ABSTRACT
BACKGROUND: Tumor-infiltrating lymphocytes (TILs) constitute a prognostic factor in hepatocellular carcinoma (HCC). However, different methods of assessing TILs have various pre-analytical, analytical, and post-analytical challenges. The evaluation of TILs in hematoxylin and eosin (H&E)-stained tumor sections proposed by the International Immuno-Oncology Biomarker Working Group was demonstrated to be a reproducible, affordable and easily applied method in many tumors. AIM: To evaluate the prognostic significance of TILs in H&E-stained slides of HCCs. METHODS: This was a retrospective study performed in the hospital. HCC patients who underwent liver resection between 2015 and 2017 in Zhongshan Hospital were enrolled in this study. Patients who experienced recurrence or received therapy in addition to antiviral therapy before surgery at this time were excluded. A total of 204 patients were enrolled in the study. The ILs were counted manually in tumor sections stained with H&E under an optical microscope at 400 ×. The ILs were assessed separately in the center of the tumor (TILsCT), the invasive front (TILsIF), and peritumor (PILs) areas. Univariate and multivariate survival analyses were performed using a Cox regression model. P < 0.05 was considered statistically significant and all P-values were two-sided. RESULTS: Among the 204 patients, univariate analysis indicated that macrovascular invasion (MaVI) (P = 0.001), microvascular invasion (MVI) (P = 0.012), multiple tumors (P = 0.008), large tumors (> 10 cm) (P = 0.001), absence of a tumor capsule (P = 0.026), macrotrabecular histological subtype (P = 0.001), low density of TILsCT (P = 0.039), TILsIF (P = 0.014), and PILs (P = 0.010) were predictors of progression-free survival (PFS). Cox multivariate analysis indicated that MaVI (P = 0.009), absence of a tumor capsule (P = 0.031), low-density of TILsIF (P = 0.047) and PILs (P = 0.0495) were independent predictors of PFS. A three-category analysis was carried out by combining TILsCT, TILsIF, and PILs, after which HCCs were classified into immunehigh [(TILsCT)high, (TILsIF)high, and PILshigh, 83 cases], immunemod (tumors other than immunehigh and immunelow subtypes, 94 cases), and immunelow [(TILsCT)low, (TILsIF)low, and PILslow, 27 cases)] subtypes. The immunehigh subtype had a lower rate of MVI (40.96%) than the immunemod (61.70%, P = 0.017) and immunelow (66.67%, P = 0.020) subtypes. The recurrence rates of the immunehigh, immunemod and immunelow subtypes were 10.8%, 25.5% and 33.3%, respectively. CONCLUSION: HCC patients with high infiltrating lymphocytes tend to have a lower recurrence rate and less MVI. The evaluation of TILs in H&E-stained specimens could be a prognostic parameter for HCC.
ABSTRACT
Considering the vital role of mitochondria in the anti-cancer mechanism of organic arsenical, the mitochondria-targeted precursor PDT-PAO-TPP was designed and synthesized. PDT-PAO-TPP, as a delocalization lipophilic cation (DLCs) which mainly accumulated in mitochondria, contributed to improve anti-cancer efficacy and selectivity towards NB4 cells. In detail, PDT-PAO-TPP inhibited the activity of PDHC resulting in the suppression of ATP synthesis and thermogenesis disorder. Additionally, the inhibition of respiratory chain complex I and IV by short-time incubation of PDT-PAO-TPP also accelerated the respiration dysfunction and continuous generation of ROS. These results led to the release of cytochrome c and activation of caspase family-dependent apoptosis. Different from the mechanism of PDT-PAO in HL-60 cells, it mainly induced the mitochondrial metabolic disturbance resulting in the intrinsic apoptosis via inhibiting the activity of PDHC in NB4 cells, which also implied that the efficacy exertion of organic arsenical was a complex process involved in many aspects of cellular function. This study systematically clarifies the anti-cancer mechanism of mitochondria-targeted organic arsenical PDT-PAO-TPP and confirms the new target PDHC of organic arsenicals, which further supports the organic arsenical as a promising anticancer drug.
