Cooper, Talbert

Abstract Neither diagnostically significant features nor consistent abnormalities of other character were demonstrated in the specimens of sternal marrow obtained in 15 cases of Hodgkin’s disease. With improvements in technic, particularly in patients presenting clinical evidence of bone or bone marrow involvement, the procedure might become more valuable. As an aid in diagnosis in cases of obscure malignant lymphoma, sternal aspiration is likely to prove of greatest value in cases of lymphosarcoma. In 7 of 10 proved cases, abnormal lymphocytic cell types were encountered and in 3 instances bone marrow infiltrations were demonstrated in fixed section preparations. The latter were felt to be diagnostic of lymphosarcoma. In 2 cases of follicular lymphoma the specimens of sternal marrow presented no striking abnormalities. However, because of the apparently close relationship which this disease bears to lymphosarcoma it is felt that study of a larger number of cases may prove the procedure of some diagnostic value.

Abstract 1. A group of 64 myeloma patients was given a loading dose of Melphalan, 0.15 mg./Kg./Dx7. This was followed by a rest period to allow bone marrow recovery to occur, after which maintenance therapy with a maximum of 0.05 mg./Kg./D was started. 2. To obtain good results, drug doses were required which produced significant bone marrow depression. 3. Subjective improvement was noticed in about 65 per cent of patients; objective improvement, in 78 per cent. 4. Fifty-five per cent of the patients had a response as defined in this study. 5. No difference in survival was found between males and females, nor between patients with Bence Jones proteinuria and those without. 6. Patients who have been on treatment for 3 months and were then found to be responders lived longer than similarly treated patients classified as nonresponders.

Abstract The efficacy of three therapeutic programs for acute leukemia were compared. These programs included (1) Methotrexate (Phase I) followed by 6-mercaptopurine (Phase II); (2) 6-mercaptopurine (Phase I) followed by Methotrexate (Phase II); and (3) Combination Therapy, i.e., 6-mercaptopurine given in combination with Methotrexate. In children with acute lymphocytic leukemia the remission rate was 59 per cent for combination therapy, 47 per cent for 6-mercaptopurine, and 29 per cent for Methotrexate. The better remission rate for combination therapy is consistent with that predicted if it is assumed that 6-mercaptopurine and Methotrexate act independently. The median duration of complete remissions for the three treatments was not different (4 to 5 months). However, long lasting remissions were more frequent in patients receiving combination therapy. The median survival from the onset of therapy to death was 9 months. There were no differences between the three treatment programs as regards survival. In adults the remission rate was 15 per cent for combination therapy, 21 per cent for 6-mercaptopurine and 7 per cent for Methotrexate. As regards survival in adults, early deaths were more common in patients who received MTX as initial therapy, whereas after 5 months survival was somewhat better in those patients receiving combination therapy. In both children and adults there was no evidence that prior treatment with one of the antimetabolites altered response to the other antimetabolite. This result differs from those in animal models, and its effect on our concept of the mechanism of resistance is discussed. Responsiveness to the second course of antimetabolite therapy (Phase II) was as good as that to the first course of treatment. This was true for the remission rate, remission duration, and even for survival when appropriate corrections were made. Thus, responsiveness to drug therapy is maintained as the disease progresses temporally. It may be concluded therefore that new agents can be effectively studied in patients with "late" disease. Responsiveness to Phase II therapy was independent of responsiveness to Phase I. The most common and severe toxic manifestations related to the bone marrow and gastrointestinal tract. There were no major differences quantitatively in the toxicity for the three treatment programs in children in spite of the fact that the drugs were given in full dosage in the combination program. Oral ulcers and a generalized erythematous rash occurred significantly more frequently in patients receiving Methotrexate. Jaundice was significantly more frequent in adults and in patients receiving 6-MP.

