The interplay among iron metabolism, endothelium and inflammatory cascade in dysmetabolic disorders.

PURPOSE: Metabolic syndrome (MetS) is considered as a proinflammatory and prothrombotic state with atherogenic risk factors including dyslipidemia, obesity and glucose intolerance. Oxidative stress is a unifying basis of several disorders including diabetes mellitus (DM) and MetS. We therefore designed this cross-sectional study to investigate the potential interaction among iron metabolism, inflammation and endothelial plexus in MetS and DM patients. METHODS: A total of 62 patients [median age 54 (23-76) years; male/female 16/46] and 18 healthy controls [median age 38 (30-64) years; male/female 6/12] were included in the study. Patient population was classified as MetS (n = 30) and DM (n = 32). RESULTS: Leukocyte count (p = 0.002) and osteopontin (OPN) levels (p = 0.008) were significantly higher, while C-reactive protein (CRP) (p = 0.056) and IL-6 (p = 0.059) represented a relative increase in the patient group. Leptin, endothelin 1 (ET1), hepcidin, nitric oxide synthase (NOS), erythrocyte sedimentation rate (ESR), iron, transferrin saturation (TS) and ferritin levels were not significantly different between the patient and control groups. Endothelin 1 was found to be higher in the DM group compared to MetS group (p = 0.15, p = 0.049). Leukocyte count, leptin, hepcidin, OPN, NOS, IL-6, ESR, CRP, iron, TS and ferritin levels were not different between DM and MetS groups. A positive correlation was demonstrated between leptin and OPN (p = 0.001, r = 0.360), ferritin and hepcidin (p < 0.01, r = 0.633), IL-6 and CRP (p = 0.023, r = 0.319), leptin and NOS (p = 0.005, r = 0.309) and OPN and NOS (p < 0.001, r = 0.803). There was a negative correlation between hepcidin and NOS (p = 0.009, r = -0.289). When the study cohort was divided into two particular groups based on median ferritin and hepcidin levels, hepcidin (p = 0.002), ALT (p = 0.001) and LDL (p = 0.049) levels were higher in the high-ferritin group. Nitric oxide synthase levels (p = 0.033) were lower, whereas ferritin levels (p = 0.004) were higher in the high-hepcidin group. CONCLUSION: Mechanisms involved in the vicious circle of MetS including inflammation, endothelial vasculature and iron metabolism remain to be elucidated. The role of iron metabolism in this complex interaction should be confirmed with further studies.

Pro-oxidative/antioxidative imbalance: a key indicator of adverse outcome in hematopoietic stem cell transplantation.

INTRODUCTION: Pretransplantation iron overload (IO) is considered as a predictor of adverse outcome in hematopoietic stem cell transplantation (HSCT). Peroxidative tissue injury caused by IO leads to progressive organ dysfunction. METHODS: This is a retro-prospective study which explores the possible relationship between IO, oxidative stress and transplant outcome. Serum samples of 149 consecutive HSCT candidates were subjected to analysis of iron parameters, including nontransferrin bound iron (NTBI) and pro-oxidant/antioxidant status. RESULTS: Serum ferritin was found to be positively correlated with NTBI and negatively correlated with glutathione peroxidase (GPx) and superoxide dismutase (SOD). An inverse correlation of NTBI with SOD, total antioxidant potential (TAP) and malonyldialdehide (MDA) was also demonstrated. An adverse impact of serum ferritin level on early posttransplant complications including pulmonary toxicity, fungal infections and sinusoidal obstruction syndrome (SOS) was shown. A significant impact of NTBI on +30 day (P = 0.027) and +100 day survival (P = 0.028) was shown in auto-transplanted patients. MDA levels had a significant impact on +30 day and +100 day survival in autologous (P = 0.047; P = 0.026) and allogeneic (P = 0.053; P = 0.059) groups. GPx (P = 0.016) and MDA (P = 0.021) were identified as independent prognostic parameters for overall survival in allo-transplanted patients. CONCLUSION: Pretransplantation IO might be a major contributor to adverse outcome in HSCT recipients through an impaired pro-oxidative/antioxidative homeostasis. The reversible nature of IO and oxidative stress suggests that early preventive strategies might have a potential to improve transplant outcome.

