Noninvasive imaging of osteoclasts in parathyroid hormone-induced osteolysis using a 64Cu-labeled RGD peptide.

Bone diseases are often a result of increased numbers of osteoclasts, or bone-resorbing cells. Bone metastases are a significant cause of morbidity in many types of cancer. An imaging agent targeting osteoclasts, which are upregulated in osteolytic lesions, may facilitate earlier follow-up in patients with osteolytic or mixed bone metastases. Osteoclasts express high levels of alpha(v)beta3 integrin, to which peptides containing the Arg-Gly-Asp (RGD) sequence are known to bind. We proposed that radiolabeled RGD peptides could be used to detect osteoclasts in lytic bone lesions. METHODS: The cross-bridged macrocyclic chelator 4,11-bis(carboxymethyl)-1,4,8,11-tetraazabicyclo[6.6.2]hexadecane (CB-TE2A) was conjugated to c(RGDyK) for radiolabeling with 64Cu (t(1/2), 12.7 h; beta+, 17.4%; E(beta+ max), 656 keV; beta-, 39%; E(beta- max), 573 keV). The in vitro affinity of Cu(II)-CB-TE2A-c(RGDyK) for alpha(v)beta3 and alpha(v)beta5 was evaluated in a heterologous competitive binding assay. Ex vivo uptake was examined in osteoclasts prepared from bone marrow macrophages. As a proof of principle, biodistribution and imaging studies were performed on parathyroid hormone (PTH)-induced osteolysis in the calvarium. RESULTS: Cu-CB-TE2A-c(RGDyK) was shown to have a 30-fold higher affinity for alpha(v)beta3 than for alpha(v)beta5. Osteoclasts were shown to specifically take up (64)Cu-CB-TE2A-c(RGDyK). However, bone marrow macrophages showed only nonspecific uptake. PTH treatment increased calvarial uptake of 64Cu-CB-TE2A-c(RGDyK), compared with uptake in mice receiving a sham treatment. In addition, calvarial uptake correlated linearly with the number of osteoclasts on the bone surface. CONCLUSION: These results suggest that 64Cu-CB-TE2A-c(RGDyK) selectively binds alpha(v)beta3 on osteoclasts and may potentially be used to identify increased numbers of osteoclasts in osteolytic bone diseases such as osteolytic bone metastasis and inflammatory osteolysis.     

Physiopathological basis of bone turnover.

Bone remodeling involves the continuous removal of bone (bone resorption) followed by synthesis of new bone matrix and subsequent mineralization (bone formation). The principal cells that mediate the boneforming processes of the skeleton are osteoblast cells. They are responsible for the production of the matrix constituents and the differentiation of osteoblasts from stromal cell precursors is stimulated by several hormonal and non-hormonal molecules. On the other hand, the osteoclasts are giant multinucleated cells responsible of bone resorption. They are formed in the bone marrow and mature cells are stimulated by PTH and locally acting agents such as transforming growth factor alpha (TGFalpha), tumor necrosis factor (TNF) interleukin 1 (IL-1) and interleukin 6 (IL-6). The first events during bone remodeling is osteoclast activation, followed by osteoclast formation, polarization constitution of the ruffled border, resorption and ultimately apoptosis. Osteoclast apoptosis is followed by a series of sequential changes in cells in the osteoblast lineage, including osteoblast chemotaxis, proliferation and differentiation, which in turn is followed by formation of mineralized bone and cessation of osteoblast activity. The final phase of the formation process is cessation of osteoblast activity. The resorption lacunae are usually repaired either completely or almost completely. Understanding the sequence of cellular events may be important to better know the mechanisms responsible for bone loss that occurs in age and in several pathological conditions.     

