Showing papers in "American Journal of Hematology in 2007"

Methemoglobin—It's not just blue: A concise review

Abstract: Hemoglobin has functions besides carrying oxygen to the tissues, and regulates vascular tone and inflammation via a redox couple with methemoglobin. Hemoglobin has iron in the reduced valance Fe(II) and methemoglobin has iron in the oxidized valance Fe (III), with a free energy capable of producing water from oxygen. In generating methemoglobin the couple functions as a nitrite reductase. The degree of oxidation of hemoglobin senses the oxygen level in the blood and uses its ability to produce nitric oxide from nitrite to control vascular tone, increasing blood flood when the proportion of oxygenated hemoglobin falls. Additional cardiovascular damage is produced by methemoglobin mediated oxidation of light density lipoproteins, accelerating arteriosclerosis. In addition, the release of heme from methemoglobin is an important factor in inflammation. These physiologic functions are paralleled by thewell-described role in the oxidation of various drugs resulting in methemoglobinemia. Am. J. Hematol., 2006. © 2006 Wiley-Liss, Inc.

Estimated annual numbers of US acute-care hospital patients at risk for venous thromboembolism

Abstract: Venous thromboembolism (VTE) is a major US health problem. However, the total number of US inpatients who are at risk for VTE is unknown. Our objective was to estimate the number of US acute-care hospital inpatients who were at risk for VTE according to criteria established by the Seventh American College of Chest Physicians (ACCP) Consensus Conference on Antithrombotic and Thrombolytic Therapy guidelines for VTE prevention. Using the 2003 Nationwide Inpatient Sample from the Healthcare Cost and Utilization Project (HCUP), patient diagnoses and procedures were examined to identify major surgery patients (age > or = 18 years, length of hospital stay > or = 2 days) and medical patients (age > or = 40 years, length of hospital stay > or = 2 days). ACCP guidelines were used to estimate the number of surgical and medical patients at risk of developing VTE. Of an estimated 38,220,659 discharges in 2003, 7,786,390 (20%) were surgical inpatients; 44% of which were at low risk for VTE, while 15%, 24%, and 17% were at moderate, high, and very high risk for VTE, respectively. Of the remaining 15,161,586 medical patients, 7,742,419 (51%) met ACCP VTE risk criteria. Over 12 million patients, comprising 31% of US hospital discharges in 2003, were at risk of VTE. Given the existence of internationally-accepted evidence-based guidelines for prevention of VTE, research is required to establish if this patient population is receiving recommended VTE prophylaxis.

Cryopreservation of hematopoietic stem cells.

Abstract: Stem cell transplantation represents a critical approach for the treatment of many malignant and non-malignant diseases. The foundation for these approaches is the ability to cryopreserve marrow cells for future use. This technique is routinely employed in all autologous settings and is critical for cord blood transplantation. A variety of cryopreservatives have been used with multiple freezing and thawing techniques as outlined in the later chapters. Freezing efficiency has been proven repeatedly and the ability of long-term stored marrow to repopulate has been established. Standard approaches outlined here are used in many labs as the field continues to evolve.

Anemia in celiac disease is multifactorial in etiology

Abstract: Anemia in celiac disease (CD) has been attributed to nutritional deficiencies; however, the clinical manifestations of CD have changed with nongastrointestinal presentations predominating. We collected hematologic parameters from a cohort of patients seen at a tertiary care center for CD to assess the characteristics of anemia in this population. Hematological parameters measured 1995 was analyzed. Ferritin levels were compared with population controls (NHANES III). Iron deficiency was common, occurring in 33% of men and 19% of women (P 50th percentile was more common in anemic men (24%) than in anemic women (9%; P > 0.20). Macrocytic anemia with concurrent B12 or folate deficiency was rare (3%). Elevated ESR was observed in patients with ferritin 50th. A gluten-free diet resulted in increased serum ferritin in iron-deficient patients, and decreased ferritin levels in those with high ferritin (r(2) = 0.46, P < 0.001). Although anemia is still a common presentation of celiac disease, nutritional deficiencies alone do not explain this phenomenon in all cases; inflammation appears to contribute as evidenced by the presence of anemia of chronic disease in some individuals.

What is the potential for overdiagnosis of heparin-induced thrombocytopenia?

