AIDS-associated non-Hodgkin's lymphomas as primary and secondary AIDS diagnoses in hemophiliacs. Hemophilia Malignancy Study Group.

We studied the characteristics and temporal trends of AIDS- associated non-Hodgkin's lymphoma (AIDS-NHL) in individuals with hemophilia. Prospective data were collected on 33 HIV-positive hemophiliacs with AIDS-NHL enrolled in the Hemophilia Malignancy Study (HMS), of whom 21 had primary and 12 had secondary or subsequent AIDS-defining illnesses, and analyzed for frequency and temporal trends. As compared with primary AIDS- NHL, secondary AIDS-NHL occurred at an older mean age, 37 versus 29 years (p = 0.12); at a lower mean CD4 count, 46 versus 154 (p = 0.07); after a longer period of immunosuppression (CD4 < 200/microl), 41 versus 16 months (p = 0.03); and with shorter median survival, 2 versus 7 months (p = 0.09). The presence of EBV in tumor tissue was associated with shorter survival, 1 versus 7 months (p = 0.17). Between 1981 and 1988 and 1989 and 1994, the proportion of primary AIDS diagnoses that were AIDS-NHL changed minimally, 4.6 versus 6.1%, whereas there were significant decreases in Pneumocystis carinii pneumonia (PCP, p = 0.02) and wasting (p = 0.07), and an increase in Candida (p = 0.004). These findings confirm that an increasing proportion of AIDS-NHL in hemophiliacs are occurring as secondary or later AIDS diagnoses, and they are associated with prolonged duration of immunosuppression.

Anemia of malignancy.

Anemia is a common association of malignant disease. It may be the first diagnostic clue to an underlying malignant disease, it may contribute to the patient's symptoms from the disease, and it may affect treatment decisions. It is important to recognize that a number of underlying mechanisms may contribute to the anemia, and to exclude those that are treatable. The recognition that tumor-associated cytokine production is a major factor in the anemia of malignancy, and that recombinant EPO can overcome this suppression, are major steps forward.

Thrombocytopenia. Issues in diagnosis and therapy.

Thrombocytopenia is defined by clinical characteristics and pathophysiologic mechanisms. The patient with thrombocytopenia often presents diagnostic and management challenges simultaneously. The differential diagnosis is broad because the disorders leading to thrombocytopenia are diverse, with failed production at one extreme and accelerated destruction at the other. Reviewed in terms of diagnosis and therapy are pseudothrombocytopenia, dilutional thrombocytopenia, and the three major mechanisms: decreased production, altered distribution, and increased destruction.

Effects of subcutaneous recombinant human erythropoietin in normal subjects: development of decreased reticulocyte hemoglobin content and iron-deficient erythropoiesis.

The present study evaluates the properties of the reticulocytes produced in healthy volunteers after treatment with different regimens of recombinant human erythropoietin (r-HuEPO). Twenty-four subjects were randomly assigned to one of three different subcutaneous (SC) r-HuEPO (Protcrit; Ortho Biotech) administration protocols (I: 300 U/kg on days 1, 4, 7, 10; II: 400 U/kg on days 1, 5, 9; III: 600 U/kg on days 1, 10) with oral iron supplementation (Niferex; 150 mg, twice a day). The characteristics of the reticulocytes produced were examined with a flow cytometry method that allows measurements of individual reticulocyte cell volume, hemoglobin concentration, and hemoglobin content. Administration of SC r-HuEPO was associated with a significant increase in the production of reticulocytes. The hemoglobin content of reticulocytes (CHr, in picograms of hemoglobin per cell) in the three groups was 28.5 +/- 1.0, 28.2 +/- 0.5, and 28.5 +/- 1.3, respectively, at baseline, decreased to 24.6 +/- 1.6 (p < 0.001), 24.5 +/- 2.3 (p < 0.001), and 27.5 +/- 1.8 (not significant) at day 10, and returned to baseline after r-HuEPO was discontinued (28.8 +/- 0.9, 28 +/- 0.8, and 28.8 +/- 1.4, respectively, at day 22). The percentage of reticulocytes with cell hemoglobin content less than 23 pg was taken as an indicator of iron-deficient erythropoiesis. At baseline, 5.6% +/- 2.7%, 6.9% +/- 3.4%, and 8.3% +/- 3.8% of reticulocytes had less than 23 pg hemoglobin in groups I, II, and III, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Use of recombinant human erythropoietin in allogeneic bone marrow transplant donor/recipient pairs.

