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Nuclear medicine, treat what you see and see what you treat

With a history of more than 80 years since its inception in medical science, nuclear medicine specialty has seen rapid progress.

Nuclear medicine imaging has played a pivotal role in the clinical diagnosis and treatment of disease for decades, and every year, research and technological advances expand its potential applications. Currently, nuclear medicine has a clearly defined role in clinical practice due to its usefulness in many medical disciplines. It provides relevant diagnostic and therapeutic options leading to patients’ healthcare and quality of life improvement. During the first two decades of the 21st century, the number of nuclear medicine procedures increased considerably. Clinical and research advances in nuclear medicine and molecular imaging have been based on developments in radiopharmaceuticals and equipment, namely, the introduction of multimodality imaging. In addition, new therapeutic applications of radiopharmaceuticals, mainly in oncology, are underway.

Advances in instrumentation in the form of hybrid imaging equipment (PET/CT and SPECT/CT), advances in radiochemistry, theranostics approach of treat what you see and see what you treat along with the ever widening availability of this modality have led to a revolution in the management of most solid tumors and hemato oncology. It is making its impact on management in other clinical areas such as musculoskeletal diseases, infection and inflammations, pediatrics, endocrinology, neurology, and cardiology.

Some of the recent developments in field of imaging technology in relevance to imaging of radionuclide therapy include:

SPECT and scintigraphy. This type of decay of radionuclides determines about the modality for imaging. Planar scintigraphy or SPECT is used for imaging of 177Lu, 90Y, and 131I-which are used for radionuclide therapy. These emit γ-photons (or bremsstrahlung photons), which can be imaged by a γ-camera. SPECT/CT systems which are used nowadays are used for both planar and tomographic imaging. Planar imaging is for acquiring whole-body images in when there is limitation of time. SPECT is meant for acquiring 3-dimensional data of structures which would otherwise overlap on each another on planar images. Quantitative analysis of SPECT images is determined by converting the acquired counts in terms of distribution of absorbed dose (in Gy), which is beneficial for planning and dosimetry of therapy involving radionuclide. In clinical practice scatter correction is also implemented and is generally performed employing the triple-energy window method. Quality of image can be enhanced by using resolution recovery. It is performed by characterizing the shape of the point-spread function accurately, that depends its distance from the camera and there is rotational variation due to the hexagonal pattern of the collimator septa. Reconstruction algorithm can be incorporated with point-spread function model subsequently. Effects like scatter, blurring, and attenuation which degrades image can be corrected to some extent, Although SPECT images can be degraded by partial-volume effects and quantification errors.

Dr Ankur Pruthi
Consultant and Head, Nuclear Medicine & PET CT,
Manipal Hospital

“With commercial availability of newer radiopharmaceuticals and innovations in PET and SPECT scanners, nuclear medicine is the branch to look for in coming times. Digital PET CT scanner is one such latest scientific development which allows for new opportunities in diagnostic image quality. The use of silicon-based photodiodes instead of traditional photo-multiplier tubes, faster timing resolution and use of smaller pixel sizes are some of the major advances in this technology. With better spatial resolution, better count rate performance and increased effective sensitivity, this novel technology results in significant improvement in image quality and sharpness over conventional analog PET. Digital PET CT scanners are currently commercially available in few select nuclear medicine departments in India. However, they have potential to replace conventional analog PET scanners in the coming decade”

PET. It has application in planning of treatment, dosimetry, and assessment of treatment after radionuclide therapies. Similar to SPECT quantitative PET is also used for correction techniques. Correction of attenuation for PET can be done through determination of the sonogram associated with attenuation correction, which works on the basis of co-registered CT data. Scatter correction is often done with single-scatter simulation method in clinical practice. Correction for random counts is often done using delayed-event subtraction. The difference in time between annihilation photons gives information regarding location of the annihilation and also about the line of response. Now time-of-flight information in the reconstruction at the time of back projection step enhances image quality. The availability of time-of-flight estimation has opened the opportunities for low positron abundance imaging isotopes. As intrinsic resolution of PET detectors are not freely available, so shape of the point-spread function is used to improve the quality of images by incorporating it during reconstruction method. This is called as resolution recovery. When there are high count rate radiation detection systems does not work properly due to dead-time effect caused by pulse pile-up. Because of these Dead-time losses are corrected regularly. There are better quality of PET images with enhanced resolutions and sensitivity due to regular improvement in the instrument, which provides precise determination of the SUV.

PET/MRI. The advantages of PET/MRI over PET/CT are higher soft-tissue contrast that is essential for planning of treatment, dosimetry, and assessment post radionuclide therapies. Additionally, for accurate dosimetry it is beneficial as it provides the simultaneous coregisteration of MR images. Also, MRI can be employed for determining the tolerable dose with least organ damaging activity of radionuclide. Along with it anatomic and molecular images acquisition provides better motion correction. Integrating of PET and MRI modalities is challenging as there will be interference between both the modalities. For instance, photomultiplier tubes that are present in PET detectors malfunction in magnetic fields exerted by MRI. In addition to this, PET module affects the radiofrequency signal associated with MRI. Due to this, the first generation of PET/MRI systems modalities were separated. Integration of PET detectors and MR scanner has been done to obtain PET and MR images simultaneously. Detector systems is avalanche photodiodes types or SiPMs types which are not sensitive to magnetic field. The simultaneous measurement provides better 4-dimensional acquisitions because of spatial agreement of PET and MRI data.