Abstract: Heparin-induced thrombocytopenia (HIT) is caused by platelet-activating antibodies that recognize platelet factor 4//heparin (PF4/H) complexes. According to the "iceberg model," only a subset of anti-PF4/heparin antibodies of IgG class evincing strong platelet-activating properties cause clinical HIT. Since many centers rely predominantly on an anti-PF4/polyanion enzyme-immunoassay (EIA) to diagnose HIT, we estimated the potential for overdiagnosis when only this single test is available. We examined a database of 100 patients in whom the probability of HIT had been estimated using a clinical scoring system (4Ts), and where patients underwent systematic testing for HIT antibodies using three assays: the platelet serotonin release assay (SRA), an "in-house" EIA that detects IgG anti-PF4/heparin antibodies (EIA-IgG), and a commercial EIA that detects anti-PF4/polyanion antibodies of all three immunoglobulin classes (EIA-GTI). Whereas 16 of 100 patients fulfilled a "classic" definition of HIT (intermediate/high probability plus strong platelet-activating anti-PF4/heparin IgG antibodies), an additional 16 patients fulfilled a "liberal" definition in which any investigated patient (irrespective of the pretest probability) who had a positive EIA-GTI was considered to have HIT. The clinical features of these 16 additional patients--including generally weak antibodies and low risk for thrombosis--suggest underlying non-HIT explanations for thrombocytopenia. Patients with a positive SRA generally corresponded to those with intermediate or high pretest probability of HIT who also had strong EIA-GTI reactivity (>1.20 OD units). We conclude there is the potential to overdiagnose HIT by approximately 100% if any positive EIA is considered to "confirm" the diagnosis of HIT irrespective of the clinical scenario.

Recombinant human soluble tumor necrosis factor receptor fusion protein as treatment for steroid refractory graft-versus-host disease following allogeneic hematopoietic stem cell transplantation.

Abstract: Etanercept is a recombinant human soluble tumor necrosis factor (TNF-alpha) receptor fusion protein that inhibits TNF-alpha, a major mediator in the pathogenesis of graft-versus-host disease (GVHD). The purpose of our study was to evaluate the safety and efficacy of etanercept therapy in 21 patients with steroid-refractory acute GVHD (aGVHD) (n = 13) and chronic GVHD (cGVHD) (n = 8). Etanercept 25 mg was given subcutaneously twice weekly for 4 weeks followed by 25 mg weekly for 4 weeks. At the time of initiation of etanercept, 14 patients had skin, 13 had gastro-intestinal, 5 had liver, 5 had pulmonary, and 4 had oral involvement. Twelve patients (57%) completed 12 doses of therapy. Overall, 11 of 21 patients (52%) responded to the treatment with etanercept, including 6 patients (46%) with aGVHD [n = 4 complete response (CR), n = 2 partial response (PR)] and 5 patients (62%) with cGVHD (n = 1 CR, n = 4 PR). Clinical responses were most commonly seen in patients with refractory gut aGVHD with 55% of the patients having a CR and 9% having a PR. CMV reactivation occurred in 48% of patients, bacterial infections in 14% of patients, and fungal infections in 19% of patients. Fourteen patients (67%) were alive after a median follow-up of 429 days (range 71-1007 days) since initiation of etanercept. Seven patients died, 3 of infections, 2 of refractory aGVHD, and 2 of disease progression. In conclusion, our preliminary data indicate that etanercept is well tolerated and can induce a high response rate in patients with steroid-refractory aGVHD and cGVHD, particularly in the setting of GI involvement.

Morbidity and Mortality in Chronically Transfused Subjects With Thalassemia and Sickle Cell Disease: A Report From the Multi-Center Study of Iron Overload

Abstract: A natural history study was conducted in 142 Thalassemic (Thal), 199 transfused Sickle Cell Disease (Tx-SCD, n = 199), and 64 non-Tx-SCD subjects to describe the frequency of iron-related morbidity and mortality. Subjects recruited from 31 centers in the US, Canada or the UK were similar with respect to age (overall: 25 +/- 11 years, mean +/- SD) and gender (52% female). We found that Tx-SCD subjects were hospitalized more frequently compared with Thal or non-Tx-SCD (P < 0.001). Among those hospitalized, Tx-SCD adult subjects were more likely to be unemployed compared with Thal (RR = 1.6, 95% CI 1.0-2.5) or non-Tx-SCD (RR = 3.1, 95% CI 1.3-7.3). There was a positive relationship between the severity of iron overload, assessed by serum ferritin, and the frequency of hospitalizations (r= 0.20; P = 0.009). Twenty-three deaths were reported (6 Thal, 17 Tx-SCD) in 23.5 +/- 10 months of follow-up. Within the Tx-SCD group, those who died began transfusion (25.3 vs. 12.4 years, P < 0.001) and chelation therapy later (26.8 vs. 14.2 years, P = 0.01) compared with those who survived. The unadjusted death rate in Thal was lower (2.2/100 person years) compared with that in Tx-SCD (7.0/100 person years; RR = 0.38: 95% CI 0.12-0.99). However, no difference was observed when age at death was considered. Despite improvements in therapy, death rate in this contemporary sample of transfused adult subjects with Thal or SCD is 3 times greater than the general US population. Long term follow-up of this unique cohort of subjects will be helpful in further defining the relationship of chronic, heavy iron overload to morbidity and mortality.

