Cranial Bone Marrow Research Articles

Role of CXCR4-mediated bone marrow colonization in CNS infiltration by T cell acute lymphoblastic leukemia.

Infiltration of the central nervous system is a severe trait of T cell acute lymphoblastic leukemia. Inhibition of CXC chemokine receptor 4 significantly ameliorates T cell acute lymphoblastic leukemia in murine models of the disease; however, signaling by CXC chemokine receptor 4 is important in limiting the divagation of peripheral blood mononuclear cells out of the perivascular space into the central nervous system parenchyma. Therefore, Inhibition of CXC chemokine receptor 4 potentially may untangle T cell acute lymphoblastic leukemia cells from retention outside the brain. Here, we show that leukemic lymphoblasts massively infiltrate cranial bone marrow, with diffusion to the meninges without invasion of the brain parenchyma, in mice that underwent xenotransplantation with human T cell acute lymphoblastic leukemia cells or that developed leukemia from transformed hematopoietic progenitors. We tested the hypothesis that T cell acute lymphoblastic leukemia neuropathology results from meningeal infiltration through CXC chemokine receptor 4-mediated bone marrow colonization. Inhibition of leukemia engraftment in the bone marrow by pharmacologic CXC chemokine receptor 4 antagonism significantly ameliorated neuropathologic aspects of the disease. Genetic deletion of CXCR4 in murine hematopoietic progenitors abrogated leukemogenesis induced by constitutively active Notch1, whereas lack of CCR6 and CCR7, which have been shown to be involved in T cell and leukemia extravasation into the central nervous system, respectively, did not influence T cell acute lymphoblastic leukemia development. We hypothesize that lymphoblastic meningeal infiltration as a result of bone marrow colonization is responsible for the degenerative alterations of the neuroparenchyma as well as the alteration of cerebrospinal fluid drainage in T cell acute lymphoblastic leukemia xenografts. Therefore, CXC chemokine receptor 4 may constitute a pharmacologic target for T cell acute lymphoblastic leukemia neuropathology.

The effect of head size/shape, miscentering, and bowtie filter on peak patient tissue doses from modern brain perfusion 256‐slice CT: How can we minimize the risk for deterministic effects?

To determine patient-specific absorbed peak doses to skin, eye lens, brain parenchyma, and cranial red bone marrow (RBM) of adult individuals subjected to low-dose brain perfusion CT studies on a 256-slice CT scanner, and investigate the effect of patient head size∕shape, head position during the examination and bowtie filter used on peak tissue doses. The peak doses to eye lens, skin, brain, and RBM were measured in 106 individual-specific adult head phantoms subjected to the standard low-dose brain perfusion CT on a 256-slice CT scanner using a novel Monte Carlo simulation software dedicated for patient CT dosimetry. Peak tissue doses were compared to corresponding thresholds for induction of cataract, erythema, cerebrovascular disease, and depression of hematopoiesis, respectively. The effects of patient head size∕shape, head position during acquisition and bowtie filter used on resulting peak patient tissue doses were investigated. The effect of eye-lens position in the scanned head region was also investigated. The effect of miscentering and use of narrow bowtie filter on image quality was assessed. The mean peak doses to eye lens, skin, brain, and RBM were found to be 124, 120, 95, and 163 mGy, respectively. The effect of patient head size and shape on peak tissue doses was found to be minimal since maximum differences were less than 7%. Patient head miscentering and bowtie filter selection were found to have a considerable effect on peak tissue doses. The peak eye-lens dose saving achieved by elevating head by 4 cm with respect to isocenter and using a narrow wedge filter was found to approach 50%. When the eye lies outside of the primarily irradiated head region, the dose to eye lens was found to drop to less than 20% of the corresponding dose measured when the eye lens was located in the middle of the x-ray beam. Positioning head phantom off-isocenter by 4 cm and employing a narrow wedge filter results in a moderate reduction of signal-to-noise ratio mainly to the peripheral region of the phantom. Despite typical peak doses to skin, eye lens, brain, and RBM from the standard low-dose brain perfusion 256-slice CT protocol are well below the corresponding thresholds for the induction of erythema, cataract, cerebrovascular disease, and depression of hematopoiesis, respectively, every effort should be made toward optimization of the procedure and minimization of dose received by these tissues. The current study provides evidence that the use of the narrower bowtie filter available may considerably reduce peak absorbed dose to all above radiosensitive tissues with minimal deterioration in image quality. Considerable reduction in peak eye-lens dose may also be achieved by positioning patient head center a few centimeters above isocenter during the exposure.

