Conventional Modalities and Novel, Emerging Imaging Techniques for Musculoskeletal Tumors.

BACKGROUND: Imaging of musculoskeletal tumors requires a multimodality approach and includes radiography, computed tomography (CT), and magnetic resonance imaging (MRI). METHODS: Topics related to primary bone and soft-tissue tumors are reviewed. The fundamental imaging principles are discussed as well as the applications of emerging imaging modalities. RESULTS: MRI is the preferred technique for the evaluation of musculoskeletal tumors, whereas other imaging modalities play a complementary role. Radiography is indicated as the first-line imaging modality in bone and soft-tissue tumors, whereas CT is the preferred modality for evaluating cortical osseous lesions or calcifications and in patients with contraindications to MRI. Positron emission tomography (PET)/CT and PET/MRI are helpful in identifying the glucose metabolism of the lesion. Ultrasonography is the most useful for biopsy guidance and can aid in differentiating cystic from solid masses and identifying vascularity. Novel modalities, such as diffusion-weighted imaging, spectroscopy, and habitat imaging, show promise in increasing diagnostic accuracy and affecting treatment strategies. CONCLUSIONS: Conventional modalities and emerging, novel imaging techniques can provide noninvasive methods to diagnose and evaluate musculoskeletal tumors.

An Approach to the Evaluation of Incidentally Identified Bone Lesions Encountered on Imaging Studies.

OBJECTIVE: This article discusses the strengths and weaknesses of the various anatomic and molecular imaging techniques in the evaluation of unexpected bone lesions. CONCLUSION: An approach to the imaging evaluation of chondroid, osteoblastic, and osteolytic lesions as well as focal marrow abnormalities is reviewed.

Voriconazole-associated soft tissue ossification: an undescribed cause of glenohumeral joint capsulitis.

Voriconazole-related periostitis has been increasingly described in the literature over the last several years as a recognizable disease entity, especially in lung transplant patients. This relationship should be considered when approaching immunosuppressed patients presenting with diffuse bone pain and imaging findings of periostitis. We present a case of voriconazole-associated periostitis, capsular and enthesial ossification and glenuhumeral capsulitis in a patient with a hematologic malignancy. To the authors' knowledge, soft tissue ossification associated with voriconazole has not been described in the radiology literature.

Imaging of Spondylodiscitis: An Update.

Spondylodiscitis is an infection of the vertebral body and/or intervertebral disc, which can also involve the epidural space, posterior elements, and paraspinal soft tissues. Due to high morbidity and mortality, prompt diagnosis and treatment of spondylodiscitis is critical. However, diagnosis can be challenging due to nonspecific signs and symptoms. Magnetic resonance imaging with and without contrast is the imaging modality of choice due to high sensitivity and specificity. Intravenous administration of gadolinium contrast can better demonstrate the extent of soft tissue and bone abscesses. However, magnetic resonance imaging is less useful in the evaluation of treatment response. When magnetic resonance imaging cannot be performed or is not diagnostic, radionuclide imaging is a useful alternative. Although bone scintigraphy frequently is used as a screening test, false negative results can occur early in the course of the infection and in the elderly. This test is not useful for detecting the soft tissue infections that often accompany or mimic spondylodiscitis. Gallium-67 citrate improves the specificity of the bone scan, can detect infection earlier than the bone scan, may be more sensitive, especially in elderly patients, and identifies accompanying soft tissue infection. Performing SPECT and SPECT/CT improve accuracy. The 2-3 day delay between radiopharmaceutical administration, poor image quality, and relatively high patient radiation dose are significant disadvantages of gallium-67. Furthermore gallium-67 is no longer as readily available as it once was. 18F-FDG imaging is the radionuclide test of choice for spondylodiscitis. The procedure, completed in one day, is sensitive, has a high negative predictive value, and reliably differentiates degenerative from infectious vertebral body end-plate abnormalities. 18F-FDG has outperformed bone and gallium-67 imaging in comparative studies. 18F-FDG may be able to provide an objective means for monitoring response to treatment. The potential of other agents for diagnosing spondylodiscitis has been studied. Although indium-111biotin accurately diagnoses spondylodiscitis, this radiopharmaceutical has never been commercially available. Gallium-68 citrate and 99mTc-radiolabeled antimicrobial peptides have been investigated, but their role in the diagnosis of spondylodiscitis has not been established. Labeled leukocyte scintigraphy has no role in the diagnosis of spondylodiscitis.

