Strategies to enhance the therapeutic efficacy of anti-PD-1 antibody, anti-PD-L1 antibody and anti-CTLA-4 antibody in cancer therapy.

Although immune checkpoint inhibitors (anti-PD-1 antibody, anti-PD-L1 antibody, and anti-CTLA-4 antibody) have displayed considerable success in the treatment of malignant tumors, the therapeutic effect is still unsatisfactory for a portion of patients. Therefore, it is imperative to develop strategies to enhance the effect of these ICIs. Increasing evidence strongly suggests that the key to this issue is to transform the tumor immune microenvironment from a state of no or low immune infiltration to a state of high immune infiltration and enhance the tumor cell-killing effect of T cells. Therefore, some combination strategies have been proposed and this review appraise a summary of 39 strategies aiming at enhancing the effectiveness of ICIs, which comprise combining 10 clinical approaches and 29 foundational research strategies. Moreover, this review improves the comprehensive understanding of combination therapy with ICIs and inspires novel ideas for tumor immunotherapy.

Impact of hepatic inflammation and fibrosis on the recurrence and long-term survival of hepatitis B virus-related hepatocellular carcinoma patients after hepatectomy.

BACKGROUND: Underlying liver disease is correlated with hepatocellular carcinoma (HCC) development in patients with hepatitis B virus (HBV) infection. However, the impact of hepatic inflammation and fibrosis on the patients' prognoses remains unclear. METHODS: The clinicopathological data of 638 HBV-infected patients with early-stage HCC between 2017 and 2019 were prospectively collected. Hepatic inflammation and fibrosis were evaluated by experienced pathologists using the Scheuer score system. Survival analysis was analyzed using the Kaplan-Meier analysis. RESULTS: Application of the Scheuer scoring system revealed that 50 (7.9%), 274 (42.9%), and 314 (49.2%) patients had minor, intermediate, and severe hepatic inflammation, respectively, and 125 (15.6%), 150 (23.5%), and 363 (56.9%) patients had minor fibrosis, advanced fibrosis, and cirrhosis, respectively. Patients with severe hepatitis tended to have a higher rate of HBeAg positivity, higher HBV-DNA load, elevated alanine aminotransferase (ALT) levels, and a lower proportion of capsule invasion (all Pp < 0.05). There were no significant differences in the recurrence-free and overall survival among the three groups (P = 0.52 and P = 0.66, respectively). Patients with advanced fibrosis or cirrhosis had a higher proportion of HBeAg positivity and thrombocytopenia, higher FIB-4, and larger tumor size compared to those with minor fibrosis (all P < 0.05). Patients with minor, advanced fibrosis, and cirrhosis had similar prognoses after hepatectomy (P = 0.48 and P = 0.70). The multivariate analysis results indicated that neither hepatic inflammation nor fibrosis was an independent predictor associated with prognosis. CONCLUSIONS: For HBV-related HCC patients receiving antiviral therapy, hepatic inflammation and fibrosis had little impact on the post-hepatectomy prognosis.

Analysis of the characteristics, efficiency, and influencing factors of third-party mediation mechanisms for resolving medical disputes in public hospitals in China.

BACKGROUND: Medical disputes, which are prevalent in China, are a growing global public health problem. The Chinese government has proposed third-party mediation (TPM) to resolve this issue. However, the characteristics, efficiency, and influencing factors of TPM in resolving medical disputes in public hospitals in China have yet to be determined. METHODS: We conducted a systematic study using TPM records from medical disputes in Gansu Province in China from 2014 to 2019. A χ2 test was used to compare differences between groups, and binary logistic analysis was performed to determine the factors influencing the choice of TPM for resolving medical disputes. RESULTS: We analyzed 5,948 TPM records of medical disputes in Gansu Province in China. The number of medical disputes and the amount of compensation awarded in public hospitals in the Gansu Province increased annually from 2014 to 2019, with most of the disputes occurring in secondary and tertiary hospitals. Approximately 89.01% of the medical disputes were handled by TPM; the average compensation amount with TPM was Chinese Yuan (CNY) 48,688.73, significantly less than that awarded via court judgment and judicial mediation. TPM was more likely to succeed in settling medical disputes in the < CNY10,000 compensation group than in the no-compensation group (odds ratio [OR] = 3.14, 95% confidence interval [CI] 1.53-6.45). However, as the compensation amount increased, the likelihood of choosing TPM decreased significantly. Moreover, TPM was less likely to be chosen when medical disputes did not involve death (OR = 0.49, 95% CI 0.36-0.45) or when no-fault liability was determined (vs. medical accidents; OR = 0.37, 95% CI 0.20-0.67). CONCLUSION: Our findings demonstrate that TPM mechanisms play a positive role in efficiently reducing compensation amounts and increasing medical dispute resolution rates which was the main settlement method in resolving medical disputes in public hospitals of Gansu Province in China. TPM could help greatly reduce conflicts between doctors and patients, avoid litigation, and save time and costs for both parties. Moreover, compensation amounts, non-fatal outcomes, and no-fault liability determinations influence the choice of TPM for settling medical disputes.