Consequences of diagnostic delays in type 1 Gaucher disease: the need for greater awareness among hematologists-oncologists and an opportunity for early diagnosis and intervention.

Abstract: Gaucher disease (GD) is a progressive macrophage lipidosis capable of causing disabling and life-threatening complications. Anecdotal experiences suggest that GD may go undiagnosed for many years, leading to severe complications that are preventable or reversible by enzyme replacement therapy (ERT) with imiglucerase. We conducted surveys of patients and Hematology-Oncology specialists to assess the frequency of diagnostic delays. Additionally, we report a series of patients who suffered diagnostic delays and as a result developed disabilities including potentially life-threatening manifestations of GD. Of 136 patients surveyed, the average time from first appearance of GD symptoms to final diagnosis was 48.7 +/- 123.6 months. More than two-thirds were evaluated and managed by a hematologist-oncologist (Hem-Onc). A global survey of 406 Hem-Oncs found that only 20% considered GD in the differential diagnosis for all of its classic symptoms (cytopenia, hepatosplenomegaly, bone pain); the diagnosis considered most likely included leukemia, lymphoma, and multiple myeloma. To illustrate actual consequences of diagnostic delays, we describe 14 patients with GD who suffered from symptoms for up to 10 years before correct diagnosis. Diagnostic delays led to complications that are preventable or reversible with ERT (i.e., avascular necrosis, severe bleeding, chronic bone pain, life-threatening sepsis, pathologic fractures, growth failure, liver pathology). Patients homozygous for N370S mutation in this series were vulnerable to diagnostic delays. In conclusion, prolonged diagnostic delays occur in GD and may result in severe disease manifestations. Our findings suggest that physician education will increase the likelihood of prompt detection of GD and improve its management with ERT with imiglucerase when indicated.

The use of desmopressin as a hemostatic agent: a concise review.

Abstract: Desmopressin, a synthetic derivative of the antidiuretic hormone vasopressin, is the treatment of choice for most patients with von Willebrand disease and mild hemophilia A. Moreover, the compound has been shown to be useful in a variety of inherited and acquired hemorrhagic conditions, including some congenital platelet function defects, chronic liver disease, uremia, and hemostatic defects induced by the therapeutic use of antithrombotic drugs such as aspirin and ticlopidine. Finally, desmopressin has been used as a blood saving agent in patients undergoing operations characterized by large blood loss and transfusion requirements, but studies suggest that this is not as effective as other methods. This review briefly summarizes the current clinical indications on the use of desmopressin as a hemostatic agent.

Mechanisms of iron loading and toxicity.

Abstract: Normal iron homeostasis is a finely balanced system that reflects iron absorption, loss and utilization. The body has no mechanism for the active excretion of iron, so body iron levels are controlled at the point of absorption in the small intestine. Disturbances in this equilibrium, such as those leading to enhanced absorption, can have significant clinical consequences. Continued excessive iron uptake is followed by iron deposition in various tissues, ultimately leading to tissue damage, and possibly end-organ failure. In this review, current concepts in normal iron homeostasis, and iron loading are explained. The clinical consequences as well as the differences between primary and secondary iron loading are also reviewed, and some future research priorities are discussed.

Follicular dendritic cell sarcoma: a report of 14 cases and a review of the literature.

Abstract: Follicular dendritic cell sarcomas (FDCS) are grouped with the histiocytic and dendritic cell neoplasms. The natural history and response to different treatments have not been well established. The cases of 14 patients with FDCS who were seen at M. D. Anderson between 1995 and 2005 were reviewed. Median patient age was 48 years (range, 25-69 years). Histologically, four cases showed low-grade features, three cases showed low-grade features with focal high-grade features, and five cases showed high-grade features. Tumors were positive for CD21, CD23, and CD35 in 83, 90, and 44% of cases, respectively. Twelve (92%) of 13 tumors were strongly positive for epidermal growth factor receptor. Information on initial treatment was available in 11 patients, which included surgery alone in one patient, surgery and radiation in two, surgery and chemotherapy in one, chemotherapy alone in three, chemotherapy and radiation in one, surgery followed by radiation and chemotherapy in three patients. In eight patients the initial chemotherapy regimen was cyclophosphamide, doxorubicin, vincristine, and prednisone. Complete remission was achieved in 7 (63%) of 11 patients. Ten patients were alive at a median follow up of 22 months, 3 (23%) of 13 had no evidence of disease, and 7 (53%) of 13 patients were alive with disease. Follicular sarcoma is an aggressive neoplasm. Although most of the patients initially responded to treatment, the majority of them (81%) relapsed. A better understanding of the biology of FDCS could guide our efforts in the development of new treatment modalities for this rare disease.

