Interleukin-34 is associated with hepatocellular carcinoma in chronic hepatitis B patients

Abstract Backgrounds: IL‑34 is involved in a number of auto-immunities and cancers. We explored the relationship between serum/hepatic IL‑34 and hepatitis B virus (HBV) related hepatocellular carcinoma (HBV‑HCC) patients.Methods: Serum was obtained from the HBV patients or healthy control with written consents. Liver tissue was obtained from liver biopsy in CHB, HBV related cirrhosis patients or curative resection in HBV‑HCC patients. Serum IL‑34 and MCSF were measured, using ELISA. HepaticIL‑34, MCSF and CD68 were determined, using immunohistochemistry.Results: Serum IL‑34 was 1.7, 1.6 or 1.7 fold higher in HBV‑HCC than that of the other three groups (CHB, HBV related cirrhosis, and healthy control). Serum IL‑34 was significantly reduced after trans‑hepatic arterial chemoembolization (TACE) in HBV‑HCC patients. There was significant correlation between the incidence of HBV‑HCC and IL‑34 (rs=0.160, p<0.05) as well as AFP (rs=0.442, p<0.01). Furthermore, intra-hepatic IL‑34 was higher in HBV‑HCC than that of the other three groups. Intra-hepatic IL‑34 was associated with high HBV‑DNA, HBeAg-, low tumor differentiation and small tumor size of HBV‑HCC patients. Intra-hepaticCD68+ TAMs were increased 1.6 or 1.3 fold in HBV‑HCC compared to that from CHB or HBV-cirrhosis. Intra-hepatic CD68+ TAMs were associated with high HBV‑DNA, high tumor differentiation, big tumor size, abnormal AFP and more tumor number.Conclusions: IL‑34, correlated with HBV‑HCC and IL‑34, may be used as a therapeutic target in precise medicine for management of HBV‑HCC.

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272 Use of LioCyx-M, autologous hepatitis B virus (HBV)-Specific T cell receptor (TCR) T-cells, in advanced HBV-related hepatocellular carcinoma (HCC)

Journal for ImmunoTherapy of Cancer ◽

10.1136/jitc-2020-sitc2020.0272 ◽

2020 ◽

Vol 8 (Suppl 3) ◽

pp. A297-A297

Author(s):

Fu-Sheng Wang ◽

Fanping Meng ◽

Jiehua Jin ◽

Yuanyuan Li ◽

Regina Wanju Wong ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

T Cells ◽

Hepatitis B Virus ◽

T Cell ◽

Hepatitis B ◽

T Cell Receptor ◽

Dose Level ◽

Cell Receptor ◽

Hbv Dna ◽

B Virus

BackgroundWe have demonstrated the ability of Hepatitis-B-virus (HBV)-specific T cell receptor (TCR) bioengineered T cells to recognize and lyse Hepatocellular carcinoma (HCC) cells expressing HBV antigens derived from HBV-DNA integration in patients with liver transplant.1 LioCyx-M is an immunotherapeutic product composing of autologous T cells transiently modified with in-vitro transcribed mRNA encoding HBV-specific TCR. The transient TCR expression makes LioCyx -M amenable to a dose escalating posology.MethodsThe primary endpoint of this phase 1 trial is to assess the safety and tolerability of LioCyx-M in patients with advanced HBV-HCC without curative treatment options. Eligible patients were diagnosed with Barcelona clinic liver cancer stage B or C HCC (Child-Pugh < 7 points), receiving >1 year antiviral treatment prior to enrollment. These patients had matching HLA class I genotypes which present HBV encoded antigen. Peripheral blood was collected from each patient prior to each dose for LioCyx-M manufacturing. Patients received 4 escalating doses of 1×104 cells/kg, 1×105 cells/kg, 1×106 cells/kg, 5×106 cells/kg bodyweight (BW) in the first treatment cycle, each intravenously administered weekly. Patients underwent 1-month safety assessment post the 4th infusion, according to Common Terminology NCI CTCAE Version 4.0.3. If there were no dose associated toxicities, patients were eligible to continue administration of LioCyx-M at dose of 5 × 106 cells/kg BW weekly. Tumor response per RECIST 1.1 criteria and survival time were assessed.ResultsAt data cutoff (30 April 2020), eight patients were enrolled, with a median age of 53 (range: 49 - 67). These patients received a median number of 6 (range: 4 - 12) infusions of LioCyx-M. 1 patient developed Grade 3 elevations in alanine aminotransferase (ALT), gamma-glutamyl transferase (GGT), aspartate aminotransferase (AST) and bilirubin after receiving LioCyx-M at dose level of 1×105 cells/kg BW. Another patient had Grade 1 transient fever after receiving LioCyx-M at dose level 5×106 cells/kg BW in the 4th, 5th and 6th infusions. No treatment-related adverse events (trAEs) such as cytokine release syndrome or neurotoxicity were observed. No fatal trAEs were observed. The median time to progression was 1.9 months (range: 0.2 - 9.5 months). The median overall survival was 34 months (range: 3 - 38.2 months).ConclusionsThe encouraging clinical outcome and tolerable safety highlight the good benefit-risk profile of LioCyx-M. Therefore, further exploration of efficacy of LioCyx-M treatment for advanced HBV-HCC is warranted in a Phase 2 proof-of-concept clinical study.AcknowledgementsFunding: Lion TCR.Trial RegistrationNCT03899415Ethics ApprovalThe study was approved by Fifth Medical Center of Chinese PLA General Hospital’s Ethics Board, approval number R2016185DI010.ReferenceTan AT, Yang N, Lee Krishnamoorthy T, et al. Use of Expression Profiles of HBV-DNA Integrated Into Genomes of Hepatocellular Carcinoma Cells to Select T Cells for Immunotherapy. Gastroenterology 2019;156(6):1862–1876.e9.

