Conventional and current imaging techniques in cancer research and clinics

Conventional and current imaging techniques in cancer research and clinics

CHAPTER 12 Conventional and current imaging techniques in cancer research and clinics Nezahat Pinar Barkan1, Sec¸il Karahisar Turan1, Hatice Yildiz...

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Conventional and current imaging techniques in cancer research and clinics

Nezahat Pinar Barkan1, Sec¸il Karahisar Turan1, Hatice Yildizhan2, Fatma Duygu O¨zel Demiralp2, Bengi Uslu2 and Sibel A. Ozkan2 1

Hacettepe University, Ankara, Turkey 2Ankara University, Ankara, Turkey

CHAPTER OUTLINE 12.1 Importance of Imaging in Oncology .................................................................493 12.2 Imaging Approaches.......................................................................................498 12.2.1 Anatomical-Based Imaging..........................................................498 12.2.2 Functional-Based Imaging...........................................................505 12.3 Novel Technologies........................................................................................510 12.3.1 Molecular Imaging and Nano-Oncology.........................................510 12.3.2 Bioluminescence Imaging ...........................................................513 12.3.3 Near-Infrared Fluorescence .........................................................514 12.3.4 Photoacoustic Imaging................................................................516 12.4 Future Directions............................................................................................517 12.5 Conclusion ....................................................................................................520 References .............................................................................................................521

12.1 IMPORTANCE OF IMAGING IN ONCOLOGY Cancer is considered the leading cause of death in both developed and developing countries. In 2008, 12.7 million cancer cases were reported in the world (Jemal et al., 2011). By 2012, around 14 million new cases and 8 million deaths have been reported by WHO’s International Agency for Research on Cancer (IARC) (Ferlay et al., 2015). It is estimated that cancer deaths will continue to rise due to an increase of world population, decrease in mortality from other diseases, and the increase in tobacco use by certain populations (Jha, 2009). Detection of both primary and metastatic tumors are crucial in oncology imaging as it directly affects patient survival. This makes the use of accurate imaging

Design of Nanostructures for Theranostics Applications. DOI: http://dx.doi.org/10.1016/B978-0-12-813669-0.00012-9 © 2018 Elsevier Inc. All rights reserved.

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techniques indispensable (Li et al., 2014a). According to, cancer screening should be applied for preventive purposes in individuals by which cancer can be cured or prevented (Gelband et al., 2015). This explains why it is crucial to diagnose cancer, with this much of an occurrence, at the earliest; the only way to lower mortality rates (Fass, 2008). Biomedical imaging is an essential tool for screening, diagnosis, theranostics, treatment response, and management of cancer, with many advantages, such as real-time monitoring, without harming the tissue of interest (Bentzen, 2005; Fass, 2008; Gouliamos et al., 2014). Fig. 12.1 illustrates the role of imaging in oncology. With the advances in technology, many imaging techniques have been developed which detect pathological, physiological, and morphological changes both for acquiring more precise results and predicting tumor response to therapy (Weissleder and Pittet, 2008; Harry et al., 2010). Oncology imaging has made great progress during the 20th century, thanks to the contributions of scientists from various fields (Sharma et al., 2012). Two different approaches are adopted: anatomical-based and functional-based (Rembielak et al., 2008). Anatomical-based techniques include: X-ray based techniques, ultrasound, computed tomography (CT), magnetic resonance imaging (MRI); whereas radionuclide imaging, single-photon emission tomography (SPECT), positron emission tomography (PET), hybrid imaging (PET-CT, SPECT CT, PET MRI, etc.) sentinel node mapping, and MR-based techniques for functional imaging (MR spectroscopy and functional MRI) are regarded as functional-based techniques (Rembielak et al., 2008, 2011, 2016; Sharma et al., 2012). Table 12.1 summarizes different imaging techniques indicating their advantages and disadvantages.

FIGURE 12.1 Role of imaging in oncology. Reprinted from Fass, L. 2008. Imaging and cancer: a review. Mol. Oncol. 2, 115152, with permission by Elsevier.

Table 12.1 Comparison of Imaging Techniques Common Contrast Agents/ Readout

Example Clinical Applications

Technique

Advantages

Disadvantages

Computed tomography

• Unlimited depth penetration • High spatial resolution • Whole-body imaging possible • Short acquisition time (minutes) • Moderately expensive • Anatomical imaging • Unlimited depth penetration • Whole-body imaging possible • Quantitative molecular imaging • Can be combined with CT or MRI for anatomical information • Unlimited depth penetration • Whole-body imaging possible • Quantitative molecular imaging • Theranostic: can combine imaging and radiotherapy • Can be combined with CT for anatomical information

• Radiation exposure • Poor soft-tissue contrast • Probably not used for molecular imaging; currently only anatomical and functional imaging

• • • •

Barium Iodine Krypton Xenon

• Tumor perfusion106

• Radiation exposure • Expensive • Low spatial resolution (12 mm; 48 mm3) • Long acquisition times (minutes to hours)

• • • •

11

C F 64 Cu 68 Ga

F-FDG-PET for cancer staging107 • Diagnosis of various disease (see Table 12.2)

• Radiation exposure • Low spatial resolution (0.31 mm; 1215 mm3) • Long acquisition time

• • • •

99m

• Diagnosis of various disease (see Table 12.3) • Radiotherapy for NHL: 90YBexxar or 131I-Zevalin108 • Radiotherapy of thyroid carcinoma with 131I-iodide109

Positron emission tomography

Single-photonemission computed tomography

18

Tc I 111 In 177 Lu 123



18

(Continued)

Table 12.1 Comparison of Imaging Techniques Continued Common Contrast Agents/ Readout

Example Clinical Applications

Technique

Advantages

Disadvantages

Magnetic resonance imaging

• Unlimited depth penetration • Whole-body imaging possible • No ionizing irradiation • Excellent soft-tissue contrast • High spatial resolution • Whole-body imaging possible • No ionizing irradiation

• Expensive • Long acquisition time (min-hours) • Limited sensitivity for detection of molecular contrast agents

• Gadolinium (Gd31) • Iron oxide particles (SPIO, USPIO) • Manganese oxide • 19F

• SPIOs for detection of lymph node metastases of prostate cancer110 • Characterization of focal hepatic lesions111 • Perfusion imaging of the heart112

• Expensive • Long acquisition time (minutes to hours) • Low sensitivity

• • • • • •

Choline Creatine Lactate Lipids Polyamines N-Acetylaspartate • Contrast microbubbles

• Metabolite levels in brain tumours113 • Treatment monitoring of Alzheimers’s114

Magnetic resonance spectroscopy

Ultrasound

• No ionizing irradiation • Real-time imaging/short acquisition • High spatial resolution • Can be applied externally or internally (endoscopy) • Inexpensive • Highly sensitive

• Whole-body imaging not possible • Contrast agents currently limited to vasculature • Operator dependency

• Characterization of focal liver lesions31 • Echocardiography115 • Tumor perfusion of cancer30

Optical

• No ionizing irradiation • Real-time imaging/short acquisition time (seconds to minutes) • Relatively high spatial resolution • Can be applied externally or internally (endoscopy) • Inexpensive • Highly quantitative and sensitive • Multiplexing

• Limited depth penetration (#1 cm) • Whole-body imaging not possible

• Fluorescent molecules and dyes • Lightabsorbing nanoparticles

• OCT imaging of artherosclerosis116 • OCT imaging for colonoscopy screening19 • Raman imaging of skin cancer117

Reprinted from Pysz, M.A., Gambhir, S.S., Willmann, J.K., 2010. Molecular imaging: current status and emerging strategies. Clin. Radiol. 65, 500516, with permission from Elsevier.

