Prognostic significance of the histomorphometric features of bone marrow trephine biopsies in patients with chronic myeloid leukemia

OBJECTIVE: To study the correlation of histomorphometric data of bone marrow trephine biopsies at the time of initial diagnosis in chronic myeloid leukemia (CML) patients with the patient prognosis. STUDY DESIGN: A total of 40 CML patients were divided equally in group I (developed accelerated phase or blast crisis within 18 months of initial diagnosis of chronic phase of CML) and group II (developed accelerated phase or blast crisis > 30 months after initial diagnosis of chronic phase of CML). The clinical, hematologic and histomorphometric data were compared in the 2 groups of CML patients. RESULTS: The percentage of bone marrow promyelocytes was significantly increased in group I. On morphometry, the number of blasts per square millimeter, the area of reticulin fibers per square millimeter and the percentage area occupied by reticulin fibers were statistically significant. CONCLUSION: There seems to be grounds for hope for predicting prognosis of CML patients at initial diagnosis based on histomorphometric findings. The percentage area of reticulin fibers and the number of blasts per square millimeter are important prognostic predictors in histomorphometry data.     

A histomorphometric analysis of trephine biopsies of bone marrow from 65 patients with chronic myeloid leukemia. Classification of patients into subgroups with different survival patterns

A histomorphometric (planimetric) study was performed on trephine biopsies of the bone marrow taken at presentation from 65 patients (31 males and 34 females, with a median age of 48 years) with chronic myeloid leukemia (CML). Specimens from 20 patients (9 males and 11 females, with a median age of 53 years) without any hematologic disorders served as controls. Of the various histologic variables tested, only the counts of neutrophilic granulocytes per 1 sq mm, the ratio of granulocytopoiesis to megakaryopoiesis and the density of reticulin (argyrophilic) fibers revealed a significant correlation with the prognosis. The CML patients were separated into two groups with different survival patterns. Group I (34 patients with a median survival of 24 months) mostly contained cases with the so-called "megakaryocytic subtype" of CML, which is accompanied by variable degrees of fibrosis; group II (31 patients with a median survival of 36 months) mainly contained cases with the "granulocytic subtype," which is not accompanied by myelofibrosis. Among the morphometric parameters, a positive correlation existed between the megakaryocyte count and the reticulin fiber density, which underlines the important role of that cell lineage in fibrillogenesis. There were multiple interrelationships between the histomorphometric variables and the laboratory data. Consequently, multivariate regression methods (using Cox's proportional hazards model) were applied to assess the relative predictive value of the patient characteristics for survival. The derived prognostic model divided the patients into two risk groups, with median survivals of 14 and 41 months, respectively. In order of their entry into the regression model, these variables were percentage of neutrophils in the differential blood count, amount of granulopoiesis, liver size, percentage of peripheral myeloblasts and density of reticulin fibers in the bone marrow. In comparing the two patient groups, based on bone marrow histomorphometric parameters, this model revealed that two of those factors (amount of granulopoiesis and density of reticulin fibers) had a significant correlation with the prognosis.     

Bone marrow engraftment: histopathology of hematopoietic reconstitution following allogeneic transplantation in CML patients