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Clinical Outcomes of Hepatitis B Virus–Related Hepatocellular Carcinoma Patients with Undetectable Serum HBV DNA Levels

Digestive Diseases and Sciences ◽

10.1007/s10620-021-07312-8 ◽

2021 ◽

Author(s):

Jong-In Chang ◽

Dong Hyun Sinn ◽

Hyun Cho ◽

Seonwoo Kim ◽

Wonseok Kang ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Hepatitis B Virus ◽

Hepatitis B ◽

Clinical Outcomes ◽

Hbv Dna ◽

B Virus ◽

Undetectable Serum

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PROPORTION OF HBsAg AND HBeAg POSITIVE IN MATERNAL PATIENTS AND THEIR HBsAg POSITIVES BABIES WITH IMMUNOPROPHYLAXIS OF HBV IMMUNIZATION IN Dr. SOETOMO GENERAL HOSPITAL, SURABAYA

Indonesian Journal of Tropical and Infectious Disease ◽

10.20473/ijtid.v6i4.1372 ◽

2017 ◽

Vol 6 (4) ◽

pp. 79

Author(s):

Melina Rosita Tanadi ◽

Maria Inge Lusida ◽

Hermanto Tri Joewono

Keyword(s):

Hepatitis B Virus ◽

Hepatitis B ◽

General Hospital ◽

Medical Records ◽

Hbv Dna ◽

The Other ◽

Positive Hbsag ◽

B Virus ◽

Hepatitis B Immunoglobulin ◽

Spontaneous Delivery

Hepatitis B Virus (HBV) can be transmitted vertically from mother to her baby. Mothers with HBsAg and HBeAg positives have more risk of transmitting HBV to her baby rather than HBsAg positives only. The aim of this study is to determine the proportion of maternal patient with HBsAg and HBeAg positives and their HBsAg positives babies with immunoprophylaxis of HBV immunization. This study was performed by analytical observation using medical records in 2013-2014 at Obstetric and Gyn ecology Department, Dr. Soetomo Hospital. The samples were all maternal patients (3796) during that period and also their babies from HBsAg positives mothers. Unfortunately, several original medical records were not available. Thirty two (0,85%) out of 3781 maternal patients were found to be HBsAg positives, and three (9,37%) of 32 patients with HBsAg positives were HBeAg positives. From 32 mothers who were positive HBsAg, 22 complete medical records of their babies were found and all of them (100%) had been given Hepatitis B Immunoglobulin (HBIG) and hepatitis B vaccine less than twelve hours after birth. In three cases of the babies from HBeAg positives mothers which had been given prophylaxis properly, two cases each of which was with caesarean and spontaneous delivery were HBsAg negatives. Interestingly, the other one which born with spontaneous delivery was found to be HBsAg positives. Further study in this HBsAg positives baby, especially in analyzing its HBV DNA is needed. The epidemiology of hepatitis B in maternal patients, especially that with complete and neat data needs further research.

