Bone Marrow Changes Research Articles

Quantitative MRI and spectroscopy of bone marrow.

Bone marrow is one of the largest organs in the human body, enclosing adipocytes, hematopoietic stem cells, which are responsible for blood cell production, and mesenchymal stem cells, which are responsible for the production of adipocytes and bone cells. Magnetic resonance imaging (MRI) is the ideal imaging modality to monitor bone marrow changes in healthy and pathological states, thanks to its inherent rich soft‐tissue contrast. Quantitative bone marrow MRI and magnetic resonance spectroscopy (MRS) techniques have been also developed in order to quantify changes in bone marrow water–fat composition, cellularity and perfusion in different pathologies, and to assist in understanding the role of bone marrow in the pathophysiology of systemic diseases (e.g. osteoporosis). The present review summarizes a large selection of studies published until March 2017 in proton‐based quantitative MRI and MRS of bone marrow. Some basic knowledge about bone marrow anatomy and physiology is first reviewed. The most important technical aspects of quantitative MR methods measuring bone marrow water–fat composition, fatty acid composition, perfusion, and diffusion are then described. Finally, previous MR studies are reviewed on the application of quantitative MR techniques in both healthy aging and diseased bone marrow affected by osteoporosis, fractures, metabolic diseases, multiple myeloma, and bone metastases. Level of Evidence: 3 Technical Efficacy: Stage 2J. Magn. Reson. Imaging 2018;47:332–353.

Adiponectin Enhances Quiescence Exit of Murine Hematopoietic Stem Cells and Hematopoietic Recovery Through mTORC1 Potentiation.

Myelotoxic injury, such as chemotherapeutic agents and ionizing radiation, unlocks the vigorous power of hematopoietic stem cells (HSCs) to replenish the hematopoietic system, making quiescent HSCs enter the cell cycle. Considering that both HSC-intrinsic and -extrinsic mechanisms enforce quiescence of HSCs, the drastic change in bone marrow (BM) environment after injury, represented by massive expansion of BM adipocytes, might trigger HSC activation. BM adipocytes, the major cellular component in the ablated marrow, however, reportedly suppress proliferation of hematopoietic cells, which may indicate the BM adipocytogenesis is an irrational response of injured organism. Given that adipose tissue is an endocrine organ with pleiotropic functions, we hypothesized that adipocyte-derived factors, especially adiponectin, an anti-inflammatory adipokine involved in regulation of granulopoiesis, are implicated in HSC activation. Myeloablative intervention increased BM adiponectin by multiple mechanisms, including adipocyte expansion and increased diffusion from the blood. Adiponectin-null (Adipoq -/- ) mice showed delayed hematopoietic recovery after BM injury, with Adipoq-/- HSCs more quiescent and defective in mammalian target of rapamycin complex 1 (mTORC1) activation. Recombinant adiponectin promoted not only HSC activation in vivo but cytokine-induced activation in vitro, and shortened the time for exit from quiescence in an mTORC1-dependent manner. These data illustrate a scarcely-reported example of a cell-extrinsic factor, adiponectin, enhancing quiescence exit of HSCs, and subsequent hematopoietic recovery. Our findings also highlight adipocytes as a source of adiponectin to ensure the proliferative burst of hematopoietic cells in ablated marrow. Stem Cells 2017;35:1835-1848.

Relative thrombocytosis following chemoradiation of patients with glioblastoma to predict survival.