Dendritic cell neoplasms: An overview

Abstract: Dendritic cell neoplasms are rare tumors that are being recognized with increasing frequency. They were previously classified as lymphomas, sarcomas, or histiocytic neoplasms. The World Health Organization (WHO) classifies dendritic cell neoplasms into five groups: Langerhans' cell histiocytosis, Langerhans' cell sarcoma, Interdigitating dendritic cell sarcoma/tumor, Follicular dendritic cell sarcoma/tumor, and Dendritic cell sarcoma, not specified otherwise (Jaffe, World Health Organization classification of tumors 2001; 273-289). Recently, Pileri et al. provided a comprehensive immunohistochemical classification of histiocytic and dendritic cell tumors (Pileri et al., Histopathology 2002;59:161-167). In this article, a concise overview regarding the pathological, clinical, and therapeutic aspects of follicular dendritic, interdigitating dendritic, and Langerhans' cell tumors is presented.

Rituximab‐induced interstitial lung disease

Abstract: The aim of this study is to characterize rituximab-induced interstitial lung disease (R-ILD). The information on all reported cases of R-ILD was reviewed. This analysis focused on patient characteristics, underlying disease, rituximab dosing schedule, and R-ILD characteristic-like symptoms, diagnosis, treatment, and outcomes. Sixteen cases of R-ILD, including our two cases, have been reported in the literature. Commonalities include older age, clinical presentation, computerized tomography findings, pulmonary function tests, and biopsy findings. Therapy included corticosteroids and broad spectrum antibiotics. Prognosis has been variable. Patients who worsen despite corticosteroids have a poor outcome. The pathogenesis of R-ILD is largely unknown. Potential explanations for R-ILD may include the induction and release of cytotoxic substances. R-ILD is a rare but potentially fatal pulmonary toxicity due to rituximab. R-ILD should be considered in patients who present with dyspnea, fever, and cough, and there is no clear evidence of infection. Prompt diagnosis and treatment with corticosteroids is essential.

Acquired von Willebrand syndrome: An update

Abstract: Acquired von Willebrand syndrome (aVWS) is a rare bleeding disorder with laboratory findings similar to those for congenital von Willebrand disease (VWD). However, unlike congenital VWD, it arises in individuals with no personal or family history of bleeding. aVWS occurs in association with a variety of underlying disorders, most frequently in lymphoproliferative disorders, myeloproliferative disorders, and cardiovascular diseases. Through an analysis of the more recent literature data, the pathophysiology and the clinical, laboratory, and therapeutic aspects of this syndrome are concisely reported in this review.

Concepts and goals in the management of transfusional iron overload

Abstract: In this review, current concepts and goals of iron chelation therapy for thalassemias, sickle cell disease, and myelodysplastic syndromes are discussed. The primary goal of iron chelation therapy is to prevent the accumulation of iron reaching harmful levels by matching iron intake from blood transfusion, with iron excreted by iron chelation. Over 30 years of experience with deferoxamine has shown iron chelation to be an effective therapeutic modality. However, chelation efficiency is limited because most of the body's iron stores are not directly chelatable, and only a small fraction of body iron is chelatable at any moment. Once iron has been deposited in organs other than the liver, for example the heart, removal by chelation is slow and inefficient. Chelation efficiency can be improved by designing regimes where chelators are available 24 hr a day to bind labile iron pools in cells and plasma. Deferoxamine has a short plasma half-life and the parenteral infusions required to achieve steady plasma levels are demanding, with consequent variable adherence to therapy. Once-daily oral administration of deferasirox achieves continuous chelation with trough concentrations sufficient to decrease plasma labile iron species progressively, and achieves an efficiency of chelation not obtainable with deferiprone or deferoxamine monotherapy.

Superwarfarin poisoning: a report of two cases and review of the literature.

Abstract: Superwarfarins are anticoagulant rodenticides similar to warfarin, but which have various substituted phenyl groups replacing the terminal methyl group, resulting in a fat-soluble, long-acting anticoagulant that is nearly 100 times more potent than the parent compound. Since their development, many accidental and intentional cases of consumption have been reported. We describe two cases of consumption, one related to unknown etiology, and the other related to utilization of the superwarfarin to potentiate a drug of abuse. The clinical manifestations including bleeding symptoms and abnormal coagulation assays are discussed. The differential diagnosis is quite broad, and includes all causes of vitamin K deficiency, factor deficiency or inhibitor, disseminated intravascular coagulation (DIC), and liver disease. Differentiating superwarfarin ingestion from the other causes can be quite difficult, but extremely important, as management requires prolonged administration of vitamin K. Other treatment options are discussed as well including, fresh frozen plasma (FFP), and recombinant factor VIIa. Finally, the significance of “lacing” drugs of abuse with superwarfarin to potentiate their effect is discussed, as well as the complications that could develop from such a habit. Am. J. Hematol., 2006. © 2006 Wiley-Liss, Inc.

Patient-controlled analgesia versus continuous infusion of morphine during vaso-occlusive crisis in sickle cell disease, a randomized controlled trial.