Diagnostic imaging and image-guided therapy of skeletal metastases.

BACKGROUND: The high incidence of skeletal metastases in cancer patients warrants careful detection with imaging and follow-up. Efforts are needed to manage pain associated with skeletal metastases as part of overall patient management. METHODS: This article reviews the current methods of diagnostic imaging in the evaluation of skeletal metastases and image-guided treatment of bone metastases for the palliation of pain based primarily on the assessment of imaging and interventional radiologic literature. RESULTS: Approaches to diagnostic imaging of skeletal metastases are summarized. Skeletal scintigraphy provides high sensitivity for detecting skeletal metastases, but targeted computed tomography (CT) or magnetic resonance imaging (MRI) may be needed to increase specificity. Newer imaging modalities, such as positron emission tomography (PET)/CT, improve detection of both lytic and blastic metastases. Minimally invasive percutaneous ablative treatment techniques, including radiofrequency ablation, microwave ablation, and cryoablation, are examined. They provide alternative approaches to radiation therapy to effectively palliate pain of bone metastases. Preliminary results of MR-guided focused ultrasound surgery (MRgFUS) demonstrate its effectiveness in palliating pain from skeletal metastases. CONCLUSIONS: Skeletal scintigraphy is the most common imaging modality for detecting skeletal metastases. Additional imaging may be required based on the type of tumor, the disease state, or treatment options. External-beam radiation therapy remains the mainstay for palliation of pain from bone metastases. Alternative minimally invasive and noninvasive image-guided treatment options can provide effective pain palliation.

Creating an Artificial 3-Dimensional Ovarian Follicle Culture System Using a Microfluidic System.

We hypothesized that the creation of a 3-dimensional ovarian follicle, with embedded granulosa and theca cells, would better mimic the environment necessary to support early oocytes, both structurally and hormonally. Using a microfluidic system with controlled flow rates, 3-dimensional two-layer (core and shell) capsules were created. The core consists of murine granulosa cells in 0.8 mg/mL collagen + 0.05% alginate, while the shell is composed of murine theca cells suspended in 2% alginate. Somatic cell viability tests and hormonal assessments (estradiol, progesterone, and androstenedione) were performed on days 1, 6, 13, 20, and 27. Confocal microscopy confirmed appropriate compartmentalization of fluorescently-labeled murine granulosa cells to the inner capsule and theca cells to the outer shell. Greater than 78% of cells present in capsules were alive up to 27 days after collection. Artificially constructed ovarian follicles exhibited intact endocrine function as evidenced by the production of estradiol, progesterone, and androstenedione. Oocytes from primary and early secondary follicles were successfully encapsulated, which maintained size and cellular compartmentalization. This novel microfluidic system successfully encapsulated oocytes from primary and secondary follicles, recapitulating the two-compartment system necessary for the development of the mammalian oocyte. Importantly, this microfluidic system can be easily adapted for sterile, high throughput applications.

A Morphometric Analysis of Platelet Dense Granules of Patients with Unexplained Bleeding: A New Entity of Delta-Microgranular Storage Pool Deficiency.