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12.2 IMAGING APPROACHES 12.2.1 ANATOMICAL-BASED IMAGING 12.2.1.1 X-ray First imaging applications had started with the invention of X-rays by Wilhelm Conrad Ro¨ntgen in 1895, where he used Crookes and Lenard tubes. When Ro¨ntgen first observed invisible light rays, what he later named as “X-rays,” he found out that human bones were opaque to these rays when covered with organic matter such as human flesh. This meant that, bones could be visualized without the flesh being visualized on the plate, due to its transparent nature (Sharma et al., 2012; Dunn, 2001). Although the invention of X-rays is associated with Ro¨ntgen, a year earlier, Nikola Tesla had already known about X-rays, however much of his work was lost, due to a fire in his laboratory. The following year he sent images of the human body of what he referred to as shadowgraphs to Ro¨ntgen; his work was appreciated. He pointed out later on the use of X-rays in the detection of lung diseases. He never got credit for his invention, his shadowgraphs and findings on the benefits of X-ray on human health is still not known to many radiologists (Dunn, 2001; Sharma et al., 2012; Hrabak et al., 2008). It was not until 1896 that cancer was visualized by using X-rays. Franz Ko¨nig was the first one to visualize cancer. Almost 20 years later, with the invention of X-tube by Wiliiam Coolidge, radiographs had better quality and were acquired faster (Sharma et al., 2012). The same year, the concept of mammography was put forward by Albert Salomon (Picard, 1997). Undoubtedly, invention of X-rays became an indispensable tool in medicine, especially in perinatal medicine (Dunn, 2001). In the following several years after X-rays were discovered, radiologists became aware of the hazard in ionizing radiation. Tesla had described its effects on skin and eyes. His suggestion was to keep a considerable amount of distant and to shorten exposure time. It was not until the 1960s that its impact on the fetus was first stated. X-ray use in the perinatal period was abandoned for a while and was replaced by ultrasonography and MRI (Dunn, 2001; Hrabak et al., 2008). With the invention of tomographic imaging in 1932, geometric tomography was developed, where slices of human anatomy were examined. Geometric tomography lead to the development of CT, MRI and many other threedimensional (3D) imaging technologies. However, geometric tomography had its pittfalls, such as high exposure of X-ray to the patient when more than one slice was wanted to be examined (Dobbins III and Godfrey, 2003). Later on, these drawbacks were improved with new technologies. X-ray imaging has many advantages. Firstly, it is quick to obtain and easy to reproduce. In the 20th century, X-ray imaging systems were especially useful in detecting lung and bone cancer signs. Currently, they are fundamental in

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assessing early signs of cancer and detecting metastatic lung and bone cancers. However, they are not informative on soft-tissue. Moreover, individuals who are already prone to cancer are exposed to radiation (Fass, 2008; Rembielak et al., 2016; Sharma et al., 2012). Furthermore, X-ray systems have millimole/kilogram sensitivity while this is up to 10 mmol/kg in MR (Fass, 2008). Moreover, the thermionic cathodes in a conventional X-ray tube have slow response times and consume higher power. To overcome these limitations, macroscopic CNT cathodes and carbon nanotube field-emission cathodes are being used instead (McBain et al., 2006; Yue et al., 2002). Another drawback of X-ray applications is planar radiography. It is known as the earliest clinical application of X-ray imaging, where 3D anatomy is interpreted as two-dimensional (2D) because of the 2D plane of the X-ray detector. For this reason, certain abnormalities may not be seen, which may lead to misdiagnosis. This problem was overcome by tomosynthesis, which will be discussed further (Anastasio and La Riviere, 2012). X-rays have vast areas of use in oncology imaging and therapy, including volumetric imaging and phototherapy. X-rays are being used in mammography, ultrasonography, X-ray CT, and tomosynthesis (Dunn, 2001; Johns and Yaffe, 1987) which will be discussed in the following subsections.

12.2.1.2 Ultrasonography Ultrasonography, where high-frequency sounds are used, followed the invention of X-rays. It was not until the 1930s that Karl Theodore Dussik used ultrasonography to detect brain tumors. Considered as the father of medical ultrasound, John Wilde was the first one to describe echometry, which enabled him to distinguish healthy cells from cancerous ones. Twenty years later, Ian Donald used ultrasonography in obstetrics (Sharma et al., 2012). Ultrasonography has been a useful approach in oncology imaging. It is an inexpensive technique with no radiation exposure. The transducers are cheaper than X-ray tubes and magnets used in MRI. Its resolution is high in soft-tissue; the nature and size of the lesions can be determined. It is mainly useful for superficial organs such as thyroid and breast. In cancer patients with dense breast tissue, mammography cannot be used efficiently in detection. However, ultrasonography is useful with patients in such cases (Sharma et al., 2012). However, stages of lesions cannot be determined accurately, especially deepseated ones (Anastasio and La Riviere, 2012; Rembielak et al., 2008, 2011; Sharma et al., 2012). Endoscopic ultrasonography is important in tumor and nodal stages, especially in pancreatic cancer (Palazzo et al., 1993; Ro¨sch et al., 1991; Yasuda et al., 1988). Moreover, thyroid nodules can also be detected by ultrasonography (Ezzat et al., 1994; Sugitani et al., 2008). Endovaginal ultrasonography can be used to determine endometrial thickness (Granberg et al., 1991). Transrectal ultrasonography is used in prostate cancer detection (Cooner et al., 1990; Holm et al., 1983), and endorectal ultrasonography in rectal tumors (Kulig

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et al., 2006). Abdominal ultrasonography can be used to monitor liver metastases (Rembielak et al., 2011). It is also important in detecting lymph nodes as well as head and neck lesions (Sharma et al., 2012). As a result of advances in technology, new approaches have been adopted in ultrasound imaging. One of these techniques is contrast-enhanced ultrasonography (CEUS). This approach has become one of the most popular imaging techniques due to its lower cost and safe-to-use properties. Targeted contrast-enhanced ultrasound imaging (molecular imaging), where molecularly targeted ultrasound agents such as antibodies and small peptides are being used, has emerged as a promising tool in many diseases, including cardiovascular diseases. These contrast agents are microbubbles, which are micron-sized gas bubbles encapsulated in biodegradable shells, perfluorocarbon (PFC) nanodroplets, liposomes, polylactic acid (PLA) nanobubbles and solid nanoparticles (Fig. 12.2) (Deshpande et al., 2010). It has also been used in oncology imaging, including pancreas and colon cancer. Liver

FIGURE 12.2 Types of ultrasound contrast agents. (A) Microbubbles, gaseliquid emulsions with a polyethylene gycol (PEG) polymer on the surface for aggregation prevention, (B) perfluorocarbon emulsion (PFC) nanodroplets, liquidliquid emulsions that can be vaporized into echogenic gas bubbles following administration of acoustic energy, (C) liposomes, phospholipid bilayers that can enclose air pockets for ultrasound imaging, (D) nanobubbles, gaseliquid emulsions that can fuse into echogenic microbubbles at the target site, (E) solid nanoparticles, solid amorphous substances with gas entrapped in their pores or fissures increasing echogenicity. Reprinted from Deshpande, N., Needles, A., Willmann, J.K., 2010. Molecular ultrasound imaging: current status and future directions. Clin. Radiol., 65, 567581, with permission from Elsevier.

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lesions can also be detected by using this approach. In contrast to CT- and MRIbased functional imaging modalities, CEUS can be used in visualizing tissue capillary networks. This can be achieved by its high sensitivity to even one single bubble, which is used as a contrast agent. The advantages of this approach include its application in real time, which enables attaining knowledge on tissue perfusion characteristics (Kaufmann and Lindner, 2007; Luna et al., 2013). A more advanced version of CEUS is double contrast-enhanced ultrasound (DCUS), which can be used efficiently in improving gastric cancer detection. The main principle of this technique is to use an oral ultrasound agent, which can be used to visualize the gastric wall including its three-layered structures. Another application is an intravenous contrast agent for revealing tumor vascularity. The main advantage of DCUS is its ability to detect the depth of tumor penetration. Moreover, lymph node metastases can also be identified (Luna et al., 2013).