Abstract: Intravenous morphine is the treatment of choice for severe pain during vaso- occlusive crisis in sickle cell disease (SCD). However, side effects of morphine may hamper effective treatment, and high plasma levels of morphine are associated with severe complications such as acute chest syndrome. Furthermore, adequate dosing remains a problem since no objective measurement of pain severity exists and analgesia should be titrated upon the patient's reported pain. Patient-controlled analgesia (PCA) may therefore be an interesting alternative since patients can titrate the level of analgesia themselves. In this randomized controlled study, the efficacy of intravenous morphine administration with PCA was compared with continuous infusion (CI) of morphine in patients with SCD during vaso-occlusive crisis. Twenty five consecutive episodes of vaso-occlusive crisis in 19 patients with SCD were included in the study. Patients in the PCA-group had a markedly and significant lower mean and cumulative morphine consumption when compared with the patients in the CI-group (0.5 mg/hr versus 2.4 mg/hr (P < 0.001) and 33 mg versus 260 mg (P = 0.018, respectively). The mean daily pain scores were comparable (4.9 versus 5.3). The lower mean and cumulative morphine consumption in the PCA-group led to significant less nausea and constipation during treatment when compared with the CI-group (area under the curve, respectively, 11 versus 18 (P = 0.045) and 30 versus 45 (P = 0.021). Furthermore, a nonsignificant reduction in the duration of hospital admission of 3 days was observed in the PCA-group. PCA results in adequate pain relief at a much lower morphine consumption and should considered to be the first choice in morphine administration to sickle cell patients admitted with vaso-occlusive crisis.

Hypocholesterolemia in chronic anemias with increased erythropoietic activity.

Abstract: Hypocholesterolemia of unknown etiology has been previously described in various chronic anemias Few small studies also suggested that those patients have a lower incidence of atherosclerotic events The aim of our study was to determine the extent of hypocholesterolemia in various types of anemias We studied 59 patients with chronic anemias associated with high-erythropoietic activity (thalassemia intermedia, congenital dyserythropoietic anemia type I, congenital spherocytosis), 8 patients with low-erythropoietic activity anemias (acquired aplastic anemia, Fanconi anemia, and Diamond Blackfan anemia), and 20 healthy controls Mean serum cholesterol, high-density lipoprotein (HDL) cholesterol, low-density lipoprotein (LDL) cholesterol, triglycerides, hemoglobin, serum ferritin, soluble transferrin receptor (STR), and serum erythropoietin levels were determined in each patient All patients with chronic anemia and increased erythropoietic activity had hypocholesterolemia, whereas none of those with low erythropoietic activity was hypocholesterolemic Mean serum cholesterol, HDL cholesterol, and LDL cholesterol levels were found to be significantly lower in the high-erythropoietic activity group (80+/-19 mg/dl; 31+/-10 mg/dl; 35+/-14 mg/dl, respectively) compared with the control group (P<0001; 0001; 0001, respectively) and the low-erythropoietic activity group (P<0001; 0001; 001, respectively) Significant inverse correlation (R2=0507) was observed between serum cholesterol and STR levels, which in the absence of iron deficiency reflect bone marrow activity Taken together, our results imply that hypocholesterolemia accompanies anemias with high-erythropoietic activity We suggest that the high-erythropoitic activity-associated hypocholesterolemia is due to increased cholesterol requirements by the proliferating erythoid cells Further studies are needed to elucidate the exact mechanism and the possible clinical consequences of this phenomenon

Remission of lymphoma after withdrawal of methotrexate in rheumatoid arthritis: Relationship with type of latent Epstein-Barr virus infection

Abstract: Rheumatoid arthritis (RA) is associated with an increased risk of developing lymphoma. Although the pathogenesis is still unclear, the increased risk appears to be related to the high inflammatory activity of RA, immunosuppressive agents, or Epstein-Barr virus (EBV) infection. We investigated the relationship between EBV latent infection and methotrexate (MTX)-associated lymphoma in RA patients. Nine patients were diagnosed with non-Hodgkin's lymphoma (NHL) during MTX treatment for RA in a multicenter study. The pathologic findings were consistent with diffuse large B-cell lymphoma in 8 patients and peripheral T-cell lymphoma, unspecified in 1. EBV infection was detected in 3 patients by in situ hybridization. Among all 9 patients who were initially treated by MTX withdrawal alone, 2 obtained spontaneous complete response (CR), 1 had partial response, 2 had stable disease (SD), and 4 had progressive disease. Both patients who had a CR and 1 who had SD were positive for EBV. Further examination of the latent EBV infection patterns revealed that 2 patients who obtained a CR had latency Type III, and the other with SD had latency Type II. These results demonstrate that immunodeficiency caused by MTX treatment is associated with the development of EBV-related NHL in RA patients. In patients who were treated by MTX for RA and developed NHL, remission can be observed following MTX withdrawal especially in NHL with latency Type III EBV infection. The analysis of EBV infection, including the latency types, is useful to decide the optimum therapeutic strategy.

