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Fusing Technology for Better Diagnosis

Nuclear Medicine is experiencing an exciting transition phase, through functional molecular imaging. Nancy Singh maps out this long and interesting journey of nuclear medicine from physiology to molecules

While politicians are busy battling over the nuclear deal, the medicine world is already witnessing the nuke power! Nuclear Medicine (NM) is evolving, and technology is driving this evolution. Development of new radiopharmaceuticals, cameras and computer software is metamorphosing NM from a functional imaging modality to a molecular imaging (MI) modality.

Fusion with other imaging modalities is providing the profession with much excitement. "Before any morphological alteration takes place, MI helps to diagnose at the cellular level, whether it is a deadly tumour of the breast, lung, lymphoma or neuro-degenerative disorders like Alzheimer's disease or even epilepsy," says Dr Rijju Naik, Department of NM, Malabar Institute of Medical Sciences, Calicut.

The diagnostic breakthrough is made possible by the effective use of NM tools and modalities employed for MI like Positron Emission Tomography (PET), Magnetic Resonance Imaging (MRI), Computed Tomography (CT) and Magnetic Resonance Spectroscopy (MRS), optical imaging and fusion imaging PET-CT, PET-MRI and CT-Single Photon Emission Computed Tomography (SPECT).

Radiology's PET

The PET-CT machine revolutionised NM in diagnosis

After the physiological age in the '50s to the immuno-receptors in the '80s, the '90s was the dawn of the era of molecules, leading to the birth of MI in the world of NM. MI, the new face of NM, is changing the landscape of diagnostics, especially with the focus now on preventive medicine. "When in 2002, David Townsend from Pittsburgh put into reality 'fusion imaging' through fusion of CT scan with PET imaging and SPECT imaging, he embarked upon a revolutionary concept. It was a clinical boon," recalls Dr BA Krishna, Consultant & Chief, Nuclear Medicine, PD Hinduja Hospital, Mumbai.

Even though NM has always had an edge in terms of diagnosis and sensitivity, it wasn't able to make a significant impact, but this changed it all. "While NM was far ahead in terms of diagnosis, as it depends on the functional change instead of structural change like in CT/MRI, NM got submerged in the big umbrella of radiology and took a backseat, as there were many technological advances in CT/MRI as well," reasons Dr RV Parameswaran, Consultant, HOD, NM & Functional MI, Manipal Health Systems, Bangalore.

Both PET and SPECT scans produce tomographic images of a patient by detecting radiation that is emitted following an injection of a radioactive tracer. The tracer helps determine whether disease is present by indicating changes in physiological activity. Today, the main applications for PET are for oncology in soft-tissue tumours. This accounts for roughly 80 per cent of all clinical utilisation.

"MRI and CT are sensitive in just determining that disease is present, but they aren't specific in identifying what particular type of disease may be present," says Dr Krishna, adding that prior to PET, surgical procedures or biopsy were the only ways to determine specificity. "PET dramatically changed that. The increased metabolic activity not only verifies the presence of cancer, but also provides evidence of staging or metastasis beyond the primary," he adds.

"It is almost criminal in clinical practice to continue a treatment of cancer without a PET-CT scan" - Dr BA Krishna Consultant & Chief- Nuclear Medicine PD Hinduja Hospital Mumbai

"I believe the ultimate breakthrough would be the marriage of PET-MRI" - Dr RV Parameswaran Consultant HOD- NM & Functional MI Manipal Health Systems Bangalore

Tracers

Experts vouch that NM is the safest diagnostic technique available currently. It is also referred to as radiation medicine as the diagnosis involves the use of radiation from isotopes (isotopes are unstable so they produce/emit radio signals). The isotopes have varying life span life such as 30 minutes, one day, four days, 15 days, etc. The isotopes used for this purpose are called half life isotopes (life of around 30 minutes).

