Hagedorn, Albert B.

THE RECENT publications of Farber and co-workers dealing with the treatment of acute leukemia in children have awakened widespread interest. Their investigations have stimulated hope for the amelioration of symptoms of this fatal disease and indicated the possibility of provoking remissions that lengthen the lives of those patients affected by it, while making them more comfortable at the same time. In investigating leukemia and allied conditions of a neoplastic nature, Farber and co-workers noted what they termed an "acceleration phenomenon" in the blood and bone marrow of leukemic children treated with folic acid or its conjugates such as diopterin (pteroyldiglutamic acid) or teropterin (pteroyltriglutamic acid). There was marked hyperplasia of the marrow as well as of other sites of leukemic involvement at postmortem examination. They reasoned that if folic acid or its conjugates speeded up the leukemic process, an antagonist to folic acid might be devised in order to retard the progress of the disease or stop it altogether. Through co-operation with the research division of one of the major pharmaceutical firms, a series of folic acid antagonists was soon developed. One of these was aminopterin (4-aminopteroylglutamic acid). It differs from folic acid only in the substitution of the NH2 group for the OH radical in the fourth position of the pteridine group. Of several compounds synthetically made, it has been the most effective and yet most toxic agent in its action on the leukemic process. Farber and co-workers first employed aminopterin in the treatment of acute leukemia of children in December 1947.

Abstract Twenty patients with hypochromic anemia were given a total of 211 intravenous injections of high molecular ferric carbohydrate compound. The hematologic response and toxic reactions are discussed. High molecular ferric carbohydrate compound can be given in large enough doses to be practical in the treatment of iron deficiency anemias. The hematologic response, as judged by the rate at which hemoglobin regenerates and the reticulocyte count increases, is good. The initial dose would be 25 to 50 mg. of elemental iron, and subsequent daily doses should not be more than 200 mg. Cases for the intravenous use of iron should be carefully selected because of the possible toxic reactions and the possible long-term damage to the tissues if excess amounts of irons are administered. The indications for the intravenous use of iron in iron deficiency anemias have been suggested. The dosage should be calculated so as to supply only enough iron to replace the irons deficiency and to allow regeneration of hemoglobin.

Abstract A simple test is proposed for evaluating the gastrointestinal absorption of iron. It begins with an oral dose of 50 µg. of stable iron labeled with 1 µc. of Fe59, to which about 300 mg. of ascorbic acid are added. Feces are assayed for Fe59 until any single stool contains less than 1 per cent of the dose. Absorption is determined on the assumption that all unrecovered Fe59 has been absorbed. The test was designed to minimize handling of stools by assaying whole specimens, and this process has the added virtue of increasing statistical accuracy of the measurement of radioactivity. The main advantage of the procedure using a 50 µg. dose is that with it one obtains a normal value for absorption which is about one-half of the dose. This permits measurement of either increased or decreased iron absorption. With our standard test method, 19 normal women absorbed an average of 62 per cent of the dose and 22 normal men absorbed 40 per cent. In addition to this sex difference, not explained by the difference in their blood hemoglobin levels, there seemed to be a tendency toward reduced absorption with greater age. Preliminary results of this test in patients with hypochromic anemia and steatorrhea are reported. Increased absorption of iron followed the administration of ascorbic acid whether the iron was in the ferric or the ferrous form. The concept that ferrous iron is better absorbed by man requires re-evaluation.

Abstract Thirty-six patients with active rheumatoid arthritis in whom anemia was slight were investigated, in part with radioiron and radiochromium, for abnormalities which might lead to anemia. The primary defect appeared to be a pronounced reduction of ability to absorb iron from the intestinal tract. There was an equally marked reduction in the serum concentration of iron which could not be attributed to the slight reduction in the iron-binding capacity of the serum. Despite the reduction level of iron in the serum, the apparent turnover of iron was so rapid that the total clearance per day was normal or moderately elevated. However, the fraction of the iron cleared from the blood and appearing in the circulation in newly synthesized erythrocytes was slighfly depressed. Erythrocyte survival was normal or very slightly shortened; hemolysis seems to play no important role. The fecal excretion of radioiron, not associated with erythrocytes, was greatly increased in two patients in whom there was no evidence of intestinal bleeding. A moderate increase in plasma vohime was common.

Abstract A total of 194 cases of leukemia or lymphoma with coexistent primary malignant disease was found reported in the literature. To this we have added 120 new cases from the files of the Mayo Clinic in which the diagnosis was made in the 10 years from 1944 through 1953. The following observations were made: 1. The presence of leukemia or lymphoma does not seem to predispose to the development of any other specific type of primary malignancy. 2. The incidence of another primary malignant lesion in patients with leukemia or lymphoma is probably comparable to, and perhaps exceeds, that in any segment of the general population of similar age. 3. The coexistence of Kaposi’s sarcoma and leukemia or lymphoma in the same patient probably represents a morphologic variation of the same basic malignant disease of the reticuloendothelial system. 4. Any patient with leukemia or lymphoma who presents signs or symptoms of a focal malignant lesion should be regarded as having another primary lesion until proved otherwise on pathologic examination.

Forty-two male and female mice, 8 weeks old, were given radioiron (Fe59) in doses of 0.006–0.1 µc, containing 0.013–0.17 µg of iron, by intraperitoneal or intravenous routes. Assays of the radioactivity of the whole body revealed an initial rapid loss of Fe59 (15–20%) lasting about 6 days. Thereafter the Fe59 left the mice at a steady rate of 0.39%/day (half-life 180 days). One 34-year-old normal man was given 10.6 µc of Fe59, containing 8.2 µg of iron, intravenously. Based on counts from the entire body, the biologic rate of loss of the Fe59 was about 0.14%/day (half-life 500 days), and there was little or no initial loss such as occurred in the mouse. The Fe59 in the circulating erythrocytes was essentially unchanged for the first 3 months. It then fell to a new level of about 90% of the previous one; the mid-point of the fall was about 120 days after the administration of the radioiron. The difference in the rates of loss of radioiron from mice and man seems to be related primarily to the life span of the circulating red cells.