12.2.1.3 Mammography, digital mammography and digital breast tomosynthesis (3D mammography) Breast cancer is regarded as the most commonly occurring cancer in women (Luna et al., 2013). Screening has great benefits on early diagnosis of breast cancer (Gangnon et al., 2015). When diagnosed at an early stage and treated successfully, death from breast cancer can decrease (Gouliamos et al., 2014). Routine check-up of the breast tissue is the most crucial step for early diagnosis every woman should follow, either at high risk, or not. Mammography has been an essential tool for this purpose. It is perhaps one of the most important contributions of X-ray. Developed by Albert Salomon who took the first images of breast tumors (Sharma et al., 2012), it involves the use of X-rays on compressed breast tissue. The main advantage is that it can detect breast cancer in a presymptomatic stage. It is especially useful in detecting small breast cancers and is highly effective in tumor detection in fatty breasts, especially when used together with ultrasound. Mammography is still the most fundamental approach in detecting calcifications in the breast tissue (Gouliamos et al., 2014; Kircher et al., 2012; Luna et al., 2013). There are certain limiting aspects of mammography. The most important fact is that it can miss tumors, making its efficacy often regarded questionable especially on young patients with dense breast tissue. Another challenge is the fact that some patients may find it rather painful (Destounis et al., 2015; Gouliamos et al., 2014; Whelehan et al., 2016). Digital tomography was developed to overcome diagnosis difficulties of breast lesions using conventional mammography. In digital tomography, mammographic X-ray is directed at the breast tissue and images of thin breast sections are acquired, enabling the visualization of lesions without any confusion. Although better detection can be achieved, there are still some limitations, such as ineffective diagnosis of patients with dense breast tissue. To overcome diagnosis problems of 2D approaches, digital breast

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tomosynthesis has been developed (Helvie, 2010). Dense breast tissue can be easily screened without any limitations. Tomosynthesis gives both 2D and 3D information (Nguyen et al., 2015). It can prevent breast tissue overlap (Destounis et al., 2015). Integrated use of both 2D and 3D mammography has also been proposed as an approach to improve breast cancer tumor diagnosis, compared to 2D mammography when applied alone (Caumo et al., 2014; Ciatto et al., 2012). Contrast-enhanced mammography is an approach where iodinated contrast agents are used. This approach, coupled with tomography, is based on the principle of visualizing contrast distribution in breast tissue. The image with the highest iodine concentration is one of the methods used to evaluate images obtained from contrast-enhanced tomography. Malignant cancers have rapid uptake of iodine, while benign tumors have a rather slow uptake. By using this hybrid technology, primary and secondary lesions can be visualized (Fass, 2008).

12.2.1.4 X-ray computed tomography Mammography is perhaps not the only field that X-ray has influenced. Nobel winners, Hounsfield and Cormack, were the ones who had developed computedassisted tomography years after CT scanning was characterized by Godfrey Hounsfield (Sharma et al., 2012). With the advances in computer technology, high-resolution 3D and virtual images can be obtained. The system is a combination of both multi-plane X-ray images and high technology image reconstruction algorithms (Histed et al., 2012). CT has many advantages, such as being affordable, a fast acquisition of images, and high resolution (Luna et al., 2013); CTs use X-rays to acquire cross-sectional images of any tissue of interest (Meinzer et al., 2002). Improvement of technology gave rise to better equipment. With the development of whole-body CT scanners, primary lesions could be detected simultaneously. Image-guided radiation therapy is a CT-based radiotherapy method by which the target can be aimed without harming other tissues (Sharma et al., 2012). The advent of helical and multi-detector CT enabled taking high speed scans (Histed et al., 2012; Sharma et al., 2012). Helical CT is especially useful in anatomical cavities. It is reported that it can enable the detection of lung cancer in earlier stages (Buthiau et al., 2003). Although CT is quite useful for capturing anatomical details, it can misdetect benign and malignant lesions, and provide no information on the functional and metabolic activity of lesions. Moreover, it is also reported that it can fail in detecting metastatic lymph nodes (Histed et al., 2012). Other disadvantages include its use of ionizing radiation and poor tissue contrast (Luna et al., 2013). It can perhaps only be used for functional and anatomical imaging (Pysz et al., 2010). To overcome such limiting factors, hybrid technologies of CT have been developed. One of these technologies, contrast-enhanced CT, is a crucial tool in detecting lymph node metastases of pulmonary, hepatic, and retroperitoneal origin

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(Luna et al., 2013). Moreover, its current application includes the chest, liver, pancreas, kidney, adrenal glands, small bowel, and colon. It also plays a critical role in calculating the exact amount of dose for the patient in radiotherapy (Rembielak et al., 2008).

12.2.1.5 Magnetic resonance imaging The invention of MRI had started with the idea of using nuclear magnetic resonance (NMR) to visualize cancer cells. This idea was developed by Peter Mansfield, who created a mathematical algorithm to acquire images in high speed. Later on, with the contribution of Paul Lauterbur, they won the Nobel Prize with their invention, the MRI (Sharma et al., 2012). In MRI technology, images of hydrogen atoms are acquired (Schober and Riemann, 2012). The image acquired by MRI represents the reaction of hydrogen nuclei to radio frequency energy. The overall information shows how the protons are distributed in the image (Antoch and Bockisch, 2009). It produces highresolution 3D images (Gore et al., 2011). Sensitivity is approximately 10 mmol/ kg (Fass, 2008). This can reach up to 20 µm (Gallagher, 2010). MRI has many advantages over CT, such as no radiation exposure. Despite the efficiency of CT in cross-sectional imaging of anatomy, it does not detect functional or metabolic changes, as they are not anatomical. The invention of MRI has overcome these disadvantages, as it offers both anatomical and functional information (Kwee et al., 2009). High-resolution images, in terms of contrast, can be obtained (Sharma et al., 2012), it has better use in soft-tissue (Pysz et al., 2010). It does not require patient repositioning as required when using CT. Furthermore, it is a radiation-free approach, which is important for nononcological or patients with curable cancer (Antoch and Bockisch, 2009). It is especially useful in detecting bone marrowlocated lesions (Nievelstein and Littooij, 2016). Despite these, there are certain disadvantages, including slow scan time and insensitivity in detecting calcifications (Rembielak et al., 2016). Moreover, it is sensitive to motion, making it an unfavourable technique for upper abdomen, chest and liver imaging (Sharma et al., 2012). Moreover, it is not very useful for detecting pulmonary lesions (Antoch and Bockisch, 2009). The efficiency of MRI has been reported for several cancer types, including prostate cancer (Dickinson et al., 2011), brain, spinal cord, and muscoskeletal tumors (Rembielak et al., 2016). A comparative study shows how MRI is a promising tool in detecting osteal metastases, compared to PET and PET-CT (Ghanem et al., 2005). Whole-body MRI (WB-MRI) has become widely and routinely used in oncology imaging. Improvement of image design enables the examining of patients more quickly than before (Schmidt et al., 2009). The main advantage is that it can detect both oncologic and non-oncologic lesions and can detect pathologic changes. It doesn’t require patient repositioning and can be performed in less than

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an hour. It can detect primary and metastatic tumors by scanning the whole body. Moreover, patients aren’t exposed to radiation (Kwee et al., 2009; Noij et al., 2014). It is preferred in pediatric oncology for the use in staging and follow-up of different cancers. In a comparative pilot study, it has been reported to be more efficient in detecting second primary tumors than 18F-FDG-PET/CT (Noij et al., 2014). It is also useful in detecting tumor spread, although it doesn’t provide functional information. This lack of knowledge can be overcome by diffusion-weighted WB-MRI. Diffusion-weighted MRI (DW-MRI) requires background body signal suppression techniques, making it useful for detecting primary and metastatic tumors. It acquires a composite image of the whole body. It is reported as an especially great tool in detecting tumors in the extraskeletal areas, lymph nodes, focal renal lesions, liver and prostate cancer, and multiple myeloma (Verma et al., 2012; Vilanova and Barcelo´, 2008; Messiou and Kaiser, 2015). Furthermore, it is reported to be efficient for pulmonary nodules and masses (Li et al., 2014a). DW-MRI can improve lesion detection when compared to functional imaging modalities such as CT and PET. It can be effectively used both alone or in combination with other contrast-enhanced imaging techniques. What CT scans can miss in ovarian cancer can be highly detected in DW-MRI, due to its high detection rates of peritoneal deposits (Luna et al., 2013).

