Background Mesenchymal circulating tumor cells (M-CTCs) may be related to tumor progression, and Ki67 expression is known to be involved in tumor proliferation. The aim of the present study was to explore the relationship between M-CTCs and Ki67 in hepatocellular carcinoma (HCC) and their ability to predict prognosis. Methods Peripheral blood samples were obtained from 105 HCC patients before radical surgery. CTCs were isolated using CanPatrol enrichment and classified via in situ hybridization. Ki67 expression in HCC tissue was assessed through immunohistochemistry. Potential relationships of M-CTC, Ki67 with clinicopathological factors and prognosis were evaluated. Overall survival (OS) was analyzed using the Kaplan–Meier method and Cox regression. The prognostic efficacy of M-CTC, Ki67 and both together (M-CTC + Ki67) was assessed in terms of time-dependent receiver operating characteristic (ROC) curves and Harrell's concordance index. Results Of the 105 patients, 50 were positive for M-CTCs (count ≥ 1 per 5 mL) and 39 showed high Ki67 expression (≥ 50% tumor cells were Ki67-positive). The presence of M-CTC was significantly associated with alpha-fetoprotein (AFP) ≥ 400 ng/mL (P = 0.007), tumor size ≥ 5 cm (P = 0.023), multiple tumors (P < 0.001), poorly differentiated tumors (P = 0.003), incomplete tumor capsule (P < 0.001), Barcelona Clinic liver cancer (BCLC) stage B or C (P < 0.001), microvascular invasion (MVI) (P = 0.05) and portal vein tumor thrombosis (PVTT) (P = 0.006). High Ki67 expression correlated with AFP ≥ 400 ng/mL (P = 0.015), tumor size ≥ 5 cm (P = 0.012), incomplete tumor capsule (P < 0.001), MVI (P = 0.001), PVTT (P = 0.003), advanced BCLC stage (P = 0.01), and vessel carcinoma embolus (VCE) (P = 0.001). M-CTC positively correlated with Ki67. Patients positive for M-CTCs had a significantly shorter OS than patients negative for them. Similarly, high Ki67 expression was associated with a significantly lower OS. The high-risk group (positive for M-CTCs and high Ki67 expression) had worse OS than the other groups (P < 0.0001). Uni- and multivariate analyses showed that OS was independently predicted by M-CTC [hazard ratio (HR) 1.115; P < 0.001], Ki67 (HR 1.666; P = 0.046) and the combination of both (HR 2.885; P = 0.008). Based on ROC curves and the concordance index, the combination of M-CTC and Ki67 was superior to either parameter alone for predicting the OS of HCC patients. Conclusions The presence of M-CTC correlates with high Ki67 expression in HCC patients, and both factors are associated with poor prognosis. Furthermore, the combination of M-CTC and Ki67 is a useful prognostic indicator for predicting OS in patients with HCC after hepatectomy, performing better than either parameter on its own.
Purpose Recent studies indicated the vital role of platelet in enhancing the survival of circulating tumor cells (CTCs) in the blood, thereby stimulating the metastasis of tumors. CTCs have been considered an indicator of early tumor recurrence. Therefore, this study evaluated the prognostic potential of platelet count in predicting the early recurrence of hepatocellular carcinoma (HCC) in the presence of CTCs. Patients and Methods 127 patients, whose preoperative CTCs were detected, were enrolled in this study. Univariate analysis was performed to identify the significant association of factors with the early recurrence of HCC, followed by multivariate analysis to determine the independent prognostic indicators. The prediction potential was evaluated using receiver operating characteristic (ROC) curves. Results A total of 81 (63.7%) patients showed early HCC recurrence. The platelet count ≥225×10 9 /L (hazard ratio, HR: 1.679, P = 0.041), CTCs >5/5 mL (HR: 2.467, P = 0.001), and presence of microvascular invasion (MVI) (HR: 2.580, P = 0.002) were independent factors correlated with the early recurrence of HCC in multivariate analysis. The prognostic potential of the combined CTCs-platelet count (0.738) was better than that of CTCs (0.703) and platelet (0.604) alone. The subgroup analysis, excluding 23 patients with pathological cirrhosis and splenomegaly, showed that the platelet count ≥225×10 9 /L and CTCs >5/5 mL were also independent factors of early HCC recurrence. The prediction potential of the combined CTCs-platelet count was 0.753, which was better than that of the whole cohort. Kaplan–Meier survival curve analysis indicated that the HCC patients with high platelet or CTCs had the worse recurrence-free survival (RFS). Conclusion The high platelet count was an independent factor of early HCC recurrence in the presence of CTCs. The combination of preoperative CTCs and platelet count could effectively predict the early recurrence of HCC. The subgroup analysis also showed similar results.
The study aimed to investigate the ability of inflammation-immunity-nutrition score (IINS) and inflammatory burden index (IBI), individually or in combination, to predict prognosis of hepatocellular carcinoma (HCC) patients after hepatectomy. Methods: A total of 701 patients who underwent HCC resection at Guangxi Medical University Cancer Hospital were enrolled in the study. An IINS ranging from 0 to 3 was defined based on preoperative C-reactive protein (CRP), lymphocyte count, and serum albumin level, while an IBI was based on CRP and neutrophil-to-lymphocyte ratio. The prognostic value of IINS and IBI was assessed using univariate and multivariate Cox regression and Kaplan-Meier survival curves. The concordance index and calibration curve were used for internal validation of models. Decision curve analysis, net reclassification index and integrated discrimination improvement were used to compare the predictive performance of the models with traditional staging systems. Results: IINS and IBI were able to predict poor prognosis in HCC patients after hepatectomy, and a nomogram based on the IINS predicted survival at 1, 3, and 5 years better than other models or traditional staging systems. Conclusion: IINS may be accurate predictors of survival in HCC patients after hepatectomy, with potentially greater prognostic value than conventional markers.
Purpose Cytokeratin 19-positive cancer stem cells (CK9 + CSCs) and their tumor-associated macrophages (TAMs) have not been fully explored yet in the hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC). Experimental Design: Single-cell RNA sequencing was performed on the viable cells obtained from 11 treatment-naïve HBV-associated HCC patients, including 8 CK19 + patients, to elucidate their transcriptomic landscape, CK19 + CSC heterogeneity, and immune microenvironment. Two in-house primary HCC cohorts (96 cases-related HBV and 89 cases with recurrence), multiple external cohorts, and in vitro and in vivo experiments were used to validate the results. Results A total of 64,581 single cells derived from the human HCC and adjacent normal tissues were sequenced, and 11 cell types were identified. The result showed that CK19 + CSCs were phenotypically and transcriptionally heterogeneous, co-expressed multiple hepatics CSC markers, and were positively correlated with worse prognosis. Moreover, the SPP1 + TAMs (TAM_SPP1) with strong M2-like features and worse prognosis were specifically enriched in the CK19 + HCC and promoted tumor invasion and metastasis by activating angiogenesis. Importantly, matrix metalloproteinase 9 (MMP9) derived from TAM_SPP1, as the hub gene of CK19 + HCC, was activated by the VEGFA signal. The patients with low TAM_SPP1 enrichment might benefit from trans-arterial chemoembolization. Conclusions This study revealed the heterogeneity and stemness characteristics of CK19 + CSCs and specific immunosuppressive TAM_SPP1 in CK19 + HCC. The VEGFA signal can activate TAM_SPP1-derived MMP9 to promote the invasion and metastasis of CK19 + HCC tumors. This might provide novel insights into the clinical treatment of HCC patients.
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