Gastrointestinal adverse events (GIAEs) are common in patients with advanced hepatocellular carcinoma (HCC) treated with sorafenib. Diarrhea is a prevalent event responsible for treatment ...interruptions and dosage modifications. Our study evaluates the role of baseline blood L-glutamine (L-Gln) levels in the prediction of gastrointestinal adverse events development early during treatment (eGIAE). Blood L-Gln was measured in 135 patients with advanced HCC prior to starting sorafenib. Any adverse events developed during therapy were registered in a prospective database. We used Mann–Whitney U and Fisher’s exact tests to compare quantitative or categorical variables, respectively, Kaplan–Meier method to analyze time to event variables, log-rank test for the survival functions and Cox regression models to estimate hazard ratios (HR). Fifteen per cent of patients developed eGIAE, with diarrhea as the most frequent one. Patients displaying the lowest L-Gln levels presented a significant higher risk of eGIAE, while those with the highest levels were protected from eGIAE and achieved better survival. Our study shows for the first time the association of baseline blood L-Gln levels with eGIAE development in HCC patients during sorafenib treatment. Low L-Gln concentrations might reflect a potentially compromised intestinal barrier that becomes clinically relevant early after treatment start.
Liver cancer is the fifth most common cancer and the second most frequent cause of cancer-related death globally. Hepatocellular carcinoma represents about 90% of primary liver cancers and ...constitutes a major global health problem. The following Clinical Practice Guidelines will give up-to-date advice for the clinical management of patients with hepatocellular carcinoma, as well as providing an in-depth review of all the relevant data leading to the conclusions herein.
HIV-seropositivity shortens survival in patients with hepatocellular carcinoma (HCC). Although risk factors for HCC including HCV infection can influence T cell phenotype, it is unknown whether HIV ...can influence functional characteristics of the T cell infiltrate.
From the Liver Cancer in HIV biorepository, we derived 129 samples of transplanted (76%) or resected (20%) HCC in eight European and North American centres. We profiled intra- and peritumoural tissue to evaluate regulatory CD4+/FOXP3+ and immune-exhausted CD8+/PD1+ T cells in HIV+ (n = 66) and HIV- (n = 63) samples. We performed targeted transcriptomics and T-cell receptor sequencing in a restricted subset of samples evaluated in relationship with HIV status. We correlated immunopathologic features with patients’ characteristics including markers of HIV infection.
Of the 66 HIV+ patients, 83% were HCV coinfected with an undetectable HIV viral load (51%) and a median blood CD4+ cell count of 430 cells/mm3 (range 15–908). Patients who were HIV+ were compared with HIV- controls with similar staging characteristics including Barcelona Clinic Liver Cancer (BCLC) stage A–B (86% vs. 83%, p = 0.16), <3 nodules (90% vs. 83%, p = 0.3) and median alpha-foetoprotein values (10.9 vs. 12.8 ng/ml, p = 0.72). HIV+ samples had higher PD-L1 expression rates in tumour tissue (51% vs. 8% p <0.0001) and displayed denser intratumoural CD4+/FOXP3+ (p <0.0001), CD8+/PD1+ (p <0.0001), with lower total peritumoural CD4+ (p <0.0001) and higher peritumoural CD8+/PD1+ (p <0.0001). Gene set analysis revealed HIV+ cases to have evidence of dysregulated adaptive and innate immunity. Tumour-infiltrating lymphocyte clonality was not influenced by HIV status.
HIV-associated HCC harbours a profoundly immune-exhausted tumour microenvironment, warranting prospective testing of immunotherapy in this treatment-deprived patient population.
Hepatocellular carcinoma is a non-AIDS defining malignancy characterised by poor survival. The programmed cell death (PD-1) pathway governs antiviral and anticancer immune exhaustion and is a therapeutic target in HCC. This study highlights how HIV infection is associated with significantly higher PD-L1 expression in HCC cells and in the surrounding microenvironment, leading to changes in cytotoxic and regulatory T cell function and dysregulation of proinflammatory pathways. Taken together, our results suggest dysfunctional T cell immunity as a mechanism of worse outcome in these patients and suggest clinical testing of checkpoint inhibitors in HIV-associated HCC.
Display omitted
•HIV+ resected HCCs are characterised by an increased expression rate of PD-L1.•HIV+ samples had an intratumoural infiltrate enriched with regulatory T cells and immune-exhausted CD8+PD-1+ T cells compared with HIV-HCC.•HIV+ HCCs show a downregulation of gene signatures related to innate and adaptive immune response on targeted transcriptomic analyses.•No association was found between HIV infection and T cell clonality within the intratumoural infiltrate.
The therapeutic management of hepatocellular carcinoma (HCC) has achieved great advances in the past few years. Before the publication of the SHARP clinical trial, which showed the effectiveness of ...sorafenib in patients with advanced HCC, no effective systemic therapy was available and only transarterial chemoembolization (TACE) had shown an impact on survival in clinical trials.
Management of HCC de Lope, Carlos Rodríguez; Tremosini, Silvia; Forner, Alejandro ...
Journal of hepatology,
2012, 2012-00-00, 2012-1-00, 20120101, Letnik:
56
Journal Article
Recenzirano
Summary Hepatocellular carcinoma (HCC) is a highly prevalent and lethal neoplasia, the management of which has significantly improved during the last few years. A better knowledge of the natural ...history of the tumor and the development of staging systems that stratify patients according to the characteristics of the tumor, the liver disease, and the performance status, such as the BCLC (Barcelona Clinic Liver Cancer) system, have led to a better prediction of prognosis and to a most appropriate treatment approach. Today curative therapies (resection, transplantation, ablation) can improve survival in patients diagnosed at an early HCC stage and offer a potential long-term cure. Patients with intermediate stage HCC benefit from chemoembolization and those diagnosed at advanced stage benefit from sorafenib, a multikinase inhibitor with antiangiogenic and antiproliferative effects. In this article we review the current management in HCC and the new advances in this field.
PDF
