Comparison of different radiological modalities on investigation of bone metastases

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THE MEDICAL ACADEMY’S FACULTY OF MEDICINE OF THE LITHANIAN UNIVERSITY OF HEALTH SCIENCES

Ella Gordon

Comparison of different radiological modalities on investigation

of bone metastases

Master Thesis

Department of Radiology

Supervised by Gražina Labanauskaitė-Šliumbienė. Lecturer, M.D, Ph.D.

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SUMMARY

Ella Gordon

Comparison between 18FDG PET, 18FDG PET-CT, MRI, BS and CT in the diagnosis of bone metasatasis in pateint with different cancer.

Research aim: There are various different radiological imaging techniques for the assessment of bone

metastses. The most widely used techniques are 18FDG PET-CT, 18FDG PET, MRI, CT and bone scintigraphy (BS). Those radiological investigation have been proved to be important in the detection of bone metastases. There are a lot of studies about the diagnostic value of those different radiological modalities but there is no one conclusion that confirms which is the optimal technique for detection of bone metastases. Each radiological modality has its own advantages and disatvanteges in diagnosis bone metastases. Thus, the purpose of my study is to compare between different meta analysis studies which are comparing the value of 18FDG PET, 18FDG PET-CT, MRI, CT and BS for the diagnosis of bone metastases and then to conclude which is the best diagnostic technique for diagnosis bone

metastases.

Methadology: Studies about 18FDG PET, 18FDG PET-CT, MRI, CT and BS for the detection of

bone metastases in various cancer patients were systematically searched in the MEDLINE, EMBASE, sciencedirect, Springerlink, Web of Knowledge, EBSCO and the Cochrane Database of Systematic Review, from 2006-2016. I have investigated the sensitivities and specificities of those different radiological modalities and then draw a coclusion.

Results: Ten elegible studies were eligible in my research. From studies [27,28,32] both 18 FDG

PET-CT and MRI have high sensitivity and specificity for detection of bone metastases when comparing them to PET, CT and BS. From studies [29-31] MRI has higher sensetivity ans specificirty for

detection of bone metastases when comparing to BS. From studies [33-36] 18FDG PET-CT has higher sensitivity and specificity for detection of bone metastases when comparing to BS.

Conclusion: 18FDG PET-CT and MRI were found to be comparable and both significantly more

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ACKNOWLEDGMENTS

No external funding was received for this study.

The author thanks Grazina Labanuskaite Lecturer, M.D, Ph.D for her assistance in making this research.

CONFLICTS OF INTEREST

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ABBREVIATIONS

ALP – alkaline phosphatase

BMP - Bone morphogenetic protein BS - Bone scintigraphy

CSF - Colony stimulating factor

CT -Computed tomography

DWI -Diffusion-weighted imaging ECM –Extracellular matrix

EGF- -Epidermal growth factor ET-1 –Endothelin 1

ETAR -Endothelin A receptor GF - Growth factor

GM-CSF –Granulocyte macrophage colony-stimulating factor H2S –Hydrogen Sulfide

HPC - Hematopoietic progenitor cells ICAM-1 –Intracellular adhesion molecule 1 IFN- –Interferon gamma

IGF 1 -Insulin growth factor 1 IL- -Intraleukines

IL-4 –Interleukin 4

LFA-1 –Lymphocyte function-associated antigen 1 M-CSF –Macrophage colony-stimulating factor MM - Multiple myeloma

MMPs –Matrix metallo proteinases MRI - magnetic resonance imaging SI - Signal intensity

TGF –Transforming growth factor TGF-ß –Transforming growth factor beta VCAM-1 –Vascular cell adhesion molecule 1 VEGF –Vascular endothelial growth factor ECM –Extra cellular metrix

OPG –Osteoprotegerin

PDGF - platelet derived growth factor PET -Positron emission tomography

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PTHrP –Parathyroid hormone releasing peptide PTH -parathyroid hormone

TNF A - tumor necrosis factor a LIF - leukemia inhibitory factor SDF-1 - stromal-derived factor 1

SPECT -Single photon emission computed tomography VLA-4 - Very long antigen 4

18FDG PET - 18FDG (2-deoxy-2-[18F]-fluoro-D-glucose or fluorodeoxyglucose) 99mTc-MDP - Technetium-99m bound to methylene diphosphonate

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INTRODUCTION

Bone metastases are the commonest malignant bone lesion. Bone metastases occurs much more often than primary bone tumor. The symptoms of bone metastases or primary bone tumors causes progressively bone pain, swelling of the affected area, tendency of the bone to fracture much more easily and some other extra skeletal symptoms such as urinary incontinence, bowel incontinence, weakness in the legs and arms, weight loss, decrease appetite, hypercalcemia which eventually may cause nausea, vomiting, constipation and confusion. At the beginning, the diagnosis of bone

metastases should be based on imaging test but it should often be confirmed with biopsy. In my research study I will compare between different radiological imaging techniques for the assessment of bone metastases. Nowadays the most widely used techniques for detection of bone metastases are: Plain radiography X-ray, 18FDG PET, 18FDG PET-CT, CT, MRI and bone scintigraphy (BS). They have been proved to be important in the detection of bone metastases. Early detection of skeletal metastasis is critical for some reasons such as:

• Accurate staging and optimal treatment

• To focus on treatment strategies such as surgical fixation, radiotherapy, or

bisphosphonate therapy. This is in order to reduce risk of complications and improve patient quality of life.

In my work I will review and write the current pathophysiological mechanism of how primary tumor can metastases to bone, what causes and stimulate the primary tumor to metastasis. I will describe the most current available radiological investigation of bone metastases, such as plain radiography, PET, CT and MRI. Lastly I will show some articles which compare different radiological modalities in diagnosis of bone metastases. I will show the comparison between the specificity and sensitivity of different radiological modalities.

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AIM AND OBJECTIVES

The aim of the thesis – To analyse which radiological modality are more accurate in their

sensitivity and specificity while diagnosis bone metastases in people who have been already diagnosed with cancer. The radiological modalities that I searched are 18FDG PET, 18FDG PET-CT, MRI and bone scintigraphy.

