Development of a marrow transplant regimen for acute leukemia using targeted hematopoietic irradiation delivered by 131I-labeled anti-CD45 antibody, combined with cyclophosphamide and total body irradiation

In an attempt to decrease the relapse rate after bone marrow transplantation (BMT) for advanced acute leukemia, we initiated studies using 131I-labeled anti-CD45 antibody (BC8) to deliver radiation specifically to hematopoietic tissues, followed by a standard transplant preparative regimen. Biodistribution studies were performed in 23 patients using 0.5 mg/kg trace 131I-labeled BC8 antibody. The BC8 antibody was cleared rapidly from plasma with an initial disappearance half-time of 1.5 +/- 0.2 hours, presumably reflecting rapid antigen- specific binding. The mean radiation absorbed doses (cGy/mCi131I administered) were as follows: marrow, 7.1 +/- 0.8; spleen, 10.8 +/- 1.4; liver, 2.7 +/- 0.2; lungs, 2.1 +/- 0.1; kidneys, 0.7 +/- 0.1; and total body, 0.4 +/- 0.03. Patients with acute myelogenous leukemia (AML) in relapse had a higher marrow dose (11.4 cGy/mCi) than those in remission (5.2 cGy/mCi; P = .001) because of higher uptake and longer retention of radionuclide in marrow. Twenty patients were treated with a dose of 131I estimated to deliver 3.5 Gy (level 1) to 7 Gy (level 3) to liver, with marrow doses of 4 to 30 Gy and spleen doses of 7 to 60 Gy, followed by 120 mg/kg cyclophosphamide (CY) and 12 Gy total body irradiation (TBI). Nine of 13 patients with AML or refractory anemia with excess blasts (RAEB) and two of seven with acute lymphocytic leukemia (ALL) are alive disease-free at 8 to 41 months (median, 17 months) after BMT. Toxicity has not been measurably greater than that of CY/TBI alone, and the maximum tolerated dose has not been reached. This study demonstrates that with the use of 131I-BC8 substantially greater doses of radiation can be delivered to hematopoietic tissues as compared with liver, lung, or kidney, which may improve the efficacy of marrow transplantation.     

Mechanism of benefit of combination thrombolytic therapy for acute myocardial infarction: a quantitative angiographic and hematologic study.

OBJECTIVES. The goal of this study was to lend insight into the mechanisms responsible for the beneficial effects of combination thrombolytic therapy. BACKGROUND. Combination thrombolytic therapy for acute myocardial infarction has been associated with less reocclusion and fewer in-hospital clinical events than has monotherapy. METHODS. Infarct-related quantitative coronary dimensions and hemostatic protein levels were evaluated in 287 patients with acute myocardial infarction during the early (90-min) and convalescent (7-day) phases after administration of recombinant tissue-type plasminogen activator (rt-PA), urokinase or combination rt-PA and urokinase. RESULTS. Minimal lumen diameter was similar in the 90-min and 7-day phases after treatment with rt-PA, urokinase and combination rt-PA and urokinase (0.72 +/- 0.45 mm, 0.62 +/- 0.53 mm and 0.75 +/- 0.58 mm, respectively, at 90 min, p = 0.16; and 1.05 +/- 0.56 mm, 1.12 +/- 0.72 mm and 0.94 +/- 0.54 mm, respectively, at 7 days, p = 0.22). In-hospital clinical event and reocclusion rates were less frequent in patients receiving combination therapy than in those receiving monotherapy (25% vs. 38% and 32% for rt-PA and urokinase, respectively, p = 0.084; and 3% vs. 13% and 9% for rt-PA and urokinase, respectively, p = 0.03), but these events were unrelated to early or late coronary dimensions. Patients receiving combination therapy or urokinase monotherapy had significantly higher peak fibrin degradation products (1,307 +/- 860 and 1,285 +/- 898 micrograms/ml vs. 435 +/- 717 micrograms/ml, respectively, p < 0.0001) and lower nadir fibrinogen levels (0.85 +/- 1.00 and 0.75 +/- 0.53 g/liter vs. 1.90 +/- 0.86 g/liter, respectively, p < 0.0001) than did those receiving rt-PA monotherapy. Peak fibrinogen degradation products indirectly correlated (p = 0.004) and baseline (p = 0.026) and nadir (p = 0.089) fibrinogen levels directly correlated with reocclusion. CONCLUSIONS: Lower in-hospital clinical event and reocclusion rates observed with combination thrombolytic therapy may relate to systemic hematologic factors rather than to the residual lumen obstruction after thrombolysis.     