Following myelo-ablative treatment and allogeneic bone marrow transplantation (BMT) in chronic myelogenous leukemia (CML) histopathological features assumed to exert a significant impact on engraftment have been rarely investigated systematically. This review is focused on immunohistochemical and morphometric techniques involving nucleated erythroid precursors, resident macrophages and their various subsets, megakaryocytes and finally argyrophilic (reticulin-collagen) fibers. Regarding standardized intervals of examination in the postgraft sequential trephine biopsies a pronounced reduction in cellularity was obvious and accompanied by a decrease in the quantity of erythro- and megakaryopoiesis. A significant correlation between the number of erythroid precursors and CD68+-macrophages could be determined in the areas of regenerating hematopoiesis. This finding is in keeping with the important functional role of the centrally localized mature macrophages during erythropoiesis. A relevant pretransplant reduction of the red cell lineage and an early to advanced reticulin fibrosis were correlated with a low hemoglobin level (anemia) and splenomegaly and furthermore associated with a significant delay to reach transfusion independence. This result was supported by corresponding findings in biopsy specimens performed shortly after day 30 following BMT (standard interval for assessment of engraftment). Samples revealed an enhancement of fiber density and a conspicuous decrease in the amount of erythropoiesis in the small fraction of patients who did not conform with the usually accepted criteria for successful hematopoietic reconstitution. Considering the compartment of histiocytic reticular cells the recurrence of Pseudo-Gaucher cells (PCGs) in the engrafted donor marrow was remarkable and most prominently expressed in the first two months following BMT. This feature was presumed to be functionally linked with a pronounced degradation of cell debris in the sequel of myelo-ablative therapy (scavenger macrophages). According to planimetric measurements in the postgraft bone marrow the atypical dwarf-like CD61+-megakaryocytes characteristic for CML disappeared. On the other hand, normalization of megakaryocyte size and nuclear lobulation were absent in sequential examination of the few patients developing a leukemic relapse. In a number of patients with manifest myelofibrosis at onset, an initial regression after BMT was followed by an insidiously occurring retrieval which was concentrated on the areas of reconstituting hematopoiesis. Similar to its relevant pretransplant association the postgraft reappearance of myelofibrosis was significantly correlated with the quantity of CD61+-megakaryocytes. Altogether a number of histological features in the pre-and postgraft bone marrow exhibited significant correlations with each other and thus indicated functional relationships. Moreover, quantity of erythropoiesis and amount of reticulin fibers (myelofibrosis) exerted a significant impact on engraftment status.     

Morphometric assessment of bone marrow fiber content in acute nonlymphatic leukemia at presentation

The number of intersections of reticulin fibers per sq mm of fat cell-free marrow parenchyma with the lines of a grid ocular (i/sq mm) represents an objective measure of the bone marrow reticulin fiber content. This method was used to assess the reticulin fiber content of bone marrow biopsies from 50 cases of acute nonlymphatic leukemia (ANLL) at presentation and 20 controls. Seventeen (34%) of the 50 patients with ANLL showed fibrosis, i.e., had a reticulin fiber score above the upper 99% confidence limit of the mean of 20 normal control biopsies. The frequencies of marrow fibrosis, as defined above, were 47% (16 of 34) in the combined subtypes of undifferentiated (M0), myeloid (M1), myelomonocytic (M4) and monocytic (M5) acute leukemia and 7% (1 of 15) in the combined subtypes of acute myeloid leukemia with partial maturation (M2) and acute promyelocytic leukemia (M3) (P less than .01). The fibrosis scores of M0/M1/M4/M5 patients were significantly higher than those of M2/M3 patients (P less than .05) and of controls (P less than .005). Finally, the survival of patients with and without fibrosis was not different.     

Primary (essential) thrombocythemia versus polycythemia vera rubra. A histomorphometric analysis of bone marrow features in trephine biopsies

A morphometric analysis of bone marrow biopsies was performed in 25 patients each with clinical diagnoses of primary (essential) thrombocythemia (PTH) and polycythemia vera rubra (P. vera) according to the rigid diagnostic criteria of the Polycythemia Vera Study Group to reveal significant differences in the histomorphologic features between these disorders. In comparison with control specimens of patients without any hematologic disease, megakaryocyte proliferation was most prominent in PTH, even exceeding that of P. vera with concomitant thrombocythemia (11 of 25 cases with a platelet count greater than 600 X 10(9)/L). Moreover, in P. vera there were wide ranges of megakaryocyte sizes, consisting of micro-megakaryocytes as well as giant forms with highly segmented nuclei (four nuclear lobes), which gave the cells a pleomorphic appearance. As compared with the normal bone marrow, the amount of neutrophilic granulopoiesis and erythropoiesis was not significantly increased in PTH, in contrast to P. vera. Similar results were obtainable regarding the density of reticulin (argyrophilic) fibers: a normal content was encountered in the control specimens and PTH, whereas P. vera displayed a minimal-to-slight increase. Finally, the bone marrow of P. vera was totally devoid of stainable iron while hemosiderin deposits were detected in about two-thirds of the patients without hematologic disorders and in PTH. The characteristic differences revealed by this morphometric study may lead to an improvement of the controversial histologic diagnosis in these disorders.     