e13527 Background: Thrombocytosis is associated with poor survival in several malignancies and is both triggered by and promoting of tumor growth. We hypothesized that an increase in circulating platelets following standard temozolamide (TMZ) CRT and/or adjuvant TMZ would predict for decreased survival in patients with glioblastoma (GBM). Methods: We reviewed data of 122 patients with newly diagnosed, pathological-proven GBM from 2007 to 2016 with documented complete blood counts before the start of CRT, after CRT, before adjuvant TMZ, and after a minimum 2 cycles of adjuvant TMZ. The association between changes in blood count levels and patient survival was analyzed by log-rank test. Multivariate analysis was performed using known prognostic co-variates, including MGMT methylation, patient age, and performance status (PS). Results: The mean change in platelets before and after CRT was -46 k/µl (range -387 to 179 k/µl) and before and after adjuvant TMZ was -25 k/µl (range -408 to 143 k/µl). As a reference, the mean change in lymphocytes was -5.7 k/µl (range -0.7 to 1.3 k/µl) and -0.0 k/µl (range -1.6 to 0.9 k/µl) for CRT and adjuvant TMZ, respectively. Patients were dichotomized based on the relative change in platelets and lymphocytes from baseline (≤30% increase, “low”, n = 101 vs > 30% increase, “high”, n = 12). The median survival of low patients vs. high patients was 30 vs 13 months (p = 0.006). Potential confounders, such as infection or thrombosis, were not associated with the high group. However, no significant survival difference was observed between groups based on platelet changes during adjuvant TMZ. Similarly, changes in lymphocyte counts were not significantly prognostic. In multivariate analysis, extent of resection, MGMT status, PS and the increase in platelets after CRT were significantly associated with survival (HR for platelets 4.0, 95% CI 1.6-10.1). Conclusions: Increased platelet counts after CRT predict for poor survival in patients with GBM. The effect is platelet specific and does not reflect general bone marrow changes, as lymphocyte changes were not significantly prognostic. These results suggest a potential interaction between platelets and tumor aggressiveness.

Cryoablation combined with allogenic natural killer cell immunotherapy improves the curative effect in patients with advanced hepatocellular cancer.

In this study, the clinical efficacy of cryosurgery combined with allogenic natural killer cell immunotherapy for advanced hepatocellular cancer was evaluated. From October 2015 to March 2017, we enrolled 61 patients who met the enrollment criteria and divided them into two groups: 1) the simple cryoablation group (Cryo group, n = 26); and 2) the cryoablation combined with allogenic natural killer cells group (Cryo-NK group, n = 35), the safety and short-term effects were evaluated firstly, then the median progression-free survival, response rate and disease control rate were assessed. All adverse events experienced by the patients were recorded, and included local (e.g., pain, pleural effusion, and ascites) and systemic (e.g., chills, fatigue, and fever) reactions, fever was more frequent. Other possible seriously side effects (e.g., blood or bone marrow changes) were not detected. Combining allogeneic natural killer cells with cryoablation had a synergistic effect, not only enhancing the immune function, improving the quality of life of the patients, but also reducing the expression of AFP and significantly exhibiting good clinical efficacy of the patients. After a median follow-up of 8.7 months (3.9 –15.1months), median progression-free survival was higher in Cryo-NK (9.1 months) than in Cryo (7.6 months, P = 0.0107), median progression-free survival who received multiple natural killer was higher than who just received single natural killer (9.7 months vs.8.4 months, P = 0.0011, respectively), the response rate in Cryo-NK (60.0%) was higher than in Cryo (46.1%, P < 0.05), the disease control rate in Cryo-NK (85.7%) was higher than in Cryo group (69.2%, P < 0.01). Percutaneous cryoablation combined with allogeneic natural killer cell immunotherapy significantly increased median progression-free survival of advanced hepatocellular cancer patients. Multiple allogeneic natural killer cells infusion was associated with better prognosis to advanced hepatocellular cancer.

Leptin receptor antagonism of iNKT cell function: a novel strategy to combat multiple myeloma.

A hallmark of bone marrow changes with aging is the increase in adipocyte composition, but how this impacts development of multiple myeloma (MM) is unknown. Here, we report the role of the adipokine leptin as master regulator of anti-myeloma tumor immunity by modulating the invariant natural killer T (iNKT) cell function. A marked increase in serum leptin levels and leptin receptor (LR) expression on iNKT cells in MM patients and the 5T33 murine MM model was observed. MM cells and leptin synergistically counteracted anti-tumor functionality of both murine and human iNKT cells. In vivo blockade of LR signaling combined with iNKT stimulation resulted in superior anti-tumor protection. This was linked to persistent IFN-γ secretion upon repeated iNKT cell stimulation and a restoration of the dynamic antigen-induced motility arrest as observed by intravital microscopy, thereby showing alleviation of iNKT cell anergy. Overall our data reveal the LR axis as novel therapeutic target for checkpoint inhibition to treat MM.

