Virtual Screening and Biological Evaluation of Potential PD-1/PD-L1 Immune Checkpoint Inhibitors as Anti-Hepatocellular Carcinoma Agents.

Blockade of the programmed cell death-1/programmed cell death ligand-1 (PD-1/PD-L1) immune checkpoint pathway is an efficient immunotherapeutic modality that provided significant advances in cancer treatment especially in solid tumors highly resistant to traditional therapy. Monoclonal antibodies (mAbs) and small-molecule inhibitors are the two main strategies used to block this axis with mAbs suffering from many limitations. Accordingly, the current alternative is the development of small-molecule PD-1/PD-L1 inhibitors. Here, we present a sequential virtual screening (VS) protocol involving pharmacophore screening followed by molecular docking for the discovery of novel PD-L1 inhibitors. The VS protocol resulted in the discovery of eight novel compounds. A 100 ns MD simulation showed two compounds, H4 and H6, exhibiting a stable binding mode at the PD-L1 dimer interface. Upon evaluation of their immunological activities, the two compounds induced higher cytokines levels (IL-2, IL-6, and INF-γ) relative to BMS-202, 72 h post treatment of PBMCs of HCC patients. Thus, the discovered hits represent potential leads for the development of novel classes targeting the PD-L1 receptor as anti-hepatocellular carcinoma agents.

Africa Guidelines for Hepatocellular Carcinoma Buildup Process.

PURPOSE: Hepatocellular carcinoma (HCC), the fourth most common cancer in Africa, has a dismal overall survival of only 3 months like in sub-Saharan Africa. This is affected by the low gross domestic product and human development index, absence of coherent guidelines, and other factors. METHODS: An open forum for HCC-experienced health care workers from Africa and the rest of the world was held in October 2021. Participants completed a survey to help assess the real-life access to screening, diagnoses, and treatment in the North and Southern Africa (NS), East and West Africa (EW), Central Africa (C), and the rest of the world. RESULTS: Of 461 participants from all relevant subspecialties, 372 were from Africa. Most African participants provided hepatitis B vaccination and treatment for hepatitis B and C. More than half of the participants use serum alpha-fetoprotein and ultrasound for surveillance. Only 20% reported using image-guided diagnostic liver biopsy. The Barcelona Clinic Liver Cancer is the most used staging system (52%). Liver transplant is available for only 28% of NS and 3% EW. C reported a significantly lower availability of resection. Availability of local therapy ranged from 94% in NS to 62% in C. Sorafenib is the most commonly used systemic therapy (66%). Only 12.9% reported access to other medications including immune checkpoint inhibitors. Besides 42% access to regorafenib in NS, second-line treatments were not provided. CONCLUSION: Similarities and differences in the care for patients with HCC in Africa are reported. This reconfirms the major gaps in access and availability especially in C and marginally less so in EW. This is a call for concerted multidisciplinary efforts to achieve and sustain a reduction in incidence and mortality from HCC in Africa.

Assessment of circulating levels of microRNA-326, microRNA-424, and microRNA-511 as biomarkers for hepatocellular carcinoma in Egyptians.

BACKGROUND: Hepatocellular carcinoma (HCC) is the fifth most common cancer. Differential expression of microRNAs (miRNAs)-326, miRNA-424, and miRNA-511 has been associated with the diagnosis and prognosis of HCC in different populations. However, limited information is available regarding their expression in Egyptian HCC patients. AIM: To assess the role of circulating miRNAs-326, miRNA-424, and miRNA-511 in Egyptian HCC patients. METHODS: This prospective observational study included 70 HCC patients and 25 healthy controls. The circulating levels of these three miRNAs were evaluated by real-time PCR. Receiver operating characteristic curve analysis was used to test the diagnostic accuracy of microRNA expression levels. RESULTS: All miRNAs were differentially expressed in HCC patients; miRNAs326 and miRNA-424 were upregulated, while miRNA-511 was downregulated. Both miRNA-326 and miRNA-424 showed sensitivity and specificity of 97%, 71.4%, and 52%, 60%, respectively, to differentiate HCC from controls. Moreover, miRNA-326 was associated with survival and could differentiate between Child grades (A vs B); miRNA-424 significantly differentiated early vs intermediate stages of HCC; while miRNA-511 was significantly correlated with response to modified Response Evaluation Criteria in Solid Tumors (mRECIST). CONCLUSION: We conclude that miRNA-326, miRNA-424, and miRNA-511 have diagnostic and prognostic roles in Egyptian patients with hepatitis C virus-related HCC and should be considered for better disease management.

Tumor behavior of hepatocellular carcinoma after hepatitis C treatment by direct-acting antivirals: comparative analysis with non-direct-acting antivirals-treated patients.

