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Background: Sorafenib is the current standard treatment for advanced hepatocellular carcinoma (HCC). We analyzed national prescription patterns and treatment outcomes of patients who received sorafenib for advanced HCC., Patients and Methods: We established a nation-wide cohort of patients who started receiving treatment with sorafenib for advanced HCC between August 2012 and July 2013 from the National Health Insurance Research Database of Taiwan and also retrieved demographic and prescription data. The databases of National Death Registry and Taiwan Cancer Registry were used for survival outcomes and cancer diagnosis information, respectively., Results: A total of 3,293 patients were enrolled. The median overall survival (OS) and time to treatment discontinuation (TTD) of all patients were 6.8 and 2.6 months, respectively. Upon the first prescription of sorafenib, 58.4% of patients received the standard dose (800 mg/day). Among them, 61.9% had subsequent dose reduction. A total of 41.6% of patients initially received lower than standard doses; 36.1% of them had subsequent dose escalation to 800 mg/day. Being male (odds ratio=1.41; p<0.001) and treatment year of 2012 (odds ratio=1.28; p=0.002) were associated with the standard initial dose. Patients who received standard initial dose of sorafenib, compared to patients who received lower initial doses, exhibited longer OS (median of 7.8 vs. 6.6 months, p<0.001) but similar TTD (median of 2.6 vs. 2.9 months, p=0.840)., Conclusion: A considerable number of patients with advanced HCC received less than the standard dose of sorafenib. The treatment outcomes in the general population were consistent with those reported in clinical trials., (Copyright© 2017, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Transarterial chemoembolization (TACE) is the main treatment for intermediate stage hepatocellular carcinoma (HCC) with Barcelona Clinic Liver Cancer classification because of its exclusive arterial blood supply. Although TACE achieves substantial necrosis of the tumor, complete tumor necrosis is uncommon, and the residual tumor generally rapidly recurs. We combined tirapazamine (TPZ), a hypoxia-activated cytotoxic agent, with hepatic artery ligation (HAL), which recapitulates transarterial embolization in mouse models, to enhance the efficacy of TACE. The effectiveness of this combination treatment was examined in HCC that spontaneously developed in hepatitis B virus X protein (HBx) transgenic mice. We proved that the tumor blood flow in this model was exclusively supplied by the hepatic artery, in contrast to conventional orthotopic HCC xenografts that receive both arterial and venous blood supplies. At levels below the threshold oxygen levels created by HAL, TPZ was activated and killed the hypoxic cells, but spared the normoxic cells. This combination treatment clearly limited the toxicity of TPZ to HCC, which caused the rapid and near-complete necrosis of HCC. In conclusion, the combination of TPZ and HAL showed a synergistic tumor killing activity that was specific for HCC in HBx transgenic mice. This preclinical study forms the basis for the ongoing clinical program for the TPZ-TACE regimen in HCC treatment., Competing Interests: The authors declare no conflict of interest.

Background: Hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) shows a higher incidence in men, mainly because of hepatitis B X (HBx)-mediated enhancement of androgen receptor (AR) activity. We aimed to examine this pathway in hepatocarcinogenesis and to identify drug(s) specifically blocking this carcinogenic event in the liver., Methods: HBx transgenic mice that spontaneously develop HCC (n = 28-34 per group) were used, either by knockout of hepatic AR or by castration. Efficacy of several HCC-targeted drugs in suppressing HBx-induced AR activity was evaluated, and cellular factors mediating suppression were investigated in cultured cells. Tissue specificity of the candidate drug was validated using mouse tissues. Data were analyzed with Chi-square and Student's t tests. All statistical tests were two-sided., Results: The androgen pathway was shown to be important in early stage hepatocarcinogenesis of HBx transgenic mice. The tumor incidence was decreased from 80% to 32% by AR knockout (P < .001) and from 90% to 25% by early castration (P < .001). Sorafenib markedly inhibited the HBx-enhanced AR activity through activating the SHP-1 phosphatase, which antagonized the activation of Akt/GSK3β and c-Src by HBx. Moreover, SHP-1 protein level was much higher in the liver than in testis, which enabled sorafenib to inhibit aberrant AR activity in the HBx-expressing liver, while not affecting the physiological AR function in normal liver or testis., Conclusions: The androgen pathway may be a druggable target for the chemoprevention of HBV-related HCC, and sorafenib might be used as a tissue- and disease-specific regimen for the chemoprevention of HBV-related HCC., (© The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

