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Patients undergoing bone marrow transplantation often receive total body or total lymphoid irradiation as part of the conditioning regimen prior to marrow infusion. The cytogenetic effects of this therapy on skin fibroblasts were studied. Fibroblast cultures from eight skin biopsies were harvested in early passages for G-banded chromosome analysis. Four biopsies were from three patients who had high-dose cyclophosphamide and total body radiotherapy; one was from within and one was from outside the radiation field of a patient who had high-dose cyclophosphamide and lymphoid radiotherapy, one was from a patient who had combination chemotherapy alone, and one was from a normal control. No abnormal mitoses were found in the control or the patient who had chemotherapy alone, and only two of 30 mitoses from skin outside the lymphoid radiotherapy field were abnormal. However, most cells (49-88%) from five biopsies within radiotherapy fields were abnormal. Typically, abnormal karyotypes were pseudodiploid and contained multiple balanced rearrangements, of which reciprocal translocations were most common. The data indicate that the radiotherapy used for bone marrow transplantation induces extensive, sustained chromosome abnormalities in vivo in skin fibroblasts.

Patients with acute lymphoblastic leukemia who have a mediastinal mass at the time of diagnosis are said to have a poor prognosis. However, many factors which may not be independent contribute to the success of treatment. We compared the disease characteristics and results of therapy in children having large mediastinal masses and lymphoblastic leukemia without mediastinal mass. Patients with a mediastinal mass had less evidence of marrow failure but were burdened with considerably more leukemic cells as measured by peripheral blood white count and extent of lymphadenopathy. Since the presence of mediastinal mass was strongly associated with these and other poor prognostic characteristics, we used multivariate techniques to determine which characteristics were independently associated with an increased risk for relapse. White count, extent of lymphadenopathy, age, and sex were significant predictors of early relapse, but when controlled for these variables the presence of a mass did not predict prognosis.

Previous series including our earlier study of survivors of childhood acute lymphoblastic leukemia have documented the presence of nonclonal chromosome abnormalities in peripheral blood lymphocytes. To investigate whether or not these abnormalities persist, we restudied nine patients, all of whom had received radiotherapy and a minimum of 3 years of systemic chemotherapy. Therapy had been discontinued a median of 3.9 years prior to study in our first report and a median of 7.2 years prior to study in this follow-up report. Thirty metaphases from short-term cultures of phytohemagglutinin-stimulated peripheral blood from each of nine patients and nine matched controls were analyzed using G-banding. Nonclonal chromosome abnormalities were present in cells from six of the nine patients and 3.0% of patients' cells overall, as compared to seven of ten patients and 3.5% of patients' cells in the earlier study. All patients studied twice had abnormalities on one or both occasions. No evidence for the development of cytogenetically abnormal clones was found. Combined data from the two evaluations indicate that all of the patients have a small population of long-lived lymphocytes with nonclonal chromosome abnormalities, the frequency of these cells appears to remain remarkably constant over time, and the proportion of cells with chromosome abnormalities is approximately threefold greater in patients than in controls. It has become apparent that survivors of acute lymphoblastic leukemia are at increased risk for development of second malignant neoplasms. The relationship between therapy-induced chromosome damage and the development of second malignant neoplasms is currently unknown. We speculate that some cells, possibly in tissues other than peripheral blood, are preneoplastic by virtue of therapy-induced chromosome rearrangements involving critical genes and, following a long latent period, may undergo subsequent genetic or cellular changes that result in malignant transformation. Unfortunately, however, estimation of genetic damage through cytogenetic studies of peripheral blood T-lymphocytes does not appear to be a useful method for prediction of second malignant neoplasms following acute lymphoblastic leukemia, since most or all of the patients have a low level of abnormal cells.

One hundred eighty-seven patients diagnosed with acute lymphoblastic leukemia (ALL) between 1972 and 1975 were evaluated for height 6.4-8.8 years (median 7.2 years) from the time of diagnosis of their disease. All patients had been treated on protocols CCG-101/143 conducted by the Childrens Cancer Study Group. After induction of remission, patients received either cranial radiation plus six doses of intrathecal methotrexate, craniospinal radiation, or craniospinal radiation plus abdominal radiation, followed by systemic maintenance chemotherapy for either 3 or 5 years. No significant difference was observed in the distribution of height percentiles at the time of diagnosis compared to expected population standards. After treatment an excess (P less than 0.001) was observed in the proportion of patients in the lower percentiles in conjunction with a decrease in the proportion of patients in the higher percentiles. After adjustment for height at diagnosis, the only factor found to have significant impact on attained height percentile was exposure to craniospinal plus abdominal radiation (P less than 0.001) where there was a fivefold excess in the proportion of patients below the fifth percentile for height. Craniospinal radiation only was not associated with a greater reduction in attained height percentile when compared to cranial radiation only.

One hundred forty-three children with refractory lymphoblastic and undifferentiated leukemia (ALL/AUL) were treated with cytosine arabinoside (Ara-C) and prednisone (Pred). The dose and duration of Ara-C was escalated during induction depending on the response seen in the peripheral blood and/or bone marrow. For those achieving a remission, Ara-C was also used to determine its maintenance capabilities. Of the 143 children, 79 attained a clinical remission, 45 having a complete bone marrow remission and 34 having a partial remission. Maintenance of remission with twice weekly Ara-C was short and did not appear to depend on the amount of Ara-C given during induction. The major toxicity of Ara-C was myelosuppression.