Activated fibronectin-secretory phenotype of mesenchymal stromal cells in pre-fibrotic myeloproliferative neoplasms

We characterized bone marrow stromal cells (BMSC) from patients with pre-fibrotic myeloproliferative neoplasms (MPN). MPN-BMSC showed decreased capacity to stimulate the proliferation of colony-forming units of normal hematopoietic stem and progenitor cells and displayed increased matrix remodelling (in particular fibronectin deposition) compared to control BMSC. This finding was confirmed in pre-fibrotic MPN bone marrow biopsies in a tissue microarray (n?=?34), which stained positive for fibronectin in the absence of reticulin as a standard myelofibrosis marker. Fibronectin expression correlated significantly with reduced haemoglobin levels in MPN-patients (p?=?0.007; R2?=?0.42). Our data show significant cell-intrinsic alterations in MPN-MSC and suggest that Fibronectin expression might be applicable as a biomarker for the identification of early myelofibrotic transformation in reticulin-negative MPN.     

Alpha-smooth muscle actin is expressed in a subset of bone marrow stromal cells in normal and pathological conditions

A series of 217 trephine bone marrow biopsies from adult patients and specimens from 16 fetuses and 5 infants were examined for the presence of stromal myoid cells (MCs) using a monoclonal antibody recognizing alpha-smooth muscle actin. In the normal adult bone marrow, stromal cells did not contain alpha-smooth muscle actin, whereas during fetal life, many alpha-smooth muscle actin-containing MCs were connected with vascular sinusoids in the primitive bone marrow. This cell type reappeared in various characteristic distribution patterns in adult bone marrow during different neoplastic and non-neoplastic conditions including metastatic carcinoma, Hodgkin's disease, multiple myeloma, hairy cell leukemia, acute myeloid leukemia (FAB M4, 5, 7) and chronic myelo-proliferative diseases. In general, the appearance of MCs was associated with a slight to pronounced increase in the deposition of reticulin and collagen fibers. We propose that bone marrow MCs represent a distinct subpopulation of fiber-associated or adventitial reticular cells undergoing cytoskeletal remodeling in response to various stimuli.     

Studies of the geographic patterns of c-myc expression in bone marrow

C-myc expression was studied semi-quantitatively in bone marrow biopsies obtained from normal individuals, patients with non-malignant haematological disorders and patients with various haematological malignancies. In normal bone marrow and in the bone marrow of patients with non-malignant haematological disorders, cells containing c-myc protein are present in small clones (average 7 +/- 2.5 cells/clone) located in the centre of the histotopographic region of the biopsy. In contrast, c-myc-containing cells are diffusely distributed in the bone marrow of patients with acute myelogenous leukaemia (AML). In the marrow of patients with myelodysplastic syndromes evolving to AML and in patients with AML in early relapse, the clones of cells containing c-myc are larger than those present in normal marrows (average clone size = 17.5 +/- 3.5 cells). Additionally, the proportion of the cells in normal bone marrow which express c-myc protein is less than that present in AML marrows (23.3 +/- 10.17 v. 60.2 +/- 6.17) and the intensity of staining is also less. Non-Hodgkin's lymphoma patients with bone marrow involvement had distribution of c-myc positive cells similar to those with leukaemic infiltration.     