Disadvantages associated with PET/MRI are high costs and the ferromagnetic metallic implants which are used in contradictory to MRI. In addition to this it is challenging to correct attenuation of PET/MRI. For dosimetry it is essential to have accurate attenuation correction. As CT images are electron-density images and MR images are proton density image, CT image are better suited for attenuation correction. But MR images can be used for attenuation correction by using techniques such as segmentation-based or template- or atlas-based which derives electron density information from MR images. Alternatively, estimation of the attenuation maps can be done by employing algorithms which uses the time-of-flight emission or transmission data.

PET/CT. Over recent years, there has been growth in PET utilization in systemic infections and inflammation for diagnosis, assessment of disease activity, and therapy monitoring. FDG PET/CT can be used for diagnosis and follow-up in multiple inflammatory conditions including rheumatoid arthritis (RA), polymyalgia rheumatica, IgG4-relate disease, large vessel vasculitis, and granulomatosis with polyangiitis, adult-onset Still disease, spondyloarthritis, chronic osteomyelitis, and multicentric reticulohistiocytosis. Increased FDG uptake in the tracheobronchial tree is a reliable sign of cartilage involvement in relapsing polychondritis. FDG PET/CT can be used for early diagnosis of RPC and follow-up. New specific PET tracers are being developed, for example, α5β1-integrin PET appears to be a promising tool for early diagnosis of RA and therapy monitoring.

Thrombus evaluation. Molecular imaging is used to investigate venous thrombosis including determination of thrombus activity and acuity which may play an important role in patient management. 99mTc apcitide binds to glycoprotein receptor GPIIb-IIIa on the membrane of activated platelets. This can identify acute deep venous thrombosis. This test has been FDA approved, but is not widely used. An additional compound 99mTc-DI-DD3B6/22-80B3 (99mTc-DI-80B3 Fab′), a humanized monoclonal Fab′ fragment that binds to D-dimer, showed good safety profile and promising accuracy in phase I and II trials. PET tracers are also under active investigation, for example, 64Cu-DOTA fibrin-targeted probes which have been tested in animal models.

Precision therapeutics. Precision or personalized medicine is often described nearly exclusively in the context of genomics. Underlying this concept is the notion that actionable cancer cell mutations may represent a cancer’s Achilles heel. Such actionable mutations include those of the epidermal growth factor receptor, BCR-ABL, BRAF, and many others. It was the success of imatinib for the treatment of chronic myelogenous leukemia and gastrointestinal stromal tumors that raised the hope that single oncogenic drivers could be identified and targeted successfully for most cancers. The goal of precision oncology has thus far remained largely elusive. Nuclear medicine techniques and assays usually are not discussed in the context of precision medicine, defined as the right treatment (drug or others), for the right patient, at the right dose, at the right time. Nevertheless, no discipline other than nuclear theranostics can provide noninvasive readouts of target expression and address the target structure successfully.

Theranostics. Theranostics, a combination of therapeutic and diagnostic approaches, is one of the most exciting areas in molecular imaging. This refers to the idea of targeted molecular imaging using radionuclide-labeled molecules not only for imaging but also for therapy delivery. Radionuclides with optimal decay characteristics can serve as delivery system for targeted radiation therapy. Radiation has proven to be a very useful treatment option for different cancers, but it is limited in that its source is external and the treatment affects all the tissue in the radiation field. With theranostics, the source of radiation is internalized targeting specific malignant cells throughout the body including micro-metastatic disease. Locally delivered radiation damages the DNA triggering apoptosis in the targeted cells. Pre-treatment scans and therapy can use the same carrier; however, a different radionuclide attached to the carrier can be used for the imaging and therapy. Certain theranostic radiopharmaceutical pairs are already in clinical use; for example, 68Ga-DOTATATE/177Lu-DOTATATE represents the theranostic pair of labeled somatostatin analogs for neuroendocrine cancers where the 68Ga-DOTATATE is used for imaging and the 177Lu-DOTATATE for therapy if the tumors are positive on the 68Ga-DOTATATE imaging which confirms they have the somatostatin receptor-2 (SSTR-2).

Heat shock proteins, also known as stress proteins, investigated for oncologic applications, appear to play a role in pathogenesis of pulmonary fibrosis. These are being investigated as potential biomarkers and therapeutic targets in idiopathic pulmonary fibrosis.

Molecular imaging is a rapidly developing field with extensive ongoing research and expanding indications. These newer imaging techniques have a substantial impact on the patient management and outcome. Nuclear medicine and molecular imaging significantly contribute to the development of targeted therapies and precision medicine leading to improved patient care. The concept of dual probe, a single molecule labeled with a radionuclide for single photon emission computed tomography (SPECT)/positron emission tomography (PET) and a light emitter for optical imaging), is gaining increasing acceptance, especially in minimally invasive radioguided surgery. The expansion of theranostics, using the same molecule for diagnosis (γ or positron emitter) and therapy (β minus or α emitter) is reshaping personalized medicine. Upcoming research and development efforts will lead to an even wider array of indications for nuclear medicine both in diagnosis and treatment.

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