Tumour antigen expression in hepatocellular carcinoma in a low-endemic western area.

BACKGROUND: Identification of tumour antigens is crucial for the development of vaccination strategies against hepatocellular carcinoma (HCC). Most studies come from eastern-Asia, where hepatitis-B is the main cause of HCC. However, tumour antigen expression is poorly studied in low-endemic, western areas where the aetiology of HCC differs. METHODS: We constructed tissue microarrays from resected HCC tissue of 133 patients. Expression of a comprehensive panel of cancer-testis (MAGE-A1, MAGE-A3/4, MAGE-A10, MAGE-C1, MAGE-C2, NY-ESO-1, SSX-2, sperm protein 17), onco-fetal (AFP, Glypican-3) and overexpressed tumour antigens (Annexin-A2, Wilms tumor-1, Survivin, Midkine, MUC-1) was determined by immunohistochemistry. RESULTS: A higher prevalence of MAGE antigens was observed in patients with hepatitis-B. Patients with expression of more tumour antigens in general had better HCC-specific survival (P=0.022). The four tumour antigens with high expression in HCC and no, or weak, expression in surrounding tumour-free-liver tissue, were Annexin-A2, GPC-3, MAGE-C1 and MAGE-C2, expressed in 90, 39, 17 and 20% of HCCs, respectively. Ninety-five percent of HCCs expressed at least one of these four tumour antigens. Interestingly, GPC-3 was associated with SALL-4 expression (P=0.001), an oncofetal transcription factor highly expressed in embryonal stem cells. SALL-4 and GPC-3 expression levels were correlated with vascular invasion, poor differentiation and higher AFP levels before surgery. Moreover, patients who co-expressed higher levels of both GPC-3 and SALL-4 had worse HCC-specific survival (P=0.018). CONCLUSIONS: We describe a panel of four tumour antigens with excellent coverage and good tumour specificity in a western area, low-endemic for hepatitis-B. The association between GPC-3 and SALL-4 is a novel finding and suggests that GPC-3 targeting may specifically attack the tumour stem-cell compartment.

Patterns of anti-TNF use and associated treatment outcomes in inflammatory bowel disease patients: results from an analysis of Dutch health insurance claims data.

INTRODUCTION: Real-life patterns of anti-tumour necrosis factor (anti-TNF) use remain largely unknown. We aimed to investigate survival rates, clinical outcomes and costs of anti-TNF agents in a large population of patients with inflammatory bowel disease (IBD). METHODS: Health insurance data from 22,082 IBD patients were provided by Achmea Healthcare. Time to anti-TNF discontinuation, treatment intensification, corticosteroid initiation and hospitalisation were analysed in patients starting on anti-TNF treatment from January 2008 until December 2014. Treatment regimens were analysed at different time points. RESULTS: In this cohort, 855 and 1199 subjects started infliximab and adalimumab treatment, respectively. The median time to anti-TNF discontinuation was 600 days (IQR 156-1693). The proportion of subjects receiving intensified treatment increased over time (infliximab at 3 vs. 24 months: 22.2% vs. 33.6%, p = 0.01; adalimumab at 3 vs. 24 months: 10.5% vs. 19.3%, p < 0.001). Cessation of anti-TNF treatment was less common in Crohn's disease patients (HR 0.79, p = 0.001) and in patients receiving intensified treatment (HR 0.62, p = 0.001). Immunomodulator use was associated with a longer time to corticosteroid initiation (HR 0.80, p = 0.048), but not with longer drug survival (HR 0.99, p = 0.617). Hospitalisation was more common in Crohn's patients (HR 1.49, p = 0.011). Corticosteroid initiation was lower in Crohn's patients (HR 0.57, p < 0.001) and in patients using infliximab (HR 0.55, p < 0.001). CONCLUSIONS: Discontinuation of anti-TNF therapy occurred earlier than previously reported and was associated with a diagnosis of ulcerative colitis and non-intensified anti-TNF treatment. Immunomodulator use at the start of anti-TNF treatment was associated with a longer time to corticosteroid initiation, but not with longer drug survival.

Optimization of anti-TNF therapy in patients with Inflammatory Bowel Disease.

After the introduction of anti-tumor necrosis factor (anti-TNF) agents, the clinical outcome of patients with Inflammatory Bowel Disease (IBD) has improved significantly. However, use of anti-TNF therapy is complicated by loss of response. In order to maintain remission, adequate serum levels are required. Hence, therapeutic drug monitoring (TDM) is important in order to optimize serum drug levels, especially in patients with loss of response to these agents. Optimization of anti-TNF therapy by applying TDM enables clinicians to regain response to TNF blockers in a significant proportion of patients. It is important to use anti-TNF agents in their most optimal way, since these therapeutic agents are expensive and the medical options after failing anti-TNF therapy are limited. Here, we will discuss how to optimize treatment with anti-TNF agents in IBD patients in order to improve treatment efficacy, prevent anti-drug antibody formation, reduce side effects, discontinue unnecessary treatment and manage costs.

SMAD4 exerts a tumor-promoting role in hepatocellular carcinoma.

Further understanding of the molecular biology and pathogenesis of hepatocellular carcinoma (HCC) is crucial for future therapeutic development. SMAD4, recognized as an important tumor suppressor, is a central mediator of transforming growth factor beta (TGFB) and bone morphogenetic protein (BMP) signaling. This study investigated the role of SMAD4 in HCC. Nuclear localization of SMAD4 was observed in a cohort of 140 HCC patients using tissue microarray. HCC cell lines were used for functional assay in vitro and in immune-deficient mice. Nuclear SMAD4 levels were significantly increased in patient HCC tumors as compared with adjacent tissues. Knockdown of SMAD4 significantly reduced the efficiency of colony formation and migratory capacity of HCC cells in vitro and was incompatible with HCC tumor initiation and growth in mice. Knockdown of SMAD4 partially conferred resistance to the anti-growth effects of BMP ligand in HCC cells. Importantly, simultaneous elevation of SMAD4 and phosphorylated SMAD2/3 is significantly associated with poor patient outcome after surgery. Although high levels of SMAD4 can also mediate an antitumor function by coupling with phosphorylated SMAD1/5/8, this signaling, however, is absent in majority of our HCC patients. In conclusion, this study revealed a highly non-canonical tumor-promoting function of SMAD4 in HCC. The drastic elevation of nuclear SMAD4 in sub-population of HCC tumors highlights its potential as an outcome predictor for patient stratification and a target for personalized therapeutic development.