The impact of bone marrow fibrosis on the outcome of hematopoietic stem cell transplantation.

We retrospectively analyzed the data of 175 patients who underwent autologous (n = 69) or allogeneic hematopoietic stem cell transplantation (HCT) (n = 106) including 19 (27.5%) and 38 (35.8%) recipients who had bone marrow fibrosis (BMF) prior to transplantation, respectively. We investigated the effects of BMF on engraftment, graft-versus-host disease (GVHD), early posttransplant complications, and survival. Pretransplantation BMF did not delay engraftment and showed no impact either on early posttransplant complications or on the development of acute and/or chronic GVHD. Probability of 1-year overall survival (OS) and progression-free survival (PFS) of autologous HCT recipients were similar, namely 76.7% versus 88.6% (P > .005) and 26.33% versus 16.5% (P > .05) among patients with versus without fibrosis, respectively. In allogeneic HCT recipients, the probability of 1-year OS was 35.2% among patients with versus 48.9% among those without fibrosis (P = .004) PFS at 1 year was inferior among allogeneic HCT recipients with BMF: 27.8% versus 51.2% (P = .0008). Cox regression analysis revealed BMF to be independently associated with age, Sorror comorbidity index, primary disease, and disease status during HCT (P = .045).

Iron overload: predictor of adverse outcome in hematopoietic stem cell transplantation.

INTRODUCTION: Iron overload is an important problem in candidates for and survivors of hematopoietic stem cell transplantation (HSCT), and affects long-term outcome and survival. The objective of the present study was to determine the effect of iron overload on early toxic or infectious complications and survival. PATIENTS AND METHODS: We retrospectively reviewed the medical records for 250 adult patients (162 men and 88 women; median [range] age, 34 [16-71] years who underwent HSCT between September 2003 and August 2008. The HSCT grafts were autologous in 102 patients, and allogeneic in 148. RESULTS: Follow-up was 315 (1-1809) days. Mean (SD) pre-HSCT serum ferritin concentration was 1402.6 (5016.2) ng/mL in the entire group, 647.6 (1204.3 ng/mL in autologous recipients, and 1410.6 (2410.4) ng/mL in allogeneic recipients. Twenty-eight autologous graft recipients (27.4%) and 102 allogeneic recipients (68.9%) demonstrated serum ferritin concentrations of 500 ng/mL or greater, and were classified as the high-ferritin group. High ferritin concentrations were significantly associated with toxic or infectious complications including mucositis, fungal infections, pneumonia, and sinusoidal obstruction syndrome in the early post-HSCT setting. A significant effect of pre-HSCT ferritin concentration on overall survival and transplant-related mortality was observed. The effect of pre-HSCT ferritin on survival was independent of the comorbidity index at Cox regression analysis. In the entire study population, the probability of survival was significantly lower when ferritin concentration was greater than 500 ng/mL. CONCLUSION: Transplant-related mortality has decreased substantially with the development of supportive treatments. Pretransplantation risk assessment and risk-adapted strategies such as decreasing iron overload might further improve transplant-related complications.

Risk factors for fungal pulmonary infections in hematopoietic stem cell transplantation recipients: the role of iron overload.

Fungal pulmonary infections (FPIs) are frequent causes of mortality in hematopoietic stem cell transplantation (HSCT) recipients. Determination of the specific risk factors may improve the prognosis. The aim of this study was to evaluate the risk factors of FPIs due to HSCT. Patient history, physical examination, chest X-rays and the consultation records of the pulmonary disease department which were a part of the routine evaluation before and at first, third, sixth, ninth and twelfth months of HSCT were retrieved in 148 adult HSCT recipients. Results of the high-resolution computed tomography, fiber-optic bronchoscopy and the microbiological data were also included. FPI was diagnosed in 22 patients (14.9%). Multivariate analysis showed that increased ferritin levels (>1000 ng/ml; OR: 3.42, 95% CI 1.03-11.42, P=0.045) and the development of sinusoidal obstruction syndrome (SOS; OR: 5.09, 95% CI 1.53-16.90, P=0.008) were significant risk factors for FPIs. The sensitivity and specificity of ferritin >1000 ng/ml for the prediction of FPIs were 67 and 70%, respectively. There was a positive correlation between the increased risk of FPIs and pretransplantation ferritin levels (r=0.413, P<0.001) and increased ferritin levels and SOS (r=0.331, P<0.001). Increased pretransplantation ferritin levels and development of SOS are predictive factors of FPIs during HSCT.

