A high angiopoietin-2/angiopoietin-1 ratio is associated with a high risk of septic shock in patients with febrile neutropenia.

INTRODUCTION: Endothelial barrier breakdown is a hallmark of septic shock, and proteins that physiologically regulate endothelial barrier integrity are emerging as promising biomarkers of septic shock development. Patients with cancer and febrile neutropenia (FN) present a higher risk of sepsis complications, such as septic shock. Nonetheless, these patients are normally excluded or under-represented in sepsis biomarker studies. The aim of our study was to validate the measurement of a panel of microvascular permeability modulators as biomarkers of septic shock development in cancer patients with chemotherapy-associated FN. METHODS: This was a prospective study of diagnostic accuracy, performed in two distinct in-patient units of a university hospital. Levels of vascular endothelial growth factor A (VEGF-A), soluble fms-like tyrosine kinase-1 (sFlt-1) and angiopoietin (Ang) 1 and 2 were measured after the onset of neutropenic fever, in conditions designed to mimic the real-world use of a sepsis biomarker, based on our local practice. Patients were categorized based on the development of septic shock by 28 days as an outcome. RESULTS: A total of 99 consecutive patients were evaluated in the study, of which 20 developed septic shock and 79 were classified as non-complicated FN. VEGF-A and sFlt-1 levels were similar between both outcome groups. In contrast, Ang-2 concentrations were increased in patients with septic shock, whereas an inverse finding was observed for Ang-1, resulting in a higher Ang-2/Ang-1 ratio in patients with septic shock (5.29, range 0.58 to 57.14) compared to non-complicated FN (1.99, range 0.06 to 64.62; P = 0.01). After multivariate analysis, the Ang-2/Ang-1 ratio remained an independent factor for septic shock development and 28-day mortality. CONCLUSIONS: A high Ang-2/Ang-1 ratio can predict the development of septic shock in cancer patients with febrile neutropenia.

Validation of the EBMT risk score in chronic myeloid leukemia in Brazil and allogeneic transplant outcome.

BACKGROUND AND OBJECTIVES: The management of chronic myeloid leukemia (CML) has changed radically since the introduction of imatinib therapy. The decision of whether to offer a patient a hematopoietic stem cell transplant (HSCT) must be based on the probability of success of the procedure. The aim of this retrospective analysis of 1,084 CML patients who received an allogeneic HSCT in 10 Brazilian Centers between February 1983 and March 2003 was to validate the EBMT risk score. DESIGN AND METHODS: The study population comprised 647 (60%) males and 437 (40%) females, with a median age of 32 years old (range 1 - 59); 898 (83%) were in chronic phase, 146 (13%) were in accelerated phase and 40 (4%) were in blast crisis; 151 (14%) were younger than 20 years old, 620 (57%) were between 20 and 40 and 313 (29%) were older than 40; 1,025 (94%) received an HLA fully matched sibling transplant and only 59 (6%) received an unrelated transplant. In 283 cases (26%) a male recipient received a graft from a female donor. The interval from diagnosis to transplantation was less than 12 months in 223 (21%) cases and greater in 861 (79%). The overall survival, disease-free survival, transplant-related mortality and relapse incidence were 49%, 50%, 45% and 25%, respectively. RESULTS: Of the 1084 patients, 179 (17%) had a risk score of 0 or 1, 397 (37%) had a score of 2, 345 (32%) had a score of 3, 135 (12%) had a score of 4 and 28 (2%) a score of 5 or 6. The overall survival (OS) rate in patients with risk scores 0-1 and 2 was similar (58% and 55%, respectively) but significantly better than that in patients with scores 3 or more (score 3 - 44%, 4 - 36 % and 5-6 - 27%, respectively) pp<0.001). Disease-free survival (DFS) and transplant related mortality (TRM) in a patients with a score of 3 or more were 46% and 49%, respectively and the relapse rate beyond score 5-6 was 77%. Disease status had a negative impact on all outcomes (OS, DFS, TRM, and relapse). The OS rate for male recipients of a graft from a female donor was 40% compared to 52% among the other donor-recipient pairs (p=0.004). DFS and TRM were significant for disease phase and female donor-male recipient (p<0.001 and p<0.003, respectively). In our experience, age and interval between diagnosis and transplant did influence OS, DFS, TRM, and relapse rate. INTERPRETATION AND CONCLUSIONS: Our results validate the EBMT risk score in the context of a developing country and confirm its usefulness for making point decisions in the imatinib era.

Relationship between cytokine gene polymorphisms and graft-versus-host disease after allogeneic stem cell transplantation in a Brazilian population.

Graft-versus-host disease (GVHD) is the major complication of allogeneic hematopoietic stem cell transplantation (HSCT), and cytokines are recognized as important mediators of GVHD. Polymorphisms in the regulatory regions of several cytokine genes have been associated with a number of immune diseases as well as organ transplant complications. In this study we have investigated the role of tumor necrosis factor-alpha(-308), interleukin (IL)-6(-174), IL-10(-1082, -819, -592), Interferon-gamma(-874), and transforming growth factor-beta1(+869, +915) polymorphisms on HSCT outcome. Donor/recipient genotypes were analyzed by polymerase chain reaction with sequence specific primers (PCR-SSP). Although we have found a small number of low IL-6, a polymorphism at position -174 of the recipient and donor IL-6 gene was associated with the increased incidence of chronic GVHD. Therefore, this study emphasizes the probable potential role of genetic variability of donor and recipient in determining outcome after transplantation.

Quality of life in patients randomized to receive a bone marrow or a peripheral blood allograft.

BACKGROUND AND OBJECTIVES: Quality of life (QOL) is an important clinical end-point to be considered in the late follow-up of patients treated with allogeneic bone marrow (BM) or peripheral blood progenitor cell (PBPC) transplantation. DESIGN AND METHODS: To assess the QOL in a group of survivors of hematologic malignancies who had been enrolled in a prospective randomized trial comparing allogeneic BM with PBPC. Sixty randomized patients had been enrolled in a study comparing BM with PBPC graft during 1995-99. At the time of this QOL study, 30 were alive and 26 (13 BM and 13 PBPC) were eligible. Clinical and demographic data were collected and psychometric instruments (WHOQOL-100 and the Hospital Anxiety and Depression Scale HAD) were used. Non-parametric and univariate analyses were performed. RESULTS: The PBPC recipients had more chronic graft-versus-host disease (p=0.03) and were on immunosuppressive treatment for a longer period (p=0.02). The WHOQOL-100 analysis demonstrated significant differences between groups with more favorable results in the BM group in the facets of Pain and Discomfort (p=0.03), Mobility (p=0.02) and Daily Living Activities (p=0.03). According to the patients' spontaneous responses, 8 individuals (6 in the PBPC group) believed that their QOL had worsened. INTERPRETATION AND CONCLUSIONS: With the limitations of a small randomized study, these findings suggest a lower QOL in recipients of allogeneic PBPC than in recipients of BM grafts, probably due to the frequency and severity of chronic graft-versus-host disease. This need to be confirmed in a large international trial.