ABSTRACT
Immunotherapy using immune checkpoint inhibitors has demonstrated durable responses and has significantly improved survival in patients with non-small cell lung cancer (NSCLC). Moreover, immunotherapy is increasingly used in combination with cytotoxic treatments such as chemotherapy and radiotherapy. Although the combined treatments are more effective, the underling mechanisms that lead to higher antitumor activity are not fully understood. Therefore, the aim of the current retrospective study was to determine the relationship between expression of immune checkpoints [programmed cell death protein 1 (PD-1) and programmed death-ligand 1 (PD-L1)] and the enzyme DNA-dependent protein kinase (DNA-PK), which is part of a key pathway involved in the repair of cytotoxic cancer therapy induced damage. Surgically excised NSCLC tissues (n=121) were histologically examined for overall extent of inflammation (score 0-3). Expression levels of PD-1 (number of PD-1 positive cells), PD-L1 [tumor proportion score (TPS); %] and DNA-PK (proportion of DNA-PK positive tumor cells; %) were determined using immunohistochemistry. Expressions of these markers were compared in different clinicopathological subgroups and later used for nonparametric Spearman correlation analysis to determine associations. In patients with NSCLC, PD-1 was significantly expressed in males (P=0.030) and in patients with no or trivial inflammation scores (P=0.030). PD-L1 expression was also significantly higher in current smokers (P=0.025). Correlation analysis was based on the individual values of patients and revealed a significant association between one of the targets of immune checkpoint inhibitors and tumor cell DNA-PK. Tumors with higher numbers of PD-1 positive cells also demonstrated higher tumor cell DNA-PK expressions (P=0.027). The results demonstrated a significant positive correlation between the PD-1/PD-L1 axis and tumor cell DNA-PK expression in patients with NSCLC. Further studies are required to clarify the significance of this correlation and its effect on the efficacy of immunotherapy and cytotoxic cancer therapy combinations.
ABSTRACT
PURPOSE: The purpose of the study is to clarify whether increased intra-abdominal pressure (IAP) is associated with sublingual microcirculatory alterations in intensive care patients. METHODS: Fifteen adult, mechanically ventilated patients were included if their IAP was at least 12 mm Hg for at least 12 hours within the first 3 days after admission to the intensive care unit. Sublingual sidestream dark field (SDF) images were recorded twice a day for 7 days. RESULTS: Median (interquartile range) IAP at inclusion was 14.5 (12.5-16.0) mm Hg. The total vascular density of small vessels at the sublingual area was 13.1 (10.6-14.3) per square millimeter at baseline; the proportion of perfused vessels, 78.9% (69.6%-86.2%); and perfused vessels density, 12.4 (10.8-13.8) per square millimeter. The calculated indices suggested relatively good blood flow in the capillaries, with a De Backer score of 9.0 (8.3-10.2) and a microvascular blood flow of 3.0 (2.9-3.0). Blood flow heterogeneity index was 0.3 (0.1-0.5) at study entry. Despite that IAP, vasopressors dose, and arterial lactate decreased significantly over time, no significant changes were observed in sublingual microvascular density or blood flow. Weak correlations of microvascular blood flow (positive) and heterogeneity index (negative) were detected with both mean arterial pressure and abdominal perfusion pressure. CONCLUSIONS: Neither grade I or II intra-abdominal hypertension (IAP from 12 to 18 mm Hg) is associated with significant changes of sublingual microcirculation in intensive care patients. Correlation analysis indicates better microvascular blood flow at higher mean arterial pressure and abdominal perfusion pressure levels.