Diagnosis and management of transfusion iron overload: The role of imaging

Abstract: The characterization of iron stores is important to prevent and treat iron overload. Serum markers such as ferritin, serum iron, iron binding capacity, transferrin saturation, and nontransferrin-bound iron can be used to follow trends in iron status; however, variability in these markers limits predictive power for any given individual. Liver iron represents the best single marker of total iron balance. Measures of liver iron include biopsy, superconducting quantum interference device, computer tomography, and magnetic resonance imaging (MRI). MRI is the most accurate and widely available noninvasive tool to assess liver iron. The main advantages of MRI include a low-rate of variability between measurements and the ability to assess iron loading in endocrine tissues, the heart and the liver. This manuscript describes the principles, validation, and clinical utility of MRI for tissue iron estimation.

No evidence for myocardial iron overload in multitransfused patients with myelodysplastic syndrome using cardiac magnetic resonance T2 technique

Abstract: The method of cardiovascular T2* magnetic resonance imaging (MRI) allows in vivo estimation of iron in the heart and liver and was used to measure the degree of iron overload in 10 transfused MDS patients (average 90 blood units) and in 3 patients with congenital hemolytic anemia. In all MDS patients iron overload was found in the liver but not in the heart. Patients with congenital anemias had iron in both organs despite iron chelation. It is possible that in MDS more time and more transfusions are required to induce iron accumulation in the myocardium. Therefore, cardiac MRI may serve as a diagnostic tool to assess if and when iron chelation is indicated. Am. J. Hematol., 2007. © 2007 Wiley-Liss, Inc.

Late‐onset cases of familial hemophagocytic lymphohistiocytosis with missense perforin gene mutations

Abstract: Since the discovery of perforin gene mutations in familial hemophagocytic lymphohistiocytosis (FHL) type 2, heterogeneous features in FHL2 patients have been identified in a report of Feldmann et al. as the beginning. This study was conducted to determine the impact of characteristic gene mutations on late-onset (age > or = 7 years) hemophagocytic lymphohistiocytosis episodes. We analyzed perforin gene mutations in three late-onset cases from our registry in Japan and an additional 10 cases from the literature. Of the 13 cases with onset ages of a median of 10 (range 7-49) years, nine had homozygous and four had compound heterozygous missense mutations of the perforin gene. None had homozygous nonsense mutations. Our data suggest that nonsense perforin gene mutations yield early onset and missense mutations late onset in FHL2 cases.

Leukapheresis and cranial irradiation in patients with hyperleukocytic acute myeloid leukemia: no impact on early mortality and intracranial hemorrhage.

Abstract: To assess the role of leukapheresis and cranial irradiation in reducing the incidence of intracranial hemorrhage (ICH) and early death in patients with hyperleukocytic acute myeloid leukemia (AML) and the impact of such treatment on survival. This study retrospectively analyzed the records of 75 patients with hyperleukocytic AML who had a white cell count over 100,000/μL. All patients had de novo AML except for two with therapy-related AML. Various factors were assessed for their impact on morbidity and mortality, particularly the role of pre-induction leukapharesis and cranial irradiation. The most significant risk factors for ICH were the presence of two or more symptoms of leukostasis (odds ratios [OR] 10.6, 95% CI: 2.67–42.02; P = 0.001) and respiratory distress (OR 5.41, 95% CI: 1.44–20.32, P = 0.012). The most significant risk factors for early death were age ≥ 65 (OR 4.21, 95% CI: 1.45–12.21, P = 0.008), respiratory failure (OR 3.34, 95% CI: 1.24–9.50, P = 0.018), and two or more symptoms (OR 3.50 95% CI: 1.16–10.52, P = 0.026). Neither leukapheresis nor cranial irradiation were significantly associated with a decreased incidence of ICH (P = 0.349 and 0.378, respectively). Leukapheresis had no significant influence on early death (P = 0.367). The median survival patients receiving no pretreatment was 10.50 months (range 2.58–18.42) and for those receiving pretreatment 1.50 months (range 0.10–3.16; log-rank test, P = 0.062). Leukapheresis and cranial irradiation do not improve survival or decrease the incidence of ICH in adults with hyperleukocytic AML. Am. J. Hematol., 2007. © 2007 Wiley-Liss, Inc.