INTRODUCTION: Scarce reports have commented on hepatocellular carcinoma (HCC) behavior after direct-acting antivirals (DAAs). AIM: To analyze differences in tumor behavior between patients with hepatitis C virus (HCV)-induced HCC and were either treated or not using DAAs. PATIENTS AND METHODS: This case-control study includes patients with HCV-related HCC who received generic DAAs (group I) and all non-DAA treated patients with HCC who presented to our clinic during the same period (group II). Patient and tumor characteristics, treatment types and outcome were compared between the two groups. RESULTS: Group I included 89 patients and group II included 207 patients. No significant difference was detected between groups regarding HCC number or size. Group I showed a more infiltrative HCC pattern, whereas group II had more circumscribed and delineated lesions. The incidence of portal vein thrombosis and significant lymphadenopathy was significantly higher in group I (P=0.03 and 0.03, respectively). Serum levels of α-fetoprotein were significantly higher in group I (P=0.02). These factors significantly affected the response to HCC management (P=0.03). Incidence of complete responses were 47.2 and 49.8% for groups I and II, respectively, whereas incomplete responses were 12.4 and 25.1%, respectively. Supportive treatment was applied to 40.4% in group I and 25.1% in group II. CONCLUSION: HCC behavior was more aggressive in DAA-treated patients regarding portal vein thrombosis, malignant lymphadenopathy, and HCC imaging characteristics, which affected the chance of ablation and the treatment response.

Liver stiffness measurement changes following hepatocellular carcinoma treatment with percutaneous microwave ablation or transarterial chemoembolization: a cohort study.

BACKGROUND: Liver stiffness increases after the development of hepatocellular carcinoma (HCC). Transient elastography for liver stiffness measurement (LSM) using fibroscan is a simple noninvasive method of proven efficacy. This study aims to assess the changes in LSM following HCC treatment. PATIENTS AND METHODS: This study included 150 patients with hepatitis C virus related HCC attending the multidisciplinary HCC clinic, Kasr Al-Ainy Hospital between March 2014 and October 2015 who underwent either transarterial chemoembolization (TACE) or microwave ablation (MWA). Baseline LSM was carried out 3 and 6 months after treatment. The response rate was calculated according to the modified Response Evaluation Criteria in Solid Tumors criteria; overall survival and LSM changes were then compared between the two procedures. RESULTS: MWA showed higher rates of complete ablation (77.4%) than did TACE (31.7%) (P=0.004). Increase in LSM 3 and 6 months after treatment was statistically significant in the TACE group (P<0.001) but not in the MWA group (P=0.4). Patients who showed complete ablation had statistically significant lower baseline LSM than those with incomplete ablation, and their 6 months increase in LSM was also significantly lower. Logistic regression revealed that with each unit increase in baseline stiffness, 3% reduction in the odds of complete ablation is expected, and this did not change after controlling for the type of treatment. Child-Pugh class, number, and size of HCCs were our independent prognostic factors by Cox proportional analysis. CONCLUSION: The increase in LSM is significant after TACE than after MWA. Moreover, lower pre-ablation LSM is a predictor of complete ablation.

Liver stiffness measurements and FIB-4 are predictors of response to sofosbuvir-based treatment regimens in 7256 chronic HCV patients.

Objectives: To assess the role of baseline liver stiffness (LS) by Transient elastography (TE) and FIB-4 in the prediction of virological response to sofosbuvir - based regimens in chronic HCV patients.Methods: A retrospective, multicenter study including 7256 chronic HCV patients who received different sofosbuvir-based regimens. Baseline demographic and laboratory data were recorded. TE was performed with FIB-4 calculation at baseline.Results: Sustained virological response at week 12 post-treatment (SVR12) was 91.4%. Pretreatment TE values and FIB-4 were significantly lower among sustained responders (17.8 ± 11.5 kPa, 2.66 ± 1.98, respectively) versus relapsers (24.5 ± 13.9 kPa, 4.02 ± 3.3, respectively). Best cutoff levels for LS by TE and FIB-4 score for prediction of failure to treatment response were 16.7 kPa and 2.4, respectively. Among different treatment protocol, patients with FIB-4 > 2.4, TE values >16.7 kPa are more prone to treatment failure except when using SOF/SIM treatment regimens.Conclusion: Baseline LS by TE and FIB-4 score may be useful for predicting treatment outcome in the new era of DAAs and could be integrated into pretreatment assessment of chronic HCV patients for better optimization of patient management.

Evaluation of liver steatosis, measured by controlled attenuation parameter, in patients with hepatitis C-induced advanced liver fibrosis and hepatocellular carcinoma.

