Detection, evaluation, and management of preoperative anaemia in the elective orthopaedic surgical patient: NATA guidelines.

Previously undiagnosed anaemia is common in elective orthopaedic surgical patients and is associated with increased likelihood of blood transfusion and increased perioperative morbidity and mortality. A standardized approach for the detection, evaluation, and management of anaemia in this setting has been identified as an unmet medical need. A multidisciplinary panel of physicians was convened by the Network for Advancement of Transfusion Alternatives (NATA) with the aim of developing practice guidelines for the detection, evaluation, and management of preoperative anaemia in elective orthopaedic surgery. A systematic literature review and critical evaluation of the evidence was performed, and recommendations were formulated according to the method proposed by the Grades of Recommendation Assessment, Development and Evaluation (GRADE) Working Group. We recommend that elective orthopaedic surgical patients have a haemoglobin (Hb) level determination 28 days before the scheduled surgical procedure if possible (Grade 1C). We suggest that the patient's target Hb before elective surgery be within the normal range, according to the World Health Organization criteria (Grade 2C). We recommend further laboratory testing to evaluate anaemia for nutritional deficiencies, chronic renal insufficiency, and/or chronic inflammatory disease (Grade 1C). We recommend that nutritional deficiencies be treated (Grade 1C). We suggest that erythropoiesis-stimulating agents be used for anaemic patients in whom nutritional deficiencies have been ruled out, corrected, or both (Grade 2A). Anaemia should be viewed as a serious and treatable medical condition, rather than simply an abnormal laboratory value. Implementation of anaemia management in the elective orthopaedic surgery setting will improve patient outcomes.

Lentiviral PU.1 overexpression restores differentiation in myeloid leukemic blasts.

PU.1, a transcription factor of the ETS family, plays a pivotal role in normal hematopoiesis, and particularly in myeloid differentiation. Altered PU.1 function is possibly implicated in leukemogenesis, as PU.1 gene mutations were identified in some patients with acute myeloid leukemia (AML) and as several oncogenic products (AML1-ETO, promyelocytic leukemia-retinoic acid receptor alpha, FMS-like receptor tyrosine kinase 3 internal tandem duplication) are associated with PU.1 downregulation. To demonstrate directly a role of PU.1 in the blocked differentiation of leukemic blasts, we transduced cells from myeloid cell lines and primary blasts from AML patients with a lentivector encoding PU.1. In NB4 cells we obtained increases in PU.1 mRNA and protein, comparable to increases obtained with all-trans retinoic acid-stimulation. Transduced cells showed increased myelomonocytic surface antigen expression, decreased proliferation rates and increased apoptosis. Similar results were obtained in primary AML blasts from 12 patients. These phenotypic changes are characteristic of restored blast differentiation. PU.1 should therefore constitute an interesting target for therapeutic intervention in AML.

Perioperative anaemia management: consensus statement on the role of intravenous iron.

A multidisciplinary panel of physicians was convened by Network for Advancement of Transfusion Alternatives to review the evidence on the efficacy and safety of i.v. iron administration to increase haemoglobin levels and reduce blood transfusion in patients undergoing surgery, and to develop a consensus statement on perioperative use of i.v. iron as a transfusion alternative. After conducting a systematic literature search to identify the relevant studies, critical evaluation of the evidence was performed and recommendations formulated using the Grades of Recommendation Assessment, Development and Evaluation Working Group methodology. Two randomized controlled trials (RCTs) and six observational studies in orthopaedic and cardiac surgery were evaluated. Overall, there was little benefit found for the use of i.v. iron. At best, i.v. iron supplementation was found to reduce the proportion of patients requiring transfusions and the number of transfused units in observational studies in orthopaedic surgery but not in cardiac surgery. The two RCTs had serious limitations and the six observational limited by the selection of the control groups. Thus, the quality of the available evidence is considered moderate to very low. For patients undergoing orthopaedic surgery and expected to develop severe postoperative anaemia, the panel suggests i.v. iron administration during the perioperative period (weak recommendation based on moderate/low-quality evidence). For all other types of surgery, no evidence-based recommendation can be made. The panel recommends that large, prospective, RCTs be undertaken to evaluate the efficacy and safety of i.v. iron administration in surgical patients. The implementation of some general good practice points is suggested.

Optimized lentiviral transduction of erythroid precursors from healthy adults and patients with myelodysplastic syndromes.