One thousand and eighty patients, having prolonged bleeding times, frequent epistaxis, menorrhagia or easy bruising or other bleeding manifestations, and excluding those with von Willebrand's disease, were evaluated for platelet dense granule deficiency. The mean diameter of platelet dense granules was determined for all patients using image analysis. Four hundred and ninety-nine had "classic" dense (delta) granule storage pool deficiency (δ-SPD). Five hundred and eighty-one individuals (53.8%) were found to have a normal mean number of dense granules, but for some of these patients, the dense granules were smaller than for the controls. Of the patients having a normal number of dense granules, 165 (28.4%) were found to have significantly smaller granules than the platelets obtained from the control subjects. Their average granule diameter was 123.35 ± 0.86 nm, that is more than three standard deviations below the mean of the control data. Total δ-granule storage pool volumes (TDGV)/platelet were calculated using these measurements. Individuals with δ-SPD had half the number of granules (2.25 ± 0.04 DG/PL) and storage pool volume (3.88 ± 1.06 × 106 nm3) when compared to our control data (4.64 ± 0.11 DG/PL; 10.79 × 106 nm3 ± 0.42). Individuals having a bleeding history but a normal average of small dense granules had a calculated storage pool volume statistically different than controls and essentially the same storage pool volume as patients with δ-SPD. We have identified a sub-classification of δ-SPD that we have defined as micro-granular storage pool deficiency (δ-MGSPD).

Imaging of Spondylodiscitis.

Spondylodiscitis is an infection of the vertebral body or disc and may also involve the epidural space, posterior elements, and paraspinal soft tissues. It is a cause of morbidity and mortality, and warrants early diagnosis and prompt treatment. Diagnosis can be difficult because of nonspecific signs and symptoms. Magnetic resonance imaging is sensitive and specific and is the imaging modality of choice for spondylodiscitis. Gadolinium contrast can show the extent of soft tissue and bone phlegmon and abscess. The test is less useful for evaluating treatment response. When magnetic resonance imaging cannot be performed or is not diagnostic, radionuclide imaging is a useful alternative. Although bone scintigraphy frequently is used as a screening test, false-negative results can occur, especially in the elderly. This test is not useful for detecting soft tissue infections that accompany or mimic spondylodiscitis. Gallium-67 citrate improves the specificity of the bone scan, can detect infection earlier than the bone scan, may be more sensitive, especially in elderly patients, and identifies accompanying soft tissue infection. Performing SPECT and SPECT/CT improves accuracy. The 2- to 3-day delay between radiopharmaceutical administration and the relatively poor image quality are significant disadvantages of gallium-67. Indium-111 biotin, alone or in combination with streptavidin, accurately diagnoses spondylodiscitis; unfortunately, this agent is not widely available. Currently, 18F-FDG imaging is the radionuclide test of choice for spondylodiscitis. The procedure, which is completed in a single session, is sensitive, has a high negative predictive value, and reliably differentiates degenerative from infectious vertebral body end plate abnormalities. In comparative investigations, 18F-FDG has outperformed bone and gallium-67 imaging. Preliminary data suggest that 18F-FDG may be able to provide an objective means to measure response to treatment. Gallium-68 citrate and 99mTc-radiolabeled antimicrobial peptides have been investigated, but their role in spondylodiscitis has yet to be established.

Tenosynovial giant cell tumors lacking giant cells: report of diagnostic pitfalls.

Tenosynovial giant cell tumors are a group of neoplastic disorders that involve synovium-lined tendon sheaths, synovial joints, and adjacent soft tissue. They are divided into localized and diffuse subtypes. TSGCTs have well-established clinical and histological diagnostic criteria; however, the subtypes and nomenclature can be confusing. They also pose diagnostic challenges when they occur in atypical locations or without multinucleated giant cells. With the possibility for systemic targeted therapy in relapsing pigmented villonodular tenosynovitis and diffuse-type giant cell tumor, accurate diagnosis and subtyping of TSGCTs is increasingly important. We report two cases of TSGCTs in order to elucidate the diagnostic nomenclature, clinicopathological features, differential diagnosis, and diagnostic pitfalls. Recent advancements in the pathogenesis and targeted therapy of TSGCTs are also discussed.

Wee1 inhibition by MK-1775 leads to tumor inhibition and enhances efficacy of gemcitabine in human sarcomas.

