Inna Kalickman

Prevalence of Hypophosphatemia in Sepsis and Infection: The Role of Cytokines ☆

BACKGROUND Sepsis occurs following the presence of bacteria in the circulation and is associated with fever, hyperthermia, and hypotension. Hypophosphatemia develops in the early stages of sepsis. High levels of inflammatory cytokines also characterize early sepsis. AIM The aim of the present study was to correlate hypophosphatemia with cytokines and cytokine receptor levels during early sepsis. We aimed to reestablish the results obtained from patients in an in vivo experimental model, in order to understand the mechanism of hypophosphatemia induction in early sepsis. METHODS Ninety-nine patients were enrolled in this study and their clinical condition was classified as the presence of infection, sepsis, and bacterial growth in blood cultures. Phosphate levels and cytokine levels were recorded. In order to determine whether hypophosphatemia is correlated to the increased inflammatory cytokines, we injected normal mice with recombinant cytokines and studied their effect on phosphate levels. RESULTS Our results revealed that 80% of the septic patients had hypophosphatemia associated with very high levels of tumor necrosis factor (TNF)alpha and interleukin (IL)-6 and of soluble IL receptor (sIL)-2R and IL-6R, especially in those patients with positive blood cultures. Injection of IL-6, TNFalpha and IL-1beta in mice markedly decreased the phosphate serum levels. CONCLUSIONS Significant associations were demonstrated between high levels of inflammatory cytokines and their receptors and between serum phosphate levels, especially in patients with positive blood culture. Our results point to a correlation between the high inflammatory cytokines levels and hypophosphatemia during early sepsis. Cytokine levels and hypophosphatemia may be included in sepsis evaluation and prognosis. Anticytokine strategies might, therefore, reverse hypophosphatemia and other parameters of sepsis.

VEGF as a Biomarker for Metastatic Uveal Melanoma in Humans

PURPOSE High levels of serum VEGF have been reported in many types of cancers, especially in the metastatic stage. The aim of this study was to examine the potential of VEGF serum level as a tumor marker for metastases in uveal melanoma (UM) patients. MATERIALS AND METHODS Levels of serum VEGF were analyzed by ELISA for 23 UM patients (none of whom developed metastases within 5 years from diagnosis) at the time of diagnosis, soon after treatment, and 3 years later, and compared with serum VEGF levels of 39 metastatic patients, 58 10-year disease-free (10yDF) patients, and 23 healthy subjects. VEGF ratios were calculated per patient between diagnosis and after treatment, and between diagnosis and 3 years later. Matched pairs univariate analysis was performed for 17 metastatic patients for whom sera were available from before and after the diagnosis of metastases. Patients were followed biannually with liver ultrasonography and liver function tests for the presence of metastases. RESULTS The inter-patient VEGF level range was large (e.g., the range for the metastatic patients was 46-1892 pg/ml). The mean ± SD levels for the control, 10yDF, and metastatic groups were: 329.65 ± 190.0, 407.66 ± 261.9 and 453.52 ± 270.2, respectively (p = 0.2456). The mean VEGF level ratio from after treatment to diagnosis was 1.08 (p = 0. 0024), and the ratio from 3 years after diagnosis to diagnosis was 1.53 (p = 0.0009). The mean ± SE post/premetastatic levels ratio was 1.35 ± 0.21 (p = 0.0595). CONCLUSIONS Serum VEGF increased significantly after metastases developed. However, the wide inter-patient variance precludes the use of any cut-off level to determine the metastatic status of an individual patient based on a single VEGF serum level. An increase in VEGF on serial measurements may indicate the development of metastases. Further investigation is warranted to assess VEGFs value as a predictive marker for metastatic disease.