In Vivo Platelet Production Occurs from an Expanding Pool of Non-Apoptotic Megakaryocytes in a Mouse Model of Passive Immune Thrombocytopenia

AbstractAbstract 1214Immune thrombocytopenia (ITP) is the most common acquired thrombocytopenia in children. Typically, external triggers as infections or vaccinations cause the rise of antibodies that crossreact with antigens expressed on the platelet surface. These anti-platelet antibodies are mostly directed against glycoprotein complexes GPIIb/IIIa or GPIb/IX/V, resulting in an increased turnover of antibody-decorated platelets which are then sequestered by the reticuloendothelial system. Recently, it has been suggested that thrombocytopenia might also be due to an insufficient platelet production as serum of some patients with ITP can impair the maturation of CD34+ hematopoietic stem cells to bone marrow megakaryocytes (MKs) in vitro or abrogate the formation of proplatelets in an in vitro culture system. The accelerated platelet turnover demands the generation of platelets de novo. Bone marrow smears often reveal normal or slightly increased MKs, although they seem to be smaller and of altered morphology. However, very little is known about the consequences of anti-platelet antibodies on bone marrow MKs in vivo and in situ. Here, we took advantage of a simple animal model of passive ITP by single or multiple intraperitoneal injections of an anti-GPIb antibody into mice. MKs were evaluated by multi-color immunofluorescence histology on whole femur sections in a modified staining procedure that bypasses decalcification. MK numbers on day 3 were doubled in response to a single injection and tripled on day 8 when mice were injected additionally on day 3 and 7. In these mice platelet counts were up to 2000/nL on day 10, indicating the power to produce platelets. MK area per section was transiently upregulated on day 3 in single injected mice and quadrupled after multiple injections on day 8 before shrinking below norm on day 14. Staining with an anti-rat IgG antibody showed that the antibody was present on MKs within the bone marrow several hours to days after injection. The signal was present for 5 days and no antibody was detected on day 7. MKs had an overall normal morphology and showed no signs of apoptosis or DNA blebbing. All MKs analyzed were negative for TdT in a classical TUNEL assay, indicating that there were no single strand breaks. As platelet counts rose markedly while the antibody was still present on the MK surface, we sought to identify whether the pool of MKs is expanded or formed de novo. To address this, mice where fed with nucleotide analogue EdU for up to 12 days and femur sections stained with Click-It-647 reagent to stain for newly incorporated DNA while mice were treated with anti-platelet antibody or isotype control. We found EdU-positive MKs after 12 days in control isotype-injected mice indicating the de novo formation from hematopoietic stem cells. In antibody-injected mice, newly formed MKs were negative or stained weakly for EdU on day 12, suggesting that they arise partially from an existing pool of progenitors. Finally, we analyzed platelet formation in vivo by imaging of the cranial bone marrow of GPIIb-eYFP-heterozygous mice. The depletion antibody was labeled with Atto-590-fluorophore and injected hours before imaging. Vasculature was counterstained by Quantum dots. We found that MKs residing at the bone marrow were decorated with the antibody and released pre- and proplatelets into the vasculature, indicating that platelet biogenesis can occur in the presence of anti-platelet antibodies on MKs. Our data thus provide novel insight into the pathomechanism of platelet production in patients with ITP. Disclosures:No relevant conflicts of interest to declare.