Objectives of the thesis:

1. To search and learn about different radiological modalities such as 18FDG PET, 18FDG PET-CT, MRI and bone scintigraphy (BS) that are common now days in diagnosis of bone metasteses in already diagnosed cancer patients.

2. To analyse the meta-analysis articles which compare different radiological modalities such as: 18FDG PET, 18FDG PET-CT, MRI and bone scintigraphy (BS). In order to understand which radiological modality has the best sensitivity and specificity for the diagnosis of bone metastases in already diagnosed cancer patient.

3. To conclude which from different radiological modalities has the best sensitivity and speceficity in diagnoses bone metastases.

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1. LITERATURE REVIEW

1.1 Normal bone remodeling

Bone is a living conective tissue that is composed of: (a) inorganic component such as hydroxyapetite crystals and carbonate content (b) organic component, which consist of: unminiralized (osteoid) matrix and bone cells. Osteoid is unmineralized, organic portion of the bone matrix that is formed prior to the maturation of bone tissue, in other words osteoid is young bone that has not yet undergone any calcification. Bone matrix composed of type 1 collagen (collagen fibers) and ground substances. The hardness of the matrix is due to inorganic salts that are in the osteoid such as hydroxyapateite crystals which are deposited between the collagen fibers. The cells in the bone are constantaly breaking down and reforming the extracellular matrix (ECM) in an active process which is called bone remodeling. The mechanism contains two processes one is modeling and the second one is remodeling. Bone modeling has its responsibility for growth and mechanically induced formation of bone, this process requires bone formation and bone removal in order to make new bone on removed one. The second process is bone remodeling which has its responsibility for removal and repair of damaged bone. It is is important in order to maintain the adult skeleton integrity. In normal healthy person the two processes of bone modeling and bone remodeling should have a tight, strict, balanced and synchronized activity in order to act perfectly together. In this modeling/remodeling process there are multiple cellular participants which will help to work together [1].

There are important types of cells within the bone that are responsible for bone remodeling and modeling process. Osteoprogenitor cells (stem cells) are located in the periosteum and endosteum. Those stem cells will differentiate into osteoblast or osteoclast. Osteoblast which produce bone, they have the capabability to produce collagen and secrete it into the surrounding to form the organic component of the matrix. Osteoblast form closely packed sheets on the surface of bone from which they extend cellular processes through the developing bone. In order to lay down bone in succeful manner osteoblast should produce molecules, including enzymes, growth factors (GF) and hormones such as: alkaline phosphatase (ALP) ,collagenase, tumor growth factor- beta (TGF-β) ,Insulin growth factor 1 (IGF-1), osteocalcin and type 1 collagen. Osteoblast also uptake calcium and phosphate from the blood and deposit it into the matrix to form hydroxyapetite crystals, which is inorganic component of the matrix. After the process of bone formation and matrix syntheses, osteoblasts have some

potential directions: Some osteoblasts become flattened and remain as quiescent lining cells at the bone surface, they are called osteocytes, some of the osteoblast die by apoptosis. However, with the deposition of new bone, the majority of osteoblasts gradually become surrounded by the bone matrix

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and as the matrix calcifies the cells (along with their associated cell products) gets trapped inside and they resulting lacunae. At this point cells of the osteoblast line age and then differentiate into

osteocytes. Osteocyte are maintainance cells of the bone, they derived from mature osteoblast. They help to maintain the bone as a living tissue. Osteocytes communicate with each other as well as with osteoblasts, via extensive cytoplasmic processes that occupy canaliculi within the bone matrix [2].

Another type of bone cells are osteoclast which resorb bone. Osteoclast are found in the bone surface which is called Howships lacunae. Once osteoclast are activated they move to the proper area and break down the matrix to calcium and phosphate. Those substances are released into the blood. Osteoclast numbers is tightly regulated, without tight regulation of osteoclast severe bone loss would occur. In order to activate osteoclast RANKL (receptor activator of nuclear factor kappa-B ligand) is produced by bone building the osteoblast. Osteoblast produce RANKL in order to increase osteoclast number. The RANKL will bind to RANK receptors on osteoclast precusors cells, inducing formation of osteoclast. Bone turnover continious through our life in order to maintain bone integrity. The process is very important because it provides bone strength and a good response to mechanical stress [2]. Malignant cells secrete factors that stimulate osteoclastic activity both directly and indirectly. There are factors that produced by tumor cells which will cause increased bone resorption, some of the factors include prostaglandin E and a variety of cytokines and growth factors, such as tumor growth factor (TGF) α and β, epidermal growth factor (EGF), vascular endothelial growth factor (VEGF), tumor necrosis factor (TNF) and interleukines (IL). Also proteolytic enzymes such as

metaloproteinases (MMP) have been involved in erarly formation of bone metastasis[3].

1.1.1 Different types of bone metastases

Bone is the third most common location for metastases after lung and liver. Bone metastases results from primary tumor invasion to the bone. Bone metastases are a frequent complication of some cancers, the most common bone metastases are from breast, prostate and thyroid, lung cancers with less frequency and lesser frequency are metastases from thyroid and kidney cancer see table 1.1[4]. More than 50% of patients with advanced breast or prostate cancer will show bone metastases. Unfortanatly, once tumors has been metastasize to bone, they are virtually incurable and result in significant morbidity for the pateint. As I mentioned earlier under normal conditions bone will undergo remodeling and modeling which is tightly regulated. The tumur cells may downregulate this process and may lead to three types of lesions: osteoblastic metastases, osteoclastic metastases or mixed type of metastases. The type of metastasis is determined by the reflection of the local interaction between tumor cells and the bone remodeling system. Thus, the development of osteolytic or osteoblastic

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lesions results from a functional interaction between tumor cells and osteoclasts or osteoblasts,

respectively. As a result of the dynamic nprocess of bone remodeling and the potential heterogenecity of metastatic lesions, patients may have both osteolytic and osteosclerotic lesions- mixed lesions that are containing both elements [5].