Pre- and postoperative magnetic resonance imaging (MRI) findings in patients treated with laparoscopic sacrocolpopexy. Is it a safe procedure for all patients?

Laparoscopic sacrocolpopexy (LSCP) is a reference operation for apical compartment prolapse repair. Aim of this study is to describe the early and midterm postoperative MRI findings of the lumbosacral region (LSR) in patients undergoing LSCP and to detect any imaging changes that the presence of the mesh may cause on patients with preexisting degenerative disease of the LSR. Patients with POP-Q grade III and IV uterovaginal or vaginal vault prolapse who were considered eligible for LSCP were invited to participate. An MRI of the LSR was performed preoperatively and then 3 and 12 months postoperatively. Patients with vaginal vault prolapse underwent LSCP, while women with uterovaginal prolapse were treated with the vaginally assisted laparoscopic sacrocolpopexy (VALS). A total of 30 patients were included in the study; 18 (60%) underwent LSCP and 12 (40%) VALS. On preoperative MRIs, 83.3% (25/30) of patients had degenerative changes and 70% (21/30) reported having low back pain (LBP). Postoperative MRIs did not reveal any imaging changes compared to the preoperative MRI findings both for patients with or without preexisting degenerative abnormalities of the LSR. No significant changes in the LBP score were observed postoperatively. Any bone marrow or soft-tissue changes at MRIs of the LSR early after the insertion of a synthetic mesh, does not constitute an expected postoperative finding and should raise the suspicion of an ongoing inflammatory or infectious spinal process (spondylodiscitis). Additionally, LSCP seems to be a safe surgical approach for women with preexisting degenerative disease of the LSR.

Bone marrow architecture reconstitution after hematopoietic grafting: A cross-sectional study

Abstract Objective Changes in bone marrow (BM) architecture and its remodeling after hematopoietic stem cell transplantation (HSCT) following a reduced-intensity conditioning regimen for treating malignant hematologic diseases are poorly documented. We assessed these changes and their correlation with the clinical course to investigate the dynamics of this process. Material and methods Hematology patients who received a reduced intensity conditioning (RIC) were followed after successful allogeneic or autologous HSCT. Patients had at least 100 days after hematopoietic grafting. Post-transplant BM architecture was assessed by expert examination of a trephine biopsy using age-adjusted scores and histopathology results were contrasted with clinical post-transplant evolution to determine meaningful associations. Results Twenty-seven HSCT recipients, 19 allogeneic and 8 autologous, were studied at a median 155 (100–721) days post-transplant. Eleven (40.7%) had hypocellular biopsies with around 50% of the expected cell composition for a normal individual at that age. Patients with increased fibrosis had lower peripheral white blood cell counts compared to those with normal reticulin distribution (p = 0.015). A decrease in overall survival (OS) was documented in the group with more severe myelofibrosis at a median 813 days of follow-up. Infectious complications were more frequent in patients receiving an allogeneic (n = 6) compared with the recipients of an autologous transplant (n = 0). Conclusions Despite normal peripheral blood count and composition, significant post-transplant hypocellularity, revealing incomplete bone marrow reconstitution, was documented after HSCT in patients conditioned with a RIC regimen. Severe BM fibrosis was associated to decrease OS.

Joint Fluid, Bone Marrow Edemalike Changes, and Ganglion Cysts in the Pediatric Wrist: Features That May Mimic Pathologic Abnormalities-Follow-Up of a Healthy Cohort.