12.2.1.6 Magnetic resonance spectroscopy Proton magnetic resonance spectroscopy (1H-MRSI) has become a complementary technique with MRI since the 1980s. The main difference between both is the fact that H-MRS can detect biochemical differences between cancerous and normal tissue (Pinker et al., 2012). Magnetic resonance spectroscopy (MRS) has been used for more than 60 years. The main principle is to expose electromagnetic pulses to the sample of interest, resulting in radio frequency signals. It is used for imaging brain, breast, and prostate cancer (Luna et al., 2013). The technique is based on NMR, which is based on the stimulation of protons in strong magnetic fields. By using Fourier transform, signal intensities can be displayed in individual spectra (Kurth et al., 2011). Its ability to perform spatial localization enables the acquisition of spectra from selected volumes (Xin and Tka´cˇ , 2016). There are reports on the use of 1H-MRS on clinical studies. According to these reports, it has been used in cervical and ovarian cancers, and on soft-tissue tumors. It is a noninvasive method used to detect changes in malignant brain tumors (Pinker et al., 2012). Combined use of H-MRS with MRI is known as MRSI. This approach is known for its efficient use in prostate cancer. 3D images of the tissue can be visualized by using MRSI. The metabolic data coming from MRSI are combined with MRI images, enabling the localization of the tumor (Mueller-Lisse and Scherr, 2007; Kurth et al., 2011; Seitz et al., 2009).

12.2 Imaging Approaches

As 1H-MRS enables the determination of chemicals from living tissue, it is a powerful approach on the study of brain metabolism. There are studies concerning its use in both animal and human brain (Xin and Tka´cˇ , 2016).

12.2.2 FUNCTIONAL-BASED IMAGING 12.2.2.1 Radionuclide imaging Anatomical approaches are, indeed, indispensable tools in oncology imaging. The conventional approach had been the measurement of tumor size and extent of tumor spread. However, this was found not enough as it did not provide information on functional or metabolic change differentiation. Researchers had to know the biological nature of the tumor. Functional-based approaches fulfilled this need. In the last few decades, much emphasis has been given on functional-based methods (Nievelstein and Littooij, 2016; Fass, 2008; Sharma et al., 2012). Radionuclide imaging involves the administration of a radiolabeled agent, either intravenously or orally. The radioactive emissions of this agent are detected. Radionuclides are used together with elements to produce chemical compounds; pharmaceutical compounds can also be used. These radiopharmaceuticals target the organ of interest. In this way, biochemical changes can be easily detected. It is informative for preclinical, clinical, and research purposes (Luna et al., 2013; Rembielak et al., 2016). Yet, solely using functional imaging techniques is also quite limiting. Despite being informative on functional properties, little information on anatomical structures are provided. This situation led to the development of many hybrid approaches, such as SPECT/CT, SPECT/MRI, PET/CT, PET/MRI (Fass, 2008; Luna et al., 2013; Rembielak et al., 2016). In the beginning, these hybrid technologies were used for experimental purposes. As a consequence of advances in high technology, these approaches are used both in routine and clinical examinations (Livieratos, 2015). The basic functional techniques used today are PET and SPECT. In order to obtain anatomic information of the tumor, these devices are usually used in combination with CT (e.g., PET/CT, SPECT/CT). While [18F]-2-fluoro-2-deoxy-dglucose (FDG) is used as a radiotracer in PET, iodine-123 metaiodobenzylguanidine (I-123 MIBG) is used in SPECT (Nievelstein and Littooij, 2016).

12.2.2.1.1 Positron emission tomography PET is used to characterize the biological and physiological aspects of the target of interest. The main mechanism of a PET scanner is to detect photons generated by an emitted positron destructing a nearby electron. PET technology underwent tremendous improvement in the 1970s. The application of bismuth germinate and thallium-doped sodium iodide started being used as scintillator materials. Eventually, reconstruction algorithms were improved (Luna et al., 2013).

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PET is commonly used with the aid of radiolabeled tracers such as 18F, 11C, O, 13N. Among these, [18F]-fluorodeoxyglucose ([18F]FDG) is the most commonly used tracer. The reason for this common use lies in its rather long half-life and appropriate chemical and nuclear properties (Chen and Conti, 2010; Farwell et al., 2014). Cancer cells use more ATP compared to normal cells. When FDG is administered to the body, cancer cells can be distinguished from normal cells by means of glucose uptake, as this uptake is higher in cancer cells. FDG-PET involves the detection of metabolic and functional aspects of tumors. FDG-PET is used with CT, so that both anatomical and morphological properties of tumors can be determined (Cintolo et al., 2013; Endo et al., 2006). Besides [18F]FDG, use of [18F]-fluoro-30 -deoxy-30 -L-fluorothymidine ([18F] FLT) has also caught the attention of many researchers in the field of cancer imaging. This molecule is used as a proliferation tracer. Proliferating cells synthesize DNA during cell cycle and PET enables the determination of proliferation in vivo. In this way, benign and malignant tumors can be separated from each other. Thymidine is a pyrimidine analogue conjugated in DNA. [18F]FLT is taken by the cell by diffusion with the aid of Na1-dependent carriers. Thymidine kinase phosphorylases [18F]FLT into [18F]FLT-monophosphate. Thymidine kinase is enzymatically active in proliferating cells; its level is four times higher in malignant cells. Based on this specific enzyme in cancer cells, [18F]FLT is used as a proliferation tracer. However, there are certain disadvantages of using this tracer. Compared to [18F]FDG, [18F]FLT uptake is lower. This situation decreases the sensitivity of [18F]FLT. Nonetheless, [18F]FLT is considered as a more cancerspecific PET tracer (Been et al., 2004). The conventional way in cancer diagnostics is to assess tumor volume. This knowledge is an indicator of disease progression. However, cancer is much more complicated than this. Functional and metabolistic information should be attained in order to make an accurate diagnosis. This situation has created the need for using hybrid technologies, such as PET/CT to overcome limiting knowledge attained from one technology. PET/CT is a hybrid technology which combines the application of both PET and CT. PET/CT combines the metabolic sensitivity of PET and spatial resolution from CT. This idea of combining these two different scanners was proposed in the 1990s. The first PET/CT scanner was introduced in 1998, which had a singleslice spiral CT scanner. David Townsend and Ronald Nutt were the scientists who made this hybrid invention. This new imaging modality was attributed as the invention of the year 2000 by Time magazine. This hybrid technology has many advantages indeed. Perhaps the most important aspect is CT-based attenuation correction. Firstly, the acquired image can be smoother and more accurate. Compared to PET alone, the examination time can be reduced by 30%. Since its first clinical use in 2000, PET/CT has gained widespread attention for clinical use in oncology imaging. However, there are certain disadvantages of the system, including high costs and exposure to radiation, as the CT scanner is added to whole-body PET which results in the increase of 15