Purpose: This open-label phase III trial evaluated efficacy and tolerability of linifanib versus sorafenib in patients with advanced hepatocellular carcinoma (HCC) without prior systemic therapy., Patients and Methods: Patients were randomly assigned in a 1:1 ratio to linifanib 17.5 mg once daily or sorafenib 400 mg twice daily. Patients were stratified by region (Outside Asia, Japan, and rest of Asia), Eastern Cooperative Oncology Group performance score (ECOG PS; 0 or 1), vascular invasion or extrahepatic spread (yes or no), and hepatitis B virus (HBV) infection (yes or no). The primary end point of the study was overall survival (OS). Secondary end points were time to progression (TTP) and objective response rate (ORR) per RECIST v1.1., Results: We randomly assigned 1,035 patients (median age, 60 years; Asian, 66.6%; ECOG PS 0, 65.2%; HBV, 49.1%; vascular invasion or extrahepatic spread, 70.1%). Median OS was 9.1 months on the linifanib arm (95% CI, 8.1 to 10.2) and 9.8 months on the sorafenib arm (95% CI, 8.3 to 11.0; hazard ratio [HR], 1.046; 95% CI, 0.896 to 1.221). For prespecified stratification subgroups, OS HRs ranged from 0.793 to 1.119 and the 95% CI contained 1.0. Median TTP was 5.4 months on the linifanib arm (95% CI, 4.2 to 5.6) and 4.0 months on the sorafenib arm (95% CI, 2.8 to 4.2; HR, 0.759; 95% CI, 0.643 to 0.895; P = .001). Best response rate was 13.0% on the linifanib arm versus 6.9% on the sorafenib arm. Grade 3/4 adverse events (AEs); serious AEs; and AEs leading to discontinuation, dose interruption, and reduction were more frequent with linifanib (all P < .001)., Conclusion: Linifanib and sorafenib had similar OS in advanced HCC. Predefined superiority and noninferiority OS boundaries were not met for linifanib and the study failed to meet the primary end point. TTP and ORR favored linifanib; safety results favored sorafenib., (© 2014 by American Society of Clinical Oncology.)

Aim: To demonstrate that administering heparanase inhibitor PI-88 at 160 mg/d is safe and promising in reducing hepatocellular carcinoma (HCC) recurrence for up to 3 year following curative resection., Methods: A total of 143 patients (83.1% of the 172 participants in the phase II study) participated in the follow-up study. Of these patients, 50 had received no treatment, 48 had received 160 mg/d PI-88, and 45 had received 250 mg/d PI-88 during the phase II trial. Safety parameters and the following efficacy endpoints were investigated: (1) time to recurrence; (2) disease-free survival; and (3) overall survival., Results: PI-88 at 160 mg/d delayed the onset and frequency of HCC recurrence, and provided a clinically significant survival advantage for up to 3 years after treatment compared with those of the control group: (1) the recurrence-free rate increased from 50% to 63%, and (2) time to recurrence at the 36th percentile was postponed by 78%. The efficacy of administering PI-88 at 250 mg/d was confounded by a high dropout rate (11 out of 54 patients). Additionally, subgroup analyses of patients with (1) multiple tumors or a single tumor ≥ 2 cm; and (2) hepatitis B or C revealed that administering PI-88 at 160 mg/d conferred the most significant survival advantage (56.8% improvement in disease-free survival, P = 0.045) for patients with both risk factors for recurrence., Conclusion: Administering PI-88 at 160 mg/d is a safe and well-tolerated dosage that may confer significant clinical benefits for patients with HCC.

