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The effect of bypassing agents is not as predictable as replacement therapy with the deficient factor in inhibitor patients. Consequently, these patients have more levels of arthropathy than patients without inhibitors. Prophylaxis for inhibitor patients has gained attention over the last decade and some papers have reported that bypassing agents could work in the prevention of arthropathy. However, there is a lack data to support any specific agent or regimen or even to recommend their use in different clinical conditions. We report ten patients with haemophilia A and inhibitors treated prophylacticaly with bypassing agents (5 with FEIBA and 5 with NovoSeven). The variable conditioning the choice of one agent or the other was the intention to initiate of immune tolerance induction therapy (ITI) in the future. In 8/10 patients (4 in FEIBA group and 4 in rFVIIa group) there was a decrease of bleeding episodes while 9/10 maintained or increased their joint range of motion (ROM). In the rFVIIa prophylaxis group, prophylaxis can be considered primary since all of them had had less than one joint bleed before prophylaxis. Economic analysis showed that prophylaxis is an expensive treatment. In our experience both agents seem to be safe and effective in reducing the number of bleeds in patients with inhibitors. The anamnestic response provoked by FEIBA could be an issue while awaiting a decline in titres before ITI can be initiated and so rFVIIa may be the best option for prophylaxis in patients with inhibitors who have not yet begun ITI.

Factor XI deficiency is a rare disease found predominantly in Ashkenazi Jews. There is a poor correlation between factor XI level and bleeding in patients with factor XI deficiency. Individuals with severe factor XI deficiency are usually at risk of excessive bleeding after surgery and injury, particularly when trauma involves tissues rich in fibrinolytic activity. Women with partial or severe deficiency are at risk of excessive uterine bleeding during labor. The unpredictable nature of factor XI deficiency complicates management during pregnancy and delivery. This review gives an overview of the management of pregnant women with factor XI deficiency.

Summary. Haemophilia patients with inhibitor have a higher level of arthropathy and more severe joint morbidity than patients without inhibitors. In recent years, interest has grown in the possibility that bypassing agent regimens could prevent bleeding and, consequently, arthropathy in inhibitor patients. Nevertheless, doubts about efficacy, complications and cost exist, questioning the justification of an uncertain prophylaxis in patients with inhibitors. Activated prothrombin complex concentrate (aPCC) has been used in more than 70 haemophilia patients with inhibitors in different clinical situations. aPCC prophylaxis seems to be safe and effective for the reduction of bleeding episodes in some patients. Recombinant activated factor VII (rFVIIa) has been employed prophylactically in over 44 haemophilia patients with inhibitors; 22 patients were included in the only randomized, prospective clinical trial of bypassing agents in prophylaxis. Bleeding frequency was reduced and this reduction was maintained during the postprophylaxis period. No thromboembolic events were reported during prophylaxis with rFVIIa. Although the effect of aPCC can last longer than that of rFVIIa, their efficacy rates are similar, suggesting that the biological effect of rFVIIa is actually much longer than indicated by its short plasma half-life. aPCC contains residual factor VIII antigen and may cause an anamnestic response in the inhibitor titre. This is crucial when immune tolerance induction is postponed to allow the inhibitor titre to decline to

Summary. Therapy with factor VIII/von Willebrand factor (FVIII/VWF) concentrate is the mainstay therapy in patients with von Willebrand disease (VWD) unresponsive to desmopressin. There are several commercially available FVIII/VWF concentrates that have been tested in VWD patients. We retrospectively analized the clinical efficacy in bleeding episodes and surgery of a highly purified FVIII/VWF complex with two inactivation steps (Fanhdi®) in VWD patients. Sixty patients were included in the study. Treatment schedule consisted of one or more doses (standard dose 40 IU/kg body weight of FVIII) of Fanhdi®. One hundred and fifty bleeding episodes were treated. These were: 28 serious bleedings; 92 moderate and 30 mild. An excellent clinical efficacy in almost 95% of cases was observed. Fanhdi® was administered during 66 surgical procedures (38 major and 28 minor) with an overall efficacy of 98%. Fanhdi® a highly purified, doubly virus-inactivated FVIII/VWF concentrate, with a high content of active VWF and an excellent record of clinical safety, is a valid choice in treating VWD.

Until recently, orthopedic surgery was strongly contraindicated in patients with hemophilia and inhibitors. However, recent advances in our knowledge of bypassing agents (particularly recombinant activated factor VII [rFVIIa]) that provide effective surgical hemostasis have allowed us to successfully perform major orthopedic procedures in these patients. Adequate hemostasis during surgery and postoperative rehabilitation is crucial, as development of a wound hematoma may jeopardize long-term outcomes. It also should be noted that success depends not only on appropriate drug therapy but also on preoperative preparations and adequate perioperative surveillance. Preoperative assessment of vascular status is very important, and strong motivation--on the part of the patient, the surgeon, and the hematologist--is needed to ensure a satisfactory result. Although inhibitor patients undergoing surgery face a higher risk of bleeding and other complications than their non-inhibitor counterparts, outcomes are generally good if a multidisciplinary team approach is applied.