In an attempt to reduce or eliminate homologous red blood cell transfusion requirements during allogeneic bone marrow transplantation (BMT), we instituted a novel program whereby recombinant human erythropoietin was administered to pairs of BMT donors and recipients. Eleven recipients and their HLA-matched donors were enrolled. Donors treated with recombinant human erythropoietin (rHuEPO) were phlebotomized a median of 6 U (range, 4 to 11 U) of blood over a 5-week period. This donor-derived blood was available to the BMT donor or recipient as needed. Transplant recipients were also treated with rHuEPO post-BMT to hasten erythropoiesis. Five of 11 BMT recipients underwent transplant receiving only donor-derived red blood cell transfusion, compared with 0 of 11 concomitant control recipients (P = .04). In addition, the time to absolute reticulocyte count > or = 10(4)/microL was statistically shorter in the rHuEPO-treated recipient group. This study serves as a paradigm for hematopoietic growth factor use in allogeneic BMT to decrease or eliminate homologous transfusion exposures and to possibly hasten hematopoietic engraftment.

Efficacy of different dosing regimens for recombinant human erythropoietin in a simulated perisurgical setting: the importance of iron availability in optimizing response.

PURPOSE: The goal of this study was to develop a short-term, practical, yet effective regimen for the perioperative use of recombinant human erythropoietin (r-HuEPO) as an alternative to autologous blood donation and/or homologous transfusion. In addition, changes in iron kinetics during accelerated erythropoiesis were examined. PATIENTS AND METHODS: A randomized trial was performed on 24 healthy, iron-replete men. Subjects were given r-HuEPO in one of three dosage schedules, receiving a total dose of 1200 U/kg r-HuEPO subcutaneously: Group I--300 U/kg on Days 1, 4, 7, and 10; Group II--400 U/kg on Days 1, 5, and 9; Group III--600 U/kg on Days 1 and 10. All subjects received 300 mg of elemental iron orally each day for 10 days beginning on Day 1. Complete blood counts (CBC), absolute reticulocyte counts, serum ferritin, serum iron, serum total iron-binding capacity (TIBC), and serum transferrin receptor protein concentrations were measured periodically during the 24-day study period. RESULTS: All groups showed a statistically significant increase in hematocrit, hemoglobin, and absolute reticulocyte count. There was no significant difference in response among the three groups with respect to hemoglobin and hematocrit. The mean maximum increases in hematocrit were 5.4 +/- 1.7, 6.0 +/- 2.1, and 7.2 +/- 2.6 in groups I, II, and III, respectively. The increase in hematocrit positively correlated with log baseline ferritin (r = 0.682, p < 0.001). Administration of r-HuEPO was associated with a highly significant (p < or = 0.0005) 74% decrease in serum ferritin, as well as a marked decrease in percent saturation of TIBC from 39% +/- 14% to 14% +/- 4% (p < or = 0.0005). This was despite the fact that subjects lost less than 250 mL of blood as a result of venipunctures during the entire course of the study. CONCLUSION: Each of these r-HuEPO dose schedules provides an effective, convenient regimen for perisurgical use. However, "normal" iron stores for basal erythropoiesis may not always be sufficient to supply optimal amounts of iron for the accelerated erythropoiesis associated with acute r-HuEPO administration, even with oral iron supplementation. Nonetheless, these findings provide support for further study of the use of r-HuEPO as an alternative to autologous blood donation in the perisurgical setting.