Sarcomas are rare and heterogeneous mesenchymal tumors affecting both pediatric and adult populations with more than 70 recognized histologies. Doxorubicin and ifosfamide have been the main course of therapy for treatment of sarcomas; however, the response rate to these therapies is about 10-20% in metastatic setting. Toxicity with the drug combination is high, response rates remain low, and improvement in overall survival, especially in the metastatic disease, remains negligible and new agents are needed. Wee1 is a critical component of the G2/M cell cycle checkpoint control and mediates cell cycle arrest by regulating the phosphorylation of CDC2. Inhibition of Wee1 by MK1775 has been reported to enhance the cytotoxic effect of DNA damaging agents in different types of carcinomas. In this study we investigated the therapeutic efficacy of MK1775 in various sarcoma cell lines, patient-derived tumor explants ex vivo and in vivo both alone and in combination with gemcitabine, which is frequently used in the treatment of sarcomas. Our data demonstrate that MK1775 treatment as a single agent at clinically relevant concentrations leads to unscheduled entry into mitosis and initiation of apoptotic cell death in all sarcomas tested. Additionally, MK1775 significantly enhances the cytotoxic effect of gemcitabine in sarcoma cells lines with different p53 mutational status. In patient-derived bone and soft tissue sarcoma samples we showed that MK1775 alone and in combination with gemcitabine causes significant apoptotic cell death. Magnetic resonance imaging (MRI) and histopathologic studies showed that MK1775 induces significant cell death and terminal differentiation in a patient-derived xenograft mouse model of osteosarcoma in vivo. Our results together with the high safety profile of MK1775 strongly suggest that this drug can be used as a potential therapeutic agent in the treatment of both adult as well as pediatric sarcoma patients.

Diffusion MRI and novel texture analysis in osteosarcoma xenotransplants predicts response to anti-checkpoint therapy.

Combinations of targeted drugs have been employed to treat sarcomas, however, response rates have not improved notably, therefore emphasizing the need for novel treatments. In addition, imaging approaches to assess therapeutic response is lacking, as currently measurable indices, such as volume and/or diameter, do not accurately correlate with changes in tumor biology. In this study, quantitative and profound analyses of magnetic resonance imaging (MRI) were developed to evaluate these as imaging biomarkers for MK1775 and Gem in an osteosarcoma xenotransplant model at early time-points following treatment. Notably, we showed that Gem and Gem+MK1775 groups had significantly inhibited tumor growth by day 4, which was presaged by elevations in mean ADC by 24 hours post treatment. Significant differences were also observed at later time points for the Gem+MK1775 combination and MK1775 therapy. ADC distribution and entropy (randomness of ADC values) were also elevated by 24 hours following therapy. Immunohistochemistry demonstrated that these treatment-related increases in ADC correlated with apoptosis and observed cell condensations (dense- and exploded bodies). These findings underline the role of ADC as a quantitative imaging biomarker for therapy-induced response and show promising clinical relevance in the sarcoma patient population.

Dynamic three-dimensional MR renography for the measurement of single kidney function: initial experience.

A three-dimensional magnetic resonance (MR) renographic method to measure single kidney glomerular filtration rate (GFR) and split renal function was developed that is based on renal signal intensity measurements during 2-3 minutes after intravenous injection of a low dose (2 mL or 0.01 mmol/kg) of gadopentetate dimeglumine. In nine subjects, single kidney MR GFR indices correlated well with technetium 99m (99mTc) diethylenetriaminepentaacetic acid (DTPA) clearance (r = 0.7-0.8) for GFR values of 7-48 mL/min. MR right kidney split renal function values (range, 32%-59%) also correlated well with 99mTc-DTPA radionuclide measurements (r = 0.76); differences between the two methods averaged 0.8% +/- 8. MR renography was performed along with contrast material-enhanced MR imaging of the kidneys and renal arteries and added 8 minutes or less to the total examination time.