α-Smooth muscle actin is expressed in a subset of bone marrow stromal cells in normal and pathological conditions

A series of 217 trephine bone marrow biopsies from adult patients and specimens from 16 fetuses and 5 infants were examined for the presence of stromal myoid cells (MCs) using a monoclonal antibody recognizing α-smooth muscle actin. In the normal adult bone marrow, stromal cells did not contain α-smooth muscle actin, whereas during fetal life, many α-smooth muscle actin-containing MCs were connected with vascular sinusoids in the primitive bone marrow. This cell type reappeared in various characteristic distribution patterns in adult bone marrow during different neoplastic and non-neoplastic conditions including metastatic carcinoma, Hodgkin’s disease, multiple myeloma, hairy cell leukemia, acute myeloid leukemia (FAB M4, 5, 7) and chronic myeloproliferative diseases. In general, the appearance of MCs was associated with a slight to pronounced increase in the deposition of reticulin and collagen fibers. We propose that bone marrow MCs represent a distinct subpopulation of fiber-associated or adventitial reticular cells undergoing cytoskeletal remodeling in response to various stimuli.     

CD34+ stem cells in chronic myeloproliferative disorders

Contrasting the wealth of information that is available about various biological and therapeutic aspects of human CD34+ stem cells, little data exist concerning their quantity and dynamics as well as their mutual relationships with other hematopoietic constituents in the bone marrow of patients with chronic myeloproliferative disorders. In comparison with a control group frequency of progenitors is significantly increased in chronic myeloid leukemia (CML). Following different therapeutic modalities their quantity reflects therapeutic efficacy (responder and non-responder patients) and therefore exerts a predictive value regarding acceleration and blastic crisis. The significant correlations between fiber content and number of these precursors elucidates the complex interactions between stroma and progenitor cell differentiation and maturation. Following allogeneic bone marrow transplantation there is a rapid recovery of the CD34+ stem cell population in the first month. A higher number of these cells is related with graft size, an earlier independence for platelet transfusion and a more extended regeneration of erythro- and megakaryopoiesis. The slight increase in reticulin fibers in these patients may be associated with the complex and so far ill-defined pathomechanism of homing (adherence to the fibrous matrix). In idiopathic myelofibrosis (IMF) an increased number of CD34+ stem cells is found predominantly in the early (prefibrotic or mild fibrotic) hypercellular stages and probably indicates a higher proliferative activity of the precursor cell pool. According to sequential biopsies most patients with early IMF that later evolved into an overt fibrosclerotic stage usually display a reduction of progenitor cells during the development of myelofibrosis. The unequal distribution of CD34+ stem cells in the bone marrow versus spleen in IMF (advanced fibrosclerotic stage) is in support of the currently discussed hypothesis of splenic filtration and concentration of precursor cells as an essential feature of myeloid metaplasia. Regarding prognosis in CML a higher amount of CD34+ stem cells is significantly associated with an unfavorable survival and thus confirms the assumed implication of an accelerated phase of disease at onset. On the other hand, in polycythemia vera (PV) and IMF a low number of progenitors is probably due to a decreased proliferation rate (reduced hematopoietic turnover index) and therefore reflects a reduction in the regenerative capacity of hematopoiesis. For this reason, a presumptive defect in the recovery of normal and clonally transformed stem cells is speculated to add to the worsening of prognosis by causing the well-known bone marrow insufficiency in terminal stage PV and IMF.     

Expression patterns of leptin receptor (OB-R) isoforms and direct in vitro effects of recombinant leptin on OB-R, leptin expression and cytokine secretion by human hematopoietic malignant cells