Normal cranial bone marrow MR imaging pattern with age-related ADC value distribution

To determine MRI appearances of normal age-related cranial bone marrow and the relationship between MRI patterns and apparent diffusion coefficient (ADC) values. Five hundred subjects were divided into seven groups based on ages. Cranial bone marrow MRI patterns were performed based on different thickness of the diploe and signal intensity distribution characteristics. ADC values of the frontal, parietal, occipital and temporal bones on DWI were measured and calculated. Correlations between ages and ADC values, between patterns and ADC values, as well as the distribution of ADC values were analyzed. Normal cranial bone marrow was divided into four types and six subtypes, Type I, II, III and IV, which had positive correlation with age increasing (χ2=266.36, P<0.01). The ADC values of normal parietal and occipital bone marrow showed significant negative correlation with age growing (r=-0.561 and -0.622, P<0.01), while there were no significant differences of that with age increasing in frontal and temporal bone marrow (P>0.05). In addition, there was significant negative correlation between the ADC values and MRI patterns in the normal parietal and occipital bones (r=-0.691 and -0.750, P<0.01). The combination of MRI features and ADC values changes in different cranial bones showed significant correlation with age increasing. Familiar with the MRI appearance of the normal bone marrow conversion pattern in different age group and their ADC value will aid the diagnosis and differential of the cranial bone pathology.

Age-related pattern of normal cranial bone marrow: MRI study

Objective To investigate the age-related pattern of normal skull bone marrow with 3. 0 T MR T1WI. Methods Cranial MR T1WI images which were defined to be normal were retrospectively reviewed in 360 cases. Patients with known diffuse bone marrow disease, focal lesions, history of radiation treatment or steroid therapy were excluded, while patients whose cranial MRI and follow-up visits were all normal were included in this study. All the subjects were divided into 7 groups according to the age: 50 years group. Mid- and para- sagittal T1WI images were used to be analyzed and the type of cranial bone marrow was classified according to the thickness of diploe and the pattern of the signal characteristics. Statistical analysis was conducted to reveal the relationship between the age and the type. Results The normal skull bone marrow could be divided into four types as follows: (1) Type- Ⅰ : 115 cases, 47 of which appeared type- Ⅰ a and the mean thickness was ( 1.24±0. 31 ) mm; 68 of which appeared type- Ⅰ b and the mean thickness was ( 1.76 ± 0. 37 ) mm. Type- Ⅱ : 57 cases and the mean thickness was (2.78 ±0.69) mm. Type-Ⅲ: 148 cases, 18 of which appeared type-Ⅲ a and the mean thickness was (2. 33±0. 65) mm; 88 of which appeared type-Ⅲ b and the mean thickness was (4. 01 ± 0. 86) mm; 42 of which appeared type-Ⅲ c and the mean thickness was (4. 31±0. 73) mm. Type-Ⅳ: 40 cases, 25 of which appeared type-Ⅳ a and the mean thickness was (5. 17 ± 1.02) mm; 15 of which appeared type-Ⅳ b and the mean thickness was (5.85±1.45) mm. (2) <1 year group: 40 cases, 20 of which appeared type- Ⅰ a, 20 type- Ⅰ b and the mean thickness of this group was ( 1.47 ± 0. 42 ) mm. 1-- 2 years group: 40 cases, 16 of which appeared type- Ⅰ a, 18 type- Ⅰ b, 6 type- Ⅱ and the mean thickness of this group was ( 1.68±0. 52) mm. 3--5 years group: 40 cases, 8 of which appeared type- Ⅰ a, 18 type-Ⅰb, 14 type-Ⅱ and the mean thickness of this group was (1.84±0.73) mm. 6--14 years group: 60 cases, 3 of which appeared type- Ⅰ a, 12 type- Ⅰ b, 27 type-Ⅱ , 12 type-Ⅲb, 6 type-Ⅲc, and the mean thickness of this group was (2.92±1. 00) mm. 15--29 years group: 60 cases, 7 of which appeared type-Ⅱ , 5 type-ma, 27 type-Ⅲb, 15 type-Ⅲc, 6 type-Ⅳa and the mean thickness of this group was (3.95 ± 0.97) mm. 30---49 years group: 60 cases, 3 of which appeared type-Ⅱ , 7 type-Ⅲa, 29 type-Ⅲb, 15 type-Ⅲc, 3 type-Ⅳa and 3 type-Ⅳb and the mean thickness of this group was (4. 30 ± 1.35) mm. ≥50 years group: 60 cases, 6 of which appeared type-Ⅲ a, 20 type-Ⅲb, 6 type-Ⅲc, 16 type-Ⅳa and 12 type-Ⅳb and the mean thickness of this group was (4.51 ± 1.40) mm. (3) There is a linear relationship between ages and types that is revealed by chi-square test (x2 = 266. 36, P < 0. 01 ). Conclusion There is characteristic in the distribution of normal skull bone marrow with age growing. And skull bone marrow transforms gradually from type- Ⅰ to Ⅳ with aging. Key words: Skull; Bone marrow; Magnetic resonance imaging