Blood product utilization in hip and knee arthroplasty: effect of gender and autologous blood on transfusion practice.

Analysis of total blood product support for a 1-year cohort of patients undergoing hip or knee total joint arthroplasty showed significant differences in transfusion therapy between patients who predeposited autologous blood and those who did not. In primary joint arthroplasty, 51% of nonpredepositing patients undergoing hip replacement and 28% of nonpredepositing patients undergoing knee replacement required red cell transfusions. In revision procedures, 58-61% were transfused. Predepositors requiring only autologous blood received less blood per patient than nonpredepositors; however, 73-87% of primary and 86-88% of revision arthroplasty patients were transfused. Predepositors receiving supplemental allogeneic blood used a volume of red cells comparable to nonpredepositing patients, which was significantly greater than the red cell requirement of predepositors using only autologous blood. Moreover, regardless of predeposit status, the extent of red cell replacement differed between men and women. Male patients presented with significantly higher hematocrits and were less likely to be transfused than females undergoing the same procedure. However, once the transfusion-decision was made, the average amount of red cells given for each procedure did not show gender-related variation. Despite differences in admission and lowest observed hematocrits, all patients were discharged with hematocrits in the same range, suggesting that men were replaced with relatively less blood than women. These differences in transfusion practice relating to gender and predeposit status could not be associated with identifiable changes in clinical outcome which might provide rationale for the observed differences in practice.

An unusual variant of congenital dyserythropoietic anaemia with mild maternal and lethal fetal disease.

An unusual variant of congenital dyserythropoietic anaemia is described presenting as mild haemolytic anaemia with multinucleated erythroblasts in the marrow of the proband. The outcome of her non-consanguineous pregnancy was a third trimester, in utero, fetal demise. The hydropic fetus had dyserythropoiesis with circulating multinucleated erythroblasts, and haemosiderosis. Re-evaluation of the proband revealed a variant of congenital dyserythropoietic anaemia with an inheritance pattern, and with morphological, serological and biochemical features which are not consistent with any of the three described variants of congenital dyserythropoietic anaemias.

An evaluation of the acidified glycerol lysis test.

The acidified glycerol lysis test (AGLT), as a screening procedure for spherocytosis, has been assessed for sensitivity and specificity. AGLT identified 24 of 26 subjects with hereditary spherocytosis and produced 19 abnormal AGLTs out of a total of 52 normal blood donors. The claims for the test as being both 100% sensitive and specific could not be confirmed.

Complement in acute leukaemia: its role in infection.

This study determines the frequency of complement system dysfunction in adult patients with acute myeloid leukaemia and its prognostic significance. Twenty four patients with acute leukaemia had complement studies performed at time of presentation and during the haematological trough occurring between 7 and 14 days after the administration of chemotherapy. At presentation 32% of patients had abnormal complement function. Only 54% of patients maintained normal complement activity throughout the period of remission induction. The aetiology of the disturbance is unclear and no single causative factor was determined. Patients with abnormal complement function had significantly greater morbidity from infection during the period of remission induction as measured by the number of febrile (greater than 38 degrees C) days (p less than 0.05), and were more likely to have pathogens isolated by blood culture during septic episodes (relative risk 4.0, p less than 0.01). These findings show a significant increase in morbidity associated with depressed complement function and emphasise the important role the complement system plays in maintenance of host defences.

Covalent binding of [35S]cysteine to the labile binding site of the third component of complement: a physiological approach.

The alternative pathway of complement was activated physiologically by agarose beads to which [35S]cysteine had been bound by a disulfide link. The activated form of the third component of complement, C3b, which had bound to the radioactive cysteine was then released from the agarose bead with dithiothreitol. The [35S]cysteine was shown to be covalently bound to the alpha' chain of C3b, and to its known major breakdown product, the 66,000-Da polypeptide. This is highly suggestive that complement activation has led to formation of a peptide bond between the radioactive cysteine and the labile binding site on the alpha' chain of C3b. This radioactive marker will enable the amino acid sequence of the labile binding site to be determined, with the knowledge that the labeling of the amino acid(s) has occurred during physiological activation.