Several studies have implicated leptin in the pathophysiology of neoplasias. We investigated the direct effect of leptin on malignant hematopoietic tissue that included: primary acute myeloid leukemia (AML) cells, leukemic cell lines and bone marrow biopsies from multiple myeloma (MM) patients. PBMC, T-cells, B-cells and monocytes from healthy subjects served as controls. We defined the patterns of OB-R isoform expression in AML cells and leukemic cell lines in comparison to control cells by RT-PCR. rLeptin upregulated the expression of OB-R and endogenous leptin in AML blasts and certain cell lines but not in control cells. Cytometric Bead Array analysis of pro- and anti-inflammatory cytokines showed that rleptin upregulates IL-6 secretion by AML cells, various cytokines by the leukemic cell lines tested and IL-10 secretion by control PBMC, contributed by monocytes. Western immunoblotting revealed that the effect of rleptin was independent of JAK-2/phospho-JAK-2 protein levels. Finally, MM biopsies stained positive for leptin and, to a lesser extend, OB-R. Immunoreactivity was confined mostly to the nucleus of the myeloma cells. Normal myelocytes, promyelocytes and megakaryocytes stained weakly positive, and erythroid cells were constantly negative. We propose that the leptin/OB-R system is strongly and directly involved in supporting the growth of hematopoietic malignancies.     

Expression patterns of leptin receptor (OB-R) isoforms and direct in vitro effects of recombinant leptin on OB-R,leptin expression and cytokine secretion by human hematopoietic malignant cells

Several studies have implicated leptin in the pathophysiology of neoplasias. We investigated the direct effect of leptin on malignant hematopoietic tissue that included: primary acute myeloid leukemia (AML) cells, leukemic cell lines and bone marrow biopsies from multiple myeloma (MM) patients. PBMC, T-cells, B-cells and monocytes from healthy subjects served as controls. We defined the patterns of OB-R isoform expression in AML cells and leukemic cell lines in comparison to control cells by RT-PCR. rLeptin upregulated the expression of OB-R and endogenous leptin in AML blasts and certain cell lines but not in control cells. Cytometric Bead Array analysis of pro- and anti-inflammatory cytokines showed that rleptin upregulates IL-6 secretion by AML cells, various cytokines by the leukemic cell lines tested and IL-10 secretion by control PBMC, contributed by monocytes. Western immunoblotting revealed that the effect of rleptin was independent of JAK-2/phospho-JAK-2 protein levels. Finally, MM biopsies stained positive for leptin and, to a lesser extend, OB-R. Immunoreactivity was confined mostly to the nucleus of the myeloma cells. Normal myelocytes, promyelocytes and megakaryocytes stained weakly positive, and erythroid cells were constantly negative. We propose that the leptin/OB-R system is strongly and directly involved in supporting the growth of hematopoietic malignancies.     

Hematopoietic stem cell expansion and distinct myeloid developmental abnormalities in a murine model of the AML1-ETO translocation

The t(8;21)(q22;q22) translocation, which fuses the ETO gene on human chromosome 8 with the AML1 gene on chromosome 21 (AML1-ETO), is one of the most frequent cytogenetic abnormalities associated with acute myelogenous leukemia (AML). It is seen in approximately 12 to 15% of AML cases and is present in about 40% of AML cases with a French-American-British classified M2 phenotype. We have generated a murine model of the t(8;21) translocation by retroviral expression of AML1-ETO in purified hematopoietic stem cells (HSC). Animals reconstituted with AML1-ETO-expressing cells recapitulate the hematopoietic developmental abnormalities seen in the bone marrow of human patients with the t(8;21) translocation. Primitive myeloblasts were increased to approximately 10% of bone marrow by 10 months posttransplant. Consistent with this observation was a 50-fold increase in myeloid colony-forming cells in vitro. Accumulation of late-stage metamyelocytes was also observed in bone marrow along with an increase in immature eosinophilic myelocytes that showed abnormal basophilic granulation. HSC numbers in the bone marrow of 10-month-posttransplant animals were 29-fold greater than in transplant-matched control mice, suggesting that AML1-ETO expression overrides the normal genetic control of HSC pool size. In summary, AMLI-ETO-expressing animals recapitulate many (and perhaps all) of the developmental abnormalities seen in human patients with the t(8;21) translocation, although the animals do not develop leukemia or disseminated disease in peripheral tissues like the liver or spleen. This suggests that the principal contribution of AML1-ETO to acute myeloid leukemia is the inhibition of multiple developmental pathways.     