Different molecular mechanisms explain the difference in bone lision phenotype. For example, mechanism involved in osteolytic bone metastases such as lung and breast cancer include PTHrP, TGF-B while in osteoblastic lesions such as prostate cancer, endothelin-1, PG and morphogenetic proteins are responsoble for the lesion see table 1.2. It is important to understand the differences of bone metastases between osteolytic and osteoblastic phenotypes to help clinicians to understand the underlying mechanisms, behaviors and therapies that are currently available for bone metastases. Cancer cells influence bone cells in two predominant ways. Most often cancer cells stimulate the osteoclast lineage to increase osteoclast differentiation and their activity while simultaneously those cancer cells inhibiting osteoblast activity. When this process happens osteoclastic bone resorption exceeds osteoblastic bone formation which results in bone degradation and the formation of osteolytic lesions, this phenotype is common in breast, lung and MM (multiple myeloma).

In osteoblastic metastases, cancer cells instead of inhibiting osteoblasts, they start to release substances to stimulate the osteoblast lineage to increase osteoblast differentiation and new bone deposition. When osteoblastic bone formation exceeds osteoclastic bone resorption there is increased bone growth that results in 'bulges’ in the bone causing osteoblastic lesions. Because osteoblastic bone metastases is characterised by increases in both bone resorption and bone formation, lesions of the bone will causes weakness, abnormal architecture of the bone and eventually those patients will have increased risk of bone fracture (common in prostate) [6].

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Taken from: Bone metastasis: mechanisms and therapeutic opportunities. Larry J. Suva, Charity Washam, Richard W. Nicholas, and Robert J. Griffin [4]

Table. 1.2 Soluble factors influencing osteoblast and osteoclast function and metastatic cancer growth in the bone.

Taken from:Mechanisms of cancer metastasis to the bone. Juan Juan YIN, Claire B POLLOCK and Kathleen KELLY[5]

1.1.2 Osteolytic metastases

In osteolytic metastases, the destruction of bone occurs due to stimulation of osteoclasts rather than the tumor cells itself. The tumor cells produce factors that directly increase the number of osteoclast and increase the amount of RANKL expressed by bone cells such as osteoblast- this

eventually will help to differentiate to more osteoclast. In addition, the bone resorption releases growth factors (GF) that are usually stored in an inactive form in bone. Once GF is activated it will cause further increase in bone destruction. The factors responsible for the activation of osteoclasts vary depending on the tumor. For example in multiple myeloma the factors that are released from the cancer cells such as IL-6, PTHrP, leukemia inhibitory factor (LIF), colony stimulating factor (CSF) causes osteoclasts to accumulate only at bone resorbing surfaces adjacent to myeloma cells and their levels are not increased in areas uninvolved with tumor. Also those factors causes increase in bone resorption but bone formation is suppressed so that bone lesions in patients with myeloma become purely lytic.

Breast cancer is another type of osteolytic metastases. The tumor cells secrete many

osteotropic cytokines which will stimulate osteolysis. Some of those factors you may see in table 1.2. PTHrP is an important osteoclast-activating factor that is elevated in 90 % of bone metastases samples. PTHrP activates osteoclasts and promotes bone resorption by binding to its receptor present on

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osteoblasts. PTHrP also upregulates RANKL and downregulates OPG (Osteoprogenitor) by interacting with parathyroid hormone receptor 1. Also, PTHrP can promote tumor cells proliferation by autocrine action and tumor angiogenesis. TGF-b released by activated osteoclasts can further increase

production of PTHrP. The elevated PTHrP increases RANKL to stimulate osteoclast formation and activity and promotes bone metastases see Figure 1.3 [7]. Osteolytic lesion in bone appears

destructive, showing loss of both cancellous and cortical bone, and are usually well circumscribed see figure1.4 [8]

Figure 1.3: The vicious cycle of osteolytic metastasis

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Figure 1.4: Example of lytic vertebral body metastasis

Example of lytic vertebral body metastasis in a 78-year-old patient with renal cell carcinoma. (a) Sagittal computed tomography image showing mid-thoracic lytic vertebral body metastasis (arrow). Lesion is hypointense on T1-weighted magnetic resonance imaging (b), hyperintense on T2-weighted magnetic resonance imaging (c), and vividly enhances with contrast administration on T1-weighted magnetic resonance imaging (d).

Taken from: Imaging characteristic analysis of metastatic spine lesions from breast, prostate, lung, and renal cell carcinoma for surgical planning: Osteolytic versus osteoblastic. Justin A. Reddington, Gustavo A. Mendez, Alex Ching [8].

1.1.3 Osteoblastic (osteosclerotic) metastases

One of the most common sites of skeletal metastases is the vertebra. Vertebral metastases most commonly occur in the lumbar region. Metastasizing prostatic carcinoma produces mainly osteoblastic metastasis. Osteoblastic metastases are caused by tumor-derived factors that lead to osteoblast

proliferation, differentiation and bone formation.In the early stages prostate cancer will produce some osteogenic factors which stimulate osteoclast activity. Some of the factors are: PDGF (Platelet derived growth factor), BMP (Bone morphogenetic protein), Endothelin-1 (ET-1). ET-1 has been suggested to be an important and central mediator of osteoblastic metastases which stimulates the new bone formation via the endothelin A receptor (ETAR). ET-1 has been found increased in patients with bone osteoblastic lesions, especially in those cancers that are androgen-independent advanced prostate cancers [12]. Moreover, ET-1 enhances the expression of bone-specific proteins such as osteocalcin, osteonectin, and alkaline phosphatase. Some factors that are abundant within bone matrix (TGF-b, TNF-a, IL-1b, BMPs) function as potent activators of ET-1 expression, see figure 1.5. Patients with osteoblastic bone metastases have high markers of bone resorption such as alkaline phospatase (ALP) [8]. Osteoblastiv lesion in bone appears hyperdense and are typically expanded, they also has poorly defined borders. See figure 1.6 [8].