12.2 Imaging Approaches

radiation doses. Exposure to high doses of radiation is especially crucial for pediatric cancer patients (Fass, 2008; Luna et al., 2013). One concern of using FDG/PET is ionization exposure and time-consuming preparation. Furthermore, this approach is rather expensive. Another concern is that [18F] FDG is a radioactive ion and is not target-specific, which means it can confuse high metabolic rate with other conditions where metabolic rate is high, such as inflammation and infection. New target-specific PET radiotracers should be produced to overcome such problems (Chen and Conti, 2010; Kwee et al., 2009; Li et al., 2014b; Nievelstein and Littooij, 2016). Another aspect of FDG/ PET is the fact that it is not suitable in detecting residual tumors following therapy. Following radiotherapy, [18F] FDG can accumulate in macrophages, resulting in resemblance with the recurrent tumor (Dhermain et al., 2010). The effectiveness of FDG/PET/CT is usually compared to that of WBI-MRI. The reason WBI-MRI can be preferred on some occasions is due to its reduced costs and radiation-free nature. However, in order for WB-MRI to replace FDG/ PET/CT, accuracy in diagnosis should be improved. Moreover, FDG/PET/CT may have poor detection in myeloma, resulting from bone marrow infiltration. Despite this problem, it is still preferred for staging, as it is quicker to acquire treatment response (Messiou and Kaiser, 2015). Despite these disadvantages, FDG/PET/CT are useful in many aspects of oncology imaging. FDG/PET/CT can detect a metastatic lesion that couldn’t be detected by CT or PET alone (Endo et al., 2006). There are many reports of different cancer types such as thyroid (Asa et al., 2014), head and neck squamous cell carcinoma (Balogova et al., 2008), B-cell lymphoma (Berthet et al., 2013), breast cancer (Cintolo et al., 2013; Constantinidou et al., 2011), and cervical cancer (Auguste et al., 2011). Antibodies are used in a variety of applications in the field of science. They are crucial in identifying highly specific protein targets. The development of therapeutic antibiotics plays an important role in cancer imaging. These therapeutic antibodies can bind specifically to cancer cells. The use of antibodies in PET imaging is known as immune-PET. Due to their long biological half-lives, antibodies are preferred for their use in cancer imaging. The main principle is the conjugation of radionuclides on antibodies. So far, promising results have been attained in the use of antibodies in PET imaging technology, especially in metastatic lymph nodes (Knowles and Wu, 2012).

12.2.2.1.2 Single-photon emission computed tomography The first SPECT was developed by David Kuhl and Roy Edwards. It possessed an external radioactive source (Hicks and Hofman, 2012). As a result of providing inaccurate anatomical information of localizing radiopharmaceutical activity, the need for developing SPECT/CT had emerged. The sensitivity increased when SPECT was used alone (Sharma et al., 2012).

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SPECT gives spatial, quantitative and temporal information of radioharmaceutical activity. However, images acquired by using SPECT had rather poor resolution, due to attenuation, which limits the number of photons obtained from the gamma camera. Furthermore, anatomical localization of radiopharmaceutical activity cannot be attained accurately. The combined use of SPECT with CT overcame this limitation through attenuation correction. The first prototype SPECT/CT modality was produced by Hasegawa in 1992, and the first clinical scanner was introduced in 1999. It had a two-headed SPECT camera and a nonspiral CT scanner. This first SPECT/CT has evolved to one with 64 detector CT unit. These first hybrid SPECT/CTs allowed crude anatomical details to be acquired. With modern SPECT/CTs, this limitation could be overcome by using scanners of low-dose CT and full diagnostic CT. Moreover, background noise can be diminished without interfering with the SPECT over CT data (Bockisch et al., 2009; Even-Sapir et al., 2009; Sharma et al., 2012). SPECT/CT is an easily accessed, inexpensive technology. There are a great variety of radiotracers in use: isotope 99mTc-based including 99mTc-sestamibi, 99m Tc-diphosphonates, 99mTc-red blood cells (RBC), 99mTc-sulfur colloid, 99mTc renal agents, and 123I-iodine. Despite these advantages, there are many arguments by which the efficiency of SPECT/CT is less compared to that of PET/CT. PET/ CT is superior to SPECT/CT by means of high sensitivity in detection and higher resolution. However, there are many advantages of SPECT that still justify it being used currently (Delbeke et al., 2009; Hicks and Hofman, 2012). There are many reports on the efficiency of SPECT/CT, such as sentinel nodes in breast cancer (Husarik and Steinert, 2007), sentinel lymph nodes in head and neck squamous cell carcinoma (Wagner et al., 2004), and brain tumors (Schillaci et al., 2007). Moreover, it is advantageous on bone scintigraphy, adrenal gland scintigraphy, parathyroid scintigraphy, and thyroid scintigraphy (Delbeke et al., 2009). The reason for the superiority of SPECT/CT on sentinel node detection is its accuracy in distinguishing true nodal signals and to locate hidden nodes (Even-Sapir et al., 2009). SPECT/CT offers sensitivity and specificity. This hybrid technology now has an important role in cancer diagnostics (Sharma et al., 2012).

12.2.2.1.3 Positron emission tomography/magnetic resonance imaging Functional imaging offers a variety of technologies in tumor diagnosis and staging. As mentioned in the previous sections, CT and MRI present morphological aspects of the tumor, while the missing functional information can be provided by FDG/PET. However, there are certain limitations of FDG/PET, such as low resolution. This creates the need to find an approach in which both morphological and functional information can be obtained at the same time. The approach which combines these two approaches is PET/MRI (Antoch and Bockisch, 2009). In this way, both functional and anatomical information can be obtained by using the same hybrid system (Luna et al., 2013).

12.2 Imaging Approaches

PET/MRI has many advantages, including low radiation exposure, better softtissue contrast and a variety of functional contrast modes (Delso et al., 2015). With PET/MRI, tumor extent staging of head-neck, intracranial, breast, and liver cancerous tissues. In Fig. 12.3, images of an osseous sarcoma shows how PET/ MRI acquires better quality images, compared to CT and PET/CT. The extent of the tumor can be easily detected in both MRI and PET/MRI (Antoch and Bockisch, 2009). PET/MRI stands out as an effective imaging modality for its detection of anatomical spread and invasion of malignant tumors. Perhaps, its being used widely in detecting brain tumors. The use of amino acid tracers used in PET technology, FET and MET, has made brain tumor detection much easier. The combination of the anatomical approach MRI and functional PET imaging modality, both anatomical and biological aspects of the tumor can be detected. Moreover, it is anticipated that PET/MRI technology can improve the accuracy of regional lymph node spreading both in pelvic and, head and neck regions (Luna et al., 2013).

FIGURE 12.3 Image of peripheral osseous sarcoma acquired from MRI (A), PET/MRI (B, fused image), CT (C), PET/C (D). Reprinted from Antoch, G., Bockisch, A., 2009. Combined PET/MRI: a new dimension in whole-body oncology imaging? Eur. J. Nucl. Med. Mol. Imaging, 36, 113120, with permission from Elsevier.

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Even though this novel hybrid approach offers potential, it involves disadvantages, too. The disadvantages include the absence of attenuation correction and severe MRI inference on PET. The system involves applying the PET insert inside the MRI scanner. Strong magnetic fields of MRI become likely to interfere with PET detectors. Moreover, it’s not very efficient for the use of imaging small lung lesions (Delso et al., 2015; Sauter et al., 2010). There are many reports on its use in oncology imaging. One report includes its efficiency on pediatric oncology (Scha¨fer et al., 2014). Other reports suggest that PET/MRI is superior to CT for brain, head and neck, breast, liver, and muscoskeletal system cancers (Czernin et al., 2014). Nevertheless, it is a novel and promising hybrid technique that needs to be tested for its efficiency in oncology imaging. The step that should be taken into account should be the improvement of MRI-based attenuation for acquiring more accurate images, and imaging protocols should be harmonized (Luna et al., 2013).

