Impact of metabolic dysfunction-associated steatotic liver disease on the efficacy of immunotherapy in patients with chronic hepatitis B-related hepatocellular carcinoma.

OBJECTIVE: To investigate the impact of metabolic dysfunction-associated steatotic liver disease (MASLD) on the efficacy of immune checkpoint inhibitor (ICI)-based therapy in patients with chronic hepatitis B (CHB)-related hepatocellular carcinoma (HCC). METHODS: A total of 155 patients with CHB-related HCC who received ICI-based therapy (in the Department of Hepatology, Tianjin Second People's Hospital and Department of Hepatobiliary Oncology, Tianjin Medical University Cancer Institute & Hospital) between April 2021 and December 2023 were evaluated. Patients were divided into two groups: MASLD concurrent with CHB [MASLD-CHB] (n = 38), and CHB (n = 117). RESULTS: The median progression-free survival (PFS, 6.9 months vs. 9.3 months; P = 0.001), progressive disease (57.89% vs. 37.61%; P = 0.028), and disease control rate (42.11% vs. 62.39%; P = 0. 028) in the MASLD-CHB group were significantly worse than the CHB group. The median overall survival was not attained. The percentage of CD4+PD1+ (17. 56% vs. 8.89%; P < 0.001) and CD8+PD1+ T cells (10.50% vs. 7.42%; P = 0.005) in patient samples from the MASLD-CHB group were significantly higher than the CHB group. Concurrent MASLD [hazard ratio (HR) = 1.921; 95% CI, 1.138-3.245; P = 0.015] and alpha-fetoprotein levels after 3 months of treatment (HR = 2.412; 95% CI, 1.360-4.279; P = 0.003) were independent risk factors for PFS in all patients. CONCLUSIONS: ICI-based therapy in patients with CHB-related HCC and concurrent MASLD resulted in poorer efficacy and shorter PFS compared to patients with CHB-related HCC alone.

Efficacy and safety of tenofovir alafenamide fumarate in nucleoside analogue treatment-naïve patients with chronic hepatitis B.

Tenofovir alafenamide fumarate (TAF) is a first-line drug for the antiviral treatment of patients with chronic hepatitis B (CHB) in China. In the present study, the efficacy and renal safety of TAF were evaluated in treatment-naive patients with CHB. Patients with CHB who had not been previously treated with nucleoside analogues (NAs) were recruited before TAF treatment was initiated. Changes in the levels of hepatitis B virus (HBV) DNA, hepatitis B e antigen (HBeAg) and hepatitis B surface antigen (HBsAg) were analyzed at 24 and 48 weeks using immunoassays. In addition, liver stiffness measurement (LSM) and controlled attenuation parameter (CAP) were analyzed using transient elastography, while alanine aminotransferase (ALT), triglyceride (TG), total cholesterol (TC) and low-density lipoprotein-cholesterol (LDL-C) levels, calcium (Ca) and inorganic phosphorus (IP) levels were measured using biochemistry assay. In addition, the estimated glomerular filtration rate (eGFR) was calculated. After 48 weeks, the ALT normalization rate was 95.24% (40/42), the complete virological response (HBV DNA <20 IU/ml) rate was 69.05% (29/42) and the HBeAg seroconversion rate was 8.57% (3/35). The levels of HBV DNA and HBsAg were significantly decreased from the baseline at 5.49±1.95 to 1.26±0.66 log10 IU/ml and from 3.59±0.81 to 3.32±0.55 log10 IU/ml after 48 weeks of treatment, respectively. Compared with that in the baseline measurements, LSM at 48 weeks was significantly decreased from 13.00±8.15 to 8.66±4.45 kPa. No significant differences were observed in the TG, TC, LDL-C, CAP, eGFR, Ca and IP measurements. According to the baseline ALT levels, patients were divided into group A [ALT ≤1 x upper limit of normal (ULN); ULN=50 U/l; n=21], group B (1 x ULN < ALT <2 x ULN; n=22) and group C (ALT ≥2 x ULN; n=18). A significant decrease in HBsAg levels was observed in group B (3.63±0.68 vs. 3.53±0.63 log10 IU/ml) and group C (4.15±0.57 vs. 3.66±0.48 log10 IU/ml) at 24 weeks compared with the baseline. In conclusion, TAF was found to be effective and safe in NA treatment-naive patients with CHB. Moreover, the higher the ALT levels, the more prominent the curative effect from TAF treatment. Therefore, NA treatment-naive CHB patients could benefit from TAF treatment in real world.

Prognostic Impact of PD-1 and Tim-3 Expression in Tumor Tissue in Stage I-III Colorectal Cancer.