Lentivectors, derived from human immunodeficiency virus-1 (HIV-1), represent a novel investigational and therapeutic tool for targeting hematopoietic progenitor cells. We describe a new protocol whereby we achieved a highly efficient lentiviral transduction of erythroid precursor cells originating from the bone marrow of healthy adults and patients with myelodysplastic syndromes (MDS). CD34(+) stem cells from healthy subjects were cultured with erythropoietin, IL-3 and stem cell factor, and thereby expanded approximately 300-fold. When these cultures were transduced with a lentiviral vector expressing GFP as a reporter gene, 70% glycophorin(+) cells were GFP(+). Although proliferation and levels of transduction were reduced in cultures of CD34(+) stem cells from patients with myelodysplastic syndromes, 50% of glycophorin(+) cells became GFP(+), amongst which 30% were sideroblastic erythroid precursors. This study demonstrates that lentiviral vectors are capable of efficiently transducing MDS precursors and offers new perspectives to investigate the influence of specific genes on normal erythroid differentiation. This may eventually help to correct defects in patients suffering from myelodysplastic syndromes.

Malignant histiocytosis in the leukaemic stage: a new entity (M5c-AML) in the FAB classification?

Malignant histiocytosis (MH) is a rare, rapidly fatal disorder, characterized by systemic proliferation of abnormal histiocytes. Most patients present with pancytopenia. We report the case of a patient with MH in the leukaemic stage, who presented extremely pronounced general symptoms and multisystemic involvement. Determination of serum cytokines showed high levels of tumor necrosis factor (TNF), interleukin 6 (IL-6) and interleukin 1 receptor antagonist (IL-1ra). Cytogenetic studies proved the monoclonality of the histiocytic proliferation. These findings strongly suggest that we are dealing with a proliferation of activated macrophages (= histiocytes). By analogy with the monoblastic (M5a) and monocytic (M5b) acute leukaemia of the French-American-British (FAB) classification, we propose a new entity, 'M5c', designating acute histiocytic leukaemia.

Epoetin alfa as an adjuvant to autologous blood donation.

The development of anemia is one factor that can limit the donation of sufficient autologous blood (AB) to meet a patient's expected blood requirements following elective orthopedic surgery. Two clinical studies have been conducted in nonanemic patients to investigate the use of epoetin alfa as an adjuvant to AB predonation to facilitate AB procurement and minimize the development of anemia. Both studies demonstrated that patients with a normal hematocrit (Hct) can donate > or = 3 units of AB prior to surgery. However, treatment with epoetin alfa minimized the decrease in Hct associated with AB donation. While there was a trend toward a reduction in allogeneic blood exposure in patients treated with epoetin alfa, the difference relative to placebo was not significant. This observation may be explained by a limited requirement for blood in this patient population that was met by predonation of 3 AB units. Thus, the use of epoetin alfa as an adjunct to AB predonation is likely to be of most benefit in patients with a normal Hct scheduled for surgical procedures where the expected blood requirements exceed 3 units. In addition, epoetin alfa may enable patients with a low Hct, low body weight, or low predicted blood volume to participate in or to complete an AB donation program, thus reducing the possibility of exposure to allogeneic blood.

Epoetin alfa: new directions in orthopedic surgery.

The introduction of autologous blood (AB) donation programs has led to a decrease in the number of orthopedic surgery patients exposed to allogeneic blood, although there is still room for improvement. For example, some patients may not be able to donate sufficient AB to meet their expected blood requirements. Virtually all nonanemic patients can donate 3 AB units prior to orthopedic surgery before further AB donation is limited by the development of anemia. In preliminary studies, the administration of epoetin alfa (150 IU/kg subcutaneously (s.c.) on alternate days; six doses) following the donation of 3 AB units reversed phlebotomy-induced anemia and enabled a further 2 units of AB to be collected. The ability of this therapeutic approach to increase AB procurement and reduce allogeneic blood requirements is being investigated in an ongoing, placebo-controlled study. An alternative approach may be to combine perisurgical treatment with epoetin alfa and normovolemic hemodilution (NVHD) prior to orthopedic surgery. Although such studies have yet to be initiated, they may demonstrate a reduction in allogeneic blood exposure in patients unable to donate AB prior to orthopedic surgery, a group of patients traditionally at high risk of exposure to allogeneic blood.

Adoptive immunotherapy for recurrent CML after BMT.