An abnormal CD34+ myeloid/CD34+ lymphoid ratio at the end of chemotherapy predicts relapse in patients with acute myeloid leukemia.

During conventional follow-up of patients with acute myeloid leukemia (AML), the emergence of cytopenias is considered to be a sign of impending relapse, and it represents an example of how leukemic hematopoiesis affects normal hemopoietic differentiation. In the present study, we have explored the possible value of the analysis of the distribution of CD34+ myeloid and CD34+ lymphoid progenitor cells in follow-up complete remission bone marrow samples from de novo AML patients as a prognostic parameter for predicting relapse. A total of 213 bone marrow samples from 36 AML patients in morphological complete remission, obtained at the end of induction, consolidation, and intensification therapy and every six months thereafter were analyzed. The normal CD34+ myeloid/CD34+ lymphoid ratio ranged between 2.4 and 8.9. In contrast, in most AML cases an abnormally high ratio (> or =10) was observed at the end of induction and consolidation therapy: 96% and 75% of cases, respectively. On the other hand, at the end of intensification, 70% of the patients displayed a normal CD34+ ratio. Patients with a myeloid/lymphoid CD34+ ratio higher than 10 at the end of intensification showed a significantly lower overall survival (median survival of 19 months versus median not reached, P = 0.05), as well as a lower disease-free survival (median of 7 months versus 30 months, P = 0.0001). Regarding sequential studies, 67% of the relapses were preceded by the re-appearance of an abnormal CD34 ratio, whereas relapse was not predicted in four patient with leukemia classified as M3 undergoing maintenance therapy. From the remaining 18 patients who are still in continuous complete remission, all except 3 cases (17%) displayed a normal CD34 myeloid/lymphoid ratio. In summary, the present study shows that the persistence at the end of chemotherapy of an abnormally high (> or =10) ratio between CD34+ myeloid and CD34+ lymphoid progenitors in the bone marrow of AML patients is associated with high risk of relapse and a shorter overall survival.     

Normal Hematopoietic Stem Cells within the AML Bone Marrow Have a Distinct and Higher ALDH Activity Level than Co-Existing Leukemic Stem Cells

Persistence of leukemic stem cells (LSC) after chemotherapy is thought to be responsible for relapse and prevents the curative treatment of acute myeloid leukemia (AML) patients. LSC and normal hematopoietic stem cells (HSC) share many characteristics and co-exist in the bone marrow of AML patients. For the development of successful LSC-targeted therapy, enabling eradication of LSC while sparing HSC, the identification of differences between LSC and HSC residing within the AML bone marrow is crucial. For identification of these LSC targets, as well as for AML LSC characterization, discrimination between LSC and HSC within the AML bone marrow is imperative. Here we show that normal CD34+CD38– HSC present in AML bone marrow, identified by their lack of aberrant immunophenotypic and molecular marker expression and low scatter properties, are a distinct sub-population of cells with high ALDH activity (ALDH^bright). The ALDH^bright compartment contains, besides normal HSC, more differentiated, normal CD34+CD38+ progenitors. Furthermore, we show that in CD34-negative AML, containing solely normal CD34+ cells, LSC are CD34– and ALDH^low. In CD34-positive AML, LSC are also ALDH^low but can be either CD34+ or CD34–. In conclusion, although malignant AML blasts have varying ALDH activity, a common feature of all AML cases is that LSC have lower ALDH activity than the CD34+CD38– HSC that co-exist with these LSC in the AML bone marrow. Our findings form the basis for combined functionally and immunophenotypically based identification and purification of LSC and HSC within the AML bone marrow, aiming at development of highly specific anti-LSC therapy.     