Toxicity related to autologous PBSC infusion is well known and traditionally attributed to the presence of DMSO as cryoprotectant. But despite DMSO depletion, adverse events continue appearing. We have conducted a retrospective study to determine the incidence of adverse events related to the PBSC infusion in a large series of 144 patients. Adverse effects were observed in 67.36% of patients, although most of them were of grade 1 or 2. The adverse events most frequently reported were allergic reactions, followed by general, gastrointestinal and respiratory symptoms. In the univariate analysis, age (P=0.01), the volume infused (P=0.005), the amount of DMSO (P=0.008), the total nucleated cells (P=0.002), the total number of granulocytes (P=0.000001) and clumping (P=0.000001) were associated with the occurrence of adverse events. In the multivariate analysis, two protective factors, age (P=0.05) and sex (P=0.004), and two risk factors, the number of granulocytes, with a relative risk of 1.18 (95% confidence interval, 1.06-1.31) (P=0.002), and clumping, with an relative risk of 1.94 (95% confidence interval, 1.15-3.29) (P=0.013), were identified. The best cutoff point for the prediction of the occurrence of adverse events, with a sensitivity of 47% and specificity of 89%, was 6.065 x 10(9) granulocytes.

Hodgkin lymphomas (HL) and non-Hodgkin lymphomas (NHL) are clonal lymphoproliferative diseases that can present with different clinical manifestations that may be difficult to diagnose (Evans & Hancock, 2003; Re et al, 2005). The Ann Summary An accurate initial staging of patients with non-Hodgkin lymphoma (NHL) and Hodgkin lymphoma (HL) is critical for the selection of an appropriate treatment. Computed tomography (CT) remains the standard imaging technique, although it is based on anatomic criteria. Positron emission tomography (PET) with 2-deoxy-2-(fluorine-18)fluoro-d-glucose (FDG) provides useful functional information but requires anatomical correlation to localise lesions accurately. We have prospectively compared the accuracy of combined PET/CT with that of CT and PET alone at initial staging in lymphoma patients. Forty-seven newly diagnosed patients were evaluated. PET/CT was superior compared with CT and PET in nodal evaluation and detection of extranodal disease. Using a staging algorithm with PET/CT resulted in the disease stage being increased in 11 of 47 patients (10 NHL and 1 HL) (McNemar test P ¼ 0AE012). Therefore, a different treatment strategy based on PET/CT findings was suggested for seven patients (14AE8%). PET/CT markedly improves accuracy in the diagnostic work-up of patients with lymphoma.

Although there is a worldwide interest in the assessment of health-related quality-of-life (HRQoL) in haemophilia patients, no non-disease specific instruments (for adults) are readily available. In this paper, a haemophilia-specific quality-of-life assessment measure for adults (the Hemofilia-QoL questionnaire) has been developed and tested for psychometric properties in 121 adults with haemophilia living in Spain. The Hemofilia-QoL questionnaire is a self-report modular instrument that assesses nine relevant HRQoL domains for patients with haemophilia (e.g. physical health, daily activities, joint damage, pain, treatment satisfaction, treatment difficulties, emotional functioning, mental health, relationships and social activity). Psychometric examination involved the assessment of data quality, scaling assumptions, reliability (internal consistency and test-retest) and validity (concurrent; external clinical criterion and sensitivity). The Hemofilia-QoL 36-item version questionnaire had acceptable internal consistency and retest reliability values. The questionnaire shows excellent concurrent validity (with the SF-36 Health Survey) and external clinical criterion validity (haemophilia clinical status) and sensitivity (health status changes) as well. The Hemofilia-QoL is now available for adult assessment and is ready for use in clinical research in Spain.

Surgery in haemophilic patients with inhibitor against factor (F)VIII or FIX is high risk. Surgery may be performed with the administration of sufficiently high dose of FVIII in patients with low-response inhibitor or who, despite having a high response, present a low inhibitor titre at the time of surgery. The use of high doses of FX is more complicated in patients with a low-titre FIX inhibitor, as there is a high risk of anaphylactic reactions. In the case of patients with high-titre inhibitors, several treatments have been proposed, such as porcine FVIII, recombinant FVIIa (rFVIIa), and activated prothrombin complex concentrate (APCC). We present our 20 years' experience in the treatment and subsequent management of haemophilic patients with inhibitor in surgery and evaluate the results obtained with the products available for haemostatic control in 64 surgical procedures. The efficacy we obtained with FVIII is good in 100% of the cases described; we had no haemorrhagic complication (HC) in the 18 procedures in which it was used (three major and 15 minor surgery). With APCC we obtained excellent results with only one HC in a synoviorthesis in the form of bleeding and haematomas out of 32 procedures. Good results were obtained with rFVIIa with few haemorrhagic episodes. Thus, in major surgery there was one HC out of three cases. In minor surgery, greater efficacy was observed using extremely large doses of rFVIIa (> or =120 mg kg(-1) 2 h(-1)) because of the shorter half-life of this factor in this type of patients.