The presence of findings at wrist MRI that may mimic disease is a diagnostic problem. The purpose of this study is to examine the occurrence of bone marrow changes resembling edema, joint fluid, and ganglion cysts over time, in a cohort of healthy children. Seventy-four of 89 healthy children included in a study of normal MRI findings of the wrists were reexamined after a period of 4 years, using the same 1.5-T MRI technique-namely, a coronal T1-weighted and a T2-weighted fat-saturated sequence. A history of handedness, diseases, and sports activity was noted. Bone marrow edema or edemalike changes were seen in 29 of 74 (39.2%) wrists in 2013 as compared with 35 of 72 (48.6%) wrists in 2009 (p = 0.153), all in different locations. Changes were found in central parts of the bone, on both sides of a joint, or near bony depressions. Fifty percent of all subjects had at least one fluid pocket greater than or equal to 2 mm. The location was unchanged in 47% of the joints. In 24% of the individuals, at least one ganglion cyst was seen. Six ganglion cysts present on the first scan were not seen on the follow-up scan, and 11 new ganglion cysts had appeared. Awareness of normal MRI appearances of the growing skeleton is crucial when interpreting MRI of children, and such findings must not be interpreted as pathologic abnormalities.

The study of bone marrow cells in rats according to their age and caloric intake

The bone marrow is a central organ of haemopoiesis and a source of pluripotent hemopoietic stem cells. The age-related changes in bone marrow induce the disorder of coordination between parenchyma and stroma of the organ that negatively influences proliferative potential and differentiation of the cells. That is why it is urgent to study the age-related changes of bone marrow and influence of caloric intake limitation on it.Aim. The aim of presented work was the study of proliferative potential, index of viability and percentage ratio of the bone marrow cells in rats depending on their age and caloric intake.Methods. The following methods were used in the study: selection and cultivation of the bone marrow stem cells, assessment of proliferative potential and viability of cells, analysis of percentage ratio of cellular types.Result. It was established, that the number of cells in bone marrows increases with age. The limitation of caloric intake favors the decrease of cells number in bone marrow despite the rats’ age. The received data demonstrated that the limitation of caloric intake increases the proliferative potential of the bone marrow only in old animals. It was established, that the viability of bone marrow cells was high during all period of cultivation. The morphological population of bone marrow cells in rats of different age was heterogenic, not depending on the conditions of their feeding. It was demonstrated, that the limitation of feeding caused the increase of the number of non-differentiated blasts in bone marrow of old animals that can be connected with the activation of the processes of self-activation of stem cells pool and non-differentiated predecessors of immune system cells. The morphological analysis of the bone marrow cells culture of all animal groups despite the age and nutrition regime demonstrated that the cultivation favors the selective decrease of cells heterogeneity. At that the cells of erythroid and megakaryocytic sprouts were absent in cellular cultures.Conclusions. As a result, the limitation of caloric intake of old rats favors the restoration or activation of proliferative potential of immunocompetent cell of bone marrow in vitro system

Intravoxel incoherent motion MRI assessment of chemoradiation-induced pelvic bone marrow changes in cervical cancer and correlation with hematological toxicity.

To investigate bone marrow changes after chemoradiation (CRT) using intravoxel incoherent motion magnetic resonance imaging (IVIM-MRI) and correlate imaging changes with hematological toxicity (HT) in patients with locally advanced cervical cancer. Thirty-nine patients with newly diagnosed cervical cancer were prospectively recruited for two sequential 3.0T IVIM-MRI studies: before treatment (MRI-1) and 3-4 weeks after standardized CRT (MRI-2). The irradiated pelvic bone marrow was outlined as the regions of interest to derive the true diffusion coefficient (D) and perfusion fraction (f) based on a biexponential model. The apparent coefficient diffusion (ADC) was derived using the monoexponential model. Changes in these parameters between MRI-1 and MRI-2 were calculated as ΔD, Δf, and ΔADC. HT was defined accordingly to NCI-CTCAE (v. 4.03) of grade 3 and above. Statistical analysis was performed using Mann-Whitney U-test. The median age of patients was 54 years old (range 27-83 years old); 14 patients suffered from HT. Early bone marrow changes (3-4 weeks) of ΔD showed a significant difference between HT and non-HT groups (6.4 ± 19.7% vs. -6.4 ± 19.4%, respectively, P = 0.041). However, no significant changes were noted in Δf (3.7 ± 13.3% vs. 1.5 ± 12.5% respectively, P = 0. 592) and ΔADC (5.5 ± 26.3% vs. -3.3 ± 27.0% respectively, P = 0.303) between the HT and non-HT groups. Δf increased insignificantly for both groups. ΔD was the only significant parameter to differentiate early cellular environment changes in bone marrow after CRT, suggestive that ΔD was more sensitive than Δf and ΔADC to reflect the underlying microenvironment injury. 2 Technical Efficacy: Stage 1 J. Magn. Reson. Imaging 2017;46:1491-1498.