Copper deficiency causes reversible myelodysplasia

Abstract: Copper deficiency is a recognized but often overlooked cause of anemia and neutropenia. We began checking serum copper levels on patients referred for evaluation for unexplained anemia and neutropenia or myelodysplasia. Eight patients were identified as copper deficient (serum copper less than 70 μg/dL). The anemia was normochromic and normocytic in seven patients. Neutropenia was present in seven patients. Seven patients had been referred for evaluation of myelodysplasia. Three were seen for consideration for allogenic stem cell transplant. Five patients had concomitant peripheral neurological symptoms. Seven patients were treated with oral copper gluconate. All treated patients demonstrated a hematological response; seven had a complete remission. The improvement in anemia and neutropenia was rapid with normalization of blood counts within three to four weeks. In one patient, normalization of the underlying marrow dysplasia was demonstrated by bone marrow histology eight months after copper replacement. The cause of copper deficiency was felt to be gastrointestinal malabsorption in five of our patients. We conclude that copper deficiency should be considered in all patients with unexplained anemia and neutropenia or myelodysplasia. Am. J. Hematol., 2007. © 2007 Wiley-Liss, Inc.

Osteoporosis in young haemophiliacs from western India.

Abstract: Arthropathies and joint deformities in patients with severe hemophilia result in prolonged immobilization, reduced physical activity, and predispose them for osteoporosis This can lead to an increasing tendency of bone fragility and fractures in patients after trivial trauma The aim of this study was to find out (i) the prevalence of osteoporosis in hemophilia patients and (ii) the association of osteoporosis with hemophilic arthropathy and related restricted physical activity In this case-control study, 50 consecutive severe hemophilia patients aged between 20 and 50 years were evaluated for osteoporosis with measurement of bone mass density (BMD) by a DEXA scan and values were compared with that of 50 sex matched normal healthy controls Major joints of the limbs were evaluated to determine the extent of joint damage and related disability Forty-two patients had severe hemophilia A and 8 patients severe hemophilia B (efficient factor activity < 001 U/ml) BMD values (gms/cm(2)) of lumbar spine and left hip of the patients were significantly lower than that of controls (0825 vs 0939; P < 00001 and 0725 vs 0938; P < 00001, respectively) The incidence of osteoporosis (T score: -25 or more) was significantly higher in hemophiliacs Incidence of fractures in adult life was also significantly higher in hemophiliacs compared to controls (12% vs 0%) There was statistically significant correlation between joint evaluation scores and BMD of hip, but not with that of the lumbar spine There was no correlation between Hepatitis-C virus status and BMD of any site This shows that development of osteoporosis is a significant problem in patients with severe hemophilia in this country Hence appropriate preventive measures such as early treatment and adequate mobilization, exercises, encouragement to participate in sporting activities, early assessment of bone density, and administration of anti-osteoporotic therapy is recommended

Preclinical assessment of curcumin as a potential therapy for B-CLL

Abstract: Curcumin, the principle component of the spice turmeric, has been used as an anti-inflammatory medication in India and China for centuries. Recent studies, predominantly using actively dividing cell lines, have suggested that this compound could be used as a chemopreventative or therapeutic agent for epithelial tumors. As curcumin has been reported to inhibit the NIK/IKK complex, an activity that would be expected to induce apoptosis in B cell malignancies, we sought to determine whether curcumin induces apoptosis in vitro in primary chronic lymphocytic leukemia (B-CLL) cells. Primary leukemic cells were incubated with varying dosages of curcumin, followed by assessment for apoptosis. The role of PPARgamma or NF-kappaB signaling in curcumin-induced apoptosis was examined by cotreatment with a PPARgamma antagonist or EMSA of nuclear NFkappaB complexes. We also examined whether a clinically achievable concentration of curcumin (1 microM) would augment the apoptotic effects of fludarabine, dexamethasone, vincristine or the PDE4 inhibitor rolipram. In B-CLL cells from 14 patients, curcumin-induced apoptosis with a mean EC(50) of 5.5 microM. In contrast, the EC(50) for whole mononuclear cells from a healthy donor was 21.8 microM. In a 48 hr wash-out time course, curcumin-induced apoptosis was time-dependent, with a substantial reduction in apoptosis observed when curcumin was removed after 5 hr. Curcumin treatment reduced basal nuclear NF-kappaB levels and 1 microM curcumin augmented both vinca alkaloid and PDE4 inhibitor-induced apoptosis in B-CLL cells. Our studies suggest that curcumin may augment the efficacy of established or experimental therapies for B-CLL.

Prevention of red cell alloimmunization by CD25 regulatory T cells in mouse models