巴戟天甲基异茜草素对破骨细胞性骨吸收的影响

目的研究甲基异茜草素抑制骨吸收的细胞学机制。方法采用原代培养的成骨细胞和骨髓单核细胞联合培养的方法,在1,25-（OH）2VitaminD3和地塞米松作用下,使骨髓单核细胞分化形成破骨细胞。磷酸苯二钠法测定破骨细胞抗酒石酸酸性磷酸酶（Tartrate-resistant acid phosphatase,TRAP）的活性;计算机图像分析技术测定骨片上破骨细胞性骨吸收陷窝的面积;荧光酶标方法测定组织蛋白酶K的活性。结果甲基异茜草素在0.1～10μmol·L^-1范围内,浓度依赖性地抑制破骨细胞形成、分化、TRAP酶活性和在骨片上形成的吸收陷窝的数目和面积。结论甲基异茜草素通过抑制破骨细胞的形成、分化和骨吸收功能来减少骨质的丢失。     

A study of irradiated bone. Part II. changes in Tc-99m pyrophosphate bone imaging

Quantitative Tc-99m pyrophosphate bone imaging was carried out in locally irradiated and control areas of New Zealand albino rabbits to determine the potential role of bone imaging in assessing the time course of radiation effects in bone and surrounding tissues. In vitro Tc-99m tissue assays, and serial radiographs. from the irradiated and contralateral limbs were obtained at regular intervals over the first 12 mo following irradiation for comparison with quantitative results from the camera studies. The autoradiographic localization of TcPPi was also studied in the x-irradiated and contralateral bones of the rabbits. The results show that TcPPi bone imaging is a sensitive in vivo indicator of early radiation effects upon vasculature and bone remodeling. The findings suggest that the quantitative bone-imaging technique may be useful in the evaluation of the effects of treatment modalities on the skeleton.     

Nuclear imaging of bone tumors: FDG-PET

Positron emission tomography (PET) has become a very useful adjunct to anatomic imaging techniques, because it can provide an in vivo method for quantifying functional metabolism in normal and diseased tissues. Clinical trials with [(18)F] 2-deoxy-2-fluoro-D-glucose (FDG), the most commonly used radiolabeled tracer for PET imaging, has demonstrated increased accumulation of FDG in cancer tissue. FDG-PET is now widely used for the detection, differentiation, grading, staging, and monitoring of various neoplasms. However, the significance of FDG-PET in such evaluations of primary bone tumors and tumor-like lesions has not been extensively elucidated. In this article, we present recent advances in FDG-PET studies for evaluating primary bone tumors and tumor-like lesions.     

MR imaging of ulnar impaction

The ulnar impaction syndrome of the wrist is a well-recognized clinical entity, usually showing distinct radiographic features including a positive ulnar variance and degenerative subchondral changes of the distal ulna, proximal lunate, and proximal triquetrum. Confirmation of the clinical and plain film findings with advanced imaging is often necessary to exclude other entities with a similar clinical presentation. Although arthrography and bone scintigraphy are helpful in this work-up, magnetic resonance imaging (MRI) appears to be both a sensitive and a specific means of evaluation. The imaging studies in four patients with clinically and surgically diagnosed ulnar impaction are described, with emphasis on MRI findings. MRI appears to be the modality of choice in the evaluation of patients with suspected ulnolunate impingement.     

Imaging appearance of bone tumors of the maxillofacial region

This paper reviews the imaging appearance of benign and malignant bone tumors of the maxillofacial region.A benign bone tumor commonly appears as a well circumscribed lesion.The matrix of the tumor may be calcified or sclerotic.Malignancies often display aggressive characteristics such as cortical breakthrough, bone destruction,a permeative pattern and associated soft-tissue masses.Computed tomography scan is an excellent imaging modality for accurate localization of the lesion,characterization of the tumor matrix and detection of associated osseous changes such as bone remodeling,destruction or periosteal reaction.Magnetic resonance imaging is of limited value in the evaluation of maxillofacial bone tumors.     