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Figure 1.5 Vicious cycle of osteoblastic bone metastases. Diagrammatic representation of the interactions between tumour cells, osteoblasts and osteoclasts during the processes of bone homing

and colonisation in osteoblastic bone metastases.

Taken from: The role of osteoblasts in bone metastasis. Penelope D Ottewell

.

Figure 1.6: Example of blastic vertebral body metastasis

Example of blastic vertebral body metastasis in a 53-year-old male patient with prostate cancer. (a) Sagittal computed tomography view depicting upper and mid-thoracic blastic vertebral body metastasis (arrows). Lesions are hypointense on T1-weighted magnetic resonance imaging (b), hypointense on T2-weighted magnetic resonance imaging (c), and have patchy contrast enhancement on T1-weighted magnetic resonance imaging (d). Note the blastic anterior and posterior vertebral body resulting in moderate thoracic spinal cord compression.

Take from:Imaging characteristic analysis of metastatic spine lesions from breast, prostate, lung, and renal cell carcinomas for surgical planning: Osteolytic versus osteoblastic. Justin A. Reddington, Gustavo A. Mendez, Alex Ching [8]

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1.1.4 Mechanism of bone metastases

The term bone metastasis is when invasive carcinoma start to spread to sites that are distant to the primary tumor. Mechanism of bone metastases is still not clear but it is known to involve multistep process. The process contains the interaction between tumor cells and particular organ microenvironment. The process involves complex events. Initial process is when the tumor cells detach from the ECM. The tumor cells invade and infiltrate the surrounding normal host tissue by trying to penetrate and destruct the basement membrane. The second process is when the tumor cells migrate and transport toward the vascular blood supply or lymphatic system. The tumor cells start to penetrate the wall of the blood vessels (BV) in order to reach an access to the systemic circulation, they are avoiding the recognition and destruction of the host immune system; the next process is that the tumor cell leave the blood or the lymphatic system and seed in another rich environment. The tumor cells in order to survive in a distant site should undergo attachment an implantation. Once established in the niche, tumor cells may remain dormant for many years because of the control of the

surrounding bone microenvironment [9].

1.1.5 Molecular mechanism of tumor spread- OPG-RANKL-RANK system

There are several important factors in the development of bone metastases. One of the mechanism is by the OPG-RANKL-RANK system. This system has a very big influence and have a key role in osteoclastic activation, proliferation and differentiation. RANK (Receptor Activator of Nuclear Factor-kappa B) is a transmembrane surface receptor mainly expressed on mature osteoclasts and their progenitors. Its primary function is to induce osteoclastogenesis and control calcium

metabolism. Receptors activator of NF-κB ligand (RANKL) is a polypeptide that belongs to type II transmembrane proteins. RANKL is found on the surface of osteoblasts and bone stromal cells. RANKL on osteoblast surface, binds to its receptor RANK, on the surface of osteoclasts and their precursors see figure 1.7. Many other molecules like parathyroid hormone (PTH), parathyroid hormone related protein (PTHrP) 1, 25-dihydroxyvitamin D, TNF, interleukin (IL)-1 and IL-11 can also induce osteoclastogenesis [7,10]. This regulates the differentiation of precursors into

multinucleated osteoclasts and osteoclast activation. Pathologic activation is associated with increased bone resorption. Under physiological conditions, the stimulatory effects of RANKL on osteoclasts are

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opposed by another molecule known as OPG, which is also secreted by the osteoblasts and stromal cells .Osteoprotegerin (OPG) is secreted by osteoblasts and osteogenic stromal stem cells and protects the skeleton from excessive bone resorption by binding to RANKL and preventing it from interacting with RANK. In another words OPG competes with RANK for RANKL, thus it prevents the RANKL– RANK interaction on the osteoclast cell membrane. When RANKL binds to OPG, osteoclastogenesis is markedly inhibited leading to cessation of bone resorption. The RANKL/OPG ratio in bone marrow is thus an important determinant of bone mass in normal and disease states [7, 11].

Figure 1.7 Receptor Activator of Nuclear Factor kappa-B Ligand (RANKL) and Osteoclast Formation.

Taken from: Mechanisms of bone metastases by Roodman GD [7].

1.1.6 Pre-metastatic Niche- Seed and soil hypothesis

The concept of metastasis results when tumor cells interact with a specific organ microenvironment. Thus metastases can also be explained by the Seed and soil hypothesis.

Disseminated tumor cells (‘the seed’) which already invade the BV and penetrate toward the systemic circulation survive and extravasate into a secondary site can produce metastases only when they are seeded in the correct or appropriate ‘soil’. Next the metastatic organ should that give the opportunity for tumor invasion, colonization and growth. In other words, the metastatic organ is the fertile soil that favors tumor cell growth. As we saw PTHrP in skeletal metastases has the capacity to act on both parts of the process, nurturing the seed (tumor cells) and priming the soil (bone microenvironment).

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Bone marrow derived cells express different chemokines such as: Vascular endothelial growth factor (VEGF), Very long antigen 4 (VLA-4), stromal-derived factor 1 (SDF-1),

Hematopoietic progenitor cells (HPC), osteopontin, those chemokines play a role in the trafficking of breast cancer cells and prostate cancer cells to the bone. Those circulating bone marrow derived cells create suitable environment for subsequent colonization by tumor cells. Once the tumor cells invade at the site of the premetastatic niche they produce micrometastasis [12].

Figure 1.8 Sequential steps in the pathogenesis of cancer metastasis.

Taken from: The pathogenesis of cancer metastasis: the ‘seed and soil’ hypothesis revisited Isaiah J. Fidler[12]

1.2 Radiological diagnosis of bone metastases

Bone metastases are the most common malignant bone lesion. It is much more common than primary bone tumor. Skeletal involvement occurs in 30%–70% of all cancer patients. The most common skeletal metastases are from breast and prostate cancer, see table 1. It is very important to detect early bone metastases because it has an important influence on the disease treatment, disease outcome and the patient quality of life. More over once there is bone metastases the prognosis are decreased and there is increase in morbidity and mortality rate. Many patients with bone metastases in the beginning are asymptomatic and metastases to bone are detected incidentally such as on routine

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screening or when there is increase in tumor markers. Symptoms occur mainly when the lesion

increases in size, it will cause extensive bone destruction, which may lead to collapse or fracture, or in the presence of accompanying complications, such as spinal cord compression or nerve root invasion.