Three patients with CML who relapsed after transplantation with T-depleted BM from their HLA-identical siblings were treated with transfusions of donor peripheral blood mononuclear cells, in combination with (short) IFN alpha 2 therapy. CML was successfully controlled as shown by the complete disappearance of Philadelphia-positive metaphases within 90 days of treatment. This treatment appears to be very effective as neither bcr-abl transcripts nor markers specific for hematological cells of recipient origin could be detected by very sensitive PCR techniques. Two patients treated in chronic phase are without evidence of disease 300 and 360 days after treatment. The third patient, treated in accelerated phase, died with BM aplasia, 39 days following PBMC infusions. Failure to detect residual donor-derived granulocytes, as was the case in this patient prior to initiating adoptive immunotherapy, may indicate loss of donor-derived BM activity. This may help predict and possibly prevent the occurrence of life-threatening aplasia after successful clearance of malignant hematopoiesis.

Hypothesis for generation of the unstable Hb Bucuresti (beta 42 Phe-->Leu) mutation.

INTRODUCTION: Unstable hemoglobin disorders are characterized by a congenital, mostly familial chronic hemolytic anemia with episodes of severe hemolysis during febrile illnesses. Usually, isopropanol and heat stability tests lead to the diagnosis which is confirmed by protein and gene sequencing. Generation of the mutations is still a subject of controversy. PATIENT, MATERIALS AND METHODS: We describe a 6-year-old Swiss child with congenital hemolytic anemia and a negative family history. Hemoglobin was studied by IEF, HPLC reverse phase chromatography, heat stability and isopropranol tests. DNA was sequenced in both coding and non-coding strands. RESULTS: An unstable Hb was diagnosed on the basis of positive heat stability and isopropranol tests. The TTT-->TTG mutation at codon 42 corresponding to a Phe-->Leu substitution was found on DNA sequencing. Paternity was confirmed indicating that we are dealing with a new mutation. CONCLUSION: So far, three different mutations at codon 42 of the beta-chain, and two at the corresponding position of the alpha-chain have been described, all leading to a hemolytic anemia. These mutations can either represent random phenomena occurring at an important location in the heme pocket, or may be secondary to the two highly homologous zones present in this region. These homologous zones may indicate a hot spot for point mutations created by abnormal crossing over or formation of loops, and an imperfect DNA repair process.

Thalidomide in patients with advanced multiple myeloma.

INTRODUCTION: Recently, a report has suggested the efficacy and safety of thalidomide in refractory multiple myeloma. In an attempt to assess the efficacy and tolerance of thalidomide in advanced multiple myeloma (on behalf of the Intergroupe Franchophone dy Myelome (IFM)), we report the preliminary experience of the IFM with this drug. MATERIALS AND METHODS: Patients with advanced multiple myeloma (n=27) were treated with an oral dose of thalidomide (median 400 mg/day). At the start of treatment, all patients had active disease and 20 patients had received at least one autologous transplantation. RESULTS: Median follow-up was 105 days from the first administration. The serum and/or urine levels of the M-component were reduced by at least 75% in four patients including one patient with a >90% reduction, by at least 50% in five patients and by at least 25% in three patients, giving a total response rate of 45% (12 out of 27 patients). Nine patients had stable disease and six patients had progressed disease. Short-term side-effects of thalidomide were generally moderate. CONCLUSION: This study confirms that thalidomide is an effective agent in patients with advanced myeloma.

Ring chromosomes and hematologic disorders.

Based on 5 years of cytogenetic evaluation in hematology, we report our observations on various hematologic proliferative disorders with ring chromosomes. Comparing our data to those previously published in the literature we analyzed the occurrence of the ring in relation to the age of onset, previous history of therapeutic or professional exposure to mutagenic agents, and mean survival. It is concluded that the presence of ring chromosomes may be linked to a poor prognosis.

Cytogenetic analysis of 54 cases of myelodysplastic syndrome.

Fifty-four patients with myelodysplastic syndrome (MDS) (35 men and 19 women aged 34-92 years) were studied cytogenetically. Bone marrow cell culture and chromosome preparation were performed according to four different protocols used in parallel: methotrexate (MTX)-synchronized or thymidine (TdR)-unsynchronized techniques, and presence or absence of 5637 conditioned medium (CM). Some patients responded better to MTX; others had better results with TdR exposure only. Use of 5637 CM generally improved quantity and quality of metaphases. A cytogenetic result was obtained in 53 cases. 60% of the patients had a chromosome abnormality. Percentage of abnormality varied from one French-American-British (FAB) subtype to the other: 62% in refractory anemia with ringed sideroblasts (RARS, 8/13), 50% in refractory anemia (RA, 6/12), 60% in refractory anemia with excess of blasts (RAEB, 3/5), 77% in refractory anemia with excess of blasts in transformation (RAEB-T, 7/9), and 57% in chronic myelomonocytic leukemia (CMMoL, 8/14). Chromosome defects were subdivided into three categories: single, two, and complex defects. The most frequent chromosome abnormalities, either single or one of two or complex defects were del(5q) or monosomy 5 (13 cases), trisomy or rearrangement of chromosome 8 (eight cases), total or partial monosomy or rearrangement of chromosome 7 (eight cases), Y loss (seven cases), and del(20q) (two cases). With the exception of del(5q) in macrocytic RA, this study confirms the absence of chromosome defects specific to each FAB category of MDS. Recurrent defects in MDS are relatively limited, however, in terms of chromosomes involved and type of abnormality. Consequently, these defects, mostly of deleted type, are assumed to play a specific role in the genesis of myelodysplasia.