Objectives: Acquired hemophilia is a rare disease caused by the development of autoantibodies against factor VIII. Since 1981 we have observed 17 patients with this disorder in our institution. The objective of this survey was to assess the epidemiological features, clinical course, and mortality rate of these patients, with special emphasis on therapy-related side-effects. Also, we present our results with an immunosuppressive approach based on the severity of bleeding episodes. Methods: Clinical records of all patients with acquired hemophilia due to factor VIII inhibitor admitted or referred to our hospital between 1981 and 2001 were reviewed retrospectively. We collected each patient's sex, age, medical history, presenting symptoms, activated partial thromboplastin time, factor VIII activity, and inhibitor titre. Patient's clinical courses, including their bleeding episodes, response to therapy, and therapy-related side-effects, were also recorded. Results: Complete and partial responses were achieved in 14 and one patient, respectively (overall response rate 88%) after a median time to complete response of 3.5 months (range 30 d − 25 months). The inhibitor-related and overall mortality rates were 12% and 29%, respectively. Side-effects were frequent: two patients had blood-borne infections, three patients had thrombotic complications, and nine patients had immunosuppressive therapy-related side-effects. In five patients, discontinuation of cyclophosphamide or prednisone was required. Conclusions: Although our response rates were remarkable, this survey showed that treatment-related morbidity could also be very important. Therefore, it is pertinent to bear in mind these potential side-effects in order to decide the most appropriate therapy for each particular patient.

Over the last 4 decades, there have been very significant advances in the treatment of haemophilia. Plasma products first became available in the 1960s, beginning with cryoprecipitate and then intermediate-purity plasma concentrates, for the treatment of haemophilia A and B. The disasters of viral infections amongst people with haemophilia in the 1980s served to stimulate both the development of techniques of viral inactivation of concentrates and the manufacture of purer products. We therefore now have safe plasma products that are also pure in that they are concentrates of only the deficient protein responsible for the congenital coagulopathy. Preparations of specific coagulation proteins obtained using recombinant biotechnology techniques have been available since 1995. By contrast, pharmacological options for the treatment of the haemophilia remain very limited. The only therapeutic alternatives of real practical value which have been available in the last 30 years for the treatment of haemophilic patients are desmopressin, antifibrinolytic agents, aprotinin, concentrated oestrogens, and local haemostatic agents such as topical thrombin or fibrin glue. This article aims to assess the pharmacological basis and accumulated experience relating to these drugs when used for the prevention and treatment of bleeding in patients with haemorrhagic disorders.

Waldenström's macroglobulinemia is a low-grade lymphoma that produces monoclonal IgM. Central nervous system symptoms are frequent in Waldenström's macroglobulinemia, mostly associated with blood hyperviscosity. Nevertheless, central nervous system infiltration by malignant cells (Bing-Neel syndrome) has rarely been reported. We describe the case of a 72-year-old man with Waldenstrom's macroglobulinemia and central nervous system infiltration by malignant cells with tumor formation. All similar cases reported in the literature are reviewed and the different therapeutic approaches discussed.

Secondary myelodysplastic syndrome (MDS) and acute leukemia (AL) are well-known complications of antineoplastic therapy. The incidence of these serious complications after autologous hematopoietic transplantation ranges from 1.1% to 24%. Prior chemotherapy is its most likely cause, but other variables related to these long-term complications are seriously discussed. There is evidence that priming of progenitor cells isolated from peripheral blood with chemotherapy is also related to a higher risk of secondary MDS/AL. Whether progenitor cells isolated from bone marrow or peripheral blood after mobilization only with cytokines are related to higher risk is a controversial issue. In this paper, we analyze the incidence and variables related to these complications in a series of 99 patients diagnosed with lymphoma or multiple myeloma who underwent autologous transplantation using hematopoietic progenitors isolated from peripheral blood mobilized with granulocyte colony-stimulating factor (G-CSF). The probability of MDS/AL in patients alive 5 years after transplant in our series is 8.58%, similar to that reported in other series using bone marrow grafts. The total dose of cyclophosphamide ( p=0.099), the number of chemotherapy cycles ( p=0.04) received before transplant, and the total dose of mononuclear cells infused at the time of transplant were the only variables associated with secondary MDS/AL. Autologous transplantation with progenitor cells isolated from peripheral blood after mobilization with cytokines has probability and risk factors for secondary MDS/AL development similar to bone marrow grafts when compared with other published series.

We report our clinical experience with central venous catheters (CVCs) in 15 patients with haemophilia who, in total, had 34 catheters inserted. Eighteen devices were Hickman, six were Port-A-Cath and 10 were nontunnelled catheters (one Quinton, seven antecubital, one jugular and one subclavian vein access). All patients had factor VIII/IX inhibitors at the time of insertion. The mean age at operation was 8.8 years (range 16 months-39 years). Eight of the 15 patients (26/34 implanted catheters, 76%) presented some kind of complication. Pericatheter bleeding during the postoperative period affected a total of seven CVCs (7/34, 20%) in six patients, which required substitutive treatment for several days. Infection was reported in 15 of the CVCs (15/34, 44%), and four of these (4/15, 26%) had more than one episode, with a mean of 1.4 infection episodes per catheter (21/15). The infection rate was 0.2 infections per 1000 patient days or 0.1 per 1000 catheter days. Despite the usefulness of CVCs in haemophilic patients, the high incidence of complications requires careful assessment of the type of device as well as continuous surveillance.