12.3 NOVEL TECHNOLOGIES 12.3.1 MOLECULAR IMAGING AND NANO-ONCOLOGY Molecular imaging has become a rapidly growing field for the management of cancer. It has a critical role in cancer detection, staging, and treatment; it involves the characterization of both biomolecules and events related to the malignancy (Kircher et al., 2012). The ongoing developments involving genomics and proteomics have indeed played an important role in molecular imaging techniques. By using such technologies, personalized cancer imaging could actually be accomplished 1 day. Conventional approaches are still being widely used and will continue to so. However, for early diagnosis they may not always be informative. By using these anatomical techniques, tumors can be detected when they are centimeter-sized. By using molecular-based imaging techniques, with the aid of using biomarkers, tumor cells can be detected before they reach this size. The markers can easily detect molecular and cellular stages, enabling the detection of early signs (Weissleder, 2006). Nanotechnology, which is the study of nanoparticles for biotechnological application, has proven to be useful in almost all aspects of medicine, including oncology. With the aid of nanotechnology, molecular changes during disease pathogenesis can be accessed; diseases can be diagnosed and visualized. Nanomaterials can be used for both therapeutic and diagnostic purposes. For instance, nanocarriers are specialized nanoscale drug delivery vehicles, such as liposomes, dendrimer, nanoshells, etc. With the aid of these particles, drugs can be targeted to the tumor of interest without harming the normal tissue (Alexis et al., 2008). Another use of nanoparticles is for tumor detection, both in vitro and in vivo. The application of contrast agents on nanoparticles can be used for tumor

12.3 Novel Technologies

diagnosis. Based on the phagocytosis of colloidal particles, any tumor localized in the liver, spleen, lungs, or bone marrow can be detected by using radiodiagnosis. Use of supermagnetic nanoparticles in MRI provides contrast imaging of any localized tumor (Brigger et al., 2002). With their small size and significant potential, nanoparticles play an important role in biotechnology. They are considered multifunctional agents that can be coupled to different ligands, such as contrast agents, becoming versatile. Nanoparticles can accumulate in tumor spaces, especially ones with sizes smaller than 100 nm. They can easily escape from macrophages and reach the tumor. However, due to certain limitations, active targeting is preferred over this approach. For accomplishing this approach, nanoparticles are coupled to molecules that bind to antigens or receptors of tumor cells (Luna et al., 2013). As previously mentioned, [18F]FDG is a nanoparticle used with PET/CT in order to localize tumors. Other nanoparticles used with such equipment include MnO and SPION used in MRI (Fig. 12.4), gold nanoparticles, gold nanorods, carbon nanotubes, and graphene used in photoacoustic molecular imaging, Zn 1 AGlnS2 QD, and carbon nanodots used in two-photon-induced photoluminescence, CdSe/Zn QD and NaYF4 used in optical fluorescent, [18F]FDG and starch-based iron oxide nanoparticles used in PET. Gadolinium-coated gold nanoparticles are also being used as contrast agents in both MRI and X-ray (Fig. 12.5). Gold nanoparticles are being used in the field of nanotechnology due their biocompatibility, high quality, and high yield. As a result of their strong scattering properties, they can be used for cancer diagnosis. Nanoparticles are

FIGURE 12.4 (A) Liver MRI image with dual contrast agent Fe3O4/MnO hybrid nanocrystals. (B) MRI images of in vivo accumulation of magnetite-porous silica nanoparticle composites at a tumor site. Reprinted from Parasuraman Padmanabhan, Ajay Kumar, Sundramurthy Kumar, Ravi Kumar Chaudhary, Bala´zs Gulya´s, Nanoparticles in practice for molecular-imaging applications: An overview, In Acta Biomaterialia, Volume 41, 2016, Pages 116, ISSN 1742-7061, https://doi.org/10.1016/ j.actbio.2016.06.003. (Padmanabhan et al., 2016) with permission from Elsevier.

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FIGURE 12.5 Gadolinum coated T1-weighted images of injected gold nanoparticles (Au@DTDTPAGd50) of a mouse before (A) and after (B) and (C) injection of Au@DTDTPA-Gd50. Right, tomographic rat kidney images (RK) (D), left kidney images (LK) (E), ureter (U). Reprinted from Padmanabhan et al. (2016) with permission from Elsevier.

conjugated to anti-epidermal growth factor receptor (EGFR) antibodies. These antibodies bind specifically to cancer cells, while they bind randomly to normal cells. In this way, cancer cells can be detected. Antibody-conjugated nanorods also bind specifically to cancer cells. With these properties, tumors can be easily visualized (Huang and El-Sayed, 2010). Peptides are among other imaging probes. Peptides have low molecular weights and about 50 amino acids. They are permeable and expose almost no toxicity. As a result of these features, they are considered as important diagnostic agents. However, one limitation is their short half-life in the circulatory system. This challenge can be overcome by applying chemical modifications to ensure they are stable. They can be radiolabeled by radioiodination and radiofluorination (Luna et al., 2013). Antibodies are also being used as probes. Due to their specificity towards antigens, antibodies are important probes in detecting tumors. There are different forms of antibodies in use, such as monovalent fragments, bivalent diabodies, and minibodies. For instance, trastuzumab can be used for detecting tumors in PET imaging equipment. Performing radioimmunoscintigraphy with [99m]Tc-labeled SM3 antibody has been shown as an important detection agent for ovarian cancers (Kaur et al., 2012). Antibodies have also been used to target pancreatic cancer cells (England et al., 2015). There are some limitations on the use of antibodies for targeting tumors, such as molecular weight, Fc domains, valency, and specificity. However, all these limitations will be overcome with advances in antibody technology. The new direction will be to develop highly specific antibodies (Olafsen and Wu, 2010).

12.3 Novel Technologies

12.3.2 BIOLUMINESCENCE IMAGING In vivo bioluminescence imaging is a sensitive, optical technique used for detecting tumors. The main principle is the use of luciferase, from the firefly. This enzyme has bioluminescent properties. Cells expressing this enzyme are used in bioluminescence imaging (Cosette et al., 2016). The light produced by these cells tagged with luciferase is detected. Luciferase oxidizes luciferin, enabling the emission of yellow-green light (O’Neill et al., 2009). This imaging technique is mainly used in clinics in order to guide the operation. However, its major limitation is autofluoroscence, which affects imaging. This situation can be overcome by using nanoparticle probes such as QD-BRET. The main principle is the use of quantum dots on bioluminescence energy transfer with the aid of luciferase. Even though it is a highly efficient technique, QD are toxic with heavy metals. Nevertheless, when coupled with the near-infrared (NIR) nanoparticles, it was found efficient in visualizing lymph nodes in mice (Xiong et al., 2012). In another report using this technique, hepatocellular carcinoma cells could be seen (Thompson et al., 2013). By using bioluminescence, tumor growth and progression can be traced. With the aid of vascular endothelial growth factor (VEGF)-2 receptor, certain animal models are being used in order to assess the function of VEGF during in vivo tumor angiogenesis. As seen in Fig. 12.6, VEGF2-luc transgenic mouse model can be used to detect the angiogenesis period of wound healing (O’Neill et al., 2009). Bioluminescence has many advantages, as summarized in Table 12.2. Firstly, it is a noninvasive technique enabling good sensitivity. 3D luminescence images

FIGURE 12.6 In vivo bioluminescent imaging of tumor angiogenesis in mice. Bioluminescence coming from developing tumor can be observed when of LL2 cells are administered on the VEGFR2-luc-KI mouse model. Reprinted from O’Nneill, K., Lyons, S.K., Gallagher, W.M., Curran, K.M., Byrne, A.T., 2009. Bioluminescent imaging: a critical tool in pre-clinical oncology research. J. Pathol. 220, 317327, with permission from Elsevier.

