Biomedical subjects
Publications and source records attributed to A I Freeman.
This report describes a 10-year-old white boy who presented with acute lymphocytic leukemia (ALL) and several collapsed thoracolumbar vertebrae in 1965. His ALL was successfully treated, and he has been disease-free for over 10 years. He has now completely remodeled all of the collapsed vertebrae.
A case of acute lymphoblastic leukemia (ALL) with a near-haploid (27 chromosomes) leukemic cell population in the marrow has been described and the findings compared to those of the only other such case in the literature. In both cases the cells with 27 chromosomes, except for one chromosomal group, had karyotypic findings which were identical. Cells with 54 chromosomes, karyotypically exact duplicates of the cells with 27 chromosomes, were also encountered; on morphological basis it appeared that the marrow contained large and small lymphoblasts, possibly matching the metaphases with 54 and 27 chromosomes, respectively. The genesis of the cells with 27 chromosomes was uncertain and several postulates are discussed, as well as the relation of the findings to the cytogenetic observations encountered in ALL and their possible role in human leukemogenesis.
Chromosomes were studied in the bone marrow cells of 101 patients with acute lymphoblastic leukemia (ALL) hospitalized at or attending the clinics of Roswell Park Memorial Institute (RPMI) between January, 1968, and December, 1976. Aneuploidy was observed in about 50% (54/101) of the cases. Two cases were hypodiploid and the remaining were either pseudo or hyperdiploid. The frequency of abnormalities and the chromosomal numbers were similar to those of 106 cases studied in our laboratory prior to 1968. Of 50 recently unselected cases of ALL in whom Q- and G-banded karyotypes were attempted, 31 were successfully analyzed with these techniques. The banding patterns revealed 16 cases to have chromosome abnormalities and four of these to have a similar abnormality, i.e., partial deletion of the long arm of chromosome no. 6: two cases had a 6q- with additional abnormalities and two had 6q- as the sole karyotypic abnormality. The breakpoint in chromosome no. 6 seemed to involve a segment from q21 to q25. An isochromosome of the long arm of no. 7, i(7q), was observed in two cases, two additional no. 21 chromosomes were observed in five cases and, except for the Y, all other chromosomes participated in the karyotypic changes encountered in the 16 cases in which banding analyses were performed. Banding analysis has afforded the first reliable approach towards ascertaining karyotypic evolution in ALL, which was achieved in eight cases of the present study. The chromosomes contributing to this karyotypic evolution were distributed widely. Thus, all chromosomes except the Y participated in numerical and/or structural karyotypic changes. Even though nonrandom chromosome changes may occur early in ALL, the pristine prototypic picture of the karyotypes in ALL is often obfuscated by successive chromosomal changes and hyperdiploidy by the time the karyotypes are analyzed in this condition. Further cytogenetic studies are required, with special attention to karyotypic evolution, in order to uncover the significance of chromosomal changes in early and late ALL.
Twenty-four patients with cancer and concomitant infections with either herpes virus hominis or varicella zoster virus were treated with polyinosinic-polycytidylic acid (rIn.rCn) to determine: 1) the reliability of rIn.rCn to induce interferon production, and 2) the toxicity of the drug. Seven additional patients with herpes zoster were observed as controls. Two lots of rIn.rCn were used; Lot 1 was consistently effective in stimulating serum interferon at doses of 9 and 12 mg/kg, whereas Lot 2 was effective at doses of 3-12 mg/kg. There was no correlation between rIn.rCn doses within these ranges and the resultant interferon levels. Generally, peak serum interferon occurred within the first day. Toxicity to rIn.rCn consisted of fever in 21/24 patients, mild elevation of liver enzymes in 8/24 patients, and laboratory abnormalities of coagulation in 9 patients. The coagulation abnormalities appeared linearly related to the dose of rIn.rCn used. All these abnormalities were reversible, and none were considered severe of life-threatening. Since rIn.rCn was effective in stimulating interferon and since toxicity was considered acceptable, a randomized double-blind study was initiated to determine whether rIn.rCn is effective in the treatment of herpes zoster.