Unlabelled: Fatal hepatitis B virus (HBV) reactivation in lymphoma patients with "resolved" HBV infection (hepatitis B surface antigen [HBsAg] negative and hepatitis B core antibody [anti-HBc] positive) can occur, but the true incidence and severity remain unclear. From June 2009 to December 2011, 150 newly diagnosed lymphoma patients with resolved HBV infection who were to receive rituximab-CHOP (cyclophosphamide, doxorubicin, vincristine, prednisolone)-based chemotherapy were prospectively followed. HBV DNA was checked at baseline, at the start of each cycle of chemotherapy, and every 4 weeks for 1 year after completion of rituximab-CHOP chemotherapy. Patients with documented HBV reactivation were treated with entecavir at a dosage of 0.5 mg/day for 48 weeks. HBV reactivation was defined as a greater than 10-fold increase in HBV DNA, compared with previous nadir levels, and hepatitis flare was defined as a greater than 3-fold increase in alanine aminotransferase (ALT) that exceeded 100 IU/L. Incidence of HBV reactivation and HBV-related hepatitis flares was 10.4 and 6.4 per 100 person-year, respectively. Severe HBV-related hepatitis (ALT >10-fold of upper limit of normal) occurred in 4 patients, despite entecavir treatment. Patients with hepatitis flare exhibited significantly higher incidence of reappearance of HBsAg after HBV reactivation (100% vs. 28.5%; P=0.003)., Conclusion: In lymphoma patients with resolved HBV infections, chemotherapy-induced HBV reactivation is not uncommon, but can be managed with regular monitoring of HBV DNA and prompt antiviral therapy. Serological breakthrough (i.e., reappearance of HBsAg) is the most important predictor of HBV-related hepatitis flare. (Hepatology 2014;59:2092-2100)., (© 2014 by the American Association for the Study of Liver Diseases.)

Unlabelled: Sorafenib is the first approved targeted therapeutic reagent for hepatocellular carcinoma (HCC). Here, we report that Src homology region 2 (SH2) domain-containing phosphatase 1 (SHP-1) is a major target of sorafenib and generates a series of sorafenib derivatives to search for potent SHP-1 agonists that may act as better anti-HCC agents than sorafenib. Sorafenib increases SHP-1 activity by direct interaction and impairs the association between the N-SH2 domain and the catalytic protein tyrosine phosphatase domain of SHP-1. Deletion of the N-SH2 domain (dN1) or point mutation (D61A) of SHP-1 abolished the effect of sorafenib on SHP-1, phosphorylated signal transducer and activator of transcription 3 (p-STAT3), and apoptosis, suggesting that sorafenib may affect SHP-1 by triggering a conformational switch relieving its autoinhibition. Molecular docking of SHP-1/sorafenib complex confirmed our findings in HCC cells. Furthermore, novel sorafenib derivatives SC-43 and SC-40 displayed more potent anti-HCC activity than sorafenib, as measured by enhanced SHP-1 activity, inhibition of p-STAT3, and induction of apoptosis. SC-43 induced substantial apoptosis in sorafenib-resistant cells and showed better survival benefits than sorafenib in orthotopic HCC tumors., Conclusion: In this study, we identified SHP-1 as a major target of sorafenib. SC-43 and SC-40, potent SHP-1 agonists, showed better anti-HCC effects than sorafenib in vitro and in vivo. Further clinical investigation is warranted., (© 2013 by the American Association for the Study of Liver Diseases.)

Hepatocellular carcinoma (HCC) presents with a high burden of disease in East Asian countries. Intermediate-stage HCC as defined by the Barcelona Clinic Liver Cancer (BCLC) staging system poses a clinical challenge as it includes a heterogeneous population of patients that can vary widely in terms of tumour burden, liver function and disease aetiology. Intermediate HCC patients often have unsatisfactory clinical outcomes with repeated transarterial chemoembolization (TACE, due to non-response of the target tumour or the development of further metastasis indicating progressive disease. In September 2011, an Expert Panel Opinion on Interventions in Hepatocellular Carcinoma (EPOIHCC) was convened in HK in an attempt to provide a consensus on the practice of TACE. To that end, current clinical practice throughout Asia was reviewed in detail including safety and efficacy data on TACE alone as well as in combination with targeted systemic therapies. This review summarises the evidence discussed at the meeting and provides expert recommendation regarding the available therapeutic options for unresectable intermediate stage HCC. A key consensus of the Expert Panel was that in order to improve patient outcomes and long-term survival, the possibility of using TACE in combination with targeted agents given systemically should be explored. While the currently available clinical data is promising, the expected completion of several pivotal phase II and III RCTs will provide further evidence in support of the rationale for combination therapy regimens., (© 2013 John Wiley & Sons A/S.)