Several studies have focused on investigation of the optimal salvage regimen to induce maximum response before autologous stem cell transplantation (ASCT) in patients with relapsed or refractory Hodgkin's disease (HD). However, in most of these studies, the follow-up is relatively short. In the present study, we report on long-term results of 55 consecutive patients with HD who received Mini-BEAM [BCNU (carmustine), etoposide, cytarabine, melphalan] as salvage therapy before ASCT. Eleven patients were refractory to front-line therapy, 17 were partial responders, and 27 patients had relapsed from HD. Twenty-eight patients achieved complete response, and 18 achieved partial response with a median of two cycles of Mini-BEAM, giving a total response rate of 84%. Significant factors predicting poor response (P or = two previous chemotherapy regimens and three disease characteristics at Mini-BEAM treatment: presence of B symptoms, extranodal involvement or low serum albumin. However, only the last two factors retained independent influence on multivariate analysis. In total, 45/55 patients have been transplanted. Median follow-up after Mini-BEAM administration for living patients is 68 months. At the time of reporting, 31 out of 55 patients (56.4%) are still alive, 21 patients (38%) have relapsed, three (5.4%) have developed secondary neoplasias, and five have died of other complications not related to disease progression. The actuarial 7-year overall survival (OS) was 52%, the progression-free survival (PFS) 54% and the event-free survival (EFS) 36%. The response to Mini-BEAM was the most important prognostic factor for predicting the long-term probability of surviving the disease: none of the eight patients who did not respond to Mini-BEAM were alive at 3 years. On multivariate analysis, response to Mini-BEAM and extranodal involvement before Mini-BEAM had a significant influence on OS. Our results show the safety and efficacy of Mini-BEAM before ASCT for refractory or relapsed HD patients.

Although autologous PBPC transplantation is being used increasingly for the treatment of breast cancer, there are few data on factors influencing mobilization and engraftment in these patients. We have analyzed these factors in 70 patients with advanced or metastatic breast cancer undergoing autologous PBPC transplantation. All patients were mobilized after stimulation with G-CSF, and a median of 3.16 x 10(6)/kg CD34+ cells (range 0.75-23.33) were infused. All patients received conditioning with a combination of cyclophosphamide, thiotepa, and carboplatin, and postinfusion G-CSF was administered to 60 patients. The median times to reach 0.5 x 10(9)/L and 1 x 10(9)/L neutrophils were 10 and 11 days, respectively. The median times to obtain 20 x 10(9)/L and 50 x 10(9)/L platelets were 12 and 18 days, respectively. An analysis of factors that influence CD34+ cell collection was performed by linear regression. Previous radiation therapy and increasing age were associated with lower numbers of CD34+ cells collected. Those variables that could influence the tempo of engraftment were examined by multivariate analysis using Cox regression models. The number of CD34+ cells infused was found to influence both neutrophil and platelet recovery. The use of G-CSF after transplant, accelerated neutrophil recovery, and having more than six cycles of previous chemotherapy was an unfavorable factor for recovering50 x 10(9)/L platelets.

Veno-occlusive disease of the liver (VOD) is an important complication in hematological transplantation. The aim of this study is to analyze the risk factors for VOD and other forms of liver toxicity in a cohort of 180 peripheral stem cell transplants performed in our Center. We find that elevated pretransplant levels of serum ferritin are the most important risk marker for VOD. We believe that ferritin reflects damage induced by oxygen radicals resulting from iron-mediated catalysis. We also discuss different risk factors for VOD and other forms of liver toxicity, suggesting diferent pathogenic mechanisms.

Acquired von Willebrand syndrome (AvWS) is a rare hemorrhagic diathesis with clinical symptoms similar to those associated with the inherited form of von Willebrand disease. This syndrome is characterized by the lack of previous bleeding symptoms, negative familial history, and occurrence in a relatively older age. Most commonly, AvWS develops in the course of other conditions such as lymphoproliferative, myeloproliferative, cardiovascular and autoimmune disorders; additionally it can be associated with some non-hematological malignancies and use of certain drugs. Pathogenesis of von Willebrand syndrome is complex and not fully understood. Deficiency or impaired activity of von Willebrand factor (vWF) can result from the presence of specific antibodies against this factor, its adsorption onto the surfaces of neoplastic cells, mechanic injury or proteolysis. Diagnosis is based on the measurements of plasma concentration and activity of vWF, and multimeric analysis. Management of AvWS includes the therapy of underlying disease and the control or prevention of bleeding. Hemostatic drugs