Deferoxamine-induced bone dysplasia in the distal femur and patella of pediatric patients and young adults: MR imaging appearance

OBJECTIVE: We investigated the MR imaging appearance of deferoxamine-induced bone dysplasia in the distal femur and patella in patients with thalassemia major. MATERIALS AND METHODS: Thirty-five patients with homozygous ss-thalassemia major who were undergoing regular transfusions and chelation therapy underwent coronal T1-weighted MR imaging of the femur, including the femoral head and the distal femoral epiphysis. Additional coronal fat-saturated dual-echo and sagittal T1-weighted images of the distal femur and patella were obtained in 11 patients who were suspected of having distal femoral lesions on the basis of the coronal T1-weighted images of the entire femur. RESULTS: No dysplastic change was detected in the proximal femur on coronal T1-weighted images. In 22 distal femurs of 11 patients, the following abnormalities were detected on MR imaging: blurred physeal-metaphyseal junction (n = 22), distal metaphyseal areas of hyperintensity (n = 21), physeal widening (n = 18), metadiaphyseal lesions (n = 11), epiphyseal lesions (n = 10), and patellar lesions (n = 2). Physeal widening and distal metaphyseal hyperintense areas were all more pronounced peripherally. Of the 21 distal metaphyseal hyperintensities, lateral abnormalities were larger than medial abnormalities in 16. Of the 18 distal femurs in which physeal widening was detected, the lateral widening was more marked than the medial widening in 12. Patients with MR imaging evidence of bone dysplasia have a significantly (p = 0.003) greater height reduction than patients without such evidence of bone dysplasia. CONCLUSION: Deferoxamine-induced bone dysplasia in the distal femur and patella is represented by a spectrum of morphologic changes in the epiphysis, physis, metaphysis, and metadiaphysis on MR imaging.     

Imaging with radiolabeled antisence oligonucleotides for the detection of intracellular messenger RNA and cardiovascular disease

Conclusions  Most of the research efforts in nuclear medicine in the last two decades have focused on the development of radioactive ligands for the detection of extracellular antigens expressed on the membrane surface such as tumor markers, somatostatin receptors on tumor cells, or receptors that are more readily accessible than cytosolic or nuclear receptors. However, these general concepts of radiolabeling methods for these ligands have helped us significantly to embark on the next phase of development of gamma-emitting singlestranted ASON probes for studying gene activation. Previous studies have demonstrated the nuclease-sensitivity of ASON probes. Further modifications of phosphodiester backbone, ribose, and nucleotide subunits have identified derivatives with improved potency, desirable pharmacokinetics, and reduced toxicity. Encouraged by in vitro and in vivo inhibition studies, the oligonucleotides have been radiolabeled with nonmetallic and metallic radionuclides of I-123, In-111, and Tc-99m and demonstrated their use in imaging specific mRNA of oncogenes, c-myc, erb-b2, and telomerase present in breast tumors in the mouse model. Noninvasive imaging of mRNA of heat shock protein (HSP-70) has been shown in a pig model during an ischemic episode of cardiopulmonary bypass. The radiochemists have developed ASON probes for positron emission tomography imaging labeled whereby they were with carbon 11 and fluorine 18. The radiolabeled antisense probes may provide a novel method to image the amplified oncogenes in atherosclerotic plaques and heat shock genes in myocardial stress. The standard methods of radiolabeling and novel methods of charge neutralization may enhance the intracellular delivery for imaging a variety of activated genes in cardiovascular diseases. Development of radiolabeled probes and their applications indiagnostic imaging were funded by the University of Illinois Research Board (UI-1-2-69410     

Imaging of primary multifocal osseous lymphoma

 Objective. To review our experience with primary multifocal osseous lymphoma (PMOL), to characterize its imaging features, before and after treatment, and to correlate these features with clinical outcome. Design. Hospital charts and imaging studies of eight patients with PMOL were reviewed. These included bone radiographs, bone scans, CT and MRI. Number, distribution and appearance of lesions before treatment were evaluated; and post-treatment changes were assessed for evidence of healing or progression, correlated with clinical outcome. Results. A total of 63 lesions were identified by pre-treatment bone scan, 36 by MRI (including 10 not visible on bone scan) and 16 by radiographs. Twenty-one percent of lesions occurred about the knee, and 63% of patients had concomitant skull, distal femoral and proximal tibial lesions. The radiographic appearance ranged from lytic to sclerotic. Lesions were isointense to hematopoietic marrow on T2-weighted MR sequences. Only plain radiographic evidence of healing or progression correlated with clinical outcome. Conclusion. Distribution of PMOL was best assessed by bone scan. However, MRI revealed larger areas of marrow involvement and detected lesions in the pelvis not seen on bone scan. Marrow involvement around the knee was common, and the combination of skull, distal femoral and proximal tibial lesions may suggest the diagnosis. Radiographs underestimate the extent of disease but were the best modality for assessment of treatment response.     

