Factors associated with serum IgM concentrations: a general adult population study.

BACKGROUND AND AIM: To investigate the influence of common factors on serum immunoglobulin M (IgM) concentrations in adults, and clinical associations with high and low values. METHODS: We measured serum IgM levels using immunonephelometry in a random sample of 1510 individuals (aged 18-91 years, 44.7% male). We obtained data defining metabolic syndrome from all participants, defined atopy by skin prick tests to aeroallergens, and assessed lifestyle factors by questionnaire. RESULTS: Women showed higher IgM concentrations than men; 95 (6.3%, mostly male) individuals showed low (<0.40 g/L) IgM values, and 64 (4.2%, mostly female) showed high (>2.30 g/L) IgM values. Individuals with abnormal IgM concentrations had no history of opportunistic infections nor a different atopy prevalence. Serum IgM concentrations decreased with age, and obesity was negatively associated with IgM concentrations. Alcohol consumption, smoking, physical activity, and metabolic syndrome had no significant influence in the multivariate analyses. CONCLUSIONS: Many adults in the general population show abnormally high or low IgM concentrations with no evidence of immunodeficiency-associated diseases. Sex and age should be considered when defining reference IgM concentrations.

Evaluation of the safety and effectiveness of oral propranolol in patients with von Hippel-Lindau disease and retinal hemangioblastomas: phase III clinical trial.

BACKGROUND: von Hippel-Lindau disease (VHL) is a multisystem cancer syndrome caused by mutations in the VHL gene. Retinal hemangioblastoma is one of the most common tumours, and when it appears near the optic nerve, its treatment is challenging and risky. To date, no treatment has proven effective in changing the course of the disease. This study was designed to evaluate the safety and effectiveness of propranolol in controlling these tumours. METHODS: Seven patients were included. All patients took a daily dose of 120 mg of propranolol for 1 year. Clinical variables were assessed at baseline, and at 1, 3, 6, 9 and 12 months. The primary endpoint of the study was the number and size of retinal hemangioblastomas. On every visit, retinal outcomes and blood biomarkers (such as vascular endothelial growth factor (VEGF) and miR210) were analysed. RESULTS: Number and size of retinal hemangioblastomas remained stable in all patients. All of them had initially increased levels of VEGF and miR210. There was a gradual reabsorption of retinal exudation in two patients, correlating with a progressive decrease of both biomarkers. The only adverse effect reported was hypotension in one patient. CONCLUSIONS: Propranolol could be used to treat retinal hemangioblastomas in VHL patients, although more studies are needed to determine the ideal dose and long-term effect. VEGF and miR210 should be explored as biomarkers of disease activity. As far as we know, these are the first biomarkers proposed to monitor the VHL disease activity. TRIAL REGISTRATION NUMBER: 2014-003671-30.

Repurposing propranolol as a drug for the treatment of retinal haemangioblastomas in von Hippel-Lindau disease.

BACKGROUND: Von Hippel-Lindau (VHL) disease is a rare oncological disease with an incidence of 1:36,000, and is characterized by the growth of different types of tumours. Haemangioblastomas in the central nervous system (CNS) and retina, renal carcinoma and pheochromocytomas are the most common tumours. The absence of treatment for VHL leads to the need of repeated surgeries as the only option for these patients. Targeting VHL-derived tumours with drugs with reduced side effects is urgent to avoid repeated CNS surgeries. Recent reports have demonstrated that propranolol, a ß-blocker used for the treatment of hypertension and other cardiac and neurological diseases, is the best option for infantile hemangioma (IH). Propranolol could be an efficient treatment to control haemangioblastoma growth in VHL disease given its antiangiogenic effects that were recently demonstrated by us. The main objective of the present study was the assessment of the efficacy and safety of propranolol on retinal haemangioblastoma in von Hippel-Lindau disease (VHL). METHODS: 7 VHL patients, from different regions of Spain, affected from juxtapapillary or peripheral haemangioblastomas were administered 120 mg propranolol daily. Patients were evaluated every 3 months for 12 months, at Virgen de la Salud Hospital (Toledo). The patients had juxtapapillary or peripheral haemangioblastomas but had refused standard treatments. RESULTS: Propranolol was initiated with a progressive increase up to a final dose of 120 mg daily. All tumours remained stable, and no new tumours appeared. The reabsorption of retinal exudation was noted in the two patients having exudates. No adverse effects were recorded. VEGF and miRNA 210 levels were monitored in the plasma of patients as possible biomarkers of VHL. These levels decreased in all cases from the first month of treatment. CONCLUSIONS: Although more studies are necessary, the results of this work suggest that propranolol is a drug to be considered in the treatment of VHL patients with retinal haemangioblastomas. VEGF and miRNA 210 could be used as biomarkers of the VHL disease activity. TRIAL REGISTRATION: The study has a clinical trial design and was registered at EU Clinical Trials Register and Spanish Clinical Studies Registry, EudraCT Number: 2014-003671-30 . Registered 2 September 2014.