Between January 1989 and November 1995, 259 patients with multiple myeloma (MM), 22 stage I, 57 stage II and 180 stage III at diagnosis were treated with myeloablative high-dose therapy followed by autologous peripheral blood stem cell (PBSC) transplantation. The median time from diagnosis to transplantation was 17 months (6-112). At the time of transplant, 56 patients were in CR, 153 in PR, 25 were nonresponders and 25 had progressive disease. Mobilization of stem cells was performed with G-CSF alone in 141 cases, chemotherapy plus G-CSF in 65, chemotherapy plus GM-CSF in 36 and chemotherapy alone in 17 patients. The conditioning regimen consisted of high-dose melphalan alone in 96 patients, melphalan plus TBI in 73, busulfan plus melphalan in 56, busulfan plus cyclophosphamide in 27 and cyclophosphamide plus TBI in seven. The median durations of neutropenia (>0.5 x 10(9)/l) and thrombocytopenia (>20 x 10(9)/l) were 12 (5-118) and 13 days (5-360), respectively. Transplant-related mortality occurred in 11 patients (4%). Once a stable graft was achieved, 114 patients (44%) received maintenance treatment with recombinant alpha interferon (IFN-alpha). Among the 248 patients evaluable for response 125 (51%) had a CR and 100 had a PR (40%). The median duration of progression-free survival (PFS) and overall survival (OS) after transplantation was 23 and 35 months, respectively. Univariate analysis showed that response status pretransplant, only one line of primary induction treatment and IFN-alpha maintenance treatment post-transplant significantly influenced OS. Female sex, pretransplant responsive disease, and treatment with IFN-alpha post-transplant were the factors significantly influencing PFS. The conditioning regimen and method of stem cell mobilization had no significant impact on OS and PFS. On multivariate analysis the only independent factors associated with a longer survival were the number of chemotherapy courses prior to autologous PBSC transplantation and the pretransplant response status. The present analysis from the Spanish Registry confirms the feasibility of autologous PBSC transplantation in myeloma patients with a very low toxicity (4% toxic deaths). The high complete response rate after transplantation is encouraging. The best results are obtained when the procedure is performed early after the first line of induction therapy and in patients with chemosensitive disease. Whether early high-dose therapy followed by autotransplantation in responding patients is superior to conventional chemotherapy is currently being investigated in prospective randomized studies.

Pulmonary alveolar proteinosis (PAP) is a disease of unknown etiopathogenesis sometimes associated with malignant haematological disorders. The potential reversibility of the process in these cases seems to be related to recovery from the underlying disease. GM-CSF has acquired an important, potentially pathogenic role and BMT presents one therapeutic option effective in certain forms of human PAP. We present the case of a 43-year-old female patient with Ph+ CML. During pretransplantation evaluation, unexpected pulmonary infiltrates were noted in the chest X-ray, PAP being diagnosed on biopsy. In view of the progressive respiratory symptomatology and her CML being in accelerated phase, the patient underwent haematopoietic transplantation. She died on day +12 from invasive pulmonary aspergillosis before a response could be observed. Pathogenic implications in PAP and the role of haematopoietic transplantation in this disease are discussed.

This case report describes a patient with recurrent and refractory acute lymphoblastic leukaemia (ALL-L3), who relapsed four months after a HLA identical allogeneic Peripheral Blood Stem Cell (PBSC) transplantation; he was treated after relapse with intensive chemotherapy and then he received leukocyte infusion from her sibling donor. A long term Complete Remission (CR) was achieved, with complete chimerism and without signs of chronic GVHD. Thirteen months after Donor Leukocyte Infusion (DLI), he developed a relapse (4% blasts in BM), and a second infusion of leukocytes with the same chemotherapy schedule was performed. Six months after the second DLI the patient is alive. Since responses to Donor Lymphocyte Infusions (DLI) are uncommon in ALL, the possible causative factors for this unusual response are discussed.

To investigate the impact of frozen and non-frozen bone marrow on engraftment kinetics and disease outcome, 94 patients with non-Hodgkin's lymphoma (NHL) autografted with frozen marrow (F group) were retrospectively compared with 38 who received marrow stored at 4 degrees C or 10 degrees C (NF group). The major end points of this study were time to hematopoietic recovery and early toxicity; disease response, disease-free survival (DFS), and relapse rate were also analyzed. Upon comparison of the NF and F groups, no significant differences were found in the period of time required to achieve a granulocyte count higher than 0.5 x 10(9)/l (20 and 22 days, respectively, p = 0.47) or a platelet count higher than 20 x 10(9)/l (28 and 27 days, respectively, p = 0.54). In addition, both groups behaved similarly in respect to toxic death (NF group 13%, F group 22%, p = 0.36), response rate (complete remission rate 78% in both groups), DFS (NF group 48%, F group 49%, p = 0.66), and relapse rate (NF group 30, F group 19%, p = 0.37). This study confirms that nonfrozen bone marrow is useful to support patients with NHL treated with myeloablative therapies.

CD56 is a natural killer (NK) cell marker that has been identified in approximately 15-20% of acute myeloid leukemia (AML) cases, where it has been associated with monocytic morphology and chromosomal abnormalities such as trisomy 8, t(8;21), t(15;17), and 11q23 rearrangements. The clinical presentation, chromosomal abnormalities as detected by fluorescent in-situ hybridization (FISH), and clinical outcomes of 7 patients with AML are presented. These cases were characterized by French-American-British (FAB) M5 morphology, myeloperoxidase (MPO) negativity, and co-expression of myelomonocytic and NK cell-associated antigens (CD11c(+), CD13(+), CD15(+), CD33(+), HLA-DR(+), and CD56(+)). All patients presented lymph node, hepatic, or splenic involvement at diagnosis. Despite the homogeneous morphologic and immunophenotypic characteristics the outcomes varied considerably. Two patients died during induction therapy, but the other five patients attained complete remission (CR). Of these five patients, 4 have received a bone marrow transplantation (autologous or allogeneic) and 3 of them are in CR (median follow-up: 45 months). The three patients with 11q23 rearrangements had a poor outcome and died of their disease within 1 year of diagnosis. Further studies with a larger group of patients would help establish the actual prognostic value of these morphologic, immunophenotypic and cytogenetic features.