BACKGROUND: Programmed cell death receptor 1 (PD-1) and T cell immunoglobulin mucin-3 (Tim-3) are considered as important immunosuppressive molecules and play an important role in tumor immune escape and cancer progression. However, it remains unclear whether PD-1 and Tim-3 are coexpressed in stage I-III colorectal cancer (CRC) and how they impact on the prognosis of the disease. MATERIALS AND METHODS: A total of two cohorts with 451 patients who underwent surgery for stage I-III CRC treatment were enrolled in the study. Among which, 378 cases were from The Cancer Genome Atlas (TCGA) database and 73 cases were from the Fourth Hospital of Hebei Medical University (FHHMU) cohort. The mRNA expressions of PD-1 and Tim-3 in tumor tissue in stage I-III CRC were obtained from TCGA database. Immunohistochemistry was used to assess the expressions of PD-1 and Tim-3 in tumor tissue in stage I-III CRC in the FHHMU cohort. Interactive relationships between PD-1 and Tim-3 were retrieved through the online STRING database, which was used to study the interactions between proteins. DAVID, consisting of comprehensive biological function annotation information, was applied for the GO and KEGG pathway enrichment analysis of the interactive genes. RESULTS: In the FHHMU cohort, the high expressions of PD-1 and Tim-3 were, respectively, found in 42.47% and 84.93% of stage I-III CRC tissue. PD-1 was significantly associated with age, primary site, and lymphatic metastasis. Tim-3 was closely related to the primary site. Correlation analysis showed that PD-1 and Tim-3 were positively correlated (r = 0.5682, P < 0.001). In TCGA cohort, PD-1 and Tim-3 were associated with the prognosis of CRC patients in terms of 5-year survival (P < 0.05). In the FHHMU cohort, the 5-year survival of patients with high levels of PD-1 and Tim-3 was 54.84% and 65.85%, respectively. Among which, the high expression of PD-1 was associated with poor prognosis (5-year OS: 54.84% vs. 88.10%, P = 0.003). The 5-year survival rate of CRC patients with coexpression of PD-1 and Tim-3 was 45.00%, which was significantly worse than non-coexpression (72.73%, 85.71%, and 90.48% separately). The functional network of PD-1 and Tim-3 primarily participates in the regulation of immune cell activation and proliferation, immune cell receptor complex, cell adhesion molecules, and T cell receptor signaling pathway. CONCLUSION: In summary, upregulation of PD-1 and Tim-3 in stage I-III CRC tumor tissue could be associated with the poor prognosis of patients. Those patients with coexpression of PD-1 and Tim-3 may have a significantly worse prognosis.

Gegen Qinlian decoction enhances immunity and protects intestinal barrier function in colorectal cancer patients via gut microbiota.

BACKGROUND: We previously showed, using the Traditional Chinese Medicine System Pharmacology Database, that Gegen Qinlian decoction (GQD) had a direct antitumor effect, and was combined with programmed cell death protein (PD)-1 inhibitors to treat microsatellite stable (MSS) tumor-bearing mice. However, the effect of GQD on patients with colorectal cancer (CRC) is not clear. AIM: To determine the therapeutic mechanism of GQD in improving immune function, reducing inflammation and protecting intestinal barrier function. METHODS: Seventy patients with CRC were included in this study: 37 in the control group and 33 in the treatment group. The proportions of CD4+ T, CD8+ T, natural killer (NK), NKT and T regulatory cells were measured by flow cytometry. Levels of the cytokines tumor necrosis factor (TNF)-α, interferon (IFN)-γ, interleukin (IL)-2, IL-6, IL-10 and serotonin (5-hydroxytryptamine; 5-HT) in serum were assessed by enzyme-linked immunosorbent assay (ELISA). The expression of zonula occludens (ZO)-1, occludin, nuclear factor (NF)-κB and TNF-α in tumor and normal tissues was measured by immunohistochemistry. The composition of gut microbiota from patients in the treatment group was assessed using 16S rDNA analysis. RESULTS: There were no adverse events in the treatment group. The proportion of CD4+ T cells and NKT cells in the post-treatment group was significantly higher than that in the pre-treatment and control groups (P < 0.05). The level of TNF-α in the post-treatment group was significantly lower than that in the pre-treatment and control groups (P < 0.05). The concentration of 5-HT in the post-treatment group was significantly lower than that in the pre-treatment group (P < 0.05). The expression of ZO-1 and occludin in tumor tissues in the treatment group was significantly higher than that in the control group (P < 0.05). The expression of ZO-1 in normal tissues of the treatment group was significantly higher than that in the control group (P = 0.010). Compared with the control group, expression of NF-κB and TNF-α in tumor tissues of the treatment group was significantly decreased (P < 0.05). Compared with the pre-treatment group, GQD decreased the relative abundance of Megamonas and Veillonella. In addition, GQD increased the relative abundance of Bacteroides, Akkermansia and Prevotella. CONCLUSION: GQD enhances immunity and protects intestinal barrier function in patients with CRC by regulating the composition of gut microbiota.