Imaging is an essential part of the management of bone metastasis. There are various radiological techniques for the assessment and diagnosis bone involvement [13]. Imaging modalities are based on either direct anatomic visualization of the bone or tumor or indirect measurements of bone tumor metabolism. The most widely used techniques include radiography, PET, SPECT, CT, MRI and bone scintigraphy (BS). Now days, positron emission tomography (PET) and single photon emission computed tomography (SPECT) have a potential for evaluation of bone metastases [14].

1.2.1 Plain radiography

Plain radiography usually used for imagining where there are cortical and trabecular

abnormalities. Plain radiography will detect lytic, sclerotic (blastic) or mixed lesion. The disadvantage of plain radiography are: (a) provides only minimal data on the integrity of the bone marrow (b) bone destruction must be present before a bone metastasis is evident radiographically (c) 30%–75%

reduction in bone density is required in order to visualize bone metastasis on XR. Those limitation creates a huge problem: in order to detect bone metastases we should wait till there will be sufficient bone destruction, this may delay the diagnosis of bone metastases for several months compared to other radiological modalities such as BS [15]. Never the less plain radiography still plays an important role in the diagnostic evaluation of bone metastases. Osteolytic changes in some parts of the skeleton can be seen on plain films. Also, pathological changes in cortical bone are detectable by plain x-ray even if they are only a few millimeters wide, thus it is very useful to use plain radiography for diagnosis pathological bone fractures particularly of weight-bearing bones. Metastases measuring up to 1 cm in the spongiosa of a vertebral body or in the marrow of a long bone can be missed on plain x-ray; thus plain radiography is not generally recommended as a screening method because of poor sensitivity (Sensitivity depends partly on the location of the abnormal finding: metastases in the spongiosa of a vertebral body or in the marrow of a long bone can be missed on plain x-ray), See figure 1.9. [16, 17].

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Fig 1.9 Plain radiography vs CT of the right femur in a patient with lung carcinoma

Anteroposterior radiograph of the right femur in a patient with lung carcinoma. A lytic lesion in the proximal femur (arrow) is compatible with a metastasis. There is no obvious fracture. (B) Noncontract axial CT image from the same patient. CT confirms the presence of a slightly expansile, lytic lesion involving nearly the entire cross-sectional area of the proximal right femur. Furthermore, not seen on the radiographs, CT demonstrates significant cortical thinning with a focal cortical break (arrow) compatible with pathological fracture.

Taken from: Diagnostic Imaging and Image-Guided Therapy of Skeletal Metastases Junsung Choi, MD, and Meera Raghavan, MD [17]

1.2.2 Computed Tomography

Computed tomography (CT) scanning also has limited diagnostically properties for skeletal metastases. CT is highly sensitive for osteolytic and osteoblastic bone lesions involving cortical bone, but less sensitive for tumors restricted to the bone marrow space, see figure 1.10. As a result, CT is of limited use as a screening test for bone metastases, despite its high specificity [18].

CT provides good imaging of cortical and trabecular bone and is the imaging of choice for evaluating the ribs which have a high cortex to marrow ratio. A major advantage of CT is that

investigation for skeletal metastasis or evaluation of treatment response can be performed at the time of staging or restaging other organs which reduces the burden of imaging for the patient. A further advantage of CT is that it can used to guide percutaneous biopsy when a tissue diagnosis is required [19].

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Figure 1.10 CT scan of the proximal femur

CT scan of the proximal femur demonstrates increased density of the left-sided marrow. This is due to replacement of the normal marrow fat by tumor, a finding that may precede more obvious bone lysis.

Taken from: Radiological imaging for the diagnosis of bone metastases L. D. RYBAK, D. I. ROSENTHAl[18]

1.2.3 MRI

Bone marrow mainly composed of fat and water, thus, at least some marrow may be visible on CT and MR image. MRI is superior to other imaging modalities in evaluating bone marrow because it is remarkably sensitive in detecting lipid. Alteration in the balance of lipid versus water in bone marrow is a principal factor affecting the signal intensity of marrow on MRI. Due to its characteristic MRI can be used to detect processes that alter the relative amounts of fat and water in bone marrow such as bone metastases from primary cancer [19]. Due to its excellent soft tissue resolution, MRI is the imaging of choice for assessing metastatic spread in the marrow cavity, extension of tumor from the marrow cavity and involvement of surrounding structures. MRI is highly sensitive for detecting skeletal metastasis as it has the capability to demonstrate an intramedullary metastatic deposit in advance of cortical destruction occurs and before a pathologic osteoblastic process manifests as focal accumulation of radiotracer on a bone scan. Given that MRI does not involve ionizing radiation, it is especially suited for the investigation of suspected bony metastasis in pregnant women. The specificity of MRI is moderate because of overlap in the appearance of metastases and a variety of benign lesions. In the vertebral column, for instance, benign lesions, which may be confused with metastases, include degenerative disk disease, osteomyelitis, a benign compression fracture, infarcts, and Schmorl’s nodes. Normal bone marrow contains a high percentage of fat and demonstrates high signal intensity on T1-weighted sequences. Osseous metastases usually manifest as discrete foci of low T1 signal,

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sequence, bone metastases usually demonstrate T2 hyperintensity due to their elevated water content and gadolinium enhancement due to increased vascularity. One limitation of MRI is that cortical bone, with its very short T2 relaxation time, is very poorly interrogated. Therefore, bones with a low marrow volume such as the ribs are better evaluated with CT as described above in CT section [20, 22].

Figure 1.11 Magnetic resonance imaging is superior to plain radiography for detection of bone metastasis

Lateral lumbar spine radiograph demonstrates subtle sclerotic metastatic deposits at the inferior endplate of T12 and L1 from a primary breast malignancy; Sagittal T1 (B) and short tau inversion recovery (STIR).