Apoptotic cell death: its implications for imaging in the next millennium

Apoptosis, also known as programmed cell death, is an indispensable component of normal human growth and development, immunoregulation and homeostasis. Apoptosis is nature’s primary opponent of cell proliferation and growth. Strict coordination of these two phenomena is essential not only in normal physiology and regulation but in the prevention of disease. Programmed cell death causes susceptible cells to undergo a series of stereotypical enzymatic and morphologic changes governed by ubiquitous endogenous biologic machinery encoded by the human genome. Many of these changes can be readily exploited to create macroscopic images using existing technologies such as lipid proton magnetic resonance (MR) spectroscopy, diffusion-weighted MR imaging and radionuclide receptor imaging with radiolabeled annexin V. In this review the cellular phenomenon of apoptotic cell death and the imaging methods which can detect the process in vitro and in vivo are first discussed. Thereafter an outline is provided of the role of apoptosis in the pathophysiology of clinical disorders including stroke, neurodegenerative diseases, pulmonary inflammatory diseases, myocardial ischemia and inflammation, myelodysplastic disorders, organ transplantation, and oncology, in which imaging may play a critical role in diagnosis and patient management. Objective imaging markers of apoptosis may soon become measures of therapeutic success or failure in both current and future treatment paradigms. Since apoptosis is a major factor in many diseases, quantification and monitoring the process could become important in clinical decision making.     

Apoptotic cell death: its implications for imaging in the next millennium

Apoptosis, also known as programmed cell death, is an indispensable component of normal human growth and development, immunoregulation and homeostasis. Apoptosis is nature's primary opponent of cell proliferation and growth. Strict coordination of these two phenomena is essential not only in normal physiology and regulation but in the prevention of disease. Programmed cell death causes susceptible cells to undergo a series of stereotypical enzymatic and morphologic changes governed by ubiquitous endogenous biologic machinery encoded by the human genome. Many of these changes can be readily exploited to create macroscopic images using existing technologies such as lipid proton magnetic resonance (MR) spectroscopy, diffusion-weighted MR imaging and radionuclide receptor imaging with radiolabeled annexin V. In this review the cellular phenomenon of apoptotic cell death and the imaging methods which can detect the process in vitro and in vivo are first discussed. Thereafter an outline is provided of the role of apoptosis in the pathophysiology of clinical disorders including stroke, neurodegenerative diseases, pulmonary inflammatory diseases, myocardial ischemia and inflammation, myelodysplastic disorders, organ transplantation, and oncology, in which imaging may play a critical role in diagnosis and patient management. Objective imaging markers of apoptosis may soon become measures of therapeutic success or failure in both current and future treatment paradigms. Since apoptosis is a major factor in many diseases, quantification and monitoring the process could become important in clinical decision making.     

Clear cell chondrosarcoma: radiographic, computed tomographic, and magnetic resonance findings in 34 patients with pathologic correlation

