Better performance of PIVKA-II for detecting hepatocellular carcinoma in patients with chronic liver disease with normal total bilirubin.

BACKGROUND: Serum protein induced by vitamin K absence or antagonist-II (PIVKA-II) is a promising biomarker for hepatocellular carcinoma (HCC) surveillance. AIM: To identify the contributing factors related to the abnormal elevation of PIVKA-II level and assess their potential influence on the performance of PIVKA-II in detecting HCC. METHODS: This study retrospectively enrolled in 784 chronic liver disease (CLD) patients and 267 HCC patients in Mengchao Hepatobiliary Hospital of Fujian Medical University from April 2016 to December 2019. Logistic regression and the area under the receiver operating characteristic curve (AUC) were used to evaluate the influencing factors and diagnostic performance of PIVKA-II for HCC, respectively. RESULTS: Elevated PIVKA-II levels were independently positively associated with alcohol-related liver disease, serum alkaline phosphatase (ALP), and total bilirubin (TBIL) for CLD patients and aspartate aminotransferase (AST) and tumor size for HCC patients (all P < 0.05). Serum PIVKA-II were significantly lower in patients with viral etiology, ALP ≤ 1 × upper limit of normal (ULN), TBIL ≤ 1 × ULN, and AST ≤ 1 × ULN than in those with nonviral disease and abnormal ALP, TBIL, or AST (all P < 0.05), but the differences disappeared in patients with early-stage HCC. For patients with TBIL ≤ 1 × ULN, the AUC of PIVKA-II was significantly higher compared to that in patients with TBIL > 1 × ULN (0.817 vs 0.669, P = 0.015), while the difference between ALP ≤ 1 × ULN and ALP > 1 × ULN was not statistically significant (0.783 vs 0.729, P = 0.398). These trends were then more prominently perceived in subgroups of patients with viral etiology and HBV alone. CONCLUSION: Serum PIVKA-II has better performance in detecting HCC at an early stage for CLD patients with normal serum TBIL.

Effective expansion of forkhead box P3⁺ regulatory T cells via early secreted antigenic target 6 and antigen 85 complex B from Mycobacterium tuberculosis.

The expansion of CD4+ CD25+ forkhead box (FOX)P3+ regulatory T (Treg) cells has been observed in patients with Mycobacterium (M.) tuberculosis; however, the mechanism of expansion remains to be elucidated. The aim of the present study was to examine the role of the early secreted antigenic target 6(ESAT­6) and antigen 85 complex B (Ag85B) from M. tuberculosis on Treg cell expansion. To investigate the sensitivity of peripheral blood cultures to the M. tuberculosis ESAT­6 and Ag85B antigens, the proportion of circulating CD4+ CD25+ FOXP3+ Treg cells was determined using flow cytometry and the levels of FOXP3 mRNA were determined using reverse transcription quantitative polymerase chain reaction. The mRNA levels of FOXP3 and the proportion of circulating CD4+ CD25+ FOXP3+ Treg cells were increased in multiplicitous drug­resistant tuberculosis patients compared with those in healthy controls and patients with latent tuberculosis (TB) infection (LTBI) (P<0.001). The mycobacterial antigens ESAT­6 and Ag85B increased the expansion of the CD4+ CD25+ FOXP3+ Treg cells and the mRNA levels of FOXP3 in healthy controls and LTBI patients compared with the effect of Bacillus Calmette­Guerin (P<0.05). Additionally, the mRNA levels of FOXP3 were elevated in the LTBI patients following stimulations with the mycobacterial antigens (P=0.012). Therefore, the M. tuberculosis antigens ESAT­6 and Ag85B induced CD4+ CD25+ FOXP3+ Treg­cell expansion, particularly in patients with LTBI. These findings indicated that CD4+ CD25+ FOXP3+ Treg cells may have a primary role in the failure of the host immune system to eradicate M. tuberculosis.

Decrease in CD4+CD25+FoxP3+ Treg cells after pulmonary resection in the treatment of cavity multidrug-resistant tuberculosis.

OBJECTIVES: Immune regulatory mechanisms may limit the immunopathologic condition of infection with Mycobacterium tuberculosis and suppress cellular immune responses in the host. We investigated the CD4(+)CD25(+)FoxP3(+) circulating regulatory T cells (T(reg)) in patients with cavity multidrug-resistant tuberculosis (MDR-TB) before and after surgery. METHODS: We compared the proportion of T(reg) cells in 13 patients with cavity MDR-TB pre- and postoperatively and in 10 healthy control subjects by flow cytometry using three specific markers in peripheral blood lymphocytes: cell-surface CD4 and CD25 expression and intracellular FoxP3 expression. RESULTS: The proportion of CD4(+)CD25(high) and CD4(+)CD25(+)FoxP3(+) T(reg) was significantly higher in patients with cavity MDR-TB and at 1-month postoperatively than in healthy controls (p<0.001). The proportion of CD4(+) and CD4(+)CD25(-) cells was significantly lower in patients with cavity MDR-TB than in controls (p<0.001). Pre- and postoperative proportions of CD4(+)CD25(high) and CD4(+)CD25(+)FoxP3(+) T(reg) cells showed a positive correlation (r=0.878, p<0.001). CONCLUSION: Circulating T(reg) cells are increased in proportion in patients with cavity MDR-TB and decreased after surgery. Infection with M. tuberculosis may induce T(reg) cell-surface molecular changes with increased numbers of cells.