Taken from: Imaging of bone metastasis: An update Gerard J O’Sullivan, Fiona L Carty, Carmel G Cronin [20].

1.2.4 Nuclear medicine: SPECT,PET, Bone scintigraphy

Bone scintigraphy (BS) is a type of nuclear medicine tomographic imaging technique using gamma rays. It is one of the oldest techniques within nuclear medicine imaging. Technetium-99m bound to methylene diphosphonate (99mTc-MDP) is the most frequent radionuclide used in bone scintigraphy. In order to determine the sensitivity of bone scintigraphy we should check it by the level of osteoblastic activity. This means that in cancer where the osteoblastic activity is increased a bone scan will reveal highly intense uptake in those abnormal areas. In cancer where the osteoclastic activity is predominant, usually, normal bone tissue surrounding metastatic lesions will normally respond with compensatory osteoblastic activity, which will also lead to highly intense uptake. Only in case where there is osteoclastic lesion which is slowly growing osteolytic there can be absence of an osteoblastic reaction that would render the metastases undetectable through bone scanning. Some

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benign processes that occurs in the bone, such as fractures or degenerative changes may cause

increased bone turnover (increase osteoblastic activity), as a result this may give a high false-positive rate and to decrease the specificity of BS. False-negative findings can occasionally result when pure osteolytic metastases are growing rapidly, when bone turnover is slow or when the site is avascular [21]. As we discussed previously the incidence of lytic, blastic, and mixed type of bone metastases is different in various tumor types. Bone metastases of bladder, kidney, and thyroid cancer and lesions of multiple myeloma are lytic. Blastic lesions are frequently seen in prostate and breast cancer. The major limitation of the interpretation of bone scans is the low specificity. Moreover it is difficult to

differentiate bone metastases from other pathological conditions of the bone such as: degenerative changes, inflammatory processes, trauma, mechanical stress, Paget’s disease, fibrous dysplasia or benign or malignant primary bone tumors [22, 23].

Single photon emission computed tomography (SPECT) is another type of the nuclear medicine tomographic imaging technique using gamma rays, which gives 3D images. SPECT has greater sensitivity and specificity than bone scintigraphy for detecting vertebral and pelvis metastases. SPECT/CT increases the diagnostic accuracy of bone scans and significantly decreases the likelihood of a non-diagnostic study requiring further imaging. Like bone scintigraphy, it is possible that SPECT will not detect lytic lesions. It was shown that when using BS and SPECT, the sensitivity, specificity, positive and negative predictive values are increased dramatically. Moreover combining SPECT with CT may offer even better results. It detects increases in osteoblastic activity and the flow of the blood level. Thus it is much better to diagnose bone metastases with both of these modalities [24].

PET is a nuclear medicine imaging technique that produces tomographic images through the detection of positrons. As the radiotracer breaks inside the patient body, positrons are made and can be detected by the scan. PET visualizes the uptake of positron-emitting radioisotope by tissues and cancer cells. Two radiopharmaceuticals are typically used: 18F-Fluoride, a bone turnover tracer, and 18FDG a tumor tracer. PET can be used for whole-body scanning to detect metastases in either soft tissue or bone. PET has a great potential and has advantages in detecting metastasis. However, PET also has limitations. False-positive result will exist for PET because FDG accumulates in metabolically active tissue, including inflammation and infection, and some normal high FDG uptake tissue such as some muscles will also lead to false-positive results. Thus the specificity for PET is limited [23].

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Figure 1.12 Diffuse bone metastasis on bone scintigraphy

Abnormal accumulation of radiotracer throughout the spine, most pronounced in the upper thoracic spine with additional pelvic and bilateral rib metastases in a patient with primary breast malignancy. Focal accumulation of radiotracer in the left antecubital fossa represents artefact at the radiotracer injection site.

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2. RESEARCH METHODOLOGY AND METHODS

3.1 Lithreature search stategy:

I searched for studies which were evaluating 18 FDG PET, 18 FDG PET-CT, MRI and bone scintigraphy for detection of bone metastases in various cancer patients (such as breasr, prostate,lung cancer). The articles were identified with a search from MEDLINE, EMBASE, sciencedirect,

Springerlink, Web of Knowledge, EBSCO and the Cochrane Database of Systematic Review, from 2006-2016. I used search terms with the following combination: (“PET OR positron emission tomography OR FDG OR fluorodeoxyglucose OR MRI OR magnetic resonance imaging OR bone scan OR bone scintigraphy”) AND (“bony metastases OR skeletal metastases OR osseous

metastases”) AND (sensitivity OR specificity).

3.2 Selection of studies:

After collecting the articles that the search gave me, I read the abstracts and found the potentially eligible articles. The non sutable articles for which I couldn’t determine from the abstract I excluded from the research.Then I managed to get the full-text of these articles. I read the full text versions of these articles to determine whether they were eligible for inclusion in this study. In order to be included in this study, I choose articles that had to meet the following qualifications: (a) use 18FDG-PET–CT, 18FDG-PET, MRI and BS. (b) The articles should give data that they had evaluated patients with suspected or previously diagnosed bone metastasis (c) the bone metastases was confirmed by histopathological analysis and/or surgery (d) the articles have presented sufficient data such as sensitivity and specificity, I used some articled that also presents data about positive and negative preidcted values (e) Each study include 29 or more patients.

The exclusion criteria from this study was due to: (a) Case reports, letters, editorial, comments, reviews, animal, or in vitro studies and the studies that did not include raw data, (b)The studies were not about 18FDG PET and 99mTc-MDP BS imaging, but about other radio-pharmacy imaging such as18F PET, 18FCH PET, 99mTc-MIBI BS and 99mTcO4- BS etc.; (c) repeatedly published literatures or similar literatures were also excluded.

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3.3 Data extraction

The articles that I used all had the same data extraction, in the articles some of them had more but all of them had the following data that was extracted: (a) year of publication of the article (b) authors name (c) number of included patients (d) imaging methods (PET, PET-CT, MRI or skeletal scintigraphy).