Background: The efficacy and safety of linifanib (ABT-869), a selective inhibitor of vascular endothelial growth factor and platelet-derived growth factor receptor tyrosine kinases, were assessed in this phase 2, single-arm, open-label, multicenter trial., Methods: Eligible patients had unresectable or metastatic hepatocellular carcinoma and had received ≤ 1 prior systemic therapy. Patients received oral linifanib at a fasting dose of 0.25 mg/kg,. The primary endpoint was the progression-free rate at 16 weeks. Tumor response was assessed every 8 weeks. Secondary endpoints included the time to disease progression, overall survival, and objective response rate. Safety was also assessed., Results: Of the 44 patients enrolled, the majority were Asian (89%), had received no prior systemic therapy (82%), had Child-Pugh class A hepatic function (86%), and had hepatitis B virus infection (61%). The estimated progression-free rate at 16 weeks was 31.8% (34.2% for patients with Child-Pugh class A hepatic function), the estimated objective response rate was 9.1% (10.5% for patients with Child-Pugh class A hepatic function), the median time to disease progression was 3.7 months (3.7 months for patients with Child-Pugh class A hepatic function), and the median overall survival was 9.7 months (10.4 months for patients with Child-Pugh class A hepatic function). The most common linifanib-related adverse events were diarrhea (55%) and fatigue (52%). The most common linifanib-related grade 3/4 adverse events were hypertension (25%) and fatigue (14%). Serum levels of biomarkers cancer antigen (CA) 125, cytokeratin fragment (CYFRA)21.1, and protein induced by vitamin K absence or antagonist II (PIVKA) demonstrated potential as prognostic indicators of patient response or outcome., Conclusions: Single-agent linifanib was found to be clinically active in patients with advanced hepatocellular carcinoma, with an acceptable safety profile., (Copyright © 2012 American Cancer Society.)

Hepatocellular carcinoma (HCC) often displays resistance to recombinant tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis. Dovitinib, a multiple tyrosine kinase inhibitor, and tigatuzumab, a novel humanized anti-human death receptor 5 (DR5) agonistic antibody, are both under clinical investigations in HCC. Here, we report that dovitinib sensitizes resistant HCC cells to TRAIL- and tigatuzumab-induced apoptosis through inhibition of signal transducers and activators of transcription 3 (STAT3). Our data indicate that HCC cells showed significant resistance to TRAIL- and tigatuzumab-induced apoptosis. The combination of dovitinib and tigatuzumab restored the sensitivity of HCC cells to TRAIL- and tigatuzumab-induced apoptosis. Dovitinib down-regulated phospho-STAT3 (Tyr705) (p-STAT3) and subsequently reduced the protein levels of STAT3-regulated proteins, Mcl-1, survivin and cylcin D1, in TRAIL-treated HCC cells. Knockdown of STAT3 by RNA-interference overcame apoptotic resistance to TRAIL in HCC cells, and ectopic expression of STAT3 in HCC cells abolished the sensitizing effect of dovitinib on TRAIL-induced apoptosis. Importantly, silencing SHP-1 by RNA-interference reduced the effects of dovitinib and TRAIL on p-STAT3 and apoptosis, whereas co-treatment of TRAIL and dovitinib increased the activity of SHP-1. Moreover, in vivo the combination of tigatuzumab and dovitinib inhibited Huh-7 xenograft tumor growth. In conclusion, dovitinib sensitizes resistant HCC cells to TRAIL- and tigatuzumab-induced apoptosis through a novel machinery: SHP-1 dependent STAT3 inhibition., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Objective: To investigate the clinical efficacy of adjuvant interferon alfa-2b (IFNα-2b) therapy on recurrence-free survival (RFS) of patients with postoperative viral hepatitis-related hepatocellular carcinoma (HCC)., Background: Despite most individual trials have failed to meet their primary endpoint, recent pooled-data meta-analyses suggest that adjuvant IFN therapy may significantly reduce the incidence of recurrence in curatively ablated HCC., Methods: Patients with curative resection of viral hepatitis-related HCC were eligible, and were stratified by underlying viral etiology and randomly allocated to receive either 53 weeks of adjuvant IFNα-2b treatment or observation alone. The primary endpoint of this study was RFS., Results: A total of 268 patients were enrolled with 133 in the IFNα-2b arm and 135 in the control arm. Eighty percent of them were hepatitis B surface antigen seropositive. At a median follow-up of 63.8 months, 154 (57.5%) patients had tumor recurrence and 84 (31.3%) were deceased. The cumulative 5-year recurrence-free and overall survival rates of intent-to-treat cohort were 44.2% and 73.9%, respectively. The median RFS in the IFNα-2b and control arms were 42.2 (95% confidence interval [CI], 28.1-87.1) and 48.6 (95% CI, 25.5 to infinity) months, respectively (P = 0.828, log-rank test). Adjuvant IFNα-2b treatment was associated with a significantly higher incidence of leucopenia and thrombocytopenia. Thirty-four (24.8%) of treated patients required dose reduction, and 5 (3.8%) of these patients subsequently withdrew from therapy because of excessive toxicity. Adjuvant IFNα-2b only temporarily suppressed viral replication during treatment period., Conclusions: In this study, adjuvant IFNα-2b did not reduce the postoperative recurrence of viral hepatitis-related HCC. More potent antiviral therapy deserves to be explored for this patient population. This study is registered at ClinicalTrials.gov and carries the identifier NCT00149565.