Objective To describe the radiographic features of clear cell chondrosarcoma (CCCS), including the computed tomographic (CT) and magnetic resonance (MR) findings, and to correlate them with the histopathologic findings.Design and patients A retrospective review was carried out of 72 patients with histopathologically confirmed CCCS. Imaging studies were available for 34 patients: conventional radiographs (n=28), CT scans (n=14), and MR images (n=15). Radiographic studies were reviewed by three radiologists who rendered a consensus opinion; the studies were correlated with the histopathologic findings.Results Of the 34 patients with imaging studies, 30 were male and 4 were female (mean age 38.6 years; range 11–74 years). Twenty-two lesions were in long bones (15, proximal femur; 1, distal femur; 1, proximal tibia; 5, proximal humerus) and 11 were in flat bones (5, vertebra; 4, rib; 1, scapula; 1, innominate). One lesion occurred in the tarsal navicular bone. Typically, long bone lesions were located in the epimetaphysis (19/22) and were lucent with a well-defined sclerotic margin and no cortical destruction or periosteal new bone formation. More than one-third of the long bone lesions contained matrix mineralization with a characteristic chondroid appearance. Pathologic fractures were present in six long bone lesions (4, humerus; 2, femur). Lesions in the proximal humerus were more likely to have indistinct margins (4/5) and extend into the diaphysis. Flat bone lesions were typically lytic and expansile and occasionally demonstrated areas of cortical disruption. Typically, matrix mineralization, when present, was amorphous. MR imaging, when available, was superior to conventional radiographs for demonstrating the intramedullary extent of a lesion as well as soft tissue extension. CT images better delineated the presence of cortical destruction and the character of matrix mineralization patterns. CCCS lesions were typically low signal intensity on T1-weighted images and moderately or significantly bright on T2-weighted images. Areas of lesion heterogeneity on T1- and T2-weighted images and on post-gadolinium T1-weighted images corresponded pathologically to areas of mineralization, intralesional hemorrhage, and cystic changes. Adjacent bone marrow edema was typically absent (12/15) or only minimally observed in a few cases (3/15). No cases examined with MR imaging demonstrated periosteal new bone formation.Conclusions CCCS typically presents radiographically as a geographic lytic lesion located in the epimetaphyseal region of long bones. Most commonly lesions are found in the proximal femur, followed by the proximal humerus. Lesions within the proximal humerus may exhibit more aggressive features. Lesions in the axial skeleton are typically expansile and destructive, often with soft tissue extension and lack of mineralization. MR imaging may show the presence or absence of bone marrow edema.     

体内凋亡细胞显像的研究进展

目前,疾病的诊断及治疗已进入分子水平阶段,细胞凋亡的检测技术也不断更新和发展。活体内细胞凋亡显像符合生理代谢的特点,能够对疾病实行早期、活体、无创及定量检查。其主要显像方法有:磁共振成像、光学成像、超声检查及放射性核素显像等。其中,以放射性核素凋亡显像的研究应用尤为突出,已应用于心血管疾病、中枢神经系统疾病、移植排斥反应以及肿瘤诊治等方面。     

Radioimmunodetection of degranulated human eosinophils in mice: a potential model for imaging Hodgkin's disease and other pathologic conditions

Various human tumors such as lymphomas and carcinomas sometimes contain extensive infiltration by degranulating eosinophils. To determine if degranulated eosinophils are suitable targets for immunolocalization, we performed in vivo distribution and imaging studies in mice, using EOS (a murine monoclonal antibody directed to human eosinophil peroxidase) labeled with indium-111. Adult mice were injected intravenously with radiolabeled EOS antibody or with similarly radiolabeled normal mouse IgG before receiving an intramuscular injection into the right thigh of homogenized human eosinophils adsorbed to latex microspheres. There was striking localization in the right thigh of the radiolabeled EOS antibody detectable by gamma imaging techniques as soon as 24 hr after injection. By contrast, there was little accumulation of radiolabeled normal IgG in the right thigh. We conclude that human eosinophil peroxidase is potentially a suitable target for radioimmunodetection and therapy of neoplasms and pathologic conditions that contain degranulating eosinophils.     

Adductor insertion avulsion syndrome (thigh splints): spectrum of MR imaging features

OBJECTIVE: "Thigh splints," also known as the adductor insertion avulsion syndrome, is a painful condition affecting the proximal to mid femur at the insertion of the adductor muscles of the thigh. Scintigraphic findings in this syndrome have been described; we report a spectrum of MR imaging abnormalities involving this portion of the femur in a group of patients presenting with hip, groin, or thigh pain. CONCLUSION: Symptoms of vague hip, groin, or thigh pain may be associated with stress-related changes in the proximal to mid femoral shaft (thigh splints). When interpreting MR imaging studies of the pelvis in patients presenting with these symptoms, careful attention should be directed to this portion of the femur. This is especially important because the findings may be subtle, and this region is often at the distal edge of most MR imaging studies of the pelvis and hip.     

