RESUMEN
The insulin-like growth factor (IGF)-pathway is involved in tumor cell proliferation, metastasis, and survival. We aimed to find out what effects IGF binding protein 3 (IGFBP3) exerted on H1299 lung cancer (LC) cells in terms of tumor growth and invasion and whether IGFBP3 was associated with clinical and pathological parameters in a prospective cohort of LC patients. H1299 cells were transfected with an IGFBP3-expressing vector. Its influence on apoptosis induction via flow cytometry annexin V FITC assay, cell proliferation in 2D and 3D cell culture, and invasion were examined. Expression of several matrix metalloproteinases (MMPs) and inhibitors (TIMP-1) were also investigated in IGFBP3-transfected LC cells. Further, data on LC patients (n = 131), tumor characteristics, and survival were prospectively collected and correlated with IGFBP3 plasma levels. IGFBP3 did not influence apoptosis induction and 2D cell proliferation. However, both spheroid growth (3D proliferation) and invasion of IGFBP3-transfected cells planted in an extracellular matrix-based gel were significantly inhibited. IGFBP3 inhibited MMP-1 release, and the total MMP activity. In LC patients, higher IGFBP3 plasma levels correlated with both lower clinical tumor stage, grading, Ki-67 staining, and the absence of necrosis (P < 0.05, respectively). Increased IGFBP3 plasma levels were associated with improved overall survival (hazard ratio 0.37, P = 0.01). In conclusion, overexpressed IGFBP3 in a LC cell line inhibited tumor growth and invasion. Translating from bench to bedside, investigation of clinicopathological parameters confirmed these experimental results showing that higher IGFBP3 plasma levels were associated with less aggressive tumor growth, reduced tumor spread, and improved survival of LC patients.
RESUMEN
OBJECTIVES: Confirming the prognostic value of global QFR and evaluating the long-term prognosis of QFR-concordant therapy in stable coronary artery disease. BACKGROUND: Wire-based functional evaluation of coronary disease is linked to patient's prognosis. Quantitative Flow Ratio (QFR) is a newer index of computational physiology, linked to clinical outcomes and prognosis at 1 year follow-up. Long-term prognosis of QFR-concordant revascularization in stable coronary artery disease is however unknown hitherto. METHODS: Consecutive patients with stable coronary disease undergoing coronary angiography were included. Centralized and blinded QFR analysis of three coronary territories was performed. Three vessel QFR (3vQFR) was defined as the sum of the basal QFR of each coronary territory. QFR-concordant revascularization was met if all significant lesions (QFR ≤ 0.80) were revascularized and all non-significant lesions (QFR > 0.80) were not; otherwise, the case was defined as QFR-discordant revascularization. Patient-oriented composite end-point (POCE) of cardiac death, myocardial infarction and unscheduled revascularization was the primary endpoint. RESULTS: A total of 803 patients from six high-volume centers were included. Canadian Cardiovascular Society (CCS) class II angina was the most frequent (48.9%) clinical presentation. Median of follow-up was 68.8 months. 3vQFR was an independent predictor of POCE (HR 1.79 CI95% 1.01-3.18), with 2.75 as optimal cut-off value, irrespective of the therapy received. QFR-discordant revascularization (QFR+/Revascularization- or QFR-/Revascularization+) was an independent predictor of POCE in multivariate analysis (HR 1.65, CI 95% 1.03-2.64). CONCLUSION: Global burden of epicardial coronary atherosclerosis, as evaluated by 3vQFR, as well as QFR-discordant therapy are independent predictors of adverse clinical outcome at long-term follow-up in stable coronary artery disease.