Abstract P4-21-36: Splenic enlargement and bone marrow hyperplasia in patients receiving trastuzumab-emtansine for metastatic breast cancer

Abstract Introduction Trastuzumab emtansine (T-DM1) is an antibody-drug conjugate used for treatment of human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer. An association between T-DM1 and splenic enlargement was noted anecdotally on sequential whole-body MRI (WB-MRI) examinations. A retrospective analysis of WB-MRI examinations of patients on T-DM1 was undertaken to investigate the hypothesis that an increase in splenic volume is due to either a generalised hyperplasia of the bone marrow and reticulo-endothelial system and/or an increase in portal venous pressure. Methods 12 patients underwent 29 serial WB-MRIs before and during T-DM1 therapy. Splenic volume, portal vein diameter, bone marrow muscle-normalised signal intensity (nSI), water diffusivity (apparent diffusion coefficient, ADC) and fat fraction were measured. Changes in splenic volume were analysed, and correlations between the measured variables were obtained. Results An increase in splenic volume was observed in 92% of patients. Mean splenic volume increased from 144cm3 (95%CI 110-177cm3) to 209cm3 (95%CI 161-257cm3) on T-DM1 therapy (p=0.006). Increase in splenic volume correlated with treatment duration (r2=0.71). Increase in normal bone marrow signal was seen (nSI 3.5 to 4.8, p=0.12), along with a decrease in fat fraction (64.3% to 57.3%, p=0.12), and reduced ADC (655µm2/s to 543µm2/s, p=0.11). No consistent changes to portal vein diameter were seen. Discussion An increase in splenic volume was consistently observed in patients on T-DM1 therapy. This was unrelated to portal vein changes but correlated with bone marrow hyperplasia. Caution should be applied when assessing metastatic disease in bone to avoid incorrectly attributing T-DM1-related changes in normal bone marrow to disease progression. Citation Format: Kosmin M, Makris A, Jawad N, Miles D, Padhani AR. Splenic enlargement and bone marrow hyperplasia in patients receiving trastuzumab-emtansine for metastatic breast cancer [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P4-21-36.

Splenic Enlargement and Bone Marrow Hyperplasia in Patients Receiving Trastuzumab-Emtansine for Metastatic Breast Cancer.

An association between trastuzumab-emtansine (T-DM1) and splenic enlargement is reported in preclinical data, and has been noted anecdotally in patients receiving T-DM1 at our institution. Use of whole-body MRI examinations (WB-MRI) allows for detailed bone marrow assessment and semi-automated splenic volume calculations. To retrospectively evaluate changes in splenic volume versus evidence of bone marrow hyperplasia and/or changes in portal venous pressure in patients receiving T-DM1 for metastatic breast cancer. Twelve metastatic breast cancer patients underwent 29 WB-MRIs before and during T-DM1 therapy. Splenic volume, portal vein diameter, bone marrow diffusion-weighted normalised signal intensity (nSI), quantitative water diffusivity (apparent diffusion coefficient, ADC) and fat fraction (rF%) were measured and correlated. Splenic volume increases were observed in 92% of patients. Mean splenic volume increased from 144cm3 (95% CI 110-177cm3) to 209cm3 (95% CI 161-257cm3) on T-DM1 therapy (p = 0.006). Splenic volume increases correlated with treatment duration (r2 = 0.43). Bone marrow hyperplasia was evidenced by an increase in bone marrow nSI (3.5 to 4.8, p = 0.12), and decreases in rF% (64.3% to 57.3%, p = 0.12) and ADC (655μm2/s to 543μm2/s, p = 0.11). No changes to portal vein diameter were seen. Previously unreported increases in splenic volume and bone marrow hyperplasia are observed on WB-MRI in patients on T-DM1 therapy. Caution must be applied to avoid misinterpreting T-DM1-induced bone marrow hyperplasia as diffuse disease progression in bone.