Histopathologic Features of Multiple Myeloma Involving the Optic Nerves

We report a case of optic nerve involvement by multiple myeloma in which progressive visual loss heralded leukemic transformation and intracranial involvement. Imaging showed enhancing nodules in the intracranial segments of both optic nerves posterior to the optic canals and in the anterior optic tract, optic chiasm, and basal leptomeninges. Postmortem histopathologic examination disclosed malignant plasma cells in the subarachnoid spaces around the optic nerves and in the optic nerves. Infarctions were present in both optic nerves near their junction with the globes. Microscopic examination also showed malignant plasma cell infiltration of the leptomeninges of the cerebrum, brain stem, optic chiasm, pituitary gland, cranial bone marrow, and subarachnoid blood vessels. This is the first reported histopathologic examination in conjunction with MRI of multiple myeloma involving the anterior visual pathway. The mechanism of optic neuropathy in this case is probably related to infiltration of the optic nerve meninges by malignant plasma cells and impaired vascular supply caused by aggregated intraluminal plasma cells and monoclonal hypergammaglobulinemia.

Diffusion-Weighted Imaging with Sensitivity Encoding (SENSE) for Detecting Cranial Bone Marrow Metastases: Comparison with T1-Weighted Images

ObjectiveThis study was designed to determine whether diffusion-weighted imaging (DWI) with sensitivity encoding (SENSE) could detect bone marrow involvement in patients with cranial bone marrow (CBM) metastases. DWI results obtained were compared with T1-weighted imaging (T1WI) findings.Materials and MethodsDWI with sensitivity encoding (SENSE; b value = 1,000) was performed consecutively in 13 patients with CBM metastases diagnosed pathologically and radiologically. CBM lesions were dichotomized according to the involved site, i.e., skull base or calvarium. Two radiologists qualitatively evaluated the relative conspicuousness of CBM lesions and image qualities in B0 and in isotropic DWI and in T1WI. According to region of interest analysis of normal and pathologic marrow for these three sequences, absolute signal difference percentages (SD%) were calculated to quantitatively analyze lesion contrast.ResultsAll 20 lesions in 13 patients with CBM metastases revealed abnormal DWI signals in areas corresponding to T1WI abnormalities. Both skull base and calvarial lesions provided better lesion conspicuousness than T1WI and B0 images. Although the image quality of DWI was less satisfactory than that of T1WI, relatively good image qualities were obtained. Quantitatively, B0 images (SD%, 82.1 ±7.9%) showed better lesion contrast than isotropic DWI (SD%, 71.4 ±13.7%) and T1WI (SD%, 65.7 ±9.3%) images.ConclusionFor scan times of less than 30 seconds, DWI with SENSE was able to detect bone marrow involvement, and was superior to T1WI in terms of lesion conspicuity. DWI with SENSE may be helpful for the detection of cranial bone/bone marrow metastases when used in conjunction with conventional MR sequences.

MRI evaluation of cranial bone marrow signal intensity and thickness in chronic anemia