Sweet's syndrome is a neutrophilic dermatosis characterized clinically by raised, erythematous, tender lesions on the face, neck, upper thorax and extremities. Several diseases have been associated with this entity. We report a case of Sweet's syndrome associated with chronic myelogenous leukemia: a 48-year-old woman who developed recurrent skin lesions 3 years after the diagnosis of chronic myelogenous leukemia. Progression to an accelerated phase of the disease was detected 3 months after the beginning of the skin lesions. This case shows the convenience of evaluation and closer follow-up of patients with chronic myelogenous leukemia who develop skin lesions, especially if these lesions are recurrent.

We report on a series of 27 orthopaedic surgical procedures. It includes 20 radiosynoviortheses and seven major orthopaedic procedures, performed on 26 patients. The average age of patients was 36 years (range: 8-53) and the average follow-up time was 2.5 years (range:1-5). There were 23 good results and four fair. In the synoviorthesis group (20 patients, 20 synoviortheses) the average age was 13.5 years (range: 9-26) and the average follow-up was 4.5 years (range: 1-7). There were 19 good results and one fair. All synoviortheses were done with activated prothrombin complex concentrates (FEIBA), all the responses being good except in one case (which had the final fair result). The total dose of FEIBA used was 600 IU kg(-1,) except in a patient that had a haemorrhagic complication. In fact, he required a prolongation of treatment up to a total dose of 2000 IU kg(-1). In the group of major orthopaedic procedures, the average age of the six patients was 30.5 years (range: 11-53) and the average follow-up was 2.5 years (range: 1-5). There were six good results and one fair. Postoperative bleeding complications occurred in one of the seven major orthopaedic procedures performed (arterial pseudoaneurym after a total knee arthroplasty). Despite such complication, which had the final fair result, our study has shown that haemophilic patients with high inhibitor titres requiring orthopaedic surgery can undergo such procedures with a high expectation of success. In other words, orthopaedic surgery is now possible in haemophilia patients with high-titre inhibitors, leading to an improved quality of life for these patients.

Hematopoietic stem cell transplantation is a procedure necessitating the administration of high-dose chemoradiotherapy. This therapy may induce aggressive disruptions that can lead to special nutritional and metabolic conditions. These patients are at an increased risk for malnutrition in the phase before transplantation and afterward. Artificial nutrition, total parenteral nutrition in particular, is provided to patients undergoing hematopoietic stem cell transplantation to help minimize adverse nutritional consequences.

Severe combined immunodeficiencies are a group of rare genetic disorders characterized by a profound impairment in both cellular and humoral immune functions. This disorder is rapidly fatal without bone marrow transplantation. Unfortunately, most children lack a histocompatible donor. The development of T cell depletion allows for haploidentical transplantation with reduced risk of GVHD. In the present article, we discuss the case of a child diagnosed with X-linked severe combined immunodeficiency for whom haploidentical peripheral blood stem cell transplantation was performed by selecting CD34-positive cells followed by depletion of T cells. Both selection and purging were performed using immunoselection by the biotin-avidin system (CEPRATE System). The CD34-enriched T cell-depleted product contained 5.05 x 10(6)/kg CD34+ cells with only 0.01 [corrected] x 10(6)/kg CD3+ cells, achieving a T cell depletion of 4.2 log.

A haemophilia-specific health-related quality-of-life questionnaire (named 'Hemofilia-QoL') was developed to assess quality-of-life in adults with haemophilia, and was psychometrically tested. Seventy-three interviews with haemophilia patients and health care professionals were used to generate the items included in the questionnaire, and expert ratings on the items formulated were used to screen them for potential omission. This was followed by psychometric testing in a sample of 35 patients. Preliminary psychometric testing of the revised questionnaire version, which contains 10 domains (physical health, physical role, joint damage, pain, treatment satisfaction, emotional role, mental health, social support), showed acceptable reliability (alpha = 0.94 for the Hemofilia-QoL total score) and validity, and this will be examined in a subsequent study with a larger patient sample.

PBPC collection in children weighing/=25 kg is hampered by technical and clinical problems related to vascular access, low total blood volume, anticoagulation, side effects, and psychological impact. The aim of this study was to analyze several clinical and technical factors, other than pre-apheresis CD34(+) count, that may affect PBPC collection in these low-weight children.Data from 88 leukaphereses performed in 45 children were analyzed, including pre-apheresis CD34(+) cell count, COBE Spectra software (version 4.7 versus 6.0), apheresis volume [standard versus large-volume leukapheresis (LVL)] and patient's diagnosis, age, weight and sex.The median number of PBPC collected was 6.68 mononuclear cells (MNC)x10(8)/kg (range 2.36-19.05) and 1.69 CD34(+) cellsx10(6)/kg (range 0.08-13.79). Multivariate analysis showed that factors independently associated with the CD34(+) cell yield per apheresis were pre-apheresis CD34(+) cell count (P0.001), diagnosis (P=0.008) and apheresis volume (P=0.009). Recruitment of CD34(+) cells was also independently affected by the apheresis volume, being higher in the LVL group (P=0.008).We have demonstrated that, apart from the well-known influence of the pre-apheresis CD34(+) cell count, two other factors have a major impact on the CD34(+) cell yield: patient's diagnosis and apheresis volume. In addition, taking into account that side effects were mild and tolerable, we have confirmed that LVL is a safe and effective procedure in children/=25 kg, and that AutoPBSC software could be reliably used in these patients, provided that an experienced team performs the procedure.

