals and other grains. Of all the aflatoxins, Aflatoxin-B1 (AFB1) is considered the most toxic. Long-term exposure of AFB1 forms DNA adducts causing many genetic mutations and epigenetic alterations, ultimately leading to hepatocellular carcinoma (HCC). The liver is the major site of Aflatoxin detoxification; wherein cytochrome P-450 (CYP450) enzymes process the AFB1 into its epoxide AFB1-Exo-8,9-Epoxy (ABFO) and other less toxic metabolites. ABFO, in turn, reacts with DNA, RNA and protein molecules forming AFB adducts. The AFB1-DNA adducts in turn will induce various mutations, mainly mediated by G→T transversions. Aflatoxins are also known to cause HCC cell proliferation, growth, and invasion as well as angiogenesis by various epigenetic mechanisms including DNA methylation, histone post-translational modifications and non-coding RNA deregulation, etc. In this review, we will be emphasizing on epigenetic mechanisms by which aflatoxins induce hepatocarcinogenesis. In the last section, we will also discuss various methodologies to control aflatoxin contamination and detoxification of aflatoxin adducts using natural substances that are potentially anti-aflatoxins.

The availability of safe, highly active anti-retroviral therapy (HAART) has dramatically ameliorated the morbidity related to human immunodeficiency virus (HIV) infection, significantly improving life expectancy.¹ A parallel reduction in AIDs-defining (acquired immunodeficiency syndrome) malignancies, such as Kaposi's sarcoma, primary central nervous system lymphoma and cervical cancer has also been observed.² Despite this reduction, rates of non-AIDs defining cancers including Hodgkin's lymphoma, anal cancer and hepatocellular carcinoma (HCC) have increased driven, at least in part, by improved overall survival.²

The treatment armamentarium for advanced HCC has welcomed several new additions, with the development of multi-target tyrosine kinase inhibitors (TKIs) such as sorafenib and more recently lenvatinib, cabozantinib, regorafenib and the monoclonal antibody, ramucirumab.^3-7 The pivotal phase III RESORCE trial demonstrated regorafenib efficacy as a second-line treatment for BCLC stage B or C patients previously treated with sorafenib with preserved liver function (Child-Pugh A), improving overall survival by 3 months compared to placebo.^{6, 7}

Regulatory trials for these drugs, such as the RESORCE trial have excluded challenging patient populations, including those with concomitant HIV infection. This has led to uncertainly in terms of both safety and efficacy in these patient groups. Sorafenib has been licensed in the European Union since 2007. Following approval, evidence in the form of case reports/case series have demonstrated both the safety and utility of sorafenib in HIV-1 seropositive patients with advanced HCC.^{8, 9} The concomitant use of HAART and sorafenib also appears to be both safe and effective.¹⁰ However, for newer TKIs, such as regorafenib, there is currently no published evidence to guide safe administration.

This case report describes the first reported use of regorafenib in a patient with HIV-1 infection and advanced HCC.

A 68-year-old Nepalese gentleman with a history of HIV-1 infection and cirrhosis was diagnosed in July 2018 with multifocal HCC (largest lesion 6 cm) not amenable to curative treatment. The cirrhosis was attributed to heavy alcohol intake (~80 units/wk for >5 years) and was diagnosed following an episode of acute hepatic decompensation 4 years prior, involving variceal bleeding and encephalopathy. This resolved after conservative management and had not re-occurred following complete alcohol abstinence.

HIV-1 was diagnosed in 2011 following an episode of atypical pneumonia (presumed Pneumocystis). Tests for other viral infections, such as hepatitis B and C were negative. He was commenced on HAART at the time of diagnosis with Truvada^® (Emtricitabine/Tenofovir) and Efavirenz. He had c

The recently developed PROSASH model is proving to be a useful tool in risk-group discrimination in hepatocellular carcinoma (HCC) patients treated with sorafenib. Several studies highlighted that the neutrophil-to-lymphocyte ratio (NLR) is one of the most important predictors of survival in HCC patients treated with sorafenib. The aims of the present study were to validate the PROSASH model and determine whether the incorporation of inflammatory markers can improve risk stratification. This study included 438 patients. According to the four categories of the PROSASH model, median overall survival (OS) was 20.0, 14.9, 8.5 and 3.0 months respectively (P < .001). The Harrell's c for this categorized model was 0.621. NLR (cut-off 3) stratified OS in each of the PROSASH categories. After reclassification, median OS was 21.0, 15.1, 8.2 and 4.1 months (P < .001). The Harrell's c increased from 0.621 to 0.673 (P = .001). Integrating NLR into the PROSASH model allowed a more accurate classification of the patients in the risk groups.

Editorial

The past decades have represented a season of dramatic change in the management of solid tumours. The ‘molecular revolution’ that has pervasively affected modern cancer medicine has once and for all transformed our understanding of cancer progression, leading to a significant broadening of the therapeutic index of novel systemic anticancer treatments on the basis of a rational matching with the patients’ tumour or germline genomic information.

While treatment paradigms have shifted for good across a growing number of malignancies, liver tumours have unevenly benefitted from the advances brought forward by preclinical and translational research.

In an era that has seen the achievement of long-term survivorship in metastatic melanoma, the approval of multiple lines of anti-angiogenics in renal cell carcinoma and the broadening of molecular and chemoimmunotherapy combinations in lung cancer, hepatocellular carcinoma has, in contrast, faced a period of stagnation in drug development, fuelled by an incomplete understanding of molecular drivers that can be effectively exploited for therapy.

Similarly, the incremental benefit observed from the development of novel therapies in biliary tract cancers has been modest and although adjuvant and second-line therapies in metastatic disease have changed the landscape in routine clinical care, the hope for long-term survival is still far from being achieved in the majority of patients who are diagnosed today.

Evidence from epidemiological studies mounts further pressure by lending us a fairly stern message: primary liver tumours remain a significant healthcare problem going forward, highlighting the need to concentrate efforts on this highly lethal subset of oncological diagnoses, for which limited therapeutic options currently exist.

In addition to the burden of primary tumours, the liver is a privileged site of secondary spread across a wide array of malignancies. As well as posing peculiar therapeutic challenges, metastatic spread to the liver confers, in the context of progressive malignancy, a significant degree of morbidity, ultimately leading to organ failure and death.

Liver cancer international (LCI) is not simply the testimony of a challenging pathway towards precision medicine, but also reflects the multidisciplinary approach integral to promote significant advancements in our current understanding of the pathophysiology and treatment of liver malignancies. Building on the cross-disciplinary expertise of an experienced Editorial Board, LCI cultivates the ambition to establish itself as a leading forum for the presentation of high-quality evidence surrounding the mechanisms of pathogenesis and progression of liver tumours, as well as progress in diagnostic and therapeutic options.

in taking advantage of a fully open access platform and an efficient peer review process, LCI aims to be a global voice in the field of hepatic oncology, fac