Translocation 2;11 and other significant chromosome changes in acute monoblastic leukemia (M5) with clonal evolution: sequential clinical and cytogenetic studies.

An elderly woman presented with pancytopenia resulting from acute monoblastic leukemia (AMoL) type M5a. At the time of diagnosis, the marrow metaphase studies revealed a pseudodiploid idiogram: 46,XX,t(2;11)(q37;q23),(t(7;9;10)(q22;q22;p13). At relapse, 7 months later, a clonal derivative of the initial pseudodiploid pattern was identified. Though alterations of chromosome regions 7q22 and 9q22 are frequently seen in acute nonlymphocytic leukemia (ANLL), 11q structural anomalies are even more specific for this group of leukemias, and the involvement of band 11q23 is particularly striking in AMoL. Various chromosomes may take part in translocations with chromosome #11, but the participation of chromosome #2 as in this case is apparently rare.

Three new cases of chromosome 3 rearrangement in bands q21 and q26 with abnormal thrombopoiesis bring further evidence to the existence of a 3q21q26 syndrome.

Defects of 3q in bands q21 and q26 have been reported in more than 70 cases of acute nonlymphocytic leukemia (ANLL), myelodysplastic syndrome (MDS), and myeloproliferative disorder (MPD) in blast crisis. In this paper three additional patients are described: patient 1 with refractory anemia with excess of blasts in transformation (RAEB-T) and inv(3)(q21q26), patient 2 with RAEB-T and t(3;3)(q21;q26), and patient 3 with myelofibrosis with myeloid metaplasia (MMM) in blast crisis and inv(3)(q21q26). In addition to 3q rearrangements, monosomy 7 and del(7)(q22q36) were observed in patients 1 and 2, respectively. In the three patients, the most characteristic clinical features were elevated platelet counts, marked hyperplasia with dysplasia of the megakaryocytes, and poor prognosis. Although disturbance of thrombopoiesis was not systematically observed in all patients with t(3;3)(q21;q26), inv(3)(q21q26), and ins or dup(3)(q21----q26), study of the 77 cases reported and of the three cases presented here brings further evidence to the existence of a cytogenetic syndrome involving bands q21 and q26 simultaneously, which represents a subtype of ANLL, MDS, and MPD, characterized by normal or elevated platelet counts, hyperplasia with dysplasia of megakaryocytes, multilineage involvement, young median age of patients with MDS, preferential involvement of women in t(3;3), high incidence of chromosome 7 defects in MDS and ANLL, short duration of the MDS phase, no response to chemotherapy, short survival, and por prognosis.

Prediction of 18-month survival in patients with primary myelodysplastic syndrome. A regression model and scoring system based on the combination of chromosome findings and the Bournemouth score.

The predictive potential of six selected factors was assessed in 72 patients with primary myelodysplastic syndrome using univariate and multivariate logistic regression analysis of survival at 18 months. Factors were age (above median of 69 years), dysplastic features in the three myeloid bone marrow cell lineages, presence of chromosome defects, all metaphases abnormal, double or complex chromosome defects (C23), and a Bournemouth score of 2, 3, or 4 (B234). In the multivariate approach, B234 and C23 proved to be significantly associated with a reduction in the survival probability. The similarity of the regression coefficients associated with these two factors means that they have about the same weight. Consequently, the model was simplified by counting the number of factors (0, 1, or 2) present in each patient, thus generating a scoring system called the Lausanne-Bournemouth score (LB score). The LB score combines the well-recognized and easy-to-use Bournemouth score (B score) with the chromosome defect complexity, C23 constituting an additional indicator of patient outcome. The predicted risk of death within 18 months calculated from the model is as follows: 7.1% (confidence interval: 1.7-24.8) for patients with an LB score of 0, 60.1% (44.7-73.8) for an LB score of 1, and 96.8% (84.5-99.4) for an LB score of 2. The scoring system presented here has several interesting features. The LB score may improve the predictive value of the B score, as it is able to recognize two prognostic groups in the intermediate risk category of patients with B scores of 2 or 3. It has also the ability to identify two distinct prognostic subclasses among RAEB and possibly CMML patients. In addition to its above-described usefulness in the prognostic evaluation, the LB score may bring new insights into the understanding of evolution patterns in MDS. We used the combination of the B score and chromosome complexity to define four classes which may be considered four possible states of myelodysplasia and which describe two distinct evolutional pathways.

