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A study of treated murine acute myeloid leukemia (AML) with an emphasis on the bone marrow stromal function is reported. Leukemia was induced in C57Bl mice through intraperitoneal (i.p.) inoculation of C-1498 myelogenous leukemic cells. The leukemic mice were administered: (1) total body lethal X-irradiation (t.b.i.); (2) two i.p. cytosine-arabinoside (Ara-C) injections followed by X-irradiation. Control mice received similar regimens. Bone marrow of experimental and control mice was processed for stromal cell cultures (SCC) and in vitro engraftment of hematopoietic cells onto the cultures. The results of this study indicate that the bone marrow stromal deficiency which occurs in leukemia is aggravated by Ara-C and irradiation treatments. Moreover, SCC of treated leukemic mice sustain in vitro hematopoiesis only to a limited degree. Stromal deficiency, as possible cause for graft failure in bone marrow transplanted leukemic patients, is discussed.

A study of murine adherent marrow cells (AMC) under conditions of high and low concentrations of hematopoietic stem cells and progenitors was carried out. In one group of weanling mice, decreased marrow cellularity and increased concentrations of CFU-S, CFU-D, and CFU-C were observed two days after administration of two consecutive intraperitoneal (i.p.) cytosine arabinoside (Ara-C) injections (2 x 200 ng/kg, at 6 h interval). Fibroblast colony-forming units (CFU-F) of this marrow were studied. In a second group of mice, which were given three i.p. phenylhydrazine (PHZ) injections (3 x 60 mg/kg on days 0, 1, and 3), CFU-S and CFU-C levels were unchanged or lowered 6 days after the start of PHZ administration. In these animals, however, the number of CFU-D was four times higher than in controls. The study of CFU-F in experiments of groups 1 and 2 indicated a high concentration of these progenitors in group 1 and lower concentration in group 2. Furthermore, fibroblastoid colonies produced in vitro by CFU-F of Ara-C-treated marrow were significantly larger than colonies from control marrow, and they markedly inhibited G/M colonies in split-phase agar cultures. By contrast, fibroblastoid colonies produced by PHZ-treated marrow were of regular size and did not inhibit G/M colonies from test bone marrow.

A study of bone marrow stroma in acute myeloid leukemia (AML) in mice was carried out. AML was induced in C57B1 mice by i.v. inoculation of the C1498 cell line. There was a direct correlation between the marrow leukemic load and the degree of marrow stromal deficiency. This was expressed by reduced in vitro fibroblastoid colony formation. In co-cultures of normal mouse bone marrow and leukemic cells, and also in cultures of normal marrow with added conditioned medium (CM) of leukemic cells, marked inhibition of fibroblast-colony-forming units (CFU-F) from normal marrow was observed. In additional experiments, leukemic mice were treated with two consecutive injections of cytosine arabinoside (Ara-C) (2 X 200mg/kg) and sacrificed 48 h later. Bone marrow samples of treated animals formed in vitro an increased number of fibroblastoid colonies despite relatively high levels of marrow leukemia. It is concluded that: (a) there is a direct correlation between the incidence of marrow leukemic cells and the degree of stromal deficiency; (b) leukemic cells produce in vitro--and probably in vivo CFU-F inhibitory factors and (c) administration of restricted doses of cytosine arabinoside to leukemic mice reduces the marrow leukemic cell content to some extent and increases the capacity of CFU-F to form fibroblastoid colonies in vitro.

Occurrence of young-type stromal stem cells (defined here as "pre-CFU-f") in murine bone marrow is reported in this study. Two consecutive intraperitoneal (i.p.) cytosine arabinoside (ara-C) injections were administered to C57B1 mice (2 X 200 mg/kg at 6-h intervals). Two days later the bone marrow was collected and assayed for colony-forming units-fibroblastoid (defined here as "CFU-f"). In additional experiments, ara-C-treated marrow was exposed in vitro to hydroxyurea (HU; "hydroxyurea killing test"), prior to plating, to establish the cycling state of stromal stem cells. In separate cultures of ara-C-treated marrow, replating of adherent cells was carried out up to quaternary sub-cultures. The results indicate ara-C-treated marrow produces approximately 20% "huge" fibroblastoid colonies (approximately 5 mm diameter versus 0.5-2 mm normal size); most stromal stem cells producing huge colonies are cycling cells; and adherent cells from primary ara-C-treated marrow cultures replated to secondary cultures produce adherent layers with double the number of cells than in the control secondary cultures. We conclude that the ara-C-treated murine bone marrow contains certain young-type cycling stromal stem cells which we refer to as pre-CFU-f. These stem cells produce huge fibroblastoid colonies in culture, indicating that they probably go through more cell cycles than CFU-f during the culture period. Alternatively, pre-CFU-f may have a higher self-replicative capacity than CFU-f.