Activation of the growth plates on three-phase bone scintigraphy: the explanation for the overgrowth of fractured femurs

Children with an uncomplicated femoral fracture, treated with superimposition of fragments and intentional shortening, usually develop overgrowth of the fractured femur and the ipsilateral tibia which may compensate for the initial shortening and enable the limb in question to reach a length similar to that on the normal side. The overgrowth is evaluated clinically and by scanography. The increased metabolic activity of the growth plates that support this overgrowth has not been documented by any laboratory method. In order to evaluate the metabolic activity of the growth plates, 18 patients (11 males, seven females; mean age 6.1 years) with fractures of the femur were studied at three different time intervals (2-5 months, 6-12 months and 18-24 months). Three-phase bone scintigraphy was performed in all patients. Ten children (five males, five females; mean age 7.5 years) who had had bone imaging for other reasons were used as the control group. Visual analysis of the flow and equilibrium phases was performed for the distal femoral and proximal tibial growth plates. Visual and semi-quantitative analyses of the delayed images were performed for the distal femoral and proximal and distal tibial growth plates. Semi-quantitative analyses yielded the following activity ratios: (a) the distal femoral growth plate of the fractured femur to the contralateral one (FR); (b) the proximal growth plate of the tibia on the side of the fractured femur to the contralateral one (TpR); (c) the distal growth plate of the tibia on the side of the fractured femur to the contralateral one (TdR); and (d) in the control group, the distal growth plates of both femora (FCG) and the proximal (TCGp) and distal (TCGd) growth plates of the tibiae. Visual analysis of the blood flow, equilibrium and delayed images showed increased activity in the distal femoral growth plates during the first and second time intervals, but not during the third. No significant activity changes were found in the proximal and distal tibial growth plates during any of the phases analysed. The mean and standard deviation for FR in the three time intervals were: FRI=1.22+/-0.27, FRII=1.17+/-0.16 and FRIII=1.09+/-0.20. FR values were significantly higher than in the control group (FCG=0.99+/-0.03) (P=0.033). The mean and standard deviation for TpR in the three time intervals were: TpRI=1.08+/-0.18, TpRII=0.94+/-0.09 and TpRIII=0.96+/-0.20. TpR values were not significantly different from those in the control group (TCGp=1.00+/-0.05). However, TpRI was significantly higher than TpRII (P=0.043). The mean and standard deviation for TdR in the three time intervals were: TdRI=1.10+/-0.41, TdRII=1.05+/-0.15 and TdRIII=1.13+/-0.36. TdR values were not significantly higher than in the control group (TCGd=1.00+/-0.04) (P=0.777). These results support the concept that three-phase bone imaging is able to quantify and determine that activation occurs in the distal femoral and proximal tibial growth plates of fractured femora. This phenomenon may explain the overgrowth observed in this injured bone structure.     

Pediatric reference data for dual X-ray absorptiometric measures of normal bone density in the distal femur.

OBJECTIVE: Many children at risk for osteoporosis have substantial hip and knee contractures that prevent assessment of bone mineral density in the "usual" region, the proximal femur. As an alternative, bone density may be measured in the distal femur projected in the lateral plane. The purpose of this study was to provide normative reference data useful for interpretation of bone density measures in the distal femur of children and adolescents. SUBJECTS AND METHODS: The study was a cross-sectional, single-observational assessment of 256 healthy children and adolescents between the ages of 3 years and 18 years 6 months (mean, 10 years 5 months). Bone mineral density was measured in the nondominant proximal femur, lumbar spine, and both distal femurs using dual X-ray absorptiometry. RESULTS: We found that bone mineral density increases with age in the cortical, cancellous, and mixed regions of the distal femur, similar to the findings with other regional analyses of bone density. Bone density in the distal femur correlates very highly with bone density in the proximal femur and slightly less well with bone density in the lumbar spine. CONCLUSION: In pediatric patients who have deformities, have experienced trauma, or have undergone surgical procedures that prevent reliable measures of bone density in the proximal femur, bone mineral density may be measured in the distal femur and interpreted relative to the bone mineral density findings in healthy age- and sex-matched controls.