Attachment of [35S]cysteine to the labile site of the third component of complement via the alternative pathway.

Agarose beads to which [35S]cysteine had been attached by a disulfide bond were incubated in serum under conditions which permitted complement fixation via the alternative pathway, then washed and treated with dithiothreitol to release the cysteine. The dithiothreitol eluate contained C3b fragments which had been labeled covalently by the radioactive cysteine. Labeling was postulated to involve the reaction of the amino group of the cysteine with the "labile site," an acylating group which is exposed when C3 is converted to C3b during the operation of the alternative complement-fixing pathway.

The decision between single- and combined-modality therapy in Hodgkin's disease.

Using the technique of decision analysis to evaluate data on single-modality and combined-modality therapy in Hodgkin's disease, we have been able to determine which treatment gives the best chance for prolonged disease-free survival in given settings. Both the potential of combined-modality therapy for inducing secondary hematologic malignancies and the rate of salvage with MOPP following relapse after radiotherapy have been studied to observe the effect of different rates of these variables on the therapeutic decision. An analysis of patients with known pathologic stage endorsed the continued use of extended-mantle radiotherapy for Stages IA and IIA disease; under most of the conditions analyzed, combined-modality therapy appeared the best option for Stage IIIA disease. The results for Stages IB and IIB disease showed neither combined-modality therapy nor total nodal irradiation to have a conclusive advantage. We also analyzed management decisions for patients who had not had pathologic staging. For this, probabilities of each pathologic stage were derived from a large patient data base and were incorporated into the decision analysis. The results of this analysis indicated that, despite the mortality of laparotomy, treatment designated according to pathologic stage was more effective than immediate combined-modality therapy for most types of patients. For certain patients in whom the clinical features could be used to predict a high probability of advanced disease, the most effective management was immediate MOPP chemotherapy without staging laparotomy.

The decision to perform staging laparotomy in symptomatic Hodgin's disease.

This study defines patients with symptomatic Hodgkin's disease for whom risks of staging laparotomy (LAP) outweigh benefits conferred by accurate knowledge of stage. From a database of more than 900 pathologically-staged patients, probabilities of pathological stage are calculated for combinations of basic findings and lymphangiogram results. Decision-making thresholds are defined at which results of treatment after LAP, taking operative mortality into account, are equivalent to immediate treatment appropriate to clinical stage. These thresholds are substantially altered by varying LAP mortality estimates, by assigning a false negative rate to LAP, and by considering uncertainty in treatment results. Fifty-four combinations of findings are described for which immediate therapy with MOPP is justified; total nodal irradiation (TNI) is never indicated in B patients without prior LAP staging. Analysing 94 B patients who had LAP showed an appreciable number might have been spared this, particularly when uncertainty in treatment results is considered. With 0.03 (=3%) uncertainty in treatment, and 1% LAP mortality, LAP was not indicated in one in seven patients; nearly one third of patients should have immediate treatment with 3% LAP mortality. Threshold analysis can define those patients for whom risks of LAP outweigh benefits.

Hodgkin's disease.

During the past two decades, new approaches to the diagnosis and treatment of Hodgkin's disease have contributed to improved rates of survival and probable cure. Currently, patients with Hodgkin's disease are treated according to the stage and symptoms of their disease. The degree of certainty necessary for determining stage depends on the potential effectiveness of the therapeutic options available in a given case. Certain cases have been identified where treatment with a single modality has been disappointing, and the use of both radiotherapy and chemotherapy may be considered for these. Such decisions can be made only by evaluating the effectiveness of salvage after relapse following single-modality treatment and assessing the added hazards of initial treatment with both modalities.