**2.1 Gallium-67 citrate: Pharmacological and physiochemical characteristics**

Ga-67 citrate has been used since 1971 to detect and localize infectious and inflammatory process. The exact mechanism of uptake has been studied extensively and various factors

Radionuclide Infection Imaging: Conventional to Hybrid 75

normal anatomical imaging. FUO has numerous causes and neoplasms including lymphoma account for up to 25% of these cases. Although PET/CT and labelled leukocytes are more frequently employed for FUO but Ga-67 can still be helpful with good detection

Fig. 1. A 40-year-old male with FUO. Ga-67 scintigraphy shows intense tracer accumulation

Sarcoidosis is a systemic disorder that involves the lungs in up to 90% of the cases. Hilar lymph nodal involvement is evident in over 80% of the cases. Pulmonary accumulation of Ga-67 in these patients parallels active disease and there exists a good concordance between the Ga-67 intensity of uptake and the disease severity. Ga-67 scintigraphy has a sensitivity of 70% for detecting pulmonary parenchymal disease and a 95% for hilar adenopathy. The overall sensitivity is about 90%. If these patients are further subjected to a Thallium scintigraphic exam, it is usually negative. A characteristic Ga-67 scintigraphic pattern seen in patients with sarcoidosis is termed as the "Panda sign" (due to typically increased and

in the left side of abdomen. SPECT/CT images localize the abnormal uptake to the thickened gastric wall measuring over 50mm. SPECT/CT report raised the suspicion of lymphoma and suggested subsequent endoscopic biopsy; the report of which showed

findings consistent with gastric lymphoma.

rates where these formal are not available (Figure 1).

are thought to govern the tracer accumulation at the infection site. Most of the circulating Ga-67 is in the plasma and nearly all of it complexes with transferrin. Due to the increased blood flow and vascular membrane permeability the Ga-67/transferrin complex is delivered to the inflammatory sites or foci. Ga-67 is also thought to bind to lactoferrin which is present in high concentrations in the inflammatory foci. Direct bacterial uptake and accumulation as well as Ga-67 transportation bound to the leukocytes is also another factor studied. Bacteria and some fungi produce low molecular weight chelates called siderophores present on their cell surfaces and these have a high affinity for Ga-67. The Ga-67/siderophore complex facilitates the transport of Ga-67 within the cell itself. This mechanism of Ga-67 uptake may be attributable to the accumulation of Ga-67 within an abscess in neutropenic patients.

Ga-67 is a cyclotron produced radioisotope and emits principle gamma rays (93, 184, 296, 394 KeV). These are suitable for imaging. The dosage of Ga-67 typically used is 185-370 MBq for infection imaging, however, in our personal experience even a lesser dose did produce adequate images worth interpretation. Around 15-25% of the injected dose is excreted via the kidneys by 24 hours. After 24 hours the principle route of excretion is the colon. At 48 hours 75% of the injected dose remains in the body and is equally distributed among the liver, bone, bone marrow and soft tissues. The physical half-life of Ga-67 is 78 hours while the biological half-life of around 25 days gives ample opportunity to take delayed images even after days post injection.

#### **2.2 Gallium-67: Imaging protocols and pre-requisites**

Ga-67 imaging is usually performed 18-72 hours post injection, however, we also routinely image the patients at 6 hours post injection particularly if the suspected focus of infection is in the abdomen. This we have found to be helpful in a number of cases. Limited spot views or whole body imaging can be done depending upon the clinical indication and the use of a medium energy collimator is a standard. Patients' preparation with laxatives and enemas has been considered by some but the effectiveness of such preparation seems limited. Recent Gadolinium exposure as in an MR contrast study or multiple blood transfusions resulting in excess ferric ion may alter the Ga-67 biodistribution by saturation of the protein-binding sites. This needs to be sorted out in history while preparing the patient for injection and imaging.

### **2.3 Gallium-67: Clinical utilities and applications**

Ga-67 citrate has been extensively used in the past four decades in clinical practice for several pathological conditions particularly whenever infection or inflammation has been in question. Ga-67 has demonstrated high sensitivity for both acute and chronic infectious process as well as non-infectious inflammation. Moreover, the Ga-67 tracer activity parallels acute inflammation, returning to normal as the disease process resolves.

The most common of the clinical scenarios where Ga-67 has been and is still utilized include fever of unknown origin (FUO), sarcoidosis, pulmonary infections like pneumocystis carnii pneumonia (PCP), drug-induced pulmonary toxicity as is seen with bleomycin or amiodarone, and in cases of malignant otitis externa. Further Ga-67 has been successfully utilized in spinal discitis and vertebral osteomyelitis. Mediastinal infections in immunocompromised patients have been detected by Ga-67.

In patients with the clinical diagnosis of FUO, anatomical imaging is less helpful as functional changes occur prior to anatomical alteration at a suspected site resulting in

are thought to govern the tracer accumulation at the infection site. Most of the circulating Ga-67 is in the plasma and nearly all of it complexes with transferrin. Due to the increased blood flow and vascular membrane permeability the Ga-67/transferrin complex is delivered to the inflammatory sites or foci. Ga-67 is also thought to bind to lactoferrin which is present in high concentrations in the inflammatory foci. Direct bacterial uptake and accumulation as well as Ga-67 transportation bound to the leukocytes is also another factor studied. Bacteria and some fungi produce low molecular weight chelates called siderophores present on their cell surfaces and these have a high affinity for Ga-67. The Ga-67/siderophore complex facilitates the transport of Ga-67 within the cell itself. This mechanism of Ga-67 uptake may be attributable to the accumulation of Ga-67 within an abscess in neutropenic patients. Ga-67 is a cyclotron produced radioisotope and emits principle gamma rays (93, 184, 296, 394 KeV). These are suitable for imaging. The dosage of Ga-67 typically used is 185-370 MBq for infection imaging, however, in our personal experience even a lesser dose did produce adequate images worth interpretation. Around 15-25% of the injected dose is excreted via the kidneys by 24 hours. After 24 hours the principle route of excretion is the colon. At 48 hours 75% of the injected dose remains in the body and is equally distributed among the liver, bone, bone marrow and soft tissues. The physical half-life of Ga-67 is 78 hours while the biological half-life of around 25 days gives ample opportunity to take delayed images

Ga-67 imaging is usually performed 18-72 hours post injection, however, we also routinely image the patients at 6 hours post injection particularly if the suspected focus of infection is in the abdomen. This we have found to be helpful in a number of cases. Limited spot views or whole body imaging can be done depending upon the clinical indication and the use of a medium energy collimator is a standard. Patients' preparation with laxatives and enemas has been considered by some but the effectiveness of such preparation seems limited. Recent Gadolinium exposure as in an MR contrast study or multiple blood transfusions resulting in excess ferric ion may alter the Ga-67 biodistribution by saturation of the protein-binding sites. This needs to be sorted out in history while preparing the patient for injection and

Ga-67 citrate has been extensively used in the past four decades in clinical practice for several pathological conditions particularly whenever infection or inflammation has been in question. Ga-67 has demonstrated high sensitivity for both acute and chronic infectious process as well as non-infectious inflammation. Moreover, the Ga-67 tracer activity parallels

The most common of the clinical scenarios where Ga-67 has been and is still utilized include fever of unknown origin (FUO), sarcoidosis, pulmonary infections like pneumocystis carnii pneumonia (PCP), drug-induced pulmonary toxicity as is seen with bleomycin or amiodarone, and in cases of malignant otitis externa. Further Ga-67