Abnormal protein bands in patients with multiple myeloma after haematopoietic stem cell transplantation: does it have a prognostic significance?

Abnormal protein bands (APB) unrelated to the original monoclonal protein occasionally appear in serum immunofixation samples from patients with multiple myeloma (MM) following haematopoietic stem cell transplantation (HCT). To investigate the significance of APB, medical records and serum immunofixation patterns of 53 MM patients, who had undergone HCT (49 autologous and 4 allogeneic) at the stem cell transplantation unit of Gazi University Faculty of Medicine, were reviewed. Patients were staged according to Durie-Salmon and International staging systems (ISS) and disease response was determined according to European Bone Marrow Transplantation (EBMT) criteria. Fourteen (26.4%) of the 53 patients developed APBs after HCT. The median time for the appearance and duration of APB was 3 (range 1-24) and 5.5 (range 1.5-14) months, respectively. Probability of overall survival (OS) at the end of the follow-up was 77 and 61.4% in patients with and without APB, respectively (p = 0.334). The median duration of follow-up (767 days (range, 220-2905) vs. 726 days (range, 120-1780) p = 0.545) was not different in patients with and without APB. Probability of progression free survival (PFS) at the end of follow-up was 28.8% in patients with and 27.7% in patients without APB (p = 0.835). PFS (910 days (range 180-2905) vs. 730 days (range 90-1765) p = 0.835) was longer in patients with APB, though without statistical significance. Thus, the occurrence of APB post-transplantation is not associated with any adverse long-term consequences and does not require treatment modification.

Impact of ABO-incompatible donor on early and late outcome of hematopoietic stem cell transplantation.

ABO incompatibility is not a barrier to allogeneic hematopoietic stem cell transplantation (HSCT). However, the impact of an ABO mismatch on the outcome of the HSCT remains controversial. We analyzed whether ABO incompatibility leads to an increased risk of early/late complications, mortality, or increased transfusion requirements. The 147 consecutive allogeneic HSCTs includes 80 ABO-identical and 25 major, 30 minor, and 12 bidirectional ABO-mismatched grafts. The four groups were balanced with respect to disease status at transplantation. Transplantation-related mortality was significantly greater (P < .01) and overall survival significantly shorter (P = 0.2) among HSCT recipients with minor ABO-mismatched grafts. The relapse rate, progression-free survival, and transfusion requirements until discharge were not different between ABO-identical and ABO-mismatched groups. Pure red cell aplasia (PRCA); (P < .0001) and delayed red blood cell (RBC) engraftment (P < .001) were more frequent in HSCT recipients with major mismatched donors. Delayed RBC engraftment was associated with posttransplantation hyperferritininemia and increased mortality risk (P = .05). The greater frequency of sinusoidal obstruction syndrome and graft-versus-host disease (GVHD) in patients with minor mismatched transplants, did not show statistical significance. In contrast severe GVHD was significantly more frequent among minor mismatched patients (P = .04). ABO-mismatched HSCT might have an unfavorable impact on transplant outcomes. Selection of ABO-compatible donors when possible, strategies to prevent and treat PRCA, modifications in transfusion practice, and effective iron chelation are among the measures that can improve transplant outcomes.

The role of liver biopsy in the workup of liver dysfunction late after SCT: is the role of iron overload underestimated?