STAT3 is a transcription factor that modulates survival-directed transcription. It is persistently activated in many human cancers. Literature has shown that sorafenib, Raf kinase inhibitor, reduces Phospho-STAT3 and induces cell death. A series of sorafenib derivatives were synthesized as new inhibitors for STAT3. Urea, sulfonamide, and carboxamide linkers brought out different SARs from the end of sorafenib. Urea and carboxamide linked derivatives showed greater inhibition against STAT3 activity than sulfonamide linked derivatives. In particular, 1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(4-(4-cyanophenoxy)phenyl)urea (1), a urea linker, was as potent as sorafenib in reducing P-STAT3 level and cell death but no inhibition for Raf activity. Such result provides a new lead for the design of STAT3 inhibitors., (Copyright © 2011 Elsevier Masson SAS. All rights reserved.)

Asia has a disproportionate share of the world's burden of hepatocellular carcinoma (HCC). However, the highly regarded clinical practice guidelines and recommendations for the design and conduct of clinical trials for HCC largely reflect Western practice. In order to design mutually beneficial international clinical trials of promising targeted therapies, it is imperative to understand how the aetiology, staging and treatment of HCC differ between Asian and Western countries. Our group, comprising experts in oncology and hepatology from countries that constitute the Eastern Asian region, convened to compare and contrast our current practices, evaluate potential compliance with the clinical trial recommendations, and offer suggestions for modifications that would enhance international collaboration. Here, we describe the results of our discussions, including recommendations for appropriate patient stratification based on potentially important differences in HCC aetiology, identification of practices that may confound interpretation of clinical trial outcomes (traditional Chinese medicine; antivirals that target hepatitis B virus; heterogeneous embolization procedures), suggestions for utilizing a common staging system in study protocols, recognition that sorafenib usage is limited by financial constraints and potentially increased toxicity in Asian patients, and expansion of patient populations that should be eligible for initial clinical trials with new agents., (© 2010 John Wiley & Sons A/S.)

Background & Aims: Previously we reported that Akt inactivation determines the sensitivity of hepatocellular carcinoma (HCC) cells to bortezomib. Here we report that combined treatment with sorafenib and bortezomib shows synergistic effects in HCC., Methods: HCC cell lines (PLC/PRF/5, Huh-7, and Hep3B) were treated with sorafenib and/or bortezomib and analyzed in terms of apoptosis signal transduction. In vivo efficacy was determined in nude mice with PLC/PRF/5 xenografts., Results: Pretreatment with sorafenib enhanced bortezomib-induced apoptotic cell death by restoring bortezomib's ability to inactivate Akt in PLC/PRF/5 cells. Knocking down Akt1 by RNA-interference overcame apoptotic resistance to bortezomib in PLC/PRF/5 cells and ectopic expression of active Akt in HCC cells abolished the bortezomib sensitizing effect of sorafenib, indicating Akt inactivation plays a key role in mediating the combinational effects. Moreover, okadaic acid, a protein phosphatase 2A (PP2A) inhibitor, reversed down-regulation of phospho-Akt (P-Akt) expression induced by co-treatment with sorafenib and bortezomib, and 1, 9 di-deoxy-forskolin, a PP2A agonist, restored bortezomib's effect on P-Akt and apoptosis. Importantly, silencing of PP2A by RNA-interference reduced the apoptotic effect induced by sorafenib-bortezomib co-treatment, indicating that PP2A is indispensable for mediating the effects of these drugs. Notably, sorafenib with bortezomib increased PP2A activity in PLC/PRF/5 cells without altering protein levels of PP2A complex or the interaction between PP2A and Akt proteins. Finally, sorafenib plus bortezomib significantly suppressed PLC/PRF/5 xenograft tumor growth, down-regulated P-Akt expression, and up-regulated PP2A activity., Conclusions: The combination of sorafenib and bortezomib shows synergy in HCC through PP2A-dependent Akt inactivation.