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Intermediate-stage hepatocellular carcinoma patients with a high HBV-DNA load may benefit from postoperative anti-hepatitis B virus therapy

Medicine ◽

10.1097/md.0000000000007608 ◽

2017 ◽

Vol 96 (30) ◽

pp. e7608 ◽

Cited By ~ 2

Author(s):

Shaozhen Rui ◽

Jun Yan ◽

Hui Zhang ◽

Zhengfeng Wang ◽

Wence Zhou

Keyword(s):

Hepatocellular Carcinoma ◽

Hepatitis B Virus ◽

Hepatitis B ◽

Intermediate Stage ◽

Hbv Dna ◽

B Virus

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Real-time quantitation of hepatitis B virus (HBV) DNA in tumorous and surrounding tissue from patients with hepatocellular carcinoma

Journal of Medical Virology ◽

10.1002/jmv.10243 ◽

2002 ◽

Vol 68 (4) ◽

pp. 494-499 ◽

Cited By ~ 12

Author(s):

Isabella Zanella ◽

Angelo Rossini ◽

Daniela Domenighini ◽

Alberto Albertini ◽

Elisabetta Cariani

Keyword(s):

Hepatocellular Carcinoma ◽

Hepatitis B Virus ◽

Hepatitis B ◽

Real Time ◽

Hbv Dna ◽

Surrounding Tissue ◽

B Virus

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Mutations in TP53 and CTNNB1 in Relation to Hepatitis B and C Infections in Hepatocellular Carcinomas from Thailand

Hepatitis Research and Treatment ◽

10.1155/2011/697162 ◽

2011 ◽

Vol 2011 ◽

pp. 1-9 ◽

Cited By ~ 5

Author(s):

Olivier Galy ◽

Isabelle Chemin ◽

Emilie Le Roux ◽

Stéphanie Villar ◽

Florence Le Calvez-Kelm ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Hepatitis B ◽

Hbv Dna ◽

Hcv Infection ◽

Hbv Infection ◽

The Other ◽

Hepatocellular Carcinomas ◽

Induced Mutagenesis

Hepatocellular carcinoma (HCC) may develop according to two major pathways, one involving HBV infection and TP53 mutation and the other characterized by HCV infection and CTNNB1 mutation. We have investigated HBV/HCV infections and TP53/CTNNB1 mutations in 26 HCC patients from Thailand. HBV DNA (genotype B or C) was detected in 19 (73%) of the cases, including 5 occult infections and 3 coinfections with HCV. TP53 and CTNNB1 mutations were not mutually exclusive, and most of TP53 mutations were R249S, suggesting a significant impact of aflatoxin-induced mutagenesis in HCC development.

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Risk for hepatocellular carcinoma with respect to hepatitis B virus genotypes B/C, specific mutations of enhancer II/core promoter/precore regions and HBV DNA levels

Gut ◽

10.1136/gut.2007.119859 ◽

2007 ◽

Vol 57 (1) ◽

pp. 98-102 ◽

Cited By ~ 121

Author(s):

M-F Yuen ◽

Y Tanaka ◽

N Shinkai ◽

R T Poon ◽

D Y.-K. But ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Hepatitis B Virus ◽

Hepatitis B ◽

Core Promoter ◽

Hbv Dna ◽

B Virus ◽

Virus Genotypes ◽

Enhancer Ii

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Aflatoxin Exposure in Singapore: Blood Aflatoxin Levels in Normal Subjects, Hepatitis B Virus Carriers and Primary Hepatocellular Carcinoma Patients

Medicine Science and the Law ◽

10.1177/002580249403400404 ◽

1994 ◽

Vol 34 (4) ◽

pp. 289-298 ◽

Cited By ~ 5

Author(s):