Analysis of the characteristics and risk factors affecting the judgment results of medical damage liability disputes in 3172 second-instance and retrial cases in China.

BACKGROUND: Medical disputes remain a global public health problem. However, an analysis of the characteristics and risk factors affecting the judgment results of medical damage liability disputes in second-instance and retrial cases in China has yet to be conducted. METHODS: We conducted a systematic search and evaluation of second-instance and retrial cases among all medical damage liability disputes in China Judgments Online; SPSS 22.0 was used for the statistical analysis. A χ2 test or likelihood ratio Chi-square test was used to compare differences between groups, and multivariate logistic regression analysis was performed to determine independent risk factors that could affect the judgment results of medical disputes. RESULTS: We included 3172 second-instance and retrial cases among all medical damage liability disputes in the analysis. The results showed that 48.04% of cases were unilateral appeals by the patient, and medical institutions were responsible for providing compensation in 80.64% of these cases. Cases involving compensation ranged from Chinese Yuan (CNY) 100 000 to 500 000 ranked first (40.95%); 21.66% were non-compensation cases. Cases involving mental damage compensation of less than CNY 20 000 accounted for 39.03%. Violations of medical treatment and nursing routines accounted for 64.25% of all cases. In addition, re-identification in 54.59% of cases changed the initial appraisal opinion. Independent risk factors for medical personnel to lose a lawsuit in a multivariate logistic regression model included appeal originator [patient side: OR = 18.809 (95% CI 11.854-29.845); both sides: OR = 22.168 (95% CI 12.249-40.117)], change of the original verdict (OR = 5.936, 95% CI 3.875-9.095), judicial identification (OR = 6.395, 95% CI 4.818-8.487), violations of medical treatment and nursing routines (OR = 8.783, 95% CI 6.658-11.588), and non-standard medical document writing (OR = 8.500, 95% CI 4.805-15.037). CONCLUSION: Our study clarifies the characteristics of second-instance and retrial cases among all medical damage liability disputes in China from multiple perspectives and identifies the independent risk factors for medical personnel losing a lawsuit. This study could help medical institutions prevent and reduce medical disputes, at the same time, it could be helpful for medical institutions to provide better medical treatment and nursing services for patients.

Indocyanine green fluorescence staining based on the "hepatic pedicle first" approach during laparoscopic anatomic liver resection.

BACKGROUND: Indocyanine green (ICG) fluorescence staining is one of the most challenging procedures for laparoscopic anatomic liver resection (LALR). Here, we introduce a novel method based on the "hepatic pedicle first" approach that can improve the success rate of positive staining. METHOD: The target hepatic pedicle (even for the subsegment) was dissected through the first porta until it became visible. Five milliliters of 0.025 mg/ml ICG was injected after the target hepatic pedicle (extra-Glissonian approach) or portal vein/hepatic artery (intra-Glissonian approach) was punctured successfully using scalp acupuncture under direct vision. Then, the Glissonian pedicle or vessel was clamped immediately to prevent the intrahepatic diffusion of ICG. During the operation, a fluorescence imaging model was used repeatedly to confirm the segmental boundary. RESULTS: Finally, 24 patients underwent LALR with the "hepatic pedicle first" approach for ICG fluorescence-positive staining. In 5 patients, ICG-positive staining failed, representing a 79.17% success rate. The average staining time was 25.92 min ± 14.64 min. There were no complications associated with vessel puncture (bile leakage, hemorrhage, and thrombosis). CONCLUSION: The "hepatic pedicle first" approach is a feasible, convenient, and safe method for ICG-positive staining, with a high success rate.

Ribosome assembly factor URB1 contributes to colorectal cancer proliferation through transcriptional activation of ATF4.