3.4 Quality assessment

All the researches that I took evaluated the quality and applicability of the studies by the quality assessment for studies of diagnostic accuracy (QUADAS) tool, which is a quality assessment tool specifically developed for systematic reviews of diagnostic accuracy studies [25,26]. The QUADAS tool included 14 items, each of which was assessed as “yes” “no” and “unclear”. Due to answers to 14 questions, they should find out the reasons for bias and variation through comprehensive analysis. .

3.5 Statistical analysis

Data from each article were separately analyzed for sensitivity and specificity. I analyzed the sensitivity and specificity of radiological investigation, PET-CT, PET, MRI and BS. First I analyzed the articles which had the highest number of radiological investigation (articles with all four

radiological investigation PET, PET-CT, MRI, and BS). I wrote in a table the sensitivity and specificity which I analyzed from the articles. Then I continued to do the same with other articles which had less diagnostically radiological procedures (example: PET-CT, MRI and BS), then again I wrote their sensitivity and specificity in the same table. In the end I concluded the table with all eligible articles, their radiological modalities and the results of their sensitivity and specificity.

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4. RESULTS

4.1 Study selection and description

In this research after reading I choose 10 eligeble meta analysis articles. Those articles were discussing about different radiological modalitis of investigation in case of bone metastases. The first table see table 3.1 will show the study, origin of the article, number of articles that were included in their meta analysis, number of patient in this study and the radiological methods that were compared in this study. The second table, see table 3.2 will show specificaly the results of the sensitivity and specificity of each study and their radiological investigation.

Table 3.1 Main characteristics of the included studies.

Study Origin Number

of articles included Number of patient MRI BS 18FDG PET-CT 18FDG PET- CT 1. Hui-Lin Yang, 2011 [27] China 67 15,221 ✓ ✓ ✓ ✓ ✓ 2. Xinhua Qua, 2011 [ 28] China 17 2940 ✓ ✓ ✓ ✓ 3. Guohua Shen, 2013 [29] China 18 1100 ✓ ✓ ✓ 4. Ruimin Yang, 2013 [30] China 7 332 ✓ ✓ 5. E. Balliu 2010 [31] spain 1 40 ✓ ✓ 6. Jian Duo, 2012 [32] China 9 1116 ✓ ✓ 7. Mads H, 2013 [33] Denemark 1 50 ✓ ✓ 8. Jian Rong, 2013 [34] China 7 668 ✓ ✓

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9. Steffen Hahn,2011 [35] Germany 1 29 ✓ ✓ 10. Shie P, 2008 [36] California 3 184 ✓ ✓

Table 3.2 Diagnostic accuracy for PET, PET-CT, MRI, BS and CT. Hui-Lin Yang 2011

[27]

Sensitivity (95% CI) Specificity (95% CI)

PET 80.1(77.7–82.5) 96.9(96.2–97.5) PET/CT 94.2(92.6–95.6) 97.2(96.4–97.8) MRI 90.4(87.2–93.0) 96.0(95.2–96.8) BS 75.1(72.9–77.2) 93.6(92.8–94.2) CT 72.9(66.6–78.6) 94.8(92.4–96.6) Xinhua Qua,2011 [28] PET 0.87(0.81,0.92) 0.94(0.92,0.96) PET/CT 0.92(0.88,0.95) 0.98 (0.97,0.98) MRI 0.77(0.65,0.87) 0.92(0.88.0.95) BS 0.86(0.82,0.89) 0.88(0.86,0.89) Guohua Shen, 2013 [29] PET/CT 0.87 (0.79–0.93) 0.97 (0.93–0.99) BS 0.79 (0.73–0.83) 0.82 (0.78–0.85) MRI 0.95 (0.90–0.98) 0.96 (0.92–0.98) Ruimin Yang, 2013 [30] MRI 0.84 (0.72-0.91) 0.96 (0.81-0.99) BS 0.83 (0.73-0.89) 0.94 (0.68-0.99) E.Balliu, 2010 [31]

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BS 72.2 (48.8-95.7 75 (53.5-96.5 MRI 94.4 (81.1-100) 90 (74.4-100) Jian Duo, 2012 [32] PET/CT 0.803 (0.639-0.904 0.989 (0.973-0.994 MRI 0.837 (0.631-0.939 0.977 (0.952-0.989 Mads H, 2013 [33] PET/CT 93.1 (89.0–97.3) 54.0 (37.1–70.9 BS 50.8 (37.8–63.8) 82.2 (73.8–90.6 Jian Rong, 2013 [34] PET-CT 0.93 (0.82-0.98) 0.99 (0.95-1.00) BS 0.81 (0.58-0.93) 0.96 (0.76-1.00) Steffen Hahn,2011 [35] PET-CT 96% (67/70) 92% (54/59 BS 76% (53/70) 95% (56/59) Shie P, 2008 [36] PET 81% (70%–89%) 93% (84%–97%) BS 78% (67%–86%) 79% (40%–95%),

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INTERPERTATION OF THE RESULTS

Various imaging modalities can detect malignant bone involvement. Each of the radiological modalities has advantages and limitations and their role in the investigation may change in patients with different malignant diseases. Precise diagnosis of bone metastases is important for guiding subsequent staging and the choice of an adequate therapeutic strategy. In those meta-analysis, we investigated the diagnostic performance of 18FDG PET-CT, 18FDG PET, bone scintigraphy, MRI and CT for detection of bone metastases in pateint with various cancer (such as: breast cancer, prostate cancer, lung cancer).

18FDG PET/18FDG PET-CT/MRI/BS

From meta analysis [27] the pooled sensitivity estimates for 18FDG PET-CT, 18FDG PET, MRI and BS were 94.2%, 80.1%, 90.4% and 75.1% respectively. 18FDG PET-CT>MRI>18FDG PET>BS. The pooled specificity estimates for 18FDG PET-CT, 18FDG PET, MRI and BS were 96.9.%, 97.2%, 96.0% and 93.6% respectively. 18FDG PET>18FDG PET-CT>MRI>BS. The results showed that 18FDG PET-CT and MRI were found to be comparable and both significantly and accurate than 18FDG PET and BS for the diagnosis of bone metastases.