Abnormalities in liver function tests are common in hematopoietic SCT (HSCT) recipients. We retrospectively investigated the role of liver biopsy in determining the cause of elevated liver enzymes and its impact on the management of patients in the post-HSCT setting. A total of 24 consecutive liver biopsies were obtained from 20 patients from September 2003 to December 2007. A definite histopathologic diagnosis was obtained in 91.7% of the biopsies. Iron overload (IO) was found in 75% and GVHD in 54.2% of the patients. The initial clinical diagnosis of GVHD was confirmed in 56.5% and refuted in 43.5% of the allogeneic HSCT recipients. The median number of post transplant transfusions, percent transferrin saturation and ferritin levels were found to be higher in patients who had histologically proven hepatic IO (p1=0.007, p2=0.003 and p3=0.009, respectively). Regression analysis showed a significant correlation between serum ferritin levels and histological grade of iron in the hepatocytes. Our data suggest that hepatic IO is a frequent finding in the post-HSCT setting, which contributes to hepatic dysfunction and it should be considered in the differential diagnosis, particularly in patients with high serum ferritin levels.

Hematopoietic stem cell transplantation in patients with active fungal infection: not a contraindication for transplantation.

Increasing use of more aggressive treatment approaches in patients with hematologic malignancies leads to an increased frequency of invasive fungal infections, which is a major cause of transplant-related mortality in hematopoietic stem cell recipients. In this respect, the presence of an active fungal infection prior to transplantation may hinder subsequent hematopoietic stem cell transplantation (HSCT); which sometimes is the only curative treatment. We report here the results of 13 consecutive patients transplanted with active fungal infection. Thirteen patients (7 males and 6 females) with a median age of 34 years (range, 16-53 years) underwent 15 HSCT between September 2003 and April 2007. In this group of 15 patients, consisting of hematologic malignancies with high risk of relapse or severe aplastic anemia, 11 (73%) transplants performed in subjects with active invasive fungal infection (IFI) patients survived 30 days after transplantation. Three patients (1 patient with primary disease relapse, 1 patient with graft versus host disease [GVHD] complicated with fungal pneumonia, and 1 patient with severe sinusoidal obstruction syndrome and GVHD complicated with aspiration pneumonia) died on days +66, +74, and +62 posttransplantation, respectively, within the first 100 days of HSCT. After a median follow-up time of 306 days (range, 145-680 days), four of 13 (31%) patients with active IFI were alive and disease free. Among a population of HSCT recipients with a dismal prognosis without transplantation, performing the procedure despite active IFI saved a considerable proportion of the patients. The presence of active IFI did not seem to be an absolute contraindication for HSCT, particularly among high-risk patients in whom a treatment delay could be fatal.

Treatment of sinusoidal obstruction syndrome with defibrotide: a single-center experience.

Sinusoidal obstruction syndrome (SOS) is a frequent, troubling, and potentially fatal complication of hematopoietic stem cell transplantation. Despite promising results with defibrotide (DF), no treatment has been established as standard. DF is a single-stranded polydeoxyribonucleotide, obtained from controlled depolymerization of porcine intestinal mucosal cells. It has antithrombotic, antiischemic, antiinflammatory, and thrombolytic properties without significant side effects. We retrospectively evaluated the charts of 80 consecutive patients, with 89 hematopoietic stem cell transplants for hematologic malignancies. The results of early initiation of DF treatment in 14 patients with SOS are presented in this study. Fourteen patients, 8 males and 6 females % median age 40.5 years (range, 16-46 years) were diagnosed to have SOS. Disease severity was classified as severe in 6 (42.85%), moderate in 4 (28.57%), and mild in 4 (28.57%) patients. We treated 14 patients with DF for a median of 21.5 days (range, 4-39 days). All 14 patients received DF after the diagnosis of SOS. Three patients with severe and all of the patients with mild to moderate SOS responded to treatment with complete resolution of SOS-related signs and symptoms. All patients responding to DF were alive at 100 days posttransplantation. There was no significant drug-related side effect among patients treated with DF. With an overall response rate of 78.56% and a 50% complete response rate in severe SOS cases and minimal side effects, we suggest that DF is the best available agent to treat SOS.