RESUMO
AIM: To provide a comprehensive and more representative national data on the disease, especially on treatment options and outcomes, and to determine access of retinoblastoma patients from Luzon, Visayas and Mindanao to eye care, and determine if access is associated with delay in consultation, staging and outcomes. METHODS: Cohort study of retinoblastoma patients seen in eleven institutions located in the three major areas of the Philippines namely Luzon, Vizayas and Mindanao from 2010-2020. RESULTS: Totally 636 patients, involving 821 eyes, were included. Majority (57%) were from Luzon and were seen in institutions in Luzon (72%). Annually, 58±10 new cases were seen with 71% having unilateral disease. Median delay of consultation remained long at 9 (3, 17)mo, longest in patients with unilateral disease (P<0.02) and those from the Visayas (P<0.003). Based on the International Retinoblastoma Staging System, only 35% of patients had Stage 1 while 47% already had extraocular disease. Enucleation was the most common treatment received by 484 patients while intravenous chemotherapy was received by 469. There were 250 (39%) patients alive, 195 (31%) dead, 85 (13%) abandoned, 17 (3%) refused and 89 (14%) with no data. CONCLUSION: This study presents the largest cohort of retinoblastoma patients in the Philippines in terms of patients' and participating institutions' number and geographical location and type of institution (private and public). It also presents more comprehensive data on the treatments used and outcomes (survival, globe salvage, and vision retention rates). Delay in consultation was still long among patients leading to advanced disease stage and lower survival rate. Despite increasing capacity to diagnose and manage retinoblastoma in the country, the delay of consultation remains long primarily due to accessibility issues to eye care institutions especially in the Visayas and financial concerns. The delay was still significant that overall survival rate remain low.
RESUMO
Hypoxia leading to stabilization of hypoxia-inducible factor 1α (HIF-1α) serves as an early upstream initiator for adipose tissue (AT) dysfunction. Monocyte-derived macrophage infiltration in AT contributes to inflammation, fibrosis and obesity-related metabolic dysfunction. It was previously reported that myeloid cell-specific deletion of Hif-1α protected against high-fat diet (HFD)-induced AT dysfunction. Prolyl hydroxylases (PHDs) are key regulators of HIF-1α. We examined the effects of myeloid cell-specific upregulation and stabilization of Hif-1α via deletion of prolyl-hydroxylase 2 (Phd2) and whether interleukin-1 receptor associated kinase-M (Irak-M), a known downstream target of Hif-1α, contributes to Hif-1α-induced AT dysfunction. Our data show that with HFD, Hif-1α and Irak-M expressions were increased in the AT macrophages of Phd2flox/flox/LysMcre mice compared with LysMcre mice. With HFD, Phd2flox/flox/LysMcre mice exhibited increased AT inflammation, fibrosis, and systemic insulin resistance compared with control mice. Furthermore, Phd2flox/flox/LysMcre mice bone marrow-derived macrophages exposed to hypoxia in vitro also had increased expressions of both Hif-1α and Irak-M. In wild-type mice, HFD induced upregulation of both HIF-1a and Irak-M in adipose tissue. Despite equivalent expression of Hif-1α compared with wild-type mice, globally-deficient Irak-M mice fed a HFD exhibited less macrophage infiltration, decreased inflammation and fibrosis and improved glucose tolerance. Global Irak-M deficiency was associated with an alternatively-activated macrophage phenotype in the AT after HFD. Together, these data show for the first time that an Irak-M-dependent mechanism likely mediates obesity-related AT dysfunction in conjunction with Hif-1α upregulation.