T-cell prolymphocytic leukemia (T-PLL) is a rare lymphoproliferative disorder with distinctive clinical and laboratory features. It is often resistant to conventional chemotherapy, but complete or partial responses have been documented with the use of purine analogues. We report on two cases of T-PLL with a slightly different immunophenotype but a remarkably different response to pentostatin. We discuss the possible therapeutic implications of this finding and establish a comparison between immunophenotype and sensitivity to purine analogues in patients with T-PLL and other chronic lymphoproliferative disorders.

Acquired hemophilia is a rare disease caused by the development of autoantibodies against factor VIII. Since 1981 we have observed 17 patients with this disorder in our institution. The objective of this survey was to assess the epidemiological features, clinical course, and mortality rate of these patients, with special emphasis on therapy-related side-effects. Also, we present our results with an immunosuppressive approach based on the severity of bleeding episodes.Clinical records of all patients with acquired hemophilia due to factor VIII inhibitor admitted or referred to our hospital between 1981 and 2001 were reviewed retrospectively. We collected each patient's sex, age, medical history, presenting symptoms, activated partial thromboplastin time, factor VIII activity, and inhibitor titre. Patient's clinical courses, including their bleeding episodes, response to therapy, and therapy-related side-effects, were also recorded.Complete and partial responses were achieved in 14 and one patient, respectively (overall response rate 88%) after a median time to complete response of 3.5 months (range 30 d - 25 months). The inhibitor-related and overall mortality rates were 12% and 29%, respectively. Side-effects were frequent: two patients had blood-borne infections, three patients had thrombotic complications, and nine patients had immunosuppressive therapy-related side-effects. In five patients, discontinuation of cyclophosphamide or prednisone was required.Although our response rates were remarkable, this survey showed that treatment-related morbidity could also be very important. Therefore, it is pertinent to bear in mind these potential side-effects in order to decide the most appropriate therapy for each particular patient.

In June, 1997, we initiated a prospective study to analyze the effect of granulocyte colony-stimulating factor (G-CSF) on coagulation system in peripheral blood stem cells (PBSC) donors following G-CSF administration. Since, 25 consecutively healthy donors received G-CSF (filgrastim) to mobilize and collect PBSC and 20 donors were finally included in the study. Blood samples were collected immediately before starting G-CSF and prior to PBSC collection to analyze the following parameters: prothrombin time (PT), activated partial thromboplastin time (APTT), fibrinogen, hypercoagulability markers (D-dimer, TAT complex, F1 + 2), natural anticoagulants (antithrombin, protein C, protein S), endothelial activation markers [von Willebrand factor antigen (vWF:Ag) and angiotensin converting enzyme (ACE)], and resistance to activated protein C. We found a significant increase in F1 + 2 and D-dimer while a significant decrease of antithrombin and protein C activity was evidenced. Regarding endothelial cell activation markers, a significant increase of vWF:Ag with a slightly significant decrease of ACE were also observed. Therefore, in PBSC donors receiving G-CSF our results reveal activation of both coagulation and endothelial cells that could favor the developing of thrombotic events. In consequence, a careful monitoring should be considered in those cases with risk factors for thrombosis.

Hermansky-Pudlak syndrome is a rare autosomal recessive disorder characterized by the absence of platelet dense bodies in association with albinism. We present the use of recombinant activated factor VII (rFVIIa) in a patient with Hermansky-Pudlak syndrome who underwent total thyroidectomy because of a large richly vascularized nodule (10 cm) compressing the trachea. The patient had a prolonged bleeding time (> 20 min) that remained unchanged after platelet transfusions. However, after infusion of platelets plus rFVIIa, it diminished to 5 min. The platelet aggregation response to adenosine diphosphate and collagen was diminished. Since an early age, the patient had repeated nose bleeding and an episode of melena requiring several tampons, cauterization and transfusions of packed red cells. In this case, we used rFVIIa in bolus for 1 day (four doses of 120 microg/kg every 2 h and six doses of 100 microg/kg every 3 h) and transfusion of platelet concentrates beginning just prior to surgery. No evidence of local bleeding complication could be detected during the entire post-operative period. The hemoglobin level remained normal and no transfusions of packed red cells were necessary. No adverse events occurred.

Patients previously diagnosed with invasive aspergillosis (IA) have been considered to be at risk for relapse of mycosis during subsequent hematopoietic transplant. Even with prophylactic measures, reactivation of the infection occurs in 29% of patients undergoing bone marrow transplantation (BMT). A period of neutropenia is one of the variables considered to be a risk factor for reactivation. Peripheral blood stem cell transplant (PBSCT) results in a shorter neutropenia period leading to a lower risk of fungal infection. A retrospective data analysis performed on patients undergoing autologous PBSCT for hematological malignancies in our unit showed that nine patients were diagnosed before transplantation with IA. All patients received only medical treatment during their primary infection. Medical prophylaxis was administered in seven of these patients, and two underwent transplantation without prophylaxis. All patients developed severe neutropenia after a myeloablative regimen. All but one had neutropenic fever, although the fever was controlled and no fungal complications occurred. All patients in this series achieved complete hematological engraftment without delay in granulocyte recovery (mean: 8.78 vs 9.76; p=0.58). No significant differences were observed in toxicities with regards to transplantation between patients previously diagnosed with IA and their controls. Recurrence of IA related to transplantation was avoided since no relapse of IA was demonstrated. This series of nine patients with a previous history of IA shows that medical treatment, secondary prophylaxis, and peripheral blood as a source of stem cells could be effective measures to avoid reactivation of previous aspergillosis during hematopoietic transplantation, although prospective randomized trials should still be performed to confirm these findings in a wider setting.

