Multimodality therapy in pediatric neoplasms.
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Biomedical subjects
Publications and source records attributed to L F Sinks.
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A pharmacokinetic study of methotrexate levels in blood and cerebrospinal fluid was performed in 42 patients who received one or more courses of high-dose methotrexate at 500 mg/sq m infused i.v. over a 24-hr period. Methotrexate level in the lumbar cerebrospinal fluid reached 1.2 x 10(-7) M at 0.5 hr and remained constant at that level for the 1st 24 hr. Similar methotrexate levels were noted in the ventricular fluid obtained through an Ommaya device on three patients with brain tumors treated with high doses of methotrexate. Preliminary clinical results using high-dose methotrexate combined with simultaneous intrathecal methotrexate in 23 children with newly diagnosed acute lymphocytic leukemia indicate that this treatment program is safe to administer and to date appears effective in the prevention of central nervous system leukemia.
Human allogeneic 'one-way' mixed lymphocyte reactions between thymus cells and thymus cells were entirely absent. Of twenty-one mixed lymphocyte reactions between peripheral blood lymphocytes as responding cells and thymus cells as stimulating cells, only eleven had a weak but significant reaction. In contrast, a highly significant response was observed in each of eighteen mixed lymphocyte reactions between thymus cells as responding cells and peripheral blood lymphocytes as stimulating cells and in each of eleven mixed lymphocyte reactions between peripheral blood lymphocytes and peripheral blood lymphocytes. These findings indicate that the thymus cells (T lymphocytes) possess excellent proliferative capacity, with little or no stimulating capacity, while peripheral blood lymphocytes (T and B lymphocytes), on the other hand, are good responders, as well as good stimulators, in the mixed lymphocyte reaction.
Over 90 per cent of the thymus cells from each of twenty-six donors were T lymphocytes, identified by E-rosetting and less than 3 per cent of the cells were B lymphocytes identified by EAC-rosetting. With advancing age, the proportion of T lymphocytes decreased while that of B lymphocytes increased. The degree of (3H)thymidine incorporation of thymus cells was inversely proportional to the age of the thymus-cell donor. The PHA or PWM- induced blastogenic response of thymus cells gradually increased with advancing age when the response was expressed as the stimulation index. However, the actual rate of (3H)thymidine incorporation in all three groups was rather similar when cells were cultured with mitogens. The difference in stimulation index was due to the variation in incorporation rate in cultures without stimulants. The PHA response was approximately four-fold higher than that of PWM response. Thymus cell response to allogeneic lyphocytes, on the other hand, had no correlation with the age of thymus donor. The most surprising result in the present study was that the thymus cells from each of ten donors, aged 1-14 years, were incapable of responding to all four different recall antigens. Peripheral blood lymphocytes from nine to ten randomly selected age-matched children responded very well to one or more antigens.
Twenty children with ALL that died in 1959-1960 and 59 children with ALL that died in 1969-1970 were analyzed according to the infections at both their terminal illness and their initial presentations. Despite the availability of more effective agents for pseudomonas and staphylococcus, the pattern of infecting organisms at the terminal illness did not change appreciably in this decade. E. coli, pseudomonas, staphylococcus, and candida were the principal organisms involved as a cause of death. Thirty-five of these 79 patients were febrile when they initially presented, prior to the institution of chemotherapy. Seven of the 35 patients (20%) had proved infections. It appears that the fever in the majority of patients at their initial presentations was noninfectious in origin. In 1969-1970, 13 pulmonary aspirates were performed to aid in the etiological diagnosis of diffuse interstitial pneumonia. Only a single case (8%) of pneumonia due to pneumocystis carinii was detected, and it is our suspicion that the majority of these interstitial pneumonias were viral in origin.
Polio antibody titers were determined in 29 children with ALL in various clinical stages, including a group of five patients in continuous remission for over five years and who, at the time of study, were off all therapy for at least six months. Regardless of the stage of disease, no detectable gamma M response was elicited. The five children described above displayed the same depressed response as did the other children with ALL. This strongly suggests an inherent defect in the immune system of these children with ALL unrelated to therapy.
Measurement of erythropoietin levels was achieved in urine, plasma and tumor extract specimens in 27 Wilms tumor patients. Good correlation of the stage of the disease, the clinical judgment of inactive or responding tumor foci and erythropoietin levels was noted. Erythropoietin levels are believed to reflect ectopic hormone production by the primary or secondary tumor. Since the erythropoietin hormone assayed in these and other Wilms tumor patients was not associated with polycythemia, it is believed that Wilms tumor-associated erythropoietin differs in some manner from the hormone produced normally in man and possible in other states associated with secondary polycythemia. Etythropoietin assay with further purification and technical development can be of additional widespread assistance in the clinical classification and subsequent management of the tumor state. Our study confirms this biological potential.
Recent advances in the use of chemotherapy for treatment of osteosarcoma have altered out pessimism in this disease. Results are presented from 3 groups of investigators using different agents as adjuvant chemotherapy following immediately upon amputation of the primary. The Roswell Park Memorial Institute began a regime, immediately after amputation, of adriamycin 30 mg/M2 for 3 doses and given every 4-6 weeks. This study was subsequently expanded in a cooperative group (ALGB) and the results on 20 patients analyzed. At 19 months approximately 75 per cent are free of any pulmonary metastases compared with 10-25 per cent expected from amputation alone. Similar results have been obtained by other Centers using different chemotherapeutic agents. In Boston Children's Hospital high dose Methotrexate with citrovorum factor is used. In 12 of these patients local control of the primary by surgery was obtained and of these only 1 developed pulmonary metastases during an observation time of 23 months. At the M. D. Anderson Hospital multi-drug combinations were used including Cyclophosphamide, Vincristine, L-Phenylalamine Mustard and Adriamycin. They reported a survival rate of 55 per cent (10 out of 18). All of these neoplastic agents have toxic side effects but when carefully used these effects are minimized and the quality of life is quite good. Many questions must be answered by future controlled long term follow-up studies.
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