Eradication of replicating bone marrow cells of rat by means of combined administration of single doses of hydroxyurea and vinblastin is followed within 9--10 h by an inflow of lymphoid cells of extramedullary origin in the range of 13,200,000/femur. The rat bone marrow with a high content of lymphoid cells was previously shown to be concentrated in stem cells. The factor(s) which convey the 'information' of decrease of replicating marrow cells to extramedullary sites is at present unknown.

This study describes changes in bone marrow stroma in murine acute myelogenous leukemia (AML). The AML was induced in C57B1 mice by intravenous (i.v.) transfusion of C4198 myelogenous leukemic cells. In untreated leukemic mice, the colony-forming unit fibroblasts (CFU-F) were severely inhibited. In leukemic mice treated by three chemotherapy protocols of cytosine-arabinoside (Ara-C) and adriamycin there was a 200% increase in the life span as compared to untreated leukemic animals and marked reduction of marrow leukemic load. In these mice the stromal inhibition was temporarily relieved, expressed by peaks of CFU-F2-3 days following each protocol. In between the peaks, CFU-F decreased to subnormal levels, remaining low to the end of the disease. In normal mice administered a similar chemotherapy regimen, there were peaks of CFU-F activation after each protocol and normal levels in between the peaks. Granulocyte/macrophage progenitors (CFU-C) of leukemic-treated and normal-treated mice showed increased levels following each chemotherapy protocol. Whereas CFU-C decreased below normal levels in leukemic mice towards the end of the disease, the level of these progenitors remained high in normal mice receiving Ara-C and adriamycin. Colony-forming units in diffusion chamber (CFU-D) showed mild fluctuations in both leukemic and normal mice receiving three protocols of Ara-C and adriamycin. It is possible that despite treatment, the bone marrow stroma in leukemia becomes irreversibly deficient towards the end of the disease and cannot support the residual normal hematopoiesis.

A single dose of hydroxyurea (HU) (400 mg/kg body weight) was injected i.p. into rats. Hydroxyurea, a potent DNA synthesis inhibitor, killed bone marrow cells in the S-phase of the cell cycle. 9-10 h after HU administration, the rat bone marrow contained large numbers of necrotic cells and appeared predominantly lymphoid. Within 24-48 h of HU injection, resumption of normal haematopoiesis was observed. Rat bone marrow, 9-10 h following HU administration, was implanted in peritoneal diffusion chambers (DC) in irradiated mice. The results obtained suggest that pretreatment of donor rats with HU increases the bone marrow content of progenitor cells. The stem cell-enriched marrow was conductive to enhanced growth of DC colonies in irradiated mice.

Objectives: This study aimed to compare the accuracy of PET/CT parameters with CT parameters for directing bone biopsies. Methods: The study was an IRB-approved retrospective study of 388 patients who underwent both 2-[18F] FDG PET/CT and CT within 6 weeks before a bone biopsy. Age, sex, cancer type, lesion length, SUVmax, tumor to liver (T/L) ratio, CT attenuation, difference in CT attenuation between the lesion and normal bone (delta CT attenuation), and the absolute delta CT attenuation were used as predictors. T tests and chi-squared tests were used to compare variables. DeLong's test was used to compare receiver operator characteristic (ROC) curves. Results: We reviewed the data from 388 patients. Of these, 295 patients had bone lesion biopsies, and 93 patients had bone marrow aspirations/biopsies. Biopsies of larger bone lesions (p = 0.033) and bone lesions with higher SUVmax (p = 0.005) were more likely to show malignancy. For bone lesions, the ROC curve for the SUVmax (AUC = 0.6827) was better than the ROC curves for delta CT attenuation (AUC = 0.5766, p = 0.032) and absolute delta CT attenuation (AUC = 0.5491, p = 0.006), but not significantly better than the ROC curves for CT attenuation (AUC = 0.5894, p = 0.061) and T/L ratio (AUC = 0.6778, p = 0.774). A threshold SUVmax of 5.25 had an accuracy of 0.713, sensitivity of 0.766, and specificity of 0.549 to predict malignancy in bone lesion biopsies. None of these variables predicted malignancy in bone marrow biopsies (p > 0.05 for all). Conclusions: Metabolic 2-[18F]FDG PET/CT parameters have more clinical impact for planning bone biopsies as compared to CT parameters. Key Points: • The 2-[18F]FDG PET/CT measurement (SUVmax) has more clinical impact for planning bone biopsies as compared to CT measurements. • Neither the change in CT attenuation of the lesion relative to normal bone nor the absolute value of this change was a significant predictor of malignancy. • 2-[18F]FDG PET/CT may have clinical benefit and an additional role in directing bone biopsies. [ABSTRACT FROM AUTHOR]