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The present study demonstrates a decrease in self-renewal capacity with serial transfer of murine hematopoietic stem cells. Production of differentiated cell progeny is maintained longer than stem cell self-renewal. In normal animals the capacity for self-renewal is not decreased with increasing donor age. The stem cell compartment in normal animals, both young and old, appears to be proliferatively quiescent. After apparent recovery from the alkylating agent busulfan, the probability of stem cell self-renewal is decreased, there is a permanent defect in the capacity of the bone marrow for serial transplantation, and the stem cells are proliferatively active. These findings support a model of the hematopoietic stem cell compartment as a continuum of cells with decreasing capacities for self-renewal, increasing likelihood for differentiation, and increasing proliferative activity. Cells progress in the continuum in one direction and such progression is not reversible.

Bone marrow pluripotent stem cells (CFUs) demonstrate capacity for both proliferation and differentiation. The proliferative capacity of CFUs has been measured by serial transplantability and by the Rs, a measurement of CFU production in a single 14-day transfer. In the present study, the self-renewal capacity of both adherent and nonadherent CFUs from long-term bone marrow cultures was measured. Culture conditions were established such that nonadherent cells were derived from the adherent cell layer. Both adherent and nonadherent cells produced spleen colonies, demonstrating that significant proliferative potential was present in both locations; however, at all times in culture, the CFUs within the adherent stromal cell layer had a significantly greater self-renewal capacity than did the nonadherent CFUs. During the initial establishment of the cultures, the self-renewal capacity of the adherent CFUs decreased as the total number of CFUs per flask increased. After 3 weeks in culture, the self-renewal potential of the adherent CFUs stabilized and was maintained. These results suggest two different mechanisms of stem cell proliferation. In order to increase the most primitive stem cell pool size, there was initial proliferation of early stem cells with a concomitant decrease in self-renewal capacity. Once this pool was established, the self-renewal capacity of the adherent CFUs maintained for 13 weeks in culture suggests that CFU production and cell maintenance were achieved by clonal succession.The pluripotent hematopoietic stem cell (CFU) is the most primitive of the known hematopoietic progenitor cells. A standard assay for this cell described by Till and McCulloch (1) measures the ability of donor marrow cells to form colonies in the spleens of lethally irradiated syngeneic mice. The selfrenewal capacity of the CFUs has been measured by both the RS, a measurement of CFU production over 14 days of serial marrow transplantation, and by the maximal transplantation time in a series of passages in irradiated animals (2). The standard CFU assay cannot distinguish stem cells with different self-renewal capacities because all produce spleen colonies. By assaying marrow from mice long after the administration of certain alkylating agents, a decrease in the self-renewal potential of the CFU compartment has been demonstrated in vivo (2-5). These experiments are consistent with the notion that the CFU compartment is heterogeneous and consists of a continuum of cells varying in self-renewal capacity. Within this continuum, early CFUs would be less committed to differentiation and have a high self-renewal capacity whereas CFUs further along in the continuum would be more committed to differentiation and have a lower self-renewal potential. Busulfan and certain other alkylating agents would preferentially destroy cells early in the continuum (2, 3). Heterogeneity within the CFU compartment has also been measured in vitro (6, 7). With selective inactivation of the CFUs by rabbit anti-mouse brain antiserum, Monette...

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In order to assess the cosmetic results of treatment, the results in 239 patients with early breast cancer treated by primary radiation treatment without adjuvant chemotherapy were reviewed. Four patients had bilateral cancers, making a total of 243 breasts available for analysis. Follow‐up ranged from 24 to 78 months with a median of 33 months. The parameters measured were breast edema, retraction, telangiectasia, arm edema, and the overall cosmetic appearance. The cosmetic results declined over the first 3 years after treatment, but then stabilized. At 5 years, the overall cosmetic results were judged by physicians as excellent in 77%, good in 9%, fair in 9%, and poor in 5%. A fair or poor cosmetic result was highly correlated with the development of moderate or severe breast retraction. Telangiectasia was uncommonly the only cause of a fair or poor cosmetic result. Breast and arm edema were rarely noted to be significant, but were more common in patients who underwent axillary dissection. In 210 cases, a supplementary boost dose of radiation was delivered to the primary tumor area, and in 33 cases a boost was not used. This boost consisted of an interstitital iridium‐192 implant in 204 cases and either high‐energy photons or electrons in the remainder. At 4 years, no patient treated without a boost had a fair or poor result compared with 22% who received a boost (P = 0.13). The conclusion is that, in general, primary radiation treatment provides highly satisfactory cosmetic results for patients with early breast cancer.