From meta analysis [28] the pooled sensitivity for the detection of bone metastasis using 18FDG PET–CT, 18FDG-PET, MRI and BS were 0.92, 0.87, 0.77 and 0.86, respectively. The pooled specificity for the detection of bone metastasis using 18FDG PET–CT, 18FDG-PET, MRI and BS were 0.98, 0.94, 0.92, 0.88 respectively. The results showed that both 18FDG PET–CT and 18FDG-PET were better imaging methods for diagnosing bone metastasis than MRI and BS. 18FDG-18FDG-PET–CT has higher diagnostic value (sensitivity, specificity and DORs) for diagnosing bone metastasis from lung cancer than any other imaging methods.

18FDG PET-CT /Bone scintigraphy/MRI

From meta-analysis [29] per-pateint basis the pooled sensitivities by using 18FDG PET-CT, BS and MRI were 0.87, 0.79 and 0.95 respectively. The pooled specificities for detection of bone metastases using18FDG PET-CT, BS and MRI were 0.97, 0.82 and 0.96 respectively. The results showed that MRI was better than 18FDG PET-CT and BS on a per-patient basis.

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MRI/BS

From meta-analysis [30] whole-body MRI have similar patient-based sensitivity (0.84 vs 0.83), specificity (0.96 vs 0.94). Both whole-body MRI and skeletal scintigraphy have good diagnostic performance for detecting bone metastatic tumors. It remains inconclusive whether whole-body MRI or bone scintigraphy is superior in detecting bone metastatic tumors.

From meta analysis [31] the sensitivity of whole-body MRI and BS is 94.4 and 72.2 respectivly and the specificity of MRI and BS is 90 and 75. The results showed that whole-body MRI is more accurate and more objective than bone scintigraphy for the detection of bone metastases. Whole-body MRI can also detect lesions in tissues other than bone.

18FDG PET-CT/MRI

From meta analysis [32] FDG PET-CT and MRI has similar patient based sensitivity 0.803 vs 0.837 respectively, the specificity for FDG PET/CT and MRI is 0.989 vs 0.977 respectivly.The results showede that FDG PET-CT and gadolinium-enhanced MRI have excellent diagnostic performance for the detection of bone metastases in patients with cancer.

18FDG PET-CT/BS

From meta analysis [33] 18FDG PET-CT and BS has sensitivity of 93.1 and 50.8 respectivly. The specificity of 18FDG PET-CT and BS is 54.0 and 82.2 resepectivly.The results showed that 18FDG PET-CT is superior to BS with regard to detection of bone metastases within the spine.

From meta-analysis [34] PET-CT and BS has sensitivity of 0.93 and 0.81 respectively. The specificity of PET-CT and BS is 0.99 and 0.96 respectively. The results showed that 18FDG PET-CT has higher sensitivity and accuracy for detection of bone metastases in cancer patients.

From meta-analysis [35] PET-CT and BS has sensitivity of 96% and 76% respectively. The specificity of PET-CT and BS is 92% and 95% respectively. The results showed that FDG-PET/CT is more sensitive and equally specific for the detection of bone metastases compared with bone

scintigraphy.

From meta-analysis [36] PET-CT and BS has sensitivity of 93.1 and 50.8 respectively. The specificity of PET-CT and BS is 54.0 and 82.2 respectively. The result showed that it remains

inconclusive whether FDG-PET or bone scintigraphy is superior in detecting osseous metastasis from cancer. However, FDG-PET does have a higher specificity and may better serve as a confirmatory test than bone scintigraphy and used to monitor response to therapy.

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DISCUSSION OF THE RESULTS

The early diagnosis of bone metastatic tumors is crucial for choosing the most effective management and evaluating the outcome of patients. After analysing the articles I concluded some points regarding different radiological modalities:

• After reading studies [27,28] I could conclude that when combining 18_{F-FDG PET with CT the} sensintivity and specificity for diagnosis of bone metastases are markly improved.PET by itself

has some disadvantages such as: (a) PET may cause false-positive result, this occurs because FDG will accumulate in metabilically active tissue such as inflammtory or infectious tissues and in muscles. The increase uptake of FDG will contribute to false positive results (b) 18FDG might be less sensitive for the detection of osteoblastic metastases but PET is more sensitive for the detection of osteolytic metastases (c) PET lacks anatomical details which will not show the uptake of FDG in some places. PET/CT can add important anatomical information to that obtained by PET. In a conclusion combination of both 18F-FDG PET and CT will help to increase the sensitivity and specificty for bone metastases.

• From articles [27-31] MRI is significantly more accurate than CT and BS for the diagnosis of bone metastases. MRI has been found to have an advantage over CT and BS based on its higher soft tissue contrast. It is the optimal imaging technique for bone marrow assessment. MRI can detect an early intramedullary malignant lesion before there is any cortical destruction or reactive processes.

• From article [32] PET and MRI were found to be comparable imaging technique, they both have high sensitivity and specificty for diagnosis bone metastases.

• From articles [33-36] I can conclude that FDG-PET/CT is more sensitive for the detection of bone metastases than bone scintigraphy whereas specificity is comparable for both modalities.

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CONCLUSIONS

1. The most common radiological modalities for diagnosis bone metastases are 18FDG PET-CT, 18FDG PET, bone scintigraphy, MRI and CT.

2. After reading and analysis of meta analyses articles which compare sensitivity and specifiicity between different radiological modalities in bone metastases, I can conclude that when combining 18_{F-FDG PET with CT the sensitivity and specificity for diagnosis of bone metastases are markly} improved. MRI is significantly more accurate than CT and BS.

3. 18FDG PET-CT and MRI were found to be comparable and both significantly more accurate than CT and BS for the diagnosis of bone metastases.

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Comparison of different radiological modalities on investigation of bone metastases