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BACKGROUND: Antigen sparing is regarded as crucial for pandemic vaccine development because worldwide influenza vaccine production capacity is limited. Adjuvantation is an important antigen-sparing strategy. We assessed the safety and immunogenicity of a recombinant H5N1 split-virion vaccine formulated with a proprietary adjuvant system and investigated whether it can induce cross-reactive immunity. METHODS: Two doses of an inactivated split A/Vietnam/1194/2004 NIBRG-14 (recombinant H5N1 engineered by reverse genetics) vaccine were administered 21 days apart to eight groups of 50 volunteers aged 18-60 years. We studied four antigen doses (3.8 microg, 7.5 microg, 15 microg, and 30 microg haemagglutinin) given with or without adjuvant. Blood samples were collected to analyse humoral immune response. Adverse events were recorded up through study day 51. Safety analyses were of the whole vaccinated cohort and immunogenicity analyses per protocol. This trial is registered with the ClinicalTrials.gov, number NCT00309634. FINDINGS: All eight vaccine formulations had a good safety profile. No serious adverse events were reported. The adjuvanted vaccines induced more injection-site symptoms and general symptoms than did the non-adjuvanted vaccines, but most were mild to moderate in intensity and transient in nature. The adjuvanted formulations were significantly more immunogenic than the non-adjuvanted formulations at all antigen doses. At the lowest antigenic dose (3.8 microg), immune responses for the adjuvanted vaccine against the recombinant homologous vaccine strain (A/Vietnam/1194/2004 NIBRG-14, clade 1) met or exceeded all US Food and Drug Administration and European Union licensure criteria. Furthermore, 37 of 48 (77%) participants receiving 3.8 microg of the adjuvanted vaccine seroconverted for neutralising antibodies against a strain derived by reverse genetics from a drifted H5N1 isolate (A/Indonesia/5/2005, clade 2). INTERPRETATION: Adjuvantation conferred significant antigen sparing that could increase the production capacity of pandemic influenza vaccine. Moreover, the cross-clade neutralising antibody responses recorded imply that such a vaccine could be deployed for immunisation before a pandemic. [ABSTRACT FROM AUTHOR]

Background: Non-alcoholic fatty liver disease (NAFLD) is the most important cause of chronic liver disease in the western world. Steatosis can be accompanied by inflammation and cell damage (non-alcoholic steatohepatitis, NASH), and even liver fibrosis. Sphingolipids are a heterogeneous class of lipids and essential components of the plasma membrane and plasma lipoproteins. The atypical class of deoxy-sphingolipids has been implicated in the metabolic syndrome and type 2 diabetes. Aim: To determine if circulating (deoxy)sphingolipids are associated with NAFLD and its different entities, steatosis, inflammatory changes (inflammation and ballooning) and fibrosis. Methods: Sphingolipids were analysed by LC–MS after hydrolysing the N-acyl and O-linked headgroups in plasma of obese adults who underwent a liver biopsy in suspicion of NAFLD. Results: Two-hundred and eighty-eight patients were included. There was no association between typical sphingolipids and NAFLD and its different entities. There was a significant association between the presence of steatosis and the concentrations of deoxy-sphinganine [exp(B) 11.163 with CI (3.432, 36.306) and p < 0.001] and deoxy-sphingosine [exp(B) 8.486 with CI (3.437, 20.949) and p < 0.001]. There was no association between these deoxy-sphingolipids and activity of the steatohepatitis, nor was there any association with fibrosis. Differences in deoxy-sphingolipids also correlated independently with the presence of the metabolic syndrome, but not diabetes. Conclusion: Deoxy-sphingolipids are elevated in patients with steatosis compared to those without fatty liver, but not different between the different NAFLD subtypes, suggesting that deoxy-sphingolipid bases might be involved in steatogenesis, but not in the further progression of NAFLD to NASH nor in fibrogenesis. [ABSTRACT FROM AUTHOR]