In order to assess the potential clinical benefit of filgrastim (G-CSF) after peripheral blood stem cell (PBSC) autotransplantation a randomized study was begun in our center in July 1997: 62 patients were involved (30 received filgrastim after PBSC infusion and 32, the control group, received no cytokines). All were adults (median 40 years, range 18–65). Patients with one of three different pathologies were recruited: 28 had advanced breast carcinoma, 23 had lymphomas (12 Hodgkin’s disease and 11 non-Hodgkin’s lymphoma) and 11 had de novo AML. All of them were transplanted using myeloablative chemotherapy conditioning regimens. G-CSF was administered subcutaneously from day +5 in the treated group at a dose of 5 μg/kg body weight/day. The numbers of CD34+ and mononuclear (MNC) cells infused were similar in each group. Only minor differences regarding the use of G-CSF could be inferred from the analysis of the data. Faster granulocyte engraftment was evident in the treated group (mean of 10 vs 12 days to achieve >0.5 × 109/l granulocytes, P = 0.0008), without differences in incidence and severity of infections, days of fever or duration of antibiotic treatment between groups. There was slightly slower platelet engraftment (mean of 15 days in the group with G-CSF vs 12 days in the other group to achieve >20 × 109/l platelets, P = NS) in this series, but there were no differences in incidence and severity of haemorrhage or platelet transfusion support. Considering the economical costs, the median expenditure per inpatient stay was Eur5961 (range Eur4386–Eur17186) in the G-CSF group compared with Eur5751 (range Eur3676–Eur15640) in the control group (P = 0.47). From our data it could be concluded that for adult patients transplanted with PBSC there is no clear beneficial impact of post-infusion G-CSF administration.

The development of antibodies that inhibit or neutralize replacement therapy with factor VIII or factor IX is today the most serious complication of haemophilia and its treatment. Inhibitor patients have more severe joint morbidity than patients without inhibitors, and older adults experience significant orthopaedic disabilities. Because of the serious and disabling consequences of persistent inhibitors, there is considerable clinical and research interest in establishing effective bypassing agent regimens to prevent bleeding in inhibitor patients in much the same way as prophylaxis procedure works in noninhibitor patients. In the majority of these patients, the bypass agent was used as a secondary prophylactic. In this report, the use of recombinant factor VIIa prior to any clinically evident joint bleed in a patient with haemophilia A and high-titre inhibitor is described.

Although more than 50% of Hodgkin's disease patients are cured with conventional chemotherapy, many will relapse and eventually die from their disease. Many efforts have been made to identify poor prognostic factors that could be useful in selecting high-risk patients in 1st CR who may benefit from high-dose chemo/radiotherapy. However, the role of early transplantation in 1st CR remains unclear. We have retrospectively analyzed the results obtained with this procedure in 22 hospitals belonging to the Spanish GEL/TAMO cooperative group. Twenty-seven patients, of whom 19 were males, underwent autologous transplantation for Hodgkin's disease in 1st CR between January 1987 and January 1996. Remission had been achieved after one (n = 22) or two (n = 5) lines of treatment. Twenty-four patients had advanced stage disease, 12 patients bulky mediastinal disease, nine bone marrow involvement and 18 had extranodal disease. Peripheral blood was used as the source of hematopoietic stem cells in 15 patients, BM in nine, and both in three. All but three patients received chemotherapy-based conditioning regimens (16 CBV, four BEAM and four BEAC), while three were conditioned with CY and TBI. There were no transplant-related deaths. Median (range) times to recover0.5 x 10(9)/l neutrophils and50 x 10(9)/l platelets were 14 (8-56) days and 16 (8-240) days, respectively. With a median follow-up of 30 (8-66) months, 21 patients are alive and in continuous CR. Four patients who relapsed after transplant at 8, 17.5, 22 and 26 months achieved a second CR with conventional chemotherapy; one patient relapsed 92 months post-transplant and died 5 months afterwards. Another patient died 30.5 months post-transplant from a secondary malignancy. In conclusion, high-dose therapy in poor prognosis Hodgkin's disease in 1st CR was well tolerated with no transplant-related mortalities. Although the follow-up of this series is relatively short, our results seem promising. Nevertheless, late relapses can occur, and the role of this procedure vs conventional treatment in very high-risk patients should be assessed in prospective randomized studies.

To the Editor: We read with interest the report by Kawano et al[1][1]concerning the use of granulocyte colony-stimulating factor (G-CSF) after peripheral blood stem cell transplantation (PBSC) in pediatric patients. The main conclusions of this study are that filgrastim does not provide a marked