Abstract In order to correlate the electrophoretic alterations in the serum proteins and the findings in the bone marrow, with particular reference to atypical lymphocytic forms and plasma cells, 14 cases of lymphosarcoma, six of chronic lymphocytic leukemia and six of Hodgkin’s disease were studied. No numerical relationship could be found between the degree of lymphoid atypia and the changes in serum globulin. A correlation, however, was apparent between the plasma cell concentration in the bone marrow and the changes in the serum gamma globulin, inasmuch as pronounced hypergammaglobulinemia occurred in all four cases of malignant lymphoma associated with bone marrow plasmacytosis (ranging from 2.8 to 12.8 per cent) and hypogammaglobulinemia of moderate to marked degree was present in five of the six cases of malignant lymphoma in which plasma cells were virtually absent in the bone marrow. When the findings of the fixed sections of the marrow are included, plasmacytosis was demonstrated in bone marrow in eight of 10 cases in which serum gamma globulins were elevated. In two cases, serum globulins were qualitatively abnormal. In one, a case (case 15) of Hodgkin’s disease, a small fraction of electrophoretically homogeneous globulin was noted. In the other, case 5, in which the histologic diagnosis was lymphocytic lymphosarcoma, macroglobulins constituted 40 per cent of the serum proteins, and Bence Jones proteinuria was associated. Predominantly mature plasmacytosis of 12.8 per cent was present in the bone marrow. This case may be regarded as illustrative of the interrelationship between myeloma and lymphosarcoma and supports the view21 that, clinically and morphologically, transitional forms occur between lymphatic tumors and plasmacytomas. On the basis of this material, it is suggested that in cases of lymphosarcoma, Hodgkin’s disease and chronic lymphocytic leukemia, alterations in the plasma content of the bone marrow, either as reactive plasmacytosis or as virtual absence of plasma cells, appear to be a major pathogenetic factor in the occurrence of hypergammaglobulinemia and hypogammaglobulinemia, respectively. Hypogammaglobulinemia was observed in three of six cases of chronic lymphocytic leukemia; two of 14 cases of lymphosarcoma; and one of six classified as Hodgkin’s disease. Conversely, quantitative increases in the gamma globulin level occurred in none of the six cases of chronic lymphocytic leukemia; in six of 14 cases of lymphosarcoma (including two of three classified as lymphosarcoma, reticular cell type), and in three of the six cases of Hodgkin’s disease.

Abstract Examination of serial paraffin sections of bone-marrow aspirations has increased the known incidence of marrow involvement in malignant lymphomas. The results of this study can be seen in the table. In the 72 cases reviewed here, lesions compatible with malignant lymphoma were seen in paraffin sections in 22 cases. In 12 cases this was the only material available for diagnosis at the time. In an additional seven cases paraffin sections were considered suggestive of malignant lymphoma and in five of these a diagnosis could be made on the basis of examination of both smear and paraffin section. This procedure is particularly helpful in Hodgkin’s disease and reticulum cell sarcoma, where marrow smears are only rarely diagnostic. In general, the patients in whom lesions were found in the bone marrow tended to have more advanced disease than those in whom lesions were not found, and abnormalities in the peripheral blood were more common. This was especially true of patients with Hodgkin’s disease, less so in those with reticulum cell sarcoma. Patients with lymphosarcoma, lymphocytic type, did not show this difference, either in the extent of the disease or in findings on examination of peripheral blood. Diagnosis was most difficult in patients who had lymphocytic lymphosarcoma, since it was occasionally difficult to distinguish between the benign aggregations of lymphocytes which are not infrequently found in a large number of unrelated conditions and those aggregations which represented malignancy. Differentiation was made on the basis of number of aggregations, degree of circumscription, presence or absence of reaction centers and the cytologic appearance of the cells. Examination of the smears of the marrow is most helpful in these cases. Seven patients in this series (9.7 per cent) had granulomatous lesions in the marrow. In five of these the final diagnosis was Hodgkin’s disease, in one reticulum cell sarcoma and in one follicular lymphoma. Although these lesions were not specific, the incidence is high enough to make the finding of a granuloma of some significance in any patient suspected of having malignant lymphoma. The importance of thorough examination of any material obtained in an apparent dry tap and the value of repeated marrow-examinations is emphasized by three cases in this series. Since in many cases diagnostic lesions are found in only one portion of the material, examination of only one section of the paraffin sections of aspirated bone marrow is not sufficient for proper evaluation. This fact is emphasized by the greater incidence of positive findings in this report than in that of Cooper and Watkins. Studies of bone marrow should be particularly helpful in instances in which the diagnosis of malignant lymphoma is suggested by clinical features but cannot be proved by biopsy of peripheral nodes or other readily accessible tissue.

Abstract Limited experience with the use of urethane in the treatment of leukemia indicates that this substance presents a considerable promise as a palliative agent in chronic myelogenous leukemia. It has no apparent value in the treatment of acute leukemia. Further extensive observation will be necessary to provide a true measure of the clinical usefulness of this preparation.