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Table 12.2 List of Advantages and Disadvantages of Bioluminescence Advantages

Limitations

Easy to use High sensitivity Noninvasive Short acquisition times High-throughput capability Animals may act as own control Images metabolically active cells only

Dependent on tissue properties Light absorption by hemoglobin Signal attenuation by melanin and fur Limited 3D reconstruction Currently not applicable to human studies

Reprinted from O’Nneill, K., Lyons, S.K., Gallagher, W.M., Curran, K.M., Byrne, A.T., 2009. Bioluminescent imaging: a critical tool in pre-clinical oncology research. J. Pathol. 220, 317327, with permission from Elsevier.

can also be obtained; monitoring tumor, as well as the effect of administered drugs can be detected (Thompson et al., 2013). It is a non-radioactive imaging approach, allowing longitudinal imaging of tumor distribution and growth. However, there are certain limitations, such as interference of signal intensity, especially in hypoxic regions. It is a oxygen-dependent method and luciferaselabeled cells may be reduced, due to low oxygen concentrations. Spatial resolution may be low, as in the case of PET. Moreover, hemoglobin absorbs light-leading vascularized organs, emitting less light. Nevertheless, bioluminescence imaging is a noninvasive tool which is especially useful in imaging preclinical tumor models. By using this method, cellular processes which tumors undergo, such as proteinprotein interactions and cell signaling, can be visualized. With advances in technology, the limitations could be overcome and bioluminescence may become a crucial tool in oncology imaging (O’Neill et al., 2009).

12.3.3 NEAR-INFRARED FLUORESCENCE Molecular imaging has become an emerging approach, as it enables the visualization of molecular processes in vivo. Radiotracers and certain probes are used together with this technique. The approach which is based on the use of nearinfrared (NIR) fluorophores is known as NIR fluorescence. In this approach, fluorescence dyes are used in order to observe cancerous tissues. NIR imaging comes forward as a technique working with high sensitivity and specificity. Compared to CT, X-ray, MRI and ultrasound, this method uses optical imaging strategies, making it a radioactive-free approach. Molecular knowledge of tumors can be attained by using optical signals. With this technology, images are acquired at NIR range which is 700100 nm. Choosing this range is important, as autofluorescence and light absorption in this range are relatively low. Furthermore, background noise

12.3 Novel Technologies

can be eliminated and more sensitive images can be obtained. NIR has taken fluorescence imaging from the microscopical path to the macroscopical direction. It is especially crucial for visualizing deep tissues (Gao et al., 2014; Hilderbrand and Weissleder, 2010; Luo et al., 2011). When the excited photon travels into the tissue, it is mainly absorbed by water, lipids, oxy- and deoxyhemoglobin. This phenomenon creates the problem of autofluorescence. This limitation can be fixed by using a filter, however intestinal autofluorescence is still considered as a problem. The NIR fluorescence contrast agents are usually exogenous, some of which are: heptamethine, benzothiazole, indolyl, 2-quinoline, and 4-quinoline groups. Among these, indocyanins are the best ones. Organic fluorophores are also present, but their excitation and emission wavelengths cannot be kept constant. Nanomaterials, such as quantum dots or nanoclusters, are also in use for NIR imaging. Nanoclusters provide size-dependent fluorescence and have great optical features. Among these, Ag-based nanoclusters are especially preferred due to their very small size, nontoxic and biocompatible nature, good photostability, and elevated levels of NIR fluorescence. Moreover, the fact that their excitation and emission spectra are symmetric can eliminate color overlaps. Inorganic fluorescent semiconductor nanocrystals, also known as quantum dots, are the most efficient fluorophores, as they enable the conjugating of many targeting molecules only on quantum dots (Frangioni, 2003; Gao et al., 2014). In one report, a unique NIR heptamethine indocyanine dye, IR-780, has been determined. It can stay in the mitochondria of only tumor cells. It can accumulate in tumors very efficiently (Tan et al., 2012). In Fig. 12.7, the chemical structure of IR-780 iodide and IR-783, two NIR dyes, are shown. Different applications of heptamethine cyanine dyes are also summarized. There have been many attempts to enhance the targeting and activation of the probes used. For this purpose, many target molecules such as peptides, aptamers, and antibody-based ligands have been tried (Hilderbrand and Weissleder, 2010). There have been several reports on the efficiency of NIR imaging. It can be used for sentinel lymph node mapping in a variety of cancer types, including skin, breast, and gastric cancers (Marshall et al., 2010). In another report, hepatocellular carcinoma and colon cancer metastases were visualized by using NIR imaging technology. It seems that NIR imaging will continue to expand its use in oncology imaging. By determining multifunctional dyes, more target-specific diagnosis will be achieved using this technique (Luo et al., 2011). NIR fluorescence provides in vivo visualization of the target molecule, both in microscopical and macroscopical levels. Probe design is a fundamental aspect of this particular imaging technology. Advances in probe development technologies will contribute to more efficient results. The combined use of these molecular probes, together with optical imaging techniques and anatomical data, will contribute to the improvement of the current NIR imaging technology (Hilderbrand and Weissleder, 2010).

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FIGURE 12.7 Imaging of tumors by using heptamethine dyes. Cancer targeting and imaging by multifunctional heptamethine cyanine dyes. (A) Chemical structures of two active NIR heptamethine dyes with tumor accumulation property; (B) combined X-ray and NIR fluorescent imaging of a subcutaneous human tumor xenograft in one athymic nude mouse with IR-780 iodide dye. (C) Potential applications of multifunctional heptamethine cyanine dyes in cancer imaging. Reprinted from Luo, S., Zhang, E., Su, Y., Cheng, T., Shi, C., 2011. A review of NIR dyes in cancer targeting and imaging. Biomaterials 32, 71277138, with permission from Elsevier.

12.3.4 PHOTOACOUSTIC IMAGING Photoacoustic imaging (PAI) has become a promising tool in oncology imaging by presenting anatomical, functional, and molecular information of the tumor of interest. It is especially efficient in detecting tumors in deeply located tissues. Additionally, tumor hypoxia and tumor vasculature can also be detected using this approach. The working principle of PAI involves absorption of laser energy causing a thermoelastic expansion of the tissue. In this way, a wide-band ultrasound wave is obtained. Mechanical acoustic waves are converted to electric signals, which produces images (Mallidi et al., 2011). With the aid of exogenous contrast agents, deep-situated tumors can be easily detected. IRDye800CW, AlexaFluor 750, and indocyanine green are used as contrast agents. Au nanoparticles have a special role in PAI. Owing to their surface plasmon resonance effect, higher magnitude absorbance can be achieved, compared to that of NIR dyes. Due to their strong longitudinal plasmon resonance, gold nanosphere, nanorods, nanoshells, nanocages, and nanobeacons are being used in PAI (Mallidi et al., 2011). Endogenous cromophores are found within biological tissues generating PA signals. Among these endogenous contrast are hemoglobin, melanin, and lipids. By using these endogenous cromophores, blood vasculature and melanoma could be detected. Compared to exogenous contrast agents, they are safe to use as they are nontoxic. Moreover, pathological tissue can be easily distinguished by using