Abstract: Transfusion therapy is currently an effective therapeutic intervention in a number of diseases, including sickle cell disease. However, its use is complicated by a high incidence of red blood cell (RBC) alloimmunization in the transfusion recipients. The identification of T regulatory cells (Tregs) among the CD4+ CD25+ T cell subset as key regulators of peripheral tolerance in mice as well as humans has opened an exciting era in the prevention and treatment of autoimmune disease and for improving organ transplantation. However, their potential in inducing transfusion tolerance remains to be explored. We used red cells from mice transgenic for human glycophorin A blood group antigen as donor cells and transfused wild-type mice to induce alloantibodies, as an experimental system to study RBC alloimmunization. We found that depletion with anti-CD25 enhanced the alloantibody production, indicating that CD25 Tregs play an important role in regulation of alloantibody responses. More importantly, adoptive transfer of purified population of CD4+CD25+ but not CD4+CD25− cells from naive mice prevented the induction of IgG and IgM alloantibody production in transfusion recipients, with a concomitant reduction in activated splenic B cells and macrophages. Similarly, adoptive transfer of purified populations of CD4+CD25+ cells from naive mice into naive syngeneic recipients inhibited the anti-Ig response to rat RBCs in the recipients but transfer of control CD4+CD25− cells did not. Altogether, our results demonstrate that Tregs participate in the control of transfusion-associated RBC alloantibody responses, opening up the possibility that Treg immunotherapy may be exploited for suppressing transfusion immunization events. Am. J. Hematol., 2007. © 2007 Wiley-Liss, Inc.

Chlamydia psittaci infection and clinicopathologic analysis of ocular adnexal lymphomas in Korea.

Abstract: Ocular adnexal lymphoma (OAL) is a mostly extranodal marginal zone lymphoma (EMZL). Recent findings have suggested an association between Chlamydia psittaci (Cp) infection and OAL. We sought to confirm this issue and to analyze the clinicopathologic characteristics of OAL in Korea. Between 1993 and 2004, 33 OAL cases were identified at the Asan Medical Center, Seoul, Korea. DNA was extracted from paraffin-embedded tissues, and touchdown enzyme time release polymerase chain reaction was performed to identify three Chlamydia species (Cp, C. tracomatis, and C. pneumoniae). The same procedures were also performed in 21 samples from patients with non-neoplastic ocular adnexal disease (NNOAD). All OAL cases were EMZL. Cp DNA was detected in 26/33 (79%) OAL samples compared with 5/21 (23%) NNOAD samples (P < 0.001). With a median follow-up of 38.5 months (range: 1-105 months), the 5-year progression-free survival (PFS) and overall survival (OS) rates of OAL patients were 72% and 93%, respectively. Clinicopathologic characteristics, recurrence rate, PFS, and OS were not associated with Cp infection. Our study demonstrates an association between OAL and Cp infection in Korea, suggesting that Cp plays a role as a causative antigen in Korean OAL patients.

Hematologic reference values for African American children and adolescents

Abstract: Anemia is prevalent among African American children. When evaluating pediatric patients for anemia, clinicians refer to the normative hematological reference values in reference textbooks. These reference values are used in spite of evidence that healthy African American people of all ages have average hemoglobin concentrations from 0.5 to 0.73 g/dl below those of Whites. In an earlier study, using samples from 2,161 healthy African American children from 2 to 18 years old, we found a statistically significant difference (P < 0.0001) in the mean hemoglobin value for each age group as compared to reference normative mean hemoglobin values. Here we present the results of a comparative analysis of the data set from our previous study and the data set from the National Health and Nutrition Examination Surveys III (NHANES III) 1988-1994. We found no statistically significant difference between these data sets with respect to the hemoglobin values for any age or sex group, confirming that African American children and adolescents have lower mean hemoglobin values than do Whites. Use of the reference hemoglobin values presented here will help prevent the misdiagnosis of anemia in African American children and thereby minimize unnecessary hematological workups and treatment.

Crypt loss is a marker of clinical severity of acute gastrointestinal graft-versus-host disease.

Abstract: Background: Crypt loss is a histological finding in acute gastrointestinal Graft-Versus-Host Disease (GI-GvHD) of undefined clinical significance. Methods: Colonic crypt loss was graded in twenty-three patients treated for GI-GvHD following stem cell transplantation and then correlated with clinical parameters of disease severity and mortality. Results: Crypt loss was present in 17/23 cases, and in 11/23 cases crypt loss was deemed severe by the presence of contiguous areas of crypt loss. Nine of 11 patients with severe crypt loss had daily stool volumes in excess of 1000 ml/day, while only 3/12 of those with minimal or no crypt loss had this level of severe diarrhea. All 11 patients with severe crypt loss had a pathologic appearance at endoscopy and 10/11 had steroid refractory disease. Diarrhea resolved in only 3/9 patients with severe crypt loss. Five out of 10 patients (50%) with severe crypt loss expired within 15 months of diagnosis. All five deaths were attributable to the progression of GvHD itself or infection in the presence of continued GI-GvHD. Conversely, only 1 of 12 patients (8%) with mild or no crypt loss had a death attributable to GvHD or infection. Conclusions: This study shows that severe colonic crypt loss predicts severe clinical GI-GvHD that is more likely to be refractory to steroid treatment. In addition, crypt loss severity appears associated with higher mortality related to GvHD. Crypt loss can serve as a tool to predict clinically severe GI-GvHD. Am. J. Hematol. 82:881–886, 2007. © 2007 Wiley-Liss, Inc.