Background and purpose: The aim is to assess the magnetic resonance imaging (MRI) findings for cranial bone marrow (CBM) signal intensity and thickness in patients with chronic anemia and compared these with findings in healthy subjects. We also investigated the relationships between CBM changes and age, type of anemia (hemolytic versus non-hemolytic), and severity of anemia. Methods: We quantitatively evaluated CBM signal intensity and thickness on images from 40 patients with chronic anemia (20 with congenital hemolytic anemia (HA) and 20 with acquired anemia) and compared these to findings in 28 healthy subjects. The intensity of CBM relative to scalp, white matter (WM), gray matter (GM), and muscle intensity was also investigated in patients and subjects in the control group. The sensitivity and specificity of CBM hypointense to GM and CBM hypointense to WM as markers of anemia were evaluated. Relationships between age and CBM thickness/intensity, and between anemia severity (hemoglobin (Hb) level) and CBM thickness/intensity were evaluated. Results: Cranial bone marrow signal intensity was lower in the chronic anemia patients than in the controls ( P<0.001). In the control group, CBM intensity was higher than GM intensity, whereas the opposite was true in the patient group. The finding of CBM hypointense to GM was 85% sensitive and 67% specific as a marker of anemia. The corresponding statistics for CBM hypointense to WM were 90 and 46%. The patients had thicker CBM than the controls (temporal, P<0.05; parietal, P<0.005). The subgroup with hemolytic anemia had thicker parietal CBM than the subgroup with non-hemolytic anemia (NHA) ( P<0.05) and exhibited thicker temporal and parietal CBM than the controls (temporal, P<0.05; parietal, P<0.001). The CBM thicknesses in the non-hemolytic anemia subgroup were similar to control values ( P>0.05 for both). There were no correlations between age and CBM intensity or thickness, or between anemia severity and CBM intensity or thickness. Conclusion: Patients with chronic anemia exhibit lower CBM signal intensity on MRI than healthy subjects. Patients with hemolytic anemia have thicker CBM than patients with non-hemolytic anemia or healthy individuals. Decreased CBM intensity may indicate that the patient has anemia, and increased CBM thickness may specifically point to hemolytic anemia. These MRI findings may signal the need for further evaluation for the clinician.

Iron deposition in cranial bone marrow with sickle cell disease: MR assessment using a fat suppression technique.

Thirteen patients with sickle cell disease (SCD) undergoing transfusion therapy and 8 control patients were examined by magnetic resonance imaging to discriminate bone marrow change due to iron deposition from hematologic marrow hyperplasia. Using T1-weighted spin echo images, only two subjects showed extremely low signal intensity marrow compatible with iron deposition. However, using T2-weighted fast spin echo images with fat suppression, cranial bone marrow in SCD patients with transfusion therapy showed considerably lower signal than that of controls. The main cause of marrow signal decrease in SCD patients with transfusion therapy was considered to be iron deposition due to repeated transfusion therapy rather than red marrow hyperplasia.

Cranial bone marrow in children: assessment of normal development with MR imaging.

Magnetic resonance images of cranial bone marrow in 238 patients (246 examinations) less than 25 years old were reviewed to establish normal age-related standards. Bone marrow in the clivus and calvaria had uniformly low signal intensity (grade 1) on T1-weighted images in most infants less than 1 year old. The number of patients with grade 1 marrow decreased rapidly in early childhood, while the number of patients with marrow of low and high signal intensity (grade 2) and uniformly high signal intensity (grade 3) gradually increased with age. A grade 1 marrow was no longer observed in either the clivus or calvaria after age 7. Most patients had a grade 3 marrow by age 15. Because bone marrow in certain pathologic conditions has decreased signal on T1-weighted images and therefore resembles grade 1 or 2 appearances of normal marrow in children, these results may be useful for differentiating normal and abnormal bone marrow signal intensities in infants and children.

Pathogenesis of an experimental meningeal leukemia model

Syngeneic mice injected intravenously with a T-cell tumor line developed widespread bone marrow and visceral leukemic infiltration 10 days after inoculation. This was followed by a sequence of focal and then diffuse tumoral infiltration of the cranial duramater, subdural space, and leptomeninges. The involvement of the duramater was shown to result from direct local extension of leukemic cells from the cranial bone marrow along the adventitia of blood vessels. The leptomeningeal infiltration that followed occurred via the adventitia of veins connecting the duramater with the arachnoid. This mechanism of direct spread of marrow leukemic cells into the meninges has been shown to occur in other experimental models and has been suggested in some human autopsy studies of meningeal leukemia. It is postulated that this pathogenetic mechanism may operate in some instances of the human disease, instead of the more commonly accepted hematogenous spread of meningeal leukemia.