Oxidative Stress in Insulin-Resistant Conditions

The risk of cardiovascular disease (CVD) in patients with diabetes mellitus is increased more than 3-fold and is the major cause of mortality and morbidity in diabetic patients. Historically, diabetes has been considered an inadequate insulin response leading to elevated plasma glucose levels with morbidities attributable to hyperglycemia. However, diabetes represents a complex pathology that often includes hypertension, dyslipidemia, endothelial dysfunction, microalbuminuria, platelet disaggregation, abnormal fibrinolysis, and chronic inflammation. Furthermore, oxidative stress has been shown to contribute to the pathology of diabetic CVD, having implications in the development of hypertension, renal disease, and stroke. Hypertension is a common feature of diabetes and is the primary contributor to CVD, which highlights the importance of blood pressure control (<130/80 mm Hg). Recent investigations have also implicated the renin-angiotensin-aldosterone system in promoting oxidative stress-induced endothelial dysfunction, inflammation, and insulin resistance. These pathophysiologic considerations will be important in developing prevention strategies for CVD in diabetes. Further research is needed to identify antioxidant and insulin-sensitizing agents that will improve CVD outcomes in patients with diabetes.     

Bleeding during thrombolytic therapy for acute myocardial infarction: mechanisms and management

Hemorrhage is the major adverse effect of thrombolytic therapy, but its incidence can be reduced by careful selection of patients and avoidance of unnecessary invasive procedures. More than 70% of bleeding episodes occur at vascular puncture sites. Hypofibrinogenemia and elevation of fibrinogen degradation products have been weakly correlated with the risk of hemorrhage. Although depletion of factors V and VIII may occur, the role of such depletion in bleeding is unknown. Several in-vitro studies have shown plasmin-induced platelet dysfunction, but clinical data are limited. Nevertheless, the role of platelet inhibition should be considered because many patients are treated with antiplatelet agents. Most patients who have bleeding can be managed by interruption of thrombolytic and anticoagulant therapy, volume replacement, and manual pressure applied to an incompetent vessel. Protamine should be considered if heparin has been administered within 4 hours of the onset of bleeding. In the few patients who fail to respond to these conservative measures, judicious use of transfusion products may be indicated. Transfusion of cryoprecipitate, fresh frozen plasma, and platelets should be considered with clinical and laboratory reassessment after each administration. A target fibrinogen level of 1 g/L is desirable with cryoprecipitate infusion. Antifibrinolytic agents are available as a last alternative. We have developed an algorithm for using these products.     

How safe is diathermy in patients with cochlear implants?

INTRODUCTION

Cochlear implants are surgically inserted electrical devices that enable severely or profoundly deaf individuals to interpret sounds from their environment and communicate more effectively. As a result of their electrical nature, they are susceptible to electromagnetic interference and can be damaged by excessive electrical energy. Surgical diathermy is one source of such potentially damaging energy. The British Cochlear Implant Group guidelines advise that monopolar diathermy should not be used in the head and neck region in patients with cochlear implants and that bipolar diathermy should not be used within 2cm of the implant (http://www.bcig.org.uk/site/public/current/safety.htm).

METHODS

A questionnaire was provided to 36 surgeons working in different specialties in the head and neck region, inquiring as to their knowledge of the safety considerations when using diathermy in cochlear implant patients. Thirty-five surgeons provided responses.

RESULTS

Overall, 77% of the respondents were unaware of the existence of published guidelines. Even when given an option to seek advice, 11% erroneously felt it was safe to use monopolar diathermy above the clavicles with a cochlear implant in situ and 49% felt that there was no restriction on the use of bipolar diathermy.

CONCLUSIONS

There is a significant deficit in the knowledge of safe operating practice in the rapidly expanding population of patients with cochlear implants which threatens patient safety. Through this publication we aim to increase awareness of these guidelines among members of the surgical community and this paper is intended to act as a point of reference to link through to the published safety guidelines.     

Erythropoietin structure-function relationships: high degree of sequence homology among mammals

To investigate structure-function relationships of erythropoietin (Epo), we have obtained cDNA sequences that encode the mature Epo protein of a variety of mammals. A first set of primers, corresponding to conserved nucleotide sequences between mouse and human DNAs, allowed us to amplify by polymerase chain reaction (PCR) intron 1/exon 2 fragments from genomic DNA of the hamster, cat, lion, dog, horse, sheep, dolphin, and pig. Sequencing of these fragments permitted the design of a second generation of species-specific primers. RNA was prepared from anemic kidneys and reverse-transcribed. Using our battery of species-specific 5' primers, we were able to successfully PCR- amplify Epo cDNA from Rhesus monkey, rat, sheep, dog, cat, and pig. Deduced amino acid sequences of mature Epo proteins from these animals, in combination with known sequences for human, Cynomolgus monkey, and mouse, showed a high degree of homology, which explains the biologic and immunological cross-reactivity that has been observed in a number of species. Human Epo is 91% identical to monkey Epo, 85% to cat and dog Epo, and 80% to 82% to pig, sheep, mouse, and rat Epos. There was full conservation of (1) the disulfide bridge linking the NH2 and COOH termini; (2) N-glycosylation sites; and (3) predicted amphipathic alpha- helices. In contrast, the short disulfide bridge (C29/C33 in humans) is not invariant. Cys33 was replaced by a Pro in rodents. Most of the amino acid replacements were conservative. The C-terminal part of the loop between the C and D helices showed the most variation, with several amino acid substitutions, deletions, and/or insertions. Calculations of maximum parsimony for intron 1/exon 2 sequences as well as coding sequences enabled the construction of cladograms that are in good agreement with known phylogenetic relationships.