Aim: To investigate the long-term consequences of chemotherapy-related HBV reactivation in patients with lymphoma., Methods: This study was based on the database of published prospective study evaluating HBV reactivation in HBV lymphoma patients during chemotherapy. Deteriorated liver reserve (DLR) was defined as development of either one of the following conditions during follow-up: (1) newly onset parenchyma liver disease, splenomegaly or ascites without evidence of lymphoma involvement; (2) decrease of the ratio (albumin/globulin ratio) to less than 0.8 or increase of the ratio of INR of prothrombin time to larger than 1.2 without evidence of malnutrition or infection. Liver cirrhosis was diagnosed by imaging studies., Results: A total of 49 patients were included. The median follow-up was 6.2 years (range, 3.9-8.1 years). There were 31 patients with and 18 patients without HBV reactivation. Although there was no difference of overall survival (OS) and chemotherapy response rate between the two groups, DLR developed more frequently in patients with HBV reactivation (48.4% vs 16.7%; P = 0.0342). Among the HBV reactivators, HBV genotype C was associated with a higher risk of developing DLR (P = 0.0768) and liver cirrhosis (P = 0.003). Four of five patients with sustained high titer of HBV DNA and two of three patients with multiple HBV reactivation developed DLR. Further, patients with a sustained high titer of HBV DNA had the shortest OS among the HBV reactivators (P = 0.0000). No patients in the non-HBV reactivation group developed hepatic failure or liver cirrhosis., Conclusion: Chemotherapy-related HBV reactivation is associated with the long-term effect of deterioration of hepatic function.

Background & Aims Absence or low anti-HBV surface antibody (anti-HBs) is associated with an increased risk of HBV reactivation in patients with lymphoma and resolved HBV infection receiving rituximab-containing chemotherapy. Quantification of anti-HBV core antibody (anti-HBc) is a new marker associated with the natural history and treatment response of chronic HBV infection. This study investigated whether baseline anti-HBc and anti-HBs levels may better predict HBV reactivation. Methods We prospectively measured the HBV DNA levels of patients with lymphoma and resolved HBV infection receiving rituximab–cyclophosphamide, hydroxydaunorubicin, vincristine, and prednisolone-based chemotherapy and started an antiviral therapy upon HBV reactivation, defined as a greater than 10-fold increase in HBV DNA compared with previous nadir levels. Anti-HBs and anti-HBc were quantified by a double-sandwich assay. Receiver-operating-characteristic-curve analysis was used to determine the optimal baseline anti-HBc/anti-HBs levels for predicting HBV reactivation. Results HBV reactivation occurred in 24 of the 197 patients enrolled, with an incidence of 11.6/100 person-years. For the 192 patients with enough serum samples for analysis, low anti-HBs (<56.48 mIU/ml) and high anti-HBc (≥6.41 IU/ml) at baseline were significantly associated with high risk of HBV reactivation (hazard ratio [HR] 8.48 and 4.52, respectively; p  <0.01). The multivariate analysis indicated that (1) patients with both high anti-HBc and low anti-HBs at baseline (36 of 192 patients) had an HR of 17.29 for HBV reactivation (95% CI 3.92–76.30; p  <0.001), and (2) HBV reactivation may be associated with inferior overall survival (HR 2.41; 95% CI 1.15–5.05; p  = 0.02). Conclusions Baseline anti-HBc/anti-HBs levels may predict HBV reactivation in these patients with lymphoma and help optimize prophylactic antiviral therapy for high-risk patients. Lay summary In this study, we identified a subgroup of patients with lymphoma and resolved hepatitis B virus infection that had a high risk of hepatitis B virus reactivation after receiving rituximab-containing chemotherapy. These findings will help optimize a preventive strategy, especially in hepatitis B virus endemic regions with limited healthcare resources. Clinical trial number: NCT 00931229. [ABSTRACT FROM AUTHOR]

Abstract: Obatoclax is a linear oligopyrrole compound which antagonizes the antiapoptotic effects of the Bcl-2 family. Herein we describe the synthesis of obatoclax derivatives by replacement of the pyrrole and indole ring of obatoclax with thiophene, furan and thiazolidinedione. The in vitro cytotoxicity of the newly synthesized compounds is evaluated against hepatocellular carcinoma cells. Pyrrole and indole substituents of obatoclax analogues exhibited potent inhibition of cell growth. Among the tested compounds, 5d and 5e were active at 6.3 and 13.2 μM against PLC5 cells. Further assays confirmed a correlation between cell death, and p-STAT3 inhibition and SHP-1 activation by these analogues. [Copyright &y& Elsevier]