Specialised tracers or radiopharmaceuticals are used which after injection permeate throughout the body and reveal potentially diseased sites. Currently, PET procedures primarily use a glucose-based tracer called fluorine-18 deoxyglucose (FDG). This is specifically for metabolically active areas like the heart, brain, and cancerous tissue that absorb disproportionately high amounts of FDG's glucose. Its radioactive elements-positively charged electrons called positrons-collide from opposite directions, which are picked up by the scanner. This gives 2-D or 3-D images indicating the area. For thyroid imaging, iodine is a very common isotope. "Tecnitium 94 is another radio isotope that is used widely," says Dr Krishna.

Fusion World

Fusion of the imaging world is what the experts believe is the future of NM. The journey towards this has already begun. The biggest advantage after the fusion of PET and CT was that, now the experts were able to anatomically locate and pin-point the area, which they could not earlier on a stand-alone basis. Today, PET-CT has become a decisive tool in determining the treatment modality for various forms of cancer. "It is almost criminal in clinical practice to continue a treatment of cancer without a PET-CT scan," opines Dr Krishna. With the help of MI, oncologists now change the course of the treatment, after the scan. "For cancer treatment, even if it's at the same stage, in two different people the response would be not the same. Hence, it actually determines the behaviour of molecules and if they are not responding to the drug, the treatment is changed," says Dr Shripad Banavali, Consultant Haematologist-Oncologist, Tata Memorial Hospital, Mumbai.

Hence, prior to PET-CT, "after a full six months drug treatment when the oncologist observes that the cancer in the body is still present, which does not show in the CT scan, he realises that he was giving the wrong drug," elaborates Dr Krishna. This technique thus becomes the guiding force that determines the course of treatment. So, if a bone scan shows in the image that the cancer has spread beyond surgical limits, the oncologist administers chemotherapy and then goes back to this technique to test the efficacy of the drug. In case of cancer, metabolically active tumour alone needs to be irradiated to minimise radiation to underlying normal lung. Hence, tumour volume to be irradiated needs accurate identification, making PET-CT the ideal choice. Dr SH Advani, Consultant Oncologist, Jaslok Hospital, Mumbai, adds, "With MI, we are able to obtain information about the changes at genetic level within the tumour cells, which is currently a prominent area of research and development. The information from MI helps us to target the tumour cells by targeted therapy." Another major application of MI in MRI is the grading of tumours. Moreover, perfusion MRI and perfusion CT are effective tools to distinguish between radiation necrosis and tumour recurrence.

Matters of the Heart

NM is making quite a comeback in the field of cardiology and neurology as well. As this technique catches the disease before any structural change, today many executives are subjected to heart scan by PET-CT. If a heart scan using NM shows no blockage, the patient will not get a heart attack for at least two years. Explains Dr Krishna, "I have witnessed many patients who are perfectly alright, having no visible symptoms, who have passed the stress ECG test but fail in this one. With stress ECG 40 per cent of patients can be detected as false positives but with PET-CT 95 per cent can be accurately detected."

It is especially helpful in case of ischemia. The myocardium during normal state (normoxic) preferentially (75 per cent) utilises fatty acids as substrate for its energy. During low flow state (ischemia), the myocardium switches to glucose as energy substrate which is a protective mechanism since oxidative glycolysis needs less oxygen. Hence, glucose uptake in the myocyte is high during ischemia. The technology also has uses in diagnosing unstable plaque. Unstable plaque is a dangerous combination of macrophages and lipids, detectable through FDG and MR technique, which are the latest tools of NM.

In fact, the best ambassador of NM can be the Indian cricketer Sachin Tendulkar! He was suffering from severe ankle pain, but his X-ray and CT scan were unable to detect the cause. However, the PET scan showed the layer of bone that was torn off due to sports stress injury (see box). Today, PD Hinduja has many sports personalities opting for this test. The same condition was observed in Zaheer Khan's calf muscle.

While clinical utilisation of PET began in the 1990s, SPECT has been used for decades. SPECT scans are used for a host of applications in NM with the majority of studies being cardiac-related. "Most SPECT exams are indicated for coronary artery disease, mostly myocardial-perfusion studies while bone scanning accounts for another 25 per cent of the applications, and 25 per cent are miscellaneous like the scans of the brain, prostate, and thyroid," says Dr Parameswaran.