Intravoxel incoherent motion (IVIM) analysis of vertebral bone marrow changes after radiation exposure from diagnostic imaging and interventional procedures.

Background High cumulative radiation dose in cancer patients warrants systemic examination of possible changes in bone marrow. Purpose To assess retrospectively changes in vertebral bone marrow diffusion and perfusion using intravoxel incoherent motion diffusion-weighted imaging (IVIM-DWI) in hepatocellular carcinoma (HCC) patients after exposure to radiation from diagnostic imaging and interventional procedures. Material and Methods A total of 21 IVIM-DWI sets in 20 HCC patients, consisting of baseline and follow-up liver magnetic resonance imaging (MRI) with an interval less than 100 days, were reviewed after varying levels of radiation exposure from transarterial chemoembolization (TACE), multiphase liver CT, and abdominal radiography. IVIM parameters (apparent diffusion coefficient [ADC], true diffusion coefficient [D], pseudodiffusion coefficient [D*], and perfusion fraction [PF]) of vertebral bone marrow were analyzed for significant differences between baseline and follow-up MRI using Wilcoxon signed-rank test, and for correlations with cumulative effective dose, as well as time interval between last radiation exposure and follow-up MRI using Spearman's correlation. Results Compared to baseline MRI, ADC, D*, and PF significantly decreased on follow-up MRI (ADC: median [interquartile range], 0.405 × 103 mm2/s [0.364-0.477] versus 0.390 [0.348-0.461]; D*: 24.011 [18.141-29.584] versus 20.815 [15.022-28.347]; PF: 10.960% [8.828-12.985] versus 9.125 [8.606-12.803]) ( P < 0.05). There was no significant difference in D ( P = 0.807). Cumulative effective dose was moderately correlated with decrease in D* (r = 0.434). In addition, longer intervals between last exposure and follow-up MRI showed negative correlations with changes in D and ADC (r = -0.352 and -0.333, respectively). Conclusion Vertebral bone marrow diffusion and perfusion parameters were significantly changed after exposure to medical radiation.

"Inflamm-aging" influences immune cell survival factors in human bone marrow.

The bone marrow (BM) plays a key role in the long‐term maintenance of immunological memory. However, the impact of aging on the production of survival factors for effector/memory T cells and plasma cells in the human BM has not been studied. We now show that the expression of molecules involved in the maintenance of immunological memory in the human BM changes with age. While IL‐15, which protects potentially harmful CD8+CD28− senescent T cells, increases, IL‐7 decreases. IL‐6, which may synergize with IL‐15, is also overexpressed. In contrast, a proliferation‐inducing ligand, a plasma cell survival factor, is reduced. IFN‐y, TNF, and ROS accumulate in the BM in old age. IL‐15 and IL‐6 expression are stimulated by IFN‐y and correlate with ROS levels in BM mononuclear cells. Both cytokines are reduced by incubation with the ROS scavengers N‐acetylcysteine and vitamin C. IL‐15 and IL‐6 are also overexpressed in the BM of superoxide dismutase 1 knockout mice compared to their WT counterparts. In summary, our results demonstrate the role of inflammation and oxidative stress in age‐related changes of immune cell survival factors in the BM, suggesting that antioxidants may be beneficial in counteracting immunosenescence by improving immunological memory in old age.

Morphological Changes in Bone Marrow Post Imatinib Therapy in Chronic Phase CML: A Follow up Study on Sequential Bone Marrow Aspirates and Biopsies.

