Background:Molecularly targeted agents with anti-angiogenic activity, including bevacizumab, have demonstrated clinical activity in patients with advanced/metastatic hepatocellular carcinoma (HCC). This multicentre phase II study involving patients from several Asian countries sought to evaluate the safety and efficacy of bevacizumab plus capecitabine in this population.Methods:Histologically proven/clinically diagnosed advanced HCC patients received bevacizumab 7.5 mg kg–1 on day 1 and capecitabine 800 mg m–2 twice daily on days 1–14 every 3 weeks as first-line therapy.Results:A total of 45 patients were enrolled; 44 (96%) had extrahepatic metastasis and/or major vessel invasion and 30 (67%) had hepatitis B. No grade 3/4 haematological toxicity occurred. Treatment-related grade 3/4 non-haematological toxicities included diarrhoea (n=2, 4%), nausea/vomiting (n=1, 2%), gastrointestinal bleeding (n=4, 9%) and hand–foot syndrome (n=4, 9%). The overall response rate (RECIST) was 9% and the disease control rate was 52%. Overall, median progression-free survival (PFS) and overall survival (OS) were 2.7 and 5.9 months, respectively. Median PFS and OS were 3.6 and 8.2 months, respectively, for Cancer of the Liver Italian Programme (CLIP) score ⩽3 patients, and 1.4 and 3.3 months, respectively, for CLIP score 4 patients.Conclusion:The bevacizumab–capecitabine combination shows good tolerability and modest anti-tumour activity in patients with advanced HCC.

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The Epstein-Barr virus (EBV) has been shown to be associated with posttransplant lymphoma, Hodgkin's disease, and T-cell lymphoma, in addition to African Burkitt's lymphoma. In a retrospective study of 56 consecutive cases of T-cell lymphoma, EBV DNA was found by Southern blot and in situ DNA hybridization in 10 (20%) of 50 peripheral T-cell lymphomas, but in none of six cases of T-lymphoblastic lymphoma. Peripheral T-cell lymphomas containing EBV DNA could be subclassified into three categories according to histology and immunophenotypic studies: (1) T-cell lymphoma of the helper phenotype, five cases. Two cases had histologic features resembling angioimmunoblastic lymphadenopathy (AILD). (2) T-cell lymphoma of the cytotoxic/suppressor phenotype, four cases. AILD-like features could also be recognized in two cases. Reed-Sternberg-like giant cells were identified in three cases designated Hodgkin-like T-cell lymphoma. (3) Angiocentric T-cell lymphoma or lymphomatoid granulomatosis in one case, initially affecting the skin and nose; no T-cell subset could be defined. Six of the eight EBV DNA-positive patients tested for serum EBV antibodies had elevated titers of IgG antiviral capsid antigen (greater than 640) and/or early antigen (greater than 10). From combined studies of Southern blot hybridization by using EBV termini fragment probe and in situ DNA hybridization, the EBV genomes appeared to be clonotypically proliferated in the neoplastic T cells. The patients in all three groups usually had prolonged fever preceding the diagnosis, hepatosplenomegaly, an aggressive clinical course, and poor response to chemotherapy; nine died with a median survival of only 8 months. We propose that these EBV-associated aggressive T-cell lymphomas, like human T-cell leukemia/lymphoma virus-positive T-cell lymphoma, have characteristic clinicopathologic features and should be treated as a separate disease entity.

Methods: Patients with advanced unresectable HCC received Lenvatinib 8 mg/ d regardless of patient body weight and anti-PD-1 antibody either q2wk (nivolumab or camrelizumab) or q3wk (pembrolizumab, sintilimab or toripalimab). Patients who completed at least one efficacy and safety assessment were eligible for this study. High-dimensional single-cell mass cytometry (CyTOF) and a bioinformatics pipeline for the in-depth characterization of the immune cell subsets was used to identify T cell subsets in the peripheral blood of patients before the treatment.Results: From May 2019 to Dec. 2019, we recruited 15 patients. All the patients are assessable for efficacy. Two patients achieved complete response (CR), 7 patients achieved partial response (PR), and 6 patients achieved progressing disease (PD) per mRECIST. CyTOF identified 36 meta-clusters contained all of the major immune cell populations such as T cells, B cells, NK cells, DC cells and momocytes with a panel of 42 antibodies. Moreover, we delineated an PD1 mid KLRG1 + Tbet high effector memory T cell phenotype that was significantly more abundant in responders (CR or PR, n¼9) to combined therapy compared with non-responders (n¼6) (PD, P < 0.05).Conclusions: PD1 mid KLRG1 + Tbet high effector memory T cell in the peripheral blood may be a useful biomarker for predicting tumor response to the combination therapy in HCC.Legal entity responsible for the study: The authors.

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Background: Conventional transarterial chemoembolization (cTACE) is an effective locoregional therapy in hepatocellular carcinoma (HCC). We evaluated variations around cTACE in a-fetoprotein (AFP), circulating cell-free and tumor DNA (cfDNA and ctDNA) as a marker of therapeutic response.Methods: This prospective monocentric study enrolled consecutive patients treated by cTACE with samples collected at baseline (D-1), day 2 (D+2) and at 1 month (M+1). All cTACE were carried out by only one interventional radiologist and according to the same procedure using farmorubicin drug. cfDNA was quantified by fluorometric method and ctDNA by digital Polymerase Chain Reaction designed for two-hotspot TERT mutations. CT-scan or MRI were performed at M+1 following cTACE and independently reviewed. The objective was to identified by ROC curves the thresholds of cfDNA, ctDNA and AFP variations associated with progression.Results: A total of 38 patients was included from March 2018 to March 2019. All except one had cirrhosis and alcohol was the most frequent etiology of HCC (73.7%). A total of 24/38 (63.2%) patients were naïve for TACE. At M+1, 33/38 patients (86.8%) had a controlled disease and 5/38 (13.2%) a progressive disease (PD). ctDNA was detectable in 16/38 (42.1%) patients at D-1, 30/38 (78.9%) at D+2 and 14/35 (40.0%) at M+1 and cfDNA median value was 21.6 ng/mL, 82.3 ng/mL and 17.8 ng/mL, respectively. All markers significantly increased from D-1 to D+2 (p<0.005) and cfDNA and ctDNA significantly decreased from D+2 to M+1, (p<0.0001). The analysis of variations from D-1 to M+1 identified that thresholds at +31.4% for cfDNA and 0% for ctDNA were significantly associated with PD at M+1, 44.4% (>+31.4%) vs. 3.8% (<¼+31.4%) and 50.0% (>0%) vs. 5.0% (<¼0%), respectively. No significant threshold was identified for AFP. Using a score combining both cfDNA and ctDNA (n¼28), patients were classified into high (n¼5) or low-risk (n¼23) of PD at M+1 with a PD rate of 80.0 % vs 4.3% (p¼0.001) and a median progression-free survival of 1.3 vs 10.3 months (p¼0.002), respectively.Conclusions: This study suggests that cfDNA and ctDNA increases around TACE procedure are associated with therapeutic failure.Legal entity responsible for the study: The authors.