12.4 Future Directions

contrast endogenous agents through the detection of physiological changes (Mehrmohammadi et al., 2013). Besides endogenous and exogenous contrast agents, complex smart probes provide increase in signals. Some smart probes become activated when they contact with a tumor-specific enzyme in the tumor microenvironment. In follicular thyroid carcinoma, a peptide-dye-based agent is activated after connecting with metalloproteases (Levi et al., 2013; Wilson et al., 2013). There are many applications of PAI. The unorganized and vascularized nature of malignant tumors enhance the photoacoustic image contrast. Several reports suggest that exogenous agents can be efficient in detecting different cancer types. For instance, IRDye 800 has been used in detecting both glioblastoma and breast cancer (Li et al., 2008; Stantz et al., 2010); gold nanocages, gold nanorods, gold nanoshells and gold nanosphere have been used for melanoma, squamous cell carcinoma, prostate cancer, and breast cancer (Agarwal et al., 2007; Li and Wang, 2009; Li et al., 2008; Zhang et al., 2006). In a comparative study on breast cancer, the efficiency of PAI was compared to that of MRI. According to the results, PAI is thought to be a promising tool in detecting breast cancer tumors (Heijblom et al., 2015). In other reports on breast cancer, it was suggested to be useful in determining malignancies with high imaging contrast (Heijblom et al., 2015; Wilson et al., 2013). Photoacoustic tomography (PAT) is a hybrid technology combining both ultrasound and optical imaging approaches. PAT stands out as a noninvasive and nonionizing imaging technique which offers high spatial resolution with great efficiency on deep tissue imaging. Monitoring exogenous optical contrast agents can be achieved in high rates. Enhanced optical contrast enables simultaneous molecular and functional imaging. Several nanoparticles, including hollow gold nanospheres (HAuNS), are used for enhanced photoacoustic mapping of cerebral vasculature. In Fig. 12.8, use of PEGylated HAuNS (PEG-HAuNS) on mouse cerebral cortex is shown. It can be clearly seen that PAT shows both large blood vessels and smaller ones (Luo et al., 2011). Contrast agent-mediated PAI serves as a promising tool in detecting tumors. With the aid of both endogenous, exogenous, and nanocontrast agents, images with higher contrast and resolution could be obtained (Mallidi et al., 2011).

12.4 FUTURE DIRECTIONS As described in this chapter, there are many types of approaches that are being used in oncology imaging, ranging from conventional methods such as X-ray and ultrasound, to MRI, CT, and PAI. No matter how old the technology is, each one of them is useful for specific cancer types. However, there is an emerging need for using an imaging technique which can be efficient for all cancer types. The

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FIGURE 12.8 (A) Photoacoustic signals showing detailed structure of large (yellow-framed picture) and small (green-framed picture) blood vessels in the mouse brain at higher magnification 2 h after intravenous injection of PEG-HAuNS. Arrows showing the small blood vessels, which can be seen in the contrast-enhanced images. (BD) Distribution of PEG-HAuNS in brain vessels 2 h after injection (bar 1/4 10 mm). Brain vessels were stained with anti-CD31 antibody (red fluorescence), while the scattering signals of gold particles were detected under a dark field (pseudo-green). (B and C) Particles located on the luminal side of brain blood vessels. (D) 3D reconstruction imaging demonstrating particles colocalized or stayed adjacent to the brain capillary endothelial cells. Reprinted from Luo et al. (2010) with permission from Elsevier.

optimal imaging technique should provide both molecular, functional, anatomical, and metabolic characteristics of the cancerous tissue of interest (Mehrmohammadi et al., 2013). The majority of clinicians are focused on where the tumor is located. Computer tomography, MRI, and many hybrid technologies such as PET/CT, SPECT/CT, and PET/MRI can provide both functional and anatomical information. However, molecular and physiological knowledge on cancer with the aid of NMR and optical approaches are crucial in order to attain a better understanding of cancer (Alcantara et al., 2014). The future of oncology imaging focuses on detecting cancer at the earliest possible. The earliest way is to follow cell signaling pathways giving rise to tumor

12.4 Future Directions

growth. This is where the direction of oncology will follow. The optimal approach should be to develop radiation and ionization-free, noninvasive methods. Cellular, molecular events should be detected with high sensitivity and specificity. Among functional imaging techniques which enable the attaining of information on tumor pathophysiology, cellularity, metabolism, and molecular biology of the tumor, one approach that stands out more than others seems to be MRI technology. The reason for this is its versatility and radiation free nature. Dynamiccontrast enhanced MRI (DCE/MRI) is one of the most promising imaging approaches and is being increasingly used in characterizing cancer lesions. MRS provides metabolic imaging and is widely used for screening breast, brain, and prostate cancer. However, its use in practice is rather limited (Luna et al., 2013). Each technology has its advantages and disadvantages. This situation shows why hybrid technologies used in cancer imaging have a significant role. Among these multimodal imaging techniques, PET/MRI continues to stay as a prominent method by both providing anatomical and molecular aspects of the tumor of interest. It provides both high soft-tissue contrast and molecular information. Its nanoionizing nature makes it superior to PET/CT, especially in pediatric oncology. PET/MRI has great potential for its use in neurooncology, neurodegenerative diseases, ischemic disorders, studies focused on brain functioning. This hybrid modality stands out for being more accurate in cancer diagnostics more than any other imaging technology currently used (Sharma et al., 2012). In the future, great focus will be on the use of targeted optical contrast agents. These agents are efficient for screening the early detection of cancer. This is important for early detection of cancer; optical molecular imaging shows promising results to reduce morbidity and mortality caused by cancer. As they are cheap and easy to use, they present great potential for the future of early diagnostics in oncology imaging. Moreover, in vivo applications in humans may provide molecular information on the processes involved during carcinogenesis, as they are able to observe the biology of invasion. In the future, it seems that this approach will be of even more use, either used alone or in combination with conventional technologies such as CT or MRI. In this way, high risk lesions can be identified with the aid of molecular, structural, and phenotypic agents. Rapid detection is known to have great importance in cancer imaging. Optical molecular imaging can be used in this sense for rapid molecular detection of lesions (Hellebust and Richards-Kortum, 2012). Over the last four decades, many imaging technologies have emerged. These improvements were made by the gradual evolution of conventional techniques. Although molecular imaging provides promising results, its use by clinical means may be limited. The future of imaging needs development of nanomaterials that are immune-specific. New in vivo strategies should also be developed, as they can help predict the patients’ condition (Alcantara et al., 2014). It is anticipated that, in the long-term, both molecular imaging equipment and tracers will be available. Screening for cancer risk using molecular imaging

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techniques may be the first step in personalized medicinal approach. As it is crucial to detect cancer which is a disease with high mortality rates, it is possible to save lives of many people by detecting cancer the earliest using molecular imaging equipments. With the aid of imaging probes and equipment, the field of molecular imaging will continue to grow (England et al., 2015). Antibody-based imaging techniques provide promising results in many areas in caner diagnostics. With the aid of antibodies, cell surface tumor biomarkers can be detected, enabling more accurate target selection. In this way, more information on tumor location and phenotype can be obtained. With advances in antibody technology, this field will be one of the most promising fields in oncology imaging (Knowles and Wu, 2012). Multiple biomedical imaging techniques play a fundamental role in detecting cancer by attaining morphological, structural, metabolic, and functional information of tumor. Used together with other techniques, hybrid imaging approaches have a promising role in oncology imaging; accurate results can be obtained by improved staging of cancer. Targeted imaging of receptors, gene therapy expression, and cancer stem cells will be new approaches that will improve the field of oncology imaging for the forthcoming decades (Fass, 2008). Oncology imaging has evolved, from X-rays to fluorescence imaging technologies. With the advances of technology, optimal imaging technologies will be developed that could detect cancer at earlier stages with higher accuracy. Targetspecific approaches should be developed in order to accomplish this. Novel technologies provide promising results. Their limitations should be improved.

12.5 CONCLUSION Early diagnosis of cancer is life saving. This can be accomplished by using different imaging techniques with different principles, ranging from anatomical based to functional based, each with their own weaknesses and strengths. If cancer is caught at earlier stages, it will be easier to cope with. This makes oncology imaging a critical step for the treatment of cancer. This chapter describes the imaging techniques used in oncology imaging. Chronological order was followed. The chapter starts with anatomical imaging techniques such as X-ray, ultrasound, mammography, CT. Functional imaging techniques including PET, SPECT, MRI, MRS were described. Hybrid technologies: PET/CT, SPECT/CT, PET/MRI, were briefly explained. Lastly, novel imaging technologies were described, such as nano-oncology, bioluminescence, NIR imaging, and PAI. These high-tech approaches give promising results as they can detect cancer at the molecular level before it becomes a tumor. This chapter is a brief summary of the fundamental imaging techniques which are in use today. It is anticipated that, with the advances of technologies, many more and improved imaging techniques are to be developed.

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