急性髓细胞性白血病（AML）中IL-3Rα 基因的表达及意义

目的:检测白介素-3受体α亚基(IL-3Rα)在急性髓细胞性白血病(acute myeloid leukemia,AML)中的表达,研究其在AML发病和预后评估中的意义。方法:应用逆转录-聚合酶链反应(RT-PCR)法检测57例AML患者IL-3Rα的表达,其中包括52例初治和复发患者(6例M1、28例M2、10例M3、3例M4、5例M5)及5例缓解患者,另10例正常人作为对照。结果:①10例正常人和5例AML缓解患者未检测到IL-3Rα表达。②52例初治和复发的AML患者中IL-3Rα阳性表达21例,占40.38%,M1～M5各型患者的阳性率差异无显著性(P>0.05)。初治和复发AML患者之间IL-3Rα阳性表达无明显差异(P>0.05)。③AML患者的IL-3Rα阳性表达与外周血白细胞计数、骨髓中原始细胞比例、CD34阳性表达有关(P<0.05)。④AML患者中IL-3Rα阳性表达的患者CR率低于阴性者(P<0.05)。结论:①IL-3Rα在AML发病中有一定作用。②IL-3Rα基因可作为AML预后不良的一个指标。     

Identification of B-cell translocation gene 1 as a biomarker for monitoring the remission of acute myeloid leukemia

Acute myeloid leukemia (AML) is a biologically heterogeneous disease of the hematopoietic system characterized by a clonal accumulation of immature blast cells in bone marrow. We used a proteomic approach based on two-dimensional electrophoresis and mass spectrometry to search for biomarkers related to the complete remission (CR) state of AML patients. We detected one AML-related protein, which was identified as the B-cell translocation gene 1 (BTG1) protein that belongs to anti-proliferative protein family. In the CR state of AML-M2 and M3 patients (by French-American-British subtype classification), the BTG1 protein was upregulated in bone marrow mononuclear cells. It was also expressed robustly in normal bone marrow mononuclear cells. In addition, the BTG1 levels in AML-M2 patients in a non-remission state after therapy did not increase as they did before therapy. Overexpression of BTG1 mRNA was also observed in the CR state of all-trans-retinoic acid (ATRA)-treated AML-M3 patients and ATRA-treated HL-60 cells. Taken together, these results suggest that BTG1 may play a role in the differentiation process of myeloid cells and can therefore be used as a potential treatment-related biomarker for monitoring the remission status of AML-M2 and M3 patients.     

Magnetic resonance (MR) evaluation of bone marrow in vertebral bodies.

Magnetic Resonance (MR) imaging was used to examine the hematopoietic bone marrow in the vertebral bodies of eight healthy subjects, and of 35 cancer patients who had been previously treated with radiation therapy. MR was instrumental in distinguishing viable hematopoietic tissue (red marrow) from adipose tissue (yellow marrow), whose presence reflected the extent of radiation-induced bone marrow injury. Different water content in proliferating hematopoietic tissue and adipose tissue enabled clear distinction of the two components even inside the same vertebral body. Three patterns of bone marrow viability were observed in irradiated patients: 1. Patients undergoing therapy at the time of MR study, and patients who had received low-intermediate dose several years before MR examination showed no alteration as compared with healthy controls (i.e. homogeneous presence of red marrow). 2. Patients who had received low-intermediate dose few years before MR, showed either partial re-colonization of yellow marrow or almost complete ablation of active red marrow with rare areas of re-colonization. 3. Patients who had received high dose, showed complete depletion of red marrow (fatty substitution) independently of the length of time elapsed since radiation therapy. Therefore, bone marrow recovery after radiation therapy was associate with two variables: received dose and length of time allowed for re-colonization by surviving hematopoietic tissue. In conclusion, our results provide evidence that MR can be purposively used to study composition and distribution of normal bone marrow, and to asses the extent of radiation-induced bone marrow injury; to monitor bone marrow recovery (or the lack of it); and in the general follow-up of treated cancer patients.