A 2 1/2-year-old male child with rhabdomyosarcoma of the prostate was treated with radiation of the pelvis, consisting of 5,600 rads in 7 1/2 weeks, and combination chemotherapy of Vincristine and Actinomycin D. Surgery had been refused. The child is alive and disease-free more than 5 years after diagnosis, and over 2 years following the cessation of all therapy. Recent advances in radiotherapy and adjuvant chemotherapy have significantly improved the outlook in this aggressive childhood neoplasm and have made a less aggressive and less mutilating surgical approach often desirable. This, in turn, holds out the prospect of improved quality of survival in children so afflicted.
A pharmacokinetic study of methotrexate (MTX) was performed in 60 patients who received high-dose MTX at 500 mg/m2 infused over 24 hours. MTX levels reached 1.2 X 10(-7) M in the cerebrospinal fluid (CSF) within 10 minutes and remained constant at that level for 24 hours. Forty of these 60 patients were children with acute lymphocytic leukemia. In these 40 patients, simultaneous intrathecal MTX was given along with high-dose MTX. The resultant CSF levels (lumbar area) were higher than those obtained with either high-dose MTX alone or simultaneous intrathecal MTX alone. To date, there have been one systemic and one central nervous system relapse in these 40 children, and the treatment program appears safe to administer.
cis-Dichlorodiammineplatinum(II) (DDP) was studied in 16 children with far-advanced malignancies. Three dosage schedules were tried: regimen A, 20 mg/m2/day x 5 days for 3-4 weeks (11 patients); regimen B, 50 mg/m2 once a week (four patients); and regimen C, 60 mg/m2/day x 2 days every 3-4 weeks (one patient). Four of 16 patients (25%) showed partial response, including one with osteogenic sarcoma, one with neuroblastoma, one with seminoma, and one with medullary carcinoma of the thyroid. Two patients showed clinical improvement. The major toxic manifestations included nausea and vomiting (16 of 16), renal toxicity (three of 16), transient pancytopenia (six of 12), and hearing loss (two of 16). It is apparent that DDP has activity in pediatric tumors; however, a more precise response rate must be delineated in a larger series of patients.
From 1921 to 1973, 106 children with Hodgkin's disease under the age of 17 years were seen at Roswell Park Memorial Institute and were analyzed retrospectively. Evaluation was separated into three eras: 1921-1949 (early era), 1950-1964 (middle era), and 1965-1973 (recent era). In the early era, suboptimal radiation therapy was employed. In the middle era, radiation therapy techniques were improved, and single-agent chemotherapy was introduced. In the recent era, multiagent chemotherapy routines were frequently used; aggressive external megavoltage radiation therapy became routine in conjunction with improvement in staging procedures. The best survival was observed in the recent era where five-year survival of 96% was noted in early stage disease. Favorable prognostic features included: younger age group (5-9 years), female sex, lymphocytic predominant histology, early stage disease, and complete response to therapy. Nodular sclerosing and mixed cell types had an equal prognosis. The concept of involved area radiotherapy along with combination chemotherapy appears a reasonable approach in children and should be tested in a randomized study against more extensive radiotherapy techniques in early stage disease.
Bone-marrow cells from a patient with Bloom's syndrome cultured for 48 h in the presence of BudR exhibited a striking increase in the number of sister chromatid exchanges (SCEs) in comparison to that in the marrow cells of a patient with treated polycythemia vera (PV). Thus, it appears that an increased incidence of SCE in Bloom's syndrome occurs in various differentiated types of cells, not just blood lymphocytes, and constitutes the syndrome's most characteristic cytogenetic feature. In contrast, the incidence of SCE was not increased in marrow cells and lymphocytes of the particular PV patient studied here, whose cells did exhibit increased numbers of chromatid and chromosome gaps and breaks, presumably as result of the patient's earlier treatment. An increased frequency of SCE was demonstrated in Bloom's syndrome lymphocytes using both a technique based on BudR incorporation and one based on labeling with tritated deoxycytidine. This observation constitutes evidence against the increase of SCE being due to an unusual reaction to BudR. By conventional cytogenetic techniques, chromosome instability, including chromatid and chromosome breaks, but no homologous chromatid interchanges were also recognized in Bloom's syndrome bone-marrow cells incubated in vitro (without BudR) for either 1.k or 16 h. This observation points to the existence of chromosome instability in vivo.
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.
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.
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