Ribosome assembly factor URB1 is essential for ribosome biogenesis. However, its latent role in cancer remains unclear. Analysis of The Cancer Genome Atlas database and clinical tissue microarray staining showed that URB1 expression was upregulated in colorectal cancer (CRC) and prominently related to clinicopathological characteristics. Silencing of URB1 hampered human CRC cell proliferation and growth in vitro and in vivo. Microarray screening, ingenuity pathway analysis, and JASPAR assessment indicated that activating transcription factor 4 (ATF4) and X-box binding protein 1 (XBP1) are potential downstream targets of URB1 and could transcriptionally interact through direct binding. Silencing of URB1 significantly decreased ATF4 and cyclin A2 (CCNA2) expression in vivo and in vitro. Restoration of ATF4 effectively reversed the malignant proliferation phenotype of URB1-silenced CRC cells. Dual-luciferase reporter and ChIP assays indicated that XBP1 transcriptionally activated ATF4 by binding with its promoter region. X-box binding protein 1 colocalized with ATF4 in the nuclei of RKO cells, and ATF4 mRNA expression was positively regulated by XBP1. This study shows that URB1 contributes to oncogenesis and CRC growth through XBP1-mediated transcriptional activation of ATF4. Therefore, URB1 could be a potential therapeutic target for CRC.

Discovery of a novel inhibitor of nitric oxide production with potential therapeutic effect on acute inflammation.

Inflammation as a host's excessive immune response to stimulation, is involved in the development of numerous diseases. To discover novel anti-inflammatory agents and based on our previous synthetic work on marine natural product Chrysamide B, it and a series of derivatives were synthesized and evaluated for their anti-inflammatory activity on inhibition of LPS-induced NO production. Then the preliminary structure-activity relationships were conducted. Among them, Chrysamide B is the most potent anti-inflammatory agent with low cytotoxicity and strong inhibition on the production of NO (IC50 = 0.010 µM) and the activity of iNOS (IC50 = 0.082 µM) in LPS-stimulated RAW 264.7 cells. Primary studies suggested that the mechanism of action may be that it interfered the formation of active dimeric iNOS but not affected transcription and translation. Furthermore, its good performance of anti-inflammatory effect on LPS-induced multiple inflammatory cytokines production, carrageenan-induced paw edema, and endotoxin-induced septic mice, was observed. We believe that these findings would provide an idea for the further modification and research of these analogs in the future.

Design, synthesis and bioactivity evaluation of novel N-phenyl-substituted evodiamine derivatives as potent anti-tumor agents.

Natural products are important sources for the development of therapeutic medicine, among which evodia fruit has a wide range of medicinal properties in traditional Chinese medicine. Evodiamine, the main active component of evodia fruit, has various anti-cancer effects and has been proved to be a Topo inhibitor. From our previous attempts of modifying evodiamine, we found that the N14 phenyl substituted derivatives had showed great anti-tumor activity, which prompted us to further explore the novel structures and activities of these compounds. Compound 6f, as a N14 3-fluorinated phenyl substituted evodiamine derivative, showed a certain inhibitory activity against Topo I at 200 µM. By studying its anti-tumor effects in vitro, compound 6f could inhibit proliferation and induce apoptosis, as well as arrest the cell cycle of HGC-27 and HT-29 cell lines at G2/M phase in a concentration-dependent manner. Moreover, compound 6f could inhibit the migration and invasion of HGC-27 cell lines. Meanwhile, compound 6f could induce apoptosis of HGC-27 cells by inhibiting PI3K/AKT pathway. Overall, this work demonstrated that the N14 phenyl-substituted evodiamine derivatives had a good inhibitory effect on tumor cells in vitro, providing a promising strategy for developing potential anticancer agents for the treatment of gastrointestinal tumors.

Design, synthesis and antitumor activity evaluation of Chrysamide B derivatives.

Marine natural products derived from special or extreme environment provide an important source for the development of anti-tumor drugs due to their special skeletons and functional groups. In this study, based on our previous work on the total synthesis and structure revision of the novel marine natural product Chrysamide B, a group of its derivatives were designed, synthesized, and subsequently of which the anti-cancer activity, structure-activity relationships and cellular mechanism were explored for the first time. Compared with Chrysamide B, better anti-cancer performance of some derivatives against five human cancer cell lines (SGC-7901, MGC-803, HepG2, HCT-116, MCF-7) was observed, especially for compound b-9 on MGC-803 and SGC-7901 cells with the IC 50 values of 7.88 ± 0.81 and 10.08 ± 1.08 µM, respectively. Subsequently, cellular mechanism study suggested that compound b-9 treatment could inhibit the cellular proliferation, reduce the migration and invasion ability of cells, and induce mitochondrial-dependent apoptosis in gastric cancer MGC-803 and SGC-7901 cells. Furthermore, the mitochondrial-dependent apoptosis induced by compound b-9 is related with the JAK2/STAT3/Bcl-2 signaling pathway. To conclude, our results offer a new structure for the discovery of anti-tumor lead compounds from marine natural products.