Experts now believe that the next step forward would be PET-MRI. "A lot of research is ongoing in this area. I believe the ultimate breakthrough would be the marriage of PET-MRI," opines Dr Parameswaran.

Unlimited Vistas

As of now, the main utilisation of unstable isotopes is in cancer but experts believe that it is going to revolutionise the field of cardiology and neurology, especially Alzheimer's and Parkinson's diseases. Amyloid deposits, which occur in the brain in Alzheimer's disease, can also be imaged with PET, giving early diagnosis at cellular level. MI has now also been able to detect apoptosis, which implies programmed cell death. Now with the help of MI, one can detect the possibility of cell death and suggest solutions to reverse it. This is achieved by attaching Annexin (V) to an isotope, which targets phosphatidyl Serine expressed on cells undergoing apoptoNuclear Medicine: fusing technology for better diagnosis.

PET-CT also helps in a particular type of epilepsy that strikes in the middle of the night. The surgeon is clueless about the location of the seizures. During fits, when injected with an isotope, the blood flow is seen in the scan to increase at least six times at the area of the seizure. PET images of the brain can detect Parkinson's disease. A labelled amino-acid (F-DOPA) is used as a tracer in order to determine whether the brain has a deficiency in dopamine synthesis. If it does not, Parkinson's disease can be ruled out and possible tremors in the patient's muscles will be treated differently. "Similarly, in the case of Alzheimer's disease, the scan shows a very consistent pattern where certain brain regions have decreased metabolism at the early stages of the disease," informs Dr Parameswaran. PET imaging with the radiotracer FDG is a potential tool in detecting Alzheimer's amongst patients with Mild Cognitive Impairment (MCI).

MR spectroscopy is another important tool. It is based on the quantification of molecules through analysis of the spectra achieved during the imaging process. This helps to determine the molecular composition of tissues in health and disease.

The recent developments which will induce the biggest changes in clinical NM in the near future, are the improvements in design and utilisation of single photon emission computed tomographic devices and prolific creation of new radiopharmaceuticals, especially technetium-99m agents for cerebral and myocardial imaging and tumor agents. As PET has recently become of more interest for clinical practice, several different design trends seem to have developed. Systems today are being designed for low-cost clinical applications.

Another area would be the combination of PET-MRI. Significant progress has been made resulting in the design of a prototype small animal PET scanner connected to three multichannel photomultipliers via optical fibres, such that PET detector can function within a standard MR system.

Exciting times lie ahead for nuclear medicine with technology the driving force behind the evolution. Another significant area where scientists are researching is cancer treatment wherein DNA tracers could be further used for targeted radiotherapy. Since nuclear medicine helps in early diagnosis, with the focus shifting to preventive medicine today, it will further play a very crucial role, thus sidelining other modes of diagnosis.

Untapped Potential

If NM has so many benefits, why hasn't it been able to make a significant impact yet? The reasons are many. Before PET-CT, while the expert was able to predict the early onset of disease, he could not exactly locate the area and hence doctors preferred waiting for the CT/MRI to show visible symptoms. This unfortunately meant that the disease was allowed to progress further. But after the fusion of two techniques this issue was taken care of. However, even after five years of its market presence, one prime reason that it hasn't been able to make an impact is the cost, which runs to millions of dollars. In India, the machine approximately costs around a whopping Rs 8 crore, while in the US up to $12 million.

The NM department of JJ Hospital, Mumbai, defunct for 10 years, portrays a sad picture of the future of NM, despite having been the country's first NM department that opened in 1968. The management could not move ahead with the technological advances and felt that investing in CT scan was a better option. Furthermore, lack of trained manpower just added to the woes.

The September issue of the Journal of Nuclear Medicine for example, has an article advocating that young women at risk of having a pulmonary embolism should first undergo a ventilation/perfusion lung scan rather than a CT.

As Dr Krishna concludes, "The molecular approach with fusion imaging will act as a torch bearer to CT-MRI specialists and clinicians to see invisible disease, thus opening new avenues for early therapeutic intervention."

nancy.singh@expressindia.com