Imatinib mesylate is used extensively for first line treatment of Chronic Myeloid Leukemia (CML). However, not many studies have documented morphological changes in bone marrow biopsies produced during Imatinib therapy with reference to myelofibrosis. To document the morphological changes produced in the bone marrow during Imatinib therapy. This longitudinal study followed up 75 Philadelphia Chromosome Positive Chronic Myeloid Leukemia with chronic phase(Ph+ CML- CP) patients sequentially, receiving 400-600mg Imatinib over a period of 12 or more months. Haematologic parameters were measured at admission, 2 weeks, 1 month, 3 months, 6 months and 12 or more months. Morphologic changes in bone marrow aspirate and biopsy were evaluated at admission, 6 months and ≥12 months of treatment in accordance with National Comprehensive Cancer Network(NCCN) guidelines. Complete Haematologic Response (CHR) was seen in 47.1%, 80%, 85.4%, 90.4% at ≥1 month, 3 months, 6 months and 12 months respectively after therapy. It was noted that patients not showing CHR by 3 months were less likely to show CHR at 6 months and beyond. Bone marrow aspirates and biopsies showed reduction in cellularity and myeloid precursors with regeneration of erythroid precursors in 70-83% at ≥12 months. A significant decrease in myelofibrosis (p-value< 0.04) was noted as early as 6 months. Mild to moderate hypoplasia was noted in 31.8% of biopsies within 6 months. Pseudo gaucher cells and benign lymphoid nodules were also seen. Sequential analysis showed that Imatinib reduced the grade of myelofibrosis significantly (p-value< 0.04). It also prevented development of myelofibrosis in patients who did not have it at presentation. Hence Imatinib is effective when used early in the course of CML-CP.

Monitoring of Cellular Changes in the Bone Marrow following PTH(1-34) Treatment of OVX Rats Using a Portable Stray-Field NMR Scanner.

Osteoporosis is characterized by reduction in trabecular bone in conjunction with increased marrow cell adiposity. While these changes occur within weeks, monitoring of treatment efficacy as performed by DEXA is sensitive only to long-term changes. MRI is sensitive to bone marrow changes but is less affordable. In a recent study, we have shown that a stray-field NMR can monitor bone marrow cellular changes that are related to osteoporosis. Objectives. To demonstrate sensitivity of a low-field tabletop NMR scanner to bone marrow dynamics following hormonal treatment in rats. Methods. Two-month-old female rats (n = 36) were ovariectomized (OVX) and dosed for the ensuing 3 or 5 weeks with 20 mg/kg of PTH(1-34). Hind limbs femurs and tibiae were isolated and underwent ex vivo microradiography and histology and NMR relaxometry at 6 weeks (preventive experiment) and 11 weeks (therapeutic treatment experiment) after OVX. Results. OVX rats developed osteoporotic changes including adipogenic marrow compared to Sham and PTH treated rats. T2 and ADC NMR relaxation coefficients were found to correlate with marrow composition. Conclusions. This study suggests that stray-field NMR, an affordable method that is sensitive to the rapid cellular changes in bone marrow, may have a clinical value in monitoring hormonal treatment for osteoporosis.

Bone Marrow Endothelial Cells Induce Immature and Mature B Cell Egress in Response to Erythropoietin.

Bone marrow stromal cells, including endothelial cells and mesenchymal stromal cells, support the maintenance, differentiation, and retention of hematopoietic stem and precursor cells under steady state conditions. At the onset of an emergency, such as severe blood loss or infection, the status of hematopoiesis in the bone marrow changes rapidly to ensure efficient production of cells of specific lineages; however, the function of stromal cells in emergency hematopoiesis has not been fully elucidated. Here, we unexpectedly found that B precursor, mature B, and T cells were released from the bone marrow into the blood circulation in the early phase of hemorrhagic anemia and phenylhydrazine-induced hemolytic anemia. Administration of erythropoietin, which normally increases in response to anemia, stimulated the egress of IgDlow immature B cells and recirculating mature B cells, which usually reside in the perivascular and intravascular space, from the bone marrow within 24 h. We also observed that endothelial cells in the bone marrow expressed erythropoietin receptor, and the expression levels were higher than those in other tissues. Erythropoietin stimulation of bone marrow endothelial cells induced the phosphorylation of STAT5 in vitro. Moreover, in vivo treatment with erythropoietin decreased surface VCAM1 expression and Cxcl12 transcription in bone marrow endothelial cells, both of which are essential for immature and mature B cell retention in the bone marrow. These results suggest that bone marrow endothelial cells can sense and rapidly respond to erythropoietin increase during anemia, thereby regulating B cell emigration from the bone marrow during emergency hematopoiesis.Key words: erythropoietin, anemia, endothelial cells, B cell, bone marrow microenvironment.

