Arnold I. Freeman

Chromosomes and causation of human cancer and leukemia. XXVI. Banding studies in acute lymphoblastic leukemia (ALL)

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 #6: two cases had a 6q‐ with additional abnormalities and two had 6q‐ as the sole karyotypic abnormality. The breakpoint in chromosome #6 seemed to involve a segment from q21 to q25. An isochromosome of the long arm of #7, i(7q), was observed in two cases, two additional #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.

An autopsy study of 1206 acute and chronic leukemias (1958 to 1982).

Autopsy data on 1,206 children and adult patients with acute myelocytic leukemia (AML) (585), chronic granulocytic leukemia (CGL) (204), acute lymphocytic leukemia (ALL) (308), and chronic lymphocytic leukemia (CLL) (109) obtained from 1958 to 1982 were reviewed. This analysis has shown that, whereas the proportion of patients with residual AML at any anatomic site decreased significantly and uniformly over the entire study period, significant corresponding decreases in patients with CGL and ALL occurred only since 1976 and 1978, respectively. No significant corresponding decreases were noted in patients with CLL at any time. Significant decreases were also noted over time in the rates of extramedullary site involvement by AML, CGL, and ALL. Whereas the lymphoreticular organs, kidneys, adrenals, and pituitary were most often involved at autopsy by CLL, the testes, leptomeninges, dura mater, uterus, large bowel, and pancreas were most often involved by ALL. In general, patients with AML and CGL showed the lowest relative rates of involvement of the various organs by leukemia during the 24‐year period. Whereas patients with AML and ALL showed significant decreases in the rates of involvement of nearly all anatomic sites during the most recent study periods, those with CGL and CLL showed corresponding decreases in only a few organ sites. The lower rates of organ involvement in patients with AML and ALL attest to the more aggressive eradication of leukemic cells by therapeutic regimens in these diseases over time. In particular, the significant decrease in the rate of meningeal involvement by ALL during the most recent period is probably attributable to central nervous system prophylaxis.

Bone sarcoma as a second malignant neoplasm in children: Influence of radiation and genetic predisposition

Osteosarcoma or chondrosarcoma developed as a second malignant neoplasm (SMN) in 40 of 188 individuals with SMN whose first neoplasm occurred in childhood. A genetic susceptibility to cancer was found in 23; the SMN developed in an irradiated field in 32; both factors were present in 16; neither in one. When a genetic predisposition was present, radiation shortened the interval to SMN. The intervals between tumors and the age at which the bone sarcomas developed in relation to genetic disease and therapy were analyzed by a two‐mutation hypothesis. Studies of SMN in childhood permit us to make observations about the role of genetic factors and environmental mutagens in cancer etiology.

Chromosomes and causation of human cancer and leukemia. XXIII. Near-haploidy in acute leukemia

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.

Adjuvant adriamycin and cis‐diamminedichloroplatinum (cis‐platinum) in primary osteosarcoma

Twelve consecutive patients with osteosarcoma who were without evidence of metastases were treated with Adriamycin and cis‐platinum in an adjuvant fashion. The primary lesion was in the distal femur in five patients, proximal tibia in three, and one each in the proximal femur, proximal humerus, sacrum, and a previously irradiated orbit.

Preradiation chemotherapy in advanced medulloblastoma a pediatric oncology group pilot study

Background. Children diagnosed with medulloblastoma whose tumor involves the brain stem or has spread through the cerebrospinal fluid pathways to other areas of the brain or spinal cord have a poor prognosis despite therapy with surgery, craniospinal irradiation (CSI), and chemotherapy. Preradiation chemotherapy may improve the outlook for these patients.

An analysis of Ewing's tumor in children at Roswell Park Memorial Institute

Twenty pediatric patients with Ewings tumor seen at Roswell Park Memorial Institute, from 1954 to 1970, have been analyzed. Three patients are considered as cures. As the initial treatment, these three patients were all treated with radiotherapy to the primary tumor and adjuvant chemotherapy. Nine of the 20 patients were treated in this fashion. It was felt that the chemotherapy eradicated the subclinical micrometastasis and thus effected a cure. Five cases with reactivation of primary sites prior to, or simultaneous with, metastasis were noted, indicating incomplete sterilization of tumor by present radiotherapeutic techniques and also suggesting that more aggressive therapy be directed to the primary site along with the systemic chemotherapy.

Pharmacokinetics of methotrexate following intravenous and intraventricular administration in acute lymphocytic leukemia and non-Hodgkin's lymphoma.

A pharmacokinetic study of methotrexate (MTX) administered by the intravenous (IV) and intraventricular (via an Ommaya reservoir) route was performed in 16 children, 13 with acute lymphocytic leukemia (ALL) and three with non‐Hodgkins lymphoma. Five children with ALL were treated “prophylactically” for presumed subclinical central nervous system (CNS) leukemia. The remaining 11 patients were treated for overt meningeal involvement. MTX was administered intravenously at a dose of either 500 mg/m2 or 1500 mg/m2 with one third by rapid intravenous infusion and two thirds intravenously over 24 hours with leucovorin rescue. Intraventricular MTX was given in some treatment courses at a dose of 12 mg/m2. At either 500 mg/m2 or 1500 mg/m2, when given only IV, MTX results in a 100 fold higher concentration in plasma compared to cerebrospinal fluid (CSF). The plasma levels are three times higher with the 1500 mg/m2 dose compared to the 500 mg/m2 dose. After intraventricular administration of MTX, patients with overt CNS leukemia retained MTX in the CSF significantly longer than patients treated prophylactically. This may be due to abnormal transport of MTX out of the CSF in patients with meningeal disease. Cancer 50:1676‐1682, 1982.

Autoimmune disorders complicating adolescent hodgkin's disease

Four adolescents with Hodgkins disease also developed autoimmune diseases. There were two idiopathic thrombocytopenic purpura (ITP), one polymyositis, and one scleroderma. The first two patients developed ITP in the absence of a spleen, and with their Hodgkins disease in remission. The first patient with Hodgkins disease has been continuously free of cancer for over five years. The second patient was a 17‐year‐old male whose Hodgkins disease recurred, but whose disease was in remission at the time the ITP occurred. The polymyositis occurred in an 18‐year‐old youth when he was in his initial remission for his Hodgkins disease, but his disease subsequently recurred two years later. This youth presented with Coombs positive autoimmune hemolytic anemia. The polymyositis did not respond to therapy, and he is left with severe muscle wasting and weakness; however, the polymyositis is now quiescent. The scleroderma occurred in an 18‐year‐old female who had been continuously free of Hodgkins disease for eight years. The scleroderma did not respond to drug therapy and she now has moderate skin changes, but remains in continuous remission of her Hodgkins disease. Although there are a few reports of Hodgkins disease and concurrent autoimmune disorders, physicians dealing with cancer in adolescents should be aware of this association.

Blurring of vision. A previously undescribed complication of cyclophosphamide therapy

Five children with cancer treated with high dose cyclophosphamide experienced blurring of vision. In three patients, the blurring lasted less than one hour and disappeared abruptly, but in the other two, it was prolonged, lasting three and 14 days with gradual improvement. In all five complete restoration of normal vision occurred. We have not found other reports of this association in the literature.