Design, synthesis and bioactivity study of evodiamine derivatives as multifunctional agents for the treatment of hepatocellular carcinoma.

Topoisomerase has been found extremely high level of expression in hepatocellular carcinoma (HCC) and proven to promote the proliferation and survival of HCC. Cancer-associated fibroblasts (CAFs) as a kind of key reactive stromal cell that abundantly present in the microenvironment of HCC, could enhance the metastatic ability and drug resistance of HCC. Therefore, developing new drugs that address the above conundrums would be of the upmost significant in the fight against HCC. Evodiamine, as a multi-target natural product, has been found to exert various biological activities such as anti-cancer and anti-hepatic fibrosis via blocking topoisomerase, NF-κB, TGF-ß/HGF, and Smad2/3. Inspired by these facts, 15 evodiamine derivatives were designed and synthesized for HCC treatment by simultaneously targeting Topo I and CAFs. Most of them displayed preferable anti-HCC activities on three HCC cell lines and low cytotoxicity on one normal hepatic cell. In particular, compound 8 showed the best inhibitory effect on HCC cell lines and a good inhibition on Topo I in vitro. Meanwhile, it also induced obvious G2/M arrest and apoptosis, and significantly decreased the migration and invasion capacity of HCC cells. In addition, compound 8 down-regulated the expression of type I collagen in the activated HSC-T6 cells, and induced the apoptosis of activated HSC-T6 cells. In vivo studies demonstrated that compound 8 markedly decreased the volume and weight of tumor (TGI = 40.53%). In vitro and in vivo studies showed that its effects were superior to those of evodiamine. This preliminary attempt may provide a promising strategy for developing anti-HCC lead compounds taking effect through simultaneous inhibition on Topo I and CAFs.

Laparoscopically anatomical versus non-anatomical liver resection for large hepatocellular carcinoma.

BACKGROUND: The role of laparoscopically anatomical resection (LAR) for hepatocellular carcinoma (HCC) remains unclear due to the more demanding technique required in laparoscopy. This study is to analyze the clinical impact of LAR compared to laparoscopically non-anatomical resection (LNAR) for HCC. METHODS: All patients received laparoscopic hepatectomy for HCC (diameter 5-10 cm) from January 2015 to December 2018 were retrospectively enrolled in this study. Patients were divided into LAR and LNAR groups. The perioperative and oncological outcomes were evaluated based on propensity score matching (PSM) method. RESULTS: After PSM, 51 patients in each group were enrolled. The operative time in LAR group was longer (240 vs 195.0 min, p = 0.012) and blood loss was more (200.0 vs 150.0 mL, p = 0.030) than those of LNAR group, respectively. The total complication rates were comparable between them (21.6% vs 17.6%, p = 0.500). The 3-year overall survival rates were 59.4% in LAR group and 38.7% in LNAR group, respectively (p = 0.045). The 3-year disease-free survival rates were 52.3% in LAR group and 27.0% in LNAR group, respectively (p = 0.042). CONCLUSION: LAR could be feasibly performed with comparable perioperative outcomes and contributed to improve long-term survival in patients with HCC (diameter 5-10 cm) when compared to LNAR.

KIAA1429 contributes to liver cancer progression through N6-methyladenosine-dependent post-transcriptional modification of GATA3.