Transarterial chemoembolization (TACE) is the most widely used local treatment option for patients with hepatocellular carcinoma (HCC) who are not eligible for surgery or ablation and whose disease is confined to the liver. However, local control after TACE is limited. Although stereotactic body radiation therapy (SBRT) has demonstrated high local tumor control, there have been no randomized comparisons of the two techniques. TACE delivered with drug eluting beads (TACE-DEB) was therefore compared with SBRT in a multicenter randomized trial. Patients were potential candidates for the study if they were eligible for TACE but ineligible for surgery or ablation. They could also be recruited if they required treatment prior to liver transplantation. Other inclusion criteria were ECOG 0-1, cirrhosis Child Pugh A, and 1-3 tumors up to a cumulative diameter of ≤6cm. Exclusion criteria were macrovascular invasion, ascites, and untreated esophageal varices grade 3-4. A maximum of 4 TACE-DEB procedures and ablation after incomplete TACE were both allowed. SBRT was delivered in 6 fractions of 8-9Gy. Primary end point was time to progression (TTP). Secondary endpoints were local control (LC) (mRECIST); overall survival (OS); response rate (RR) (mRECIST); toxicity (CTCAE v4.03); and quality of life (QoL) (EORTC QLQ-C30, EORTC QLQ-HCC 18 and EuroQoL-5D). The calculated sample size was 100 patients. Between May 2015 and April 2020, 30 patients were randomized to the study. Due to slow accrual the trial was prematurely closed. Two patients in the SBRT arm were considered ineligible (low thrombocyte count, >3 tumors in the liver), leaving 16 patients in the TACE arm and 12 in the SBRT arm. One patient randomized for SBRT was subsequently treated with TACE (implanted fiducials used for SBRT tumor tracking not detectable on the Linac). Median follow-up was 28.1 months. In the intention-to-treat analyses, median TTP was 12 months for TACE and 19 months for SBRT (p=0.15). Median LC was 12 months for TACE and >40 months (not reached) for SBRT (p=0.056). Median OS was 36.8 months for TACE and 44.1 months for SBRT (p=0.36). Post-hoc analyses per protocol showed 100% for SBRT 1- and 2-year LC, and 54.4% and 43.6% for TACE (p=0.02). Both treatments resulted in RR>80%. Three episodes of possibly related toxicity grade ≥3 were observed after TACE. No episodes were observed after SBRT. QoL remained stable after both treatment arms. SBRT showed higher local antitumoral activity than TACE-DEB in this small group of HCC patients, and no detrimental effects on TTP, OS, toxicity and QoL. But, to overcome poor accrual in randomized trials including SBRT, to validate our results, and to generate the evidence needed to include SBRT in HCC treatment guidelines, international cooperation is needed. [ABSTRACT FROM AUTHOR]

Summary: Background: The composite histological endpoint comprising nonalcoholic steatohepatitis (NASH) and NAFLD activity score ≥4 and advanced fibrosis (F ≥ 2) (“fibrotic NASH”) is becoming an important diagnostic target in NAFLD: it is currently used to select patients for inclusion in phase III therapeutic trials and will ultimately be used to indicate treatment in clinical practice once the new drugs are approved. Aim: To develop a new blood test specifically dedicated for this new diagnostic target of interest. Methods: Eight Hundred and forty‐six biopsy‐proven NAFLD patients from three centres (Angers, Nice, Antwerp) were randomised into derivation and validation sets. Results: The blood fibrosis tests BARD, NFS and FIB4 had poor accuracy for fibrotic NASH with respective AUROC: 0.566 ± 0.023, 0.654 ± 0.023, 0.732 ± 0.021. In the derivation set, fibrotic NASH was independently predicted by AST, HOMA and CK18; all three were combined in the new blood test MACK‐3 (hoMa, Ast, CK18) for which 90% sensitivity and 95% specificity cut‐offs were calculated. In the validation set, MACK‐3 had a significantly higher AUROC (0.847 ± 0.030, P ≤ 0.002) than blood fibrosis tests. Using liver biopsy in the grey zone between the two cut‐offs (36.0% of the patients), MACK‐3 provided excellent accuracy for the diagnosis of fibrotic NASH with 93.3% well‐classified patients, sensitivity: 90.0%, specificity: 94.2%, positive predictive value: 81.8% and negative predictive value: 97.0%. Conclusion: The new blood test MACK‐3 accurately diagnoses fibrotic NASH. This new test will facilitate patient screening and inclusion in NAFLD therapeutic trials and will enable the identification of patients who will benefit from the treatments once approved. [ABSTRACT FROM AUTHOR]

Recently, concerns were raised of high rates of HCC recurrence in patients treated with direct-acting antivirals ( DAA) for hepatitis C infection. We investigated the HCC occurrence and recurrence rates within 6 months after treatment with DAA with or without pegylated interferon ( PEG- IFN) in real life. This is a retrospective, multicenter cohort trial, executed in 15 hospitals distributed across Belgium. Populations were matched based on fibrosis score (Metavir F3-F4). Patients with a Child-Pugh score ≥ B were excluded. In total, 567 patients were included, of whom 77 were treated with PEG- IFN+ DAA between 2008 and 2013 and 490 with DAA without PEG- IFN between 2013 and 2015. Patients treated with PEG- IFN+ DAA (53±9y) were younger than patients treated with DAA without PEG- IFN (59±12y) ( P=.001). 47% of patients treated with PEG- IFN+ DAA were in the F4 stage vs 67% of patients treated with DAA without PEG- IFN ( P=.001). Screening was inadequate in 20% of both patient groups ( P=.664). The early occurrence rate of HCC was 1.7% and 1.1% in patients treated with DAA with and without PEG- IFN, respectively ( P=.540). The early recurrence rate was 0% in patients treated with PEG- IFN+ DAA and 15.0% in patients treated with DAA without PEG- IFN ( P=.857). There is no difference in early occurrence of new HCC between patients treated with DAA with and without PEG- IFN. We did observe a high early recurrence rate of HCC in patients treated with DAA without PEG- IFN. However, these patients were at baseline more at risk for HCC. Finally, in 20%, screening for HCC was inadequate. [ABSTRACT FROM AUTHOR]