INTRODUCTION: Steatosis is a documented feature of chronic hepatitis C (CHC). There is an association between steatosis decrease and fibrosis progression. The association between steatosis and advanced fibrosis versus hepatocellular carcinoma (HCC) development has not been precisely evaluated. The controlled attenuation parameter (CAP) was applied as an immediate and efficient process to detect and quantify hepatic steatosis with adequate accuracy. AIMS: The aim of this study was to assess the difference in liver steatosis between patients with hepatitis C virus-related advanced hepatic fibrosis versus HCC. PATIENTS AND METHODS: This cross-sectional study included 130 patients with HCC, attending the multidisciplinary HCC clinic, Cairo University, and 54 patients with CHC between October 2015 and June 2016. Clinical and laboratory characteristics were recorded. Liver stiffness and CAP were obtained by using the FibroScan 502, touch. RESULTS: All included patients had genotype 4. The mean CAP value was significantly lower in HCC (209.5±57.1 dB/m) versus CHC (259.9±54.9 dB/m). Receiver operating characteristic curve revealed an area under the curve of 0.75 for the differentiation between groups. At a cutoff value of 237 dB/m, sensitivity was 72.3%, specificity was 70.7%, positive likelihood ratio was 2.5, and negative likelihood ratio was 0.4 in the differentiation between CHC versus HCC. Logistic regression analysis revealed an odds ratio of 6.4 for the diagnosis of HCC with CAP of less than 237 dB/m. Multivariate analysis, controlling for age, sex, BMI, triglycerides, and cholesterol levels, revealed a significantly increased odds for HCC diagnosis (odds ratio: 4.3, P=0.006). CONCLUSION: The progression of CHC is associated with a decrease in steatosis, particularly toward advanced fibrosis and HCC. Steatosis reduction less than 237 dB/m is likely to be associated with HCC.

De-novo versus recurrent hepatocellular carcinoma following direct-acting antiviral therapy for hepatitis C virus.

INTRODUCTION: A recent appearance of direct-acting antivirals (DAAs) led to a surge in hepatitis C virus (HCV) management. Nowadays, a large proportion of treated patients have cirrhosis with a retained possibility to develop hepatocellular carcinoma (HCC) even after complete cure. We aimed to study tumoral differences between patients who developed HCC after DAAs as either a recurrence or de-novo HCC. METHODS: We retrospectively analyzed 89 patients who presented to our HCC multidisciplinary clinic with HCC lesions following DAA therapy. A total of 45 patients had complete response to HCC according to the modified Response Evaluation Criteria in Solid Tumors before DAAs intake. Another 44 patients developed de-novo lesions after DAA treatment. Both groups were compared regarding their baseline characteristics, tumor criteria, response to DAAs as well response to HCC treatment. RESULTS: Both groups showed no significant difference regarding their baseline characteristics (age, sex, Child-Pugh score, and performance status) or response to DAAs (P=0.5). No significant difference was present between groups according to number, site, and size of lesions. However, time elapsed between the end of DAAs therapy and first diagnosis of HCC was significantly longer in de-novo group (15.22±16.39 months) versus recurrence group (6.76±5.1 months) (P=0.008). In addition, response to ablation was significantly better in de-novo lesions compared with recurrent HCC (P=0.03). CONCLUSIONS: Although de-novo HCC lesions significantly developed later than recurrent lesions in DAAs-treated patients, their response rates were significantly better. No differences were detected between both groups in their response to DAAs and their tumoral characteristics.

A new prognostic score can predict survival after hepatocellular carcinoma treatment in a cohort of 1302 Egyptian hepatocellular carcinoma patients.

INTRODUCTION: Survival of hepatocellular carcinoma (HCC) differs between regions and countries according to the different underlying factors and the degree of standard of care that enables early diagnosis and management. Our aim was to identify the most potent predictive factors of survival in Egyptian HCC patients receiving curative or palliative treatments. PATIENTS AND METHODS: This retrospective study included 1302 HCC patients attending the HCC multidisciplinary clinic, Cairo University, between February 2009 and December 2016. Clinical, laboratory, tumor characteristics, and treatment data were collected. Prognostic scores for each of the treatment categories, curative or palliative, were developed using routine laboratory tests. RESULTS: Patients were predominantly men, mean age 57.79±7.56 years. All cases developed HCC in addition to cirrhosis, mainly hepatitis C virus-related (88.2%). Most of the patients were Child-Pugh A (56.8%) or B (34.4%) and had single lesions. Transarterial chemoembolization was the most common line of treatment (42.08%). The overall median survival was 18.3 months from the date of diagnosis. Cigarette smoking, Child-Pugh score, performance status, number and size of the focal lesion, α-fetoprotein, and application of a specific treatment, particularly curative treatment, were the significant independent prognostic factors for survival. We found no impact of diabetes mellitus or hypertension on survival. Multidisciplinary HCC clinic predictive scores of survival after palliative and curative treatments were developed including independent prognostic factors, age, and portal vein status. CONCLUSION: A new Egyptian prognostic score of tumor and patients factors can predict the survival of patients with HCC after palliative and curative treatments.