Monostotic osteitis deformans of lumbar vertebra: A rare phenomenon in Eastern Asia

Osteitis deformans, also known as Paget's disease, is characterized by accelerated osteoclastic activity followed by ineffective osteoblastic activity resulting in a deformed and fragile bone. It is more prevalent in Western Europe and relatively rare in Eastern Asia. It predominantly involves the lumbar spine, pelvis, and femur, frequently as polyostotic and rarely as monostotic disease. Here, we report a 64-year-old female, who presented with severe progressive back pain with no neurological symptoms. Radiographs revealed a picture frame L1 vertebra which was deformed and enlarged with loss of normal alignment. Magnetic resonance imaging revealed bone marrow changes involving all columns of L1 vertebra. Whole-body technetium-99 bone scan showed a solitary increased uptake of radioisotope by L1 vertebra. Considering the possibility of metastatic tumors, blood investigations were drawn for tumor markers which were within normal limits. A computed tomography-guided biopsy was done to facilitate diagnosis. Histopathology sections showed a mosaic pattern of bony trabeculae with multinucleated osteoclasts causing erosions and tunneling. A diagnosis of monostotic Paget's disease was made which satisfactorily responded to single-dose zoledronic acid treatment. A comprehensive literature review is provided.

Copper deficiency-related bone marrow changes secondary to long-term total parenteral nutrition.

Key Clinical MessageTotal parenteral nutrition can be complicated by the marrow sea‐blue histiocytes as well as copper deficiency‐related bone marrow changes. Cytoplasmic vacuoles in the erythroid and myeloid precursors raise the possibility of copper deficiency anemia. If the diagnosis is delayed, the clinical course can be complicated by neurologic deficits.

Secondary myeloid neoplasms: bone marrow cytogenetic and histological features may be relevant to prognosis.

BackgroundSecondary myeloid neoplasms comprise a group of diseases arising after chemotherapy, radiation, immunosuppressive therapy or from aplastic anemia. Few studies have addressed prognostic factors in these neoplasms.MethodForty-two patients diagnosed from 1987 to 2008 with secondary myeloid neoplasms were retrospectively evaluated concerning clinical, biochemical, peripheral blood, bone marrow aspirate, biopsy, and immunohistochemistry and cytogenetic features at diagnosis as prognostic factors. The International Prognostic Scoring System was applied. Statistical analysis employed the Kaplan–Meier method, log-rank and Fisher's exact test.ResultsTwenty-three patients (54.8%) were male and the median age was 53.5 years (range: 4–88 years) at diagnosis of secondary myeloid neoplasms. Previous diseases included hematologic malignancies, solid tumors, aplastic anemia, autoimmune diseases and conditions requiring solid organ transplantations. One third of patients (33%) were submitted to chemotherapy alone, 2% to radiotherapy, 26% to both modalities and 28% to immunosuppressive agents. Five patients (11.9%) had undergone autologous hematopoietic stem cell transplantation. The median latency between the primary disease and secondary myeloid neoplasms was 85 months (range: 23–221 months). Eight patients were submitted to allogeneic hematopoietic stem cell transplantation to treat secondary myeloid neoplasms. Important changes in bone marrow were detected mainly by biopsy, immunohistochemistry and cytogenetics. The presence of clusters of CD117+ cells and p53+ cells were associated with low survival. p53 was associated to a higher risk according to the International Prognostic Scoring System. High prevalence of clonal abnormalities (84.3%) and thrombocytopenia (78.6%) were independent factors for poor survival.ConclusionThis study demonstrated that cytogenetics, bone marrow biopsy and immunohistochemistry are very important prognostic tools in secondary myeloid neoplasms.