Tzee Cheng Chao ◽

Dst Lo ◽

B Chen Bloodworth ◽

R Gunasegaram ◽

T H Koh ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Hepatitis B Virus ◽

Hepatitis B ◽

Aflatoxin B1 ◽

Internal Standard ◽

Normal Subjects ◽

The Other ◽

Primary Hepatocellular Carcinoma ◽

Aflatoxin M1 ◽

B Virus

Blood screening conducted on Singaporeans over 1991–1992 showed exposure to predominately aflatoxin B1 and to a lesser extent G1. The extent of exposure to B1 among three groups of residents in Singapore, namely normal subjects (n = 423), hepatitis B virus carriers (n = 302) and primary hepatocellular carcinoma (PHC) patients (n = 58) were extensive as reflected by the positive rates of 15.1, 0.7 and 1.7 per cent respectively. However, the degree of individual exposure to this toxin among the three groups was considered low as shown by the low respective mean blood levels of 5.4 ± 3.2 (range 3.0–17), 7.7 (range 7.5–7.9) and 7.5 picogrammes per ml of blood. It is not immediately clear whether or not such low levels would precipitate an undesirable health effect. The higher positive rate seen in normal subjects as compared with the other groups could be due to differences in dietary intake of aflatoxin B1, differences in metabolic patterns or both. About 70 per cent of PHC patients studied were carriers. The degree of aflatoxin B1 exposure among normal subjects in Singapore was a factor of 22.1 times less than that in Japan, 40.9 times less than that in Indonesia and 51.3 times less than that in the Philippines. Similarly, the extent of exposure among hepatitis B carriers in Singapore was a factor of 8.2 times, 39.6 times and 24.2 times less than those in the other three Asiatic countries respectively. The results reflected stringent Government control over the quality of food stuff imported into this country. As Singapore imports almost all its dietary needs from elsewhere, it can afford to be selective at a cost. Aflatoxin M1, a metabolite of B1, was most commonly encountered in the liver tissues of deceased (n = 154) who died of causes other than sickness or disease in 1992–93, consistent with our blood findings of prevalence of aflatoxin Bl. High performance liquid chromatography (HPLC) with fluorescence detection using one of the aflatoxins G2 or B2 as an internal standard was used for the detection and quantification of aflatoxins. The use of an internal standard structurally and chemically similar to those required to be quantified minimizes errors in quantifications. This is because differences in the quenching of fluorescence between specimen extracts and spiked-standard extracts were internally standardized and compensated for. The presence of an internal standard also helped to locate aflatoxins of interest more accurately. Strict decontamination procedures for cleaning glassware and apparatus were adhered to, to reduce cross-contaminations. Only duplicate-positive results were taken to be positive.

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Association of Virological Response to Antiviral Therapy With Survival in Intermediate-Stage Hepatitis B Virus-Related Hepatocellular Carcinoma After Chemoembolization

Frontiers in Oncology ◽

10.3389/fonc.2021.751777 ◽

2021 ◽

Vol 11 ◽

Author(s):

Meng Jin ◽

Yong Chen ◽

Shuifang Hu ◽

Meiyan Zhu ◽

Yan Wang ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Hepatitis B Virus ◽

Hepatitis B ◽

Antiviral Therapy ◽

Virological Response ◽

Cox Regression ◽

Intermediate Stage ◽

Hbv Dna ◽

Rank Test ◽

B Virus

IntroductionRole of response to antiviral therapies on survival of patients with intermediate-stage hepatitis B virus-related hepatocellular carcinoma (HBV-HCC) undergoing transarterial chemoembolization (TACE) remains unknown. We aimed to determine whether virological response (VR) or prolonged maintained virological response (MVR) to nucelos(t)ide analogues (NA) therapy could result in improved survival in HBV-HCC patients receiving TACE.MethodsBetween January 2012 and October 2018, data of patients with intermediate HBV-HCC who underwent TACE and started NA therapy within one week prior to TACE treatment at our institution were reviewed. Overall survival (OS) was compared using the Kaplan-Meier method with log-rank test between different VR status groups. Univariable and multivariable Cox regression analyses were used to determine the association between achievement of VR or MVR and OS. VR was defined as an undetectable HBV DNA level (<100 IU/ml) on two consecutive measurements during NA treatment. MVR was defined as a persistently undetectable HBV DNA level after achieving a VR.ResultsA total of 1265 patients undergoing TACE with a median follow-up time of 18 months (range, 2-78 months) were included in the analysis. Of 1265 NA-treated patients [1123 (88.8%) male, median (range) age, 56 (18-75) years], 744 patients (58.8%) achieved VR and the remaining patients (41.2%) did not. Patients with achievement of VR showed a significantly longer OS than those without VR (median OS: 21 vs 16 months; HR, 0.707; 95% CI, 0.622-0.804; P<0.001). Among patients with VR, MVR was present in 542 patients (72.8%), while the other 202 patients (27.2%) in the non-MVR group. The OS for the MVR group was significantly higher than the non-MVR group (median OS: 23.2 vs 18 months; HR, 0.736; 95% CI, 0.612-0.885; P=0.001). Additionally, patients with MVR status more than two years showed a better OS than those with just one-year (HR, 0.719; 95% CI, 0.650-0.797; P<0.001) or one-to-two-year MVR (HR, 0.612; 95% CI, 0.471-0.795; P=0.024). On multivariable analyses, splenomegaly and up-to-seven criteria were independent prognostic factors of OS in both VR and MVR cohorts.ConclusionsIn patients with intermediate-stage HBV-HCC, both VR to antiviral therapy and prolonged response are associated with prolonged OS after TACE, especially for those within up-to-seven criteria.

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