Gegen Qinlian decoction enhances the effect of PD-1 blockade in colorectal cancer with microsatellite stability by remodelling the gut microbiota and the tumour microenvironment.

Therapeutic antibodies targeting PD-1 have made major breakthroughs in cancer treatment. However, the majority of colorectal cancer (CRC) cases are microsatellite stable (MSS) and do not respond to anti-PD-1-based immunotherapy. Combination therapy will be an ideal strategy to overcome this limitation. Gegen Qinlian decoction (GQD), a classical traditional Chinese medicine (TCM) formula, has been clinically proven to be effective in the treatment of ulcerative colitis (UC) and type 2 diabetes mellitus. Here, a systemic pharmacological study revealed that GQD acts through multiple targets and pathways in the human body. Combination therapy with GQD and anti-mouse PD-1 potently inhibited the growth of CT26 tumours in a xenograft model. Gut microbiota analysis revealed that combination therapy with GQD and anti-mouse PD-1 significantly enriched for s__Bacteroides_acidifaciens and s__uncultured_organism_g__norank_f__Bacteroidales_S24-7_group. Based on metabolomic analyses, profoundly altered metabolites were identified in the combination therapy group. Two metabolic signalling pathways, namely, glycerophospholipid metabolism and sphingolipid metabolism, were explored. In particular, we found that combination therapy with GQD and anti-mouse PD-1 significantly increased the proportion of CD8+ T cells in peripheral blood and tumour tissues. Direct treatment with GQD and anti-mouse PD-1 increased the expression of IFN-γ, which is a critical factor in antitumour immunotherapy. In addition, combination therapy with GQD and anti-mouse PD-1 downregulated PD-1 and increased IL-2 levels, suggesting that the combination therapy could effectively restore T-cell functions by suppressing inhibitory checkpoints. The application of the Chinese medicinal formula GQD with PD-1 blockade-based immunotherapy can be a novel therapeutic strategy for CRC patients with MSS tumours.

Effect of the Chinese Medicine YangZheng XiaoJi on Reducing Fatigue in Mice with Orthotopic Transplantation of Colon Cancer.

BACKGROUND: Fatigue is a common, distressing, and persistent symptom for patients with malignant tumor including colorectal cancer (CRC). Although studies of cancer-related fatigue (CRF) have sprung out in recent years, the pathophysiological mechanisms that induce CRF remain unclear, and effective therapeutic interventions have yet to be established. METHODS: To investigate the effect of the traditional Chinese medicine YangZheng XiaoJi (YZXJ) on CRF, we constructed orthotopic colon cancer mice, randomly divided into YZXJ group and control (NS) group. Physical or mental fatigue was respectively assessed by swimming exhaustion time or suspension tail resting time. At the end of the experiment, serum was collected to measure the expression level of inflammatory factors by ELISA and feces to microbiota changes by 16s rDNA, and hepatic glycogen content was detected via the anthrone method. RESULT: The nutritional status of the YZXJ group was better than that of the control group, and there was no statistical difference in tumor weight. The swimming exhaustion times of YZXJ group and control group were (162.80 ± 14.67) s and (117.60 ± 13.42, P < 0.05) s, respectively; the suspension tail resting time of YZXJ group was shorter than that of the control group (49.85 ± 4.56) s and (68.83 ± 7.26) s, P < 0.05)). Serum levels of IL-1ß and IL-6 in YZXJ group were significantly lower than the control group (P < 0.05). Liver glycogen in YZXJ group was (5.18 ± 3.11) mg/g liver tissue, which was significantly higher than that in control group (2.95 ± 2.06) mg/g liver tissue (P < 0.05). At phylum level, increased abundance of Bacteroidetes, Verrucomicrobia, Actinobacteria, and Cyanobacteria and decreased Proteobacteria in YZXJ group emerged as the top differences between the two groups, and the Firmicutes/Bacteroidetes ratio was decreased in YZXJ group compared to the control group. At genus level, the abundance of Parabacteroides, unidentified Saprospiraceae, and Elizabethkingia which all belong to phylum Bacteroidetes were increased, while Arcobacter, Marinobacter, Alkanindiges, Sulfuricurvum, Haliangium, and Thiobacillus in phylum Proteobacteria were decreased after YZXJ intervention. YZXJ can also increase Pirellula, Microbacterium, and Alpinimonas and decrease Rubrobacter and Iamia. CONCLUSION: YZXJ may reduce the physical and mental fatigue caused by colorectal cancer by inhibiting inflammatory reaction, promoting hepatic glycogen synthesis, and changing the composition of intestinal microbiota.