Hematologic, clinical, and cytogenetic analysis in 109 patients with primary myelodysplastic syndrome. Prognostic significance of morphology and chromosome findings.

One hundred and nine patients with primary myelodysplastic syndrome (MDS) were classified according to the French-American-British (FAB) criteria: 27 refractory anemia (RA, 25%), 26 RA with ringed sideroblasts (RARS, 24%), 16 RA with excess of blasts (RAEB, 15%), 10 RAEB in transformation (RAEB-t, 9%), 25 chronic myelomonocytic leukemia (CMMoL, 23%), and five unclassifiable MDS (4%). Forty-three were women and 66 were men (sex ratio 2:3). Age ranged from 30-92 years (mean 69 years) with nine patients aged less than 50 years (8%). A cytogenetic result was obtained in all cases. At initial study, a chromosome defect was observed in 56% of patients. Rates of abnormality depended on FAB subtype: 52% in RA, 100% in RA 5q-, 50% in RARS, 56% in RAEB, 70% in RAEB-t and 44% in CMMoL. The most frequent single defects were del(5q), -7/del(7q), del(20q), Y loss, and +8. Except for the 5q- syndrome entity, specific chromosome defects were not associated with particular FAB subtypes. Bone marrow (BM) insufficiency (22%) and leukemic transformation (21%) were the most important causes of death. The rate of leukemic transformation increased with the number of dysplastic BM cell lineages and was also associated with karyotype complexity and the proportion of abnormal/normal metaphases. The longest median survivals were observed in RARS (142 months) and RA/RA5q- (91 months) types. Median survivals decreased with increasing Bournemouth score values. Patients with three abnormal cell lineages had a median survival shorter than those with one or two abnormal lineages. Similarly, patients with complex defects had shorter survival than those with single or double defects or a normal karyotype. There was no statistically significant difference between survival of NN (normal), AN (abnormal/normal), and AA patients or between survival of patients with del(5q), -7/del(7q), +8 or del(20q).

Blood transfusion requirements in otolaryngology--head and neck surgery.

BACKGROUND: Blood requirements for Head and Neck surgical procedures have not been studied carefully. In order to set up an autotransfusion program, the blood loss and transfusion requirements should be known precisely. METHODS: The blood bank database was used to determine which Head and Neck procedures required blood transfusion during the previous 5 years. A list of 10 transfusion-associated operations was established, the records of all patients who underwent these procedures during a 5-year period were reviewed, and average the blood loss and number of units transfused determined. RESULTS: All procedures were for cancer resection. The operations were classified in 3 groups according to their transfusion probability: high (> 80%), low (< 5%) and moderate. For the moderate transfusion group, age, preoperative hemoglobin, and past medical history of cardiac and pulmonary disease were associated with higher incidence of transfusion. An average delay of 3 weeks was found between the diagnosis and the actual surgery. CONCLUSION: The transfusion requirements of Head and Neck surgical procedures could be safely met by an autotransfusion protocol, given the average delay of 3 weeks between diagnosis and surgery.

[Current drug therapy of autoimmune diseases]. / Pharmacothérapie actuelle des maladies autoimmunes.

The aim of present-day chemotherapy treatment of chronic autoimmune diseases is to correct any disturbance in equilibrium of immune surveillance and to have a global immunosuppressive effect. Corticosteroids are the most important immunosuppressive agents. If they are administered three days out of four it is possible to preserve adrenal function. The addition of cytotoxic agents to steroids in immunosuppressive therapy allows one to preserve the immunosuppressive effect, while reducing the side effects of the steroid treatment. The use of alkylating agents must be limited because of their undoubted oncogenic effect, even though they are very effective immunosuppressive agents. Anti-lymphocyte-antithymocyte serum is a particular immunosuppressive method used primarily in autoimmune disorders associated with T lymphocyte pathology, as is cyclosporin A. Finally, plasma exchange in conjunction with immunosuppressive agents (methyl prednisolone + cyclophosphamide) administered intravenously as an intensive treatment is used only in patients with very active autoimmune disorders.