BACKGROUND: N6-methyladenosine (m6A) modification, the most abundant internal methylation of eukaryotic RNA transcripts, is critically implicated in RNA processing. As the largest known component in the m6A methyltransferase complex, KIAA1429 plays a vital role in m6A methylation. However, its function and mechanism in hepatocellular carcinoma (HCC) remain poorly defined. METHODS: Quantitative PCR, western blot and immunohistochemistry were used to measure the expression of KIAA1429 in HCC. The effects of KIAA1429 on the malignant phenotypes of hepatoma cells were examined in vitro and in vivo. MeRIP-seq, RIP-seq and RNA-seq were performed to identify the target genes of KIAA1429. RESULTS: KIAA1429 was considerably upregulated in HCC tissues. High expression of KIAA1429 was associated with poor prognosis among HCC patients. Silencing KIAA1429 suppressed cell proliferation and metastasis in vitro and in vivo. GATA3 was identified as the direct downstream target of KIAA1429-mediated m6A modification. KIAA1429 induced m6A methylation on the 3' UTR of GATA3 pre-mRNA, leading to the separation of the RNA-binding protein HuR and the degradation of GATA3 pre-mRNA. Strikingly, a long noncoding RNA (lncRNA) GATA3-AS, transcribed from the antisense strand of the GATA3 gene, functioned as a cis-acting element for the preferential interaction of KIAA1429 with GATA3 pre-mRNA. Accordingly, we found that the tumor growth and metastasis driven by KIAA1429 or GATA3-AS were mediated by GATA3. CONCLUSION: Our study proposed a complex KIAA1429-GATA3 regulatory model based on m6A modification and provided insights into the epi-transcriptomic dysregulation in hepatocarcinogenesis and metastasis.

SETD3 is regulated by a couple of microRNAs and plays opposing roles in proliferation and metastasis of hepatocellular carcinoma.

A previous study reported that histone methyltransferase SETD3 is up-regulated in tumor tissues of hepatocellular carcinoma (HCC) and is associated with the growth of HCC. However, the clinical significance and the effect of SETD3 on HCC metastasis remain unclear. In the present study, both the protein and mRNA expression levels of SETD3 were measured in a larger cohort of HCC patients. The results showed that the protein level of SETD3 in HCC tissues was significantly higher than that in non-tumorous tissues, which was inconsistent with the mRNA expression level of SETD3. The high protein level of SETD3 in HCC tissues was significantly associated with male gender, poor pathological differentiation, liver cirrhosis and unfavorable prognosis of HCC patients. Subsequently, we demonstrated that SETD3 could be regulated at post-transcriptional step by a couple of miRNAs (miR-16, miR-195 and miR-497). Additionally, in vitro and in vivo experiments revealed that SETD3 played opposing roles in proliferation and metastasis of HCC: promoting proliferation but inhibiting metastasis. Mechanistic experiments revealed that doublecortin-like kinase 1 (DCLK1) was a downstream target of SETD3. SETD3 could increase the DNA methylation level of DCLK1 promoter to inhibit the transcription of DCLK1. Further study revealed that DCLK1/PI3K/matrix metalloproteinase (MMP) 2 (MMP-2) was an important pathway that mediated the effect of SETD3 on HCC metastasis. In conclusion, the present study revealed that SETD3 is associated with tumorigenesis and is a promising biomarker for predicting the prognosis of HCC patients after surgical resection. In addition, SETD3 plays inhibitory role in HCC metastasis partly through DCLK1/PI3K/MMP-2 pathway.

Efficacy and safety of radiofrequency ablation versus minimally invasive liver surgery for small hepatocellular carcinoma: a systematic review and meta-analysis.

BACKGROUND: The aim of this study was to compare radiofrequency ablation (RFA) with minimally invasive liver surgery (MIS) in the treatment of small hepatocellular carcinoma (SHCC) and to assess short-term and long-term clinical outcomes. METHODS: PubMed, Embase, Cochrane Library, Web of science, and CBM were systematically searched for articles from inception to July 2018, comparing RFA and MIS in SHCC treatment. We evaluated overall survival (OS), disease-free survival (DFS), local recurrence, and complication rates, as well as hospitalization duration and operation times. RESULTS: Six retrospective studies were analyzed, including a total of 597 patients, 313 treated with RFA and 284 treated with MIS. OS rates were significantly higher in patients treated with MIS at 3 years, when compared to RFA (OR 0.55; 95% CI 0.36 to 0.84). The 3-year DFS MIS rates were also superior to RFA (OR 0.63; 95% CI 0.41 to 0.98). In contrast, when compared to MIS, RFA demonstrated a significantly higher rate of local intrahepatic recurrences, (OR 2.24; 95% CI 1.47 to 3.42), and a lower incidence of postoperative complications (OR 0.34; 95% CI 0.22 to 0.53), as well as shorter operation times (OR - 145.31, 95% CI - 200.24 to - 90.38) and hospitalization duration (OR - 4.02,95% CI - 4.94 to - 3.10). CONCLUSIONS: We found that MIS led to higher OS, DFS, and lower local recurrences in SHCC patients. Meanwhile, RFA treatments led to significantly lower complication rates, shorter operation times, and hospitalization duration. Considering long-term outcomes, MIS was found to be superior to RFA. However, RFA may be an alternative treatment for patients presenting a single SHCC nodule (≤ 3 cm), given its minimally invasive nature and its comparable long-term efficacy with MIS. Nevertheless, our findings should be explained with caution due to the low level of evidence obtained.

Safety and effectiveness of day-surgery laparoscopic cholecystectomy is still uncertain: meta-analysis of eight randomized controlled trials based on GRADE approach.

BACKGROUND: Currently, there is no consensus on whether laparoscopic cholecystectomy (LC) performed as day-surgery is safe and effective and can be considered as the standard for the management of symptomatic gallbladder disease. We conducted a meta-analysis of randomized controlled trials (RCTs) to evaluate the safety and effectiveness of this intervention based on the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. METHODS: We conducted a systematic search of several databases from their inception to November 10, 2016 for entries on the mortality, morbidity after discharge, readmission, postoperative morbidity, and patient satisfaction at 1 week of day-surgery LC. Pooled risk ratio (RR) with 95% confidence intervals (CI) was calculated using the fixed-effects model. Rare outcomes were presented as the Peto odds ratio (Peto OR). Meta-analysis was performed by using the RevMan 5.1 software, and the level of evidence was assessed by using the GRADE guideline and GRADEpro GDT software. RESULTS: Eight RCTs totaling 624 participants were included. The result showed no intergroup difference in short-term mortality. Compared to overnight-stay surgery, day-surgery did not show any clear evidence of reduced morbidity after discharge (Peto OR 0.89; 95% CI 0.39-2.02), lower readmission rate (Peto OR 0.68; 95% CI 0.23-2.05), or higher postoperative morbidity rates (RR 1.28; 95% CI 0.81-2.02). However, the results suggested that day-surgery may improve patient satisfaction at 1 week (RR 1.17; 95% CI 1.03-1.33). Evaluation by the GRADE approach revealed that the quality of evidence for each outcome was of low to very low quality due to the risk of bias, imprecision, and inconsistency. CONCLUSION: Our meta-analysis shows that the safety and effectiveness of day-surgery LC is still uncertain. Additional well-designed and adequately powered RCTs are required before the procedure can be recommended as the standard for clinical practice.

The efficacy and safety of glucocorticoid for perioperative patients with hepatectomy: a systematic review and meta-analysis.

OBJECTIVE: Glucocorticoids have been used in patients undergoing perioperative hepatectomy, however their safety and efficacy remain controversial. This meta-analysis was conducted to investigate this issue and further provide reference for clinical practice. METHODS: PubMed/MEDLINE, Embase, and Cochrane Library were searched for randomized controlled trials (RCTs) from database inception to December 2022. Literature screening and data extraction were performed independently by two reviewers. The methodological quality of the RCTs was assessed using the Jadad scale. RevMan 5.4 was used for the meta-analysis. RESULTS: A total of 11 RCTs involving 905 patients were included. Compared with the control group, we found perioperative glucocorticoid administration significantly lowered overall complication rate [RR = 0.67; 95% CI (0.55, 0.83); P = 0.0003], infectious complication rate [RR = 0.41; 95% CI (0.21, 0.82); P = 0.01] and postoperative liver failure [RR = 0.63; 95% CI (0.41, 0.97); P = 0.03]. In addition, glucocorticoids appear to improve liver function (TBil) [MD = -0.36, 95% CI (-0.59, -0.14), P = 0.001] and reduce the release of certain inflammatory cytokines (IL-6) [MD = -48.52, 95% CI (-56.88, -40.16), P < 0.00001]. CONCLUSION: Based on the available evidence, glucocorticoids appear to be safe and effective in patients undergoing hepatectomy, but further research is needed.

Preoperative prediction and risk assessment of microvascular invasion in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is one of the most common and highly lethal tumors worldwide. Microvascular invasion (MVI) is a significant risk factor for recurrence and poor prognosis after surgical resection for HCC patients. Accurately predicting the status of MVI preoperatively is critical for clinicians to select treatment modalities and improve overall survival. However, MVI can only be diagnosed by pathological analysis of postoperative specimens. Currently, numerous indicators in serology (including liquid biopsies) and imaging have been identified to effective in predicting the occurrence of MVI, and the multi-indicator model based on deep learning greatly improves accuracy of prediction. Moreover, several genes and proteins have been identified as risk factors that are strictly associated with the occurrence of MVI. Therefore, this review evaluates various predictors and risk factors, and provides guidance for subsequent efforts to explore more accurate predictive methods and to facilitate the conversion of risk factors into reliable predictors.

Design, Synthesis, and Biological Evaluation of Novel Evodiamine Derivatives as Potential Antihepatocellular Carcinoma Agents.

Evodiamine has many biological activities. Herein, we synthesize 23 disubstituted derivatives of N14-phenyl or the E-ring of evodiamine and conduct systematic structure-activity relationship studies. In vitro antiproliferative activity indicated that compounds F-3 and F-4 dramatically inhibited the proliferation of Huh7 (IC50 = 0.05 or 0.04 µM, respectively) and SK-Hep-1 (IC50 = 0.07 or 0.06 µM, respectively) cells. Furthermore, compounds F-3 and F-4 could double inhibit topoisomerases I and II, inhibit invasion and migration, block the cell cycle to the G2/M stage, and induce apoptosis as well. Additionally, compounds F-3 and F-4 could also inhibit the activation of HSC-T6 and reduce the secretion of collagen type I to slow down the progression of liver fibrosis. Most importantly, compound F-4 (TGI = 60.36%) inhibited tumor growth more significantly than the positive drug sorafenib. To sum up, compound F-4 has excellent potential as a strong candidate for the therapy of hepatocellular carcinoma.

Early predictive value of circulating biomarkers for sorafenib in advanced hepatocellular carcinoma.

INTRODUCTION: Sorafenib is currently the first-line therapeutic regimen for patients with advanced hepatocellular carcinoma (HCC). However, many patients did not experience any benefit and suffered extreme adverse events and heavy economic burden. Thus, the early identification of patients who are most likely to benefit from sorafenib is needed. AREAS COVERED: This review focused on the clinical application of circulating biomarkers (including conventional biomarkers, immune biomarkers, genetic biomarkers, and some novel biomarkers) in advanced HCC patients treated with sorafenib. An online search on PubMed, Web of Science, Embase, and Cochrane Library was conducted from the inception to 15 August 2021. Studies investigating the predictive or prognostic value of these biomarkers were included. EXPERT OPINION: The distinction of patients who may benefit from sorafenib treatment is of utmost importance. The predictive roles of circulating biomarkers could solve this problem. Many biomarkers can be obtained by liquid biopsy, which is a less or noninvasive approach. The short half-life of sorafenib could reflect the dynamic changes of tumor progression and monitor the treatment response. Circulating biomarkers obtained from liquid biopsy resulted as a promising assessment method in HCC, allowing for better treatment decisions in the near future. ABBREVIATIONS: Alpha-fetoprotein (AFP); American Association for the Study of Liver Diseases (AASLD); Angiopoietin (Ang); Barcelona Clinic Liver Cancer stage (BCLC); Circulating endothelial progenitor (CEP); Circulating free DNA (cfDNA); Complete response (CR); Des-γ-carboxy prothrombin (DCP); Endothelium-derived nitric oxide synthase (eNOS); Hepatocellular carcinoma (HCC); Hepatocyte growth factor (HGF); Hepatoma arterial-embolization prognosis score (HAP); High mobility group box 1 (HMgb1); Interferon-gamma (IFN-γ); Long non-coding RNA (lncRNAs); Micro RNAs (miRNAs); Monocyte-to-lymphocyte ratio (MLR); National Comprehensive Cancer Network (NCCN); Neutrophil-lymphocyte ratio (NLR); Newcastle-Ottawa Scale (NOS); Nitric oxide (NO); Overall survival (OS); Partial response (PR); Platelet-lymphocyte ratio (PLR); Prediction of survival in advanced sorafenib-treated HCC (PROSASH); Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA); Prognostic nutritional index (PNI); Progression-free survival (PFS); Progressive disease (PD); Randomized controlled trials (RCTs); Response Evaluation Criteria in Solid Tumors (RECIST); Single nucleotide polymorphisms (SNPs); Sorafenib advanced HCC prognosis score (SAP); Stable disease (SD); Time to progression (TTP); Transcatheter arterial chemoembolization (TACE); Vascular endothelial growth factor (VEGF).