Biomedical subjects
Publications and source records attributed to A Manna.
The paper describes the obstetric management of an unique case of twin, bicorial, biamniotic pregnancy in which the second twin born 36 days after the first. Both twins are living today.
Human acute myelogenous or lymphoblastic leukemia cells of the K-562 and CCRF-SB lines were mixed with an excess of normal human bone marrow cells to simulate a leukemia remission marrow. The cell mixtures were then incubated in vitro with mafosfamide (AZ) followed by the photoreactive dye merocyanine-540 (MC). Treated cells (1 x 10(4] were seeded in microwell plates, and increasing numbers of the line used to contaminate the normal marrow were added. Treatment with AZ alone produced total elimination (i.e., 6 logs) of CCRF-SB cells, while addition of merocyanine-540 increased the cloning efficiency from 22% to 24.4%. After treatment of the K-562-contaminated cell mixtures with AZ, nearly 1.6 logs of K-562 acute myelogenous blasts were still present, whereas AZ purging followed by MC-mediated photosensitization resulted in 100% elimination of clonogenic cells. Moreover, the combined treatment caused an increase of the cloning efficiency from 37.3% to 62%, clearly indicating that cleansing by the two agents combined was more effective than treatment with one agent alone.
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Twenty successive adult patients with lymphoblastic lymphoma entered a study of sequential chemotherapy consisting of an intensive LSA2-L2-type protocol to induce first complete remission. Twelve patients in first CR (median age 22 years, range 15-43), after receiving a conditioning regimen consisting of cyclophosphamide and total body irradiation, underwent autologous bone marrow transplantation. Of these 12 patients at diagnosis, one was in stage III and 11 in stage IV; 11 showed mediastinal and seven showed bone marrow involvement. The transplant procedure was well tolerated and no treatment-induced deaths occurred. At this time nine patients are alive and well 25-44 months post-transplant (median follow-up 36 months) with an actuarial disease-free survival of 75%. These early results suggest that high-dose chemoradiotherapy followed by autologous bone marrow transplantation may improve long-term disease-free survival in advanced stage adult lymphoblastic lymphoma. In order to draw definite conclusions, however, a larger and randomized study is needed.
There are many case reports of secondary neoplasms occurring after treatment with alkylating agents. A case of malignant melanoma of the glans penis in a chronic myeloid leukemia (CML) Ph'-positive patient after 13 years on busulfan treatment is described. Since neither impairment of immune status nor increased incidence of secondary neoplasm have hitherto been reported in CML, the suggestion that busulfan has a carcinogenetic effect is discussed.
To stimulate a leukemia remission marrow, cell suspensions of normal human bone marrow were mixed with human acute lymphoblastic or myelogenous leukemic cells of the CCRF-SF, Nalm-6, and K-562 lines. The cell mixtures were incubated in vitro with mafosfamide (AZ) or with the photoreactive dye merocyanine 540 (MC-540). A quantity of 10(4) cells of the treated suspensions was dispensed into microculture plates, and graded cell numbers of the line used to contaminate the normal marrow were added. Limiting-dilution analysis was used to estimate the frequency of leukemia cells persisting after treatment with the decontaminating agents. Treatment with AZ or MC-540 produced a total elimination (ie, 6 logs or 5.3 logs respectively) of B cell acute leukemia cells (CCRF-SB), whereas nearly 1.7 logs and 2 logs of K-562 acute myelogenous blasts were still present in the cell mixtures after treatment with MC-540 and AZ, respectively. Treatment of the Nalm-6-contaminated cell mixtures with AZ resulted in 100% elimination of clonogenic cells, whereas nearly 80% decontamination was obtained with MC-540. Our results suggest that treatment with AZ could be an effective method of eliminating clonogenic tumor cells from human bone marrow. MC-540, shown by previous studies to spare sufficient pluripotential stem cells to ensure hemopoietic reconstitution in the murine model and in clinical application, has comparable effects and merits trials for possible clinical use in autologous bone marrow transplantation.
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Thirteen patients with homozygous beta thalassemia underwent allogeneic marrow transplantation from sibling donors, 12 of whom were heterozygous for beta thalassemia. Six patients were transplanted in an advanced stage of their disease while seven were transplanted early in their disease course. Donors and recipients were genotypically identical for the HLA-A, -B and -D loci in 11 cases and mismatched for the D locus in two. A variety of preparative regimens was utilized involving high doses of busulphan (Bu) and/or cyclophosphamide (CY) and/or total body irradiation (TBI). Failure of engraftment or autologous hematologic recovery after transient engraftment was seen after intensive preparative regimens including: CY 200 mg/kg and 800 rad of TBI; Bu 8 mg/kg and CY 200 mg/kg; and Bu 8 mg/kg, CY 200 mg/kg, and 300 rad of TBI. A regimen of Bu 16 mg/kg, CY 200 mg/kg, and 400 rad of TBI resulted in deaths from transplant-related causes in the three patients treated with this regimen. Seven of the 13 patients are surviving 363-665 days after transplant. Five of the seven failed to achieve engraftment or had autologous reconstitution after transient engraftment. Five of the six deaths were transplant related, and one patient died of cardiac failure one year after an unsuccessful transplant attempt. Two patients are surviving with engraftment and without thalassemia major 363 and 491 days after transplantation. Both of these patients were transplanted early in their disease course.
The studies described herein were undertaken to help define the effects of certain cyclophosphamide derivatives that have been used for selective removal of leukemic cells from marrow samples used for autologous transplantation. We have tested the effect of 4-HC and another cyclophosphamide congener, ASTA-Z 7557, on pluripotent stem cells (CFU-S) and committed progenitor cells (CFU-GM) in mice. The CFU-S were evaluated by the spleen colony assay at eight days and 12 days after transplant. The eight-day colonies are transient in nature, rapidly growing, mainly erythroid, and lack pluripotential precursors. The 12-day colonies are believed to provide a measure of hemopoietic stem cells as they slowly grow and do contain primitive precursors. Our data show that at the maximum dose levels tested, both drugs caused a 100% loss of CFU-GM and about 80%-95% inhibition of early transient CFU-S. In contrast, about 70% of the pluripotent 12-day CFU-S were spared. These data appear to explain the hemopoietic recovery seen in man after transplantation with marrow cells treated with 4-HC despite their relative absence of hemopoietic progenitor cells.
The CFU-Gm content of liver, spleen and bone marrow of human fetuses was determined from the 8th to 28th week of gestational age. The study of progenitor cells from 43 fetal livers revealed that the CFU-Gm increased from 8 to 12 weeks, was relatively stable through 16 weeks and thereafter declined by 22 to 24 weeks. The total number of liver CFU-Gm rose from 10(4) to greater than 10(6) CFU-Gm by the 16th week of gestation and declined to approximately 4 X 10(5) progenitor cells by 22 to 24 weeks. Peak values of bone marrow CFU-Gm were noted at 10 to 14 weeks of gestation. Generally, the numbers of these progenitor cells declined by 16 to 18 weeks; however, several high values were obtained at later times. Splenic CFU-Gm were relatively constant in number between 12 and 28 weeks of gestation with no correlation with fetal age. Thus, these studies indicate that certain fetal tissues contain substantial numbers of hemopoietic progenitor cells. Based on the quantity of CFU-Gm obtained, it appears feasible to use fetal liver cells as a source of progenitor cells for transplantation.
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Studies were undertaken in mice to determine the effect of calusterone (a weakly androgenic steroid) on hemopoiesis. Animals were myelosuppressed with a single injection of the alkylating agent busulfan and subsequently treated with varying courses of calusterone. Simultaneous injection of calusterone did not prevent the rapid decline in CFU-S or CFU-C. Daily administration of calusterone for 12 to 14 days after busulfan had little influence on bone marrow cellularity; however, a twofold increase in peripheral blood neutrophils was observed. Bone marrow CFU-S and CFU-C were twofold to threefold higher after 8 to 14 days of treatment with calusterone, but there were no progressive increments in these hemopoietic stem cells during this time interval. In contrast to the granulocyte series, erythroid recovery was rapid after busulfan. Marrow erythroid precursors and CFU-E returned to normal levels by day 8. Daily treatment with calusterone accelerated recovery and led to an overshoot in these parameters of marrow erythropoiesis. Although an early course of calusterone treatment had only modest effects on CFU-S and CFU-C, delayed treatment was clearly stimulatory. A 10-day course of calusterone from days 14 to 24 after busulfan increased bone marrow CFU-S and CFU-C from 5% to 23% of controls to near normal values. Thus calusterone appears to stimulate all classes of hemopoietic progenitor cells. Its effects after busulfan are highly time-dependent, with greatest activity observed in those cellular compartments undergoing proliferative expansion.
Bone marrow collected from patients with hematologic malignancies were cryopreserved using DMSO as a cryoprotective agent. The growth kinetics of hemopoietic stem cells frozen to -196 degrees C were monitored immediately after thawing by the semisolid agar CFU-C assay and 2 different methods of cell reconstitution were compared. In the first way, thawed cells were plated after the removal of DMSO by washing the cell suspension, in the second, cell suspensions were cultured after a simple 1:1 dilution of DMSO with medium. The number of CFU-C per 2 X 10(5) cells plated was higher washing out the DMSO in all the groups studied. However, the absolute numbers of CFU-C contained in the whole ampoules after the freezing procedures was approximately the same with both methods. It is concluded that washing the cells only apparently yielded a better cloning efficiency, suggesting that such a procedure led to a higher mature nucleated cell loss with the consequence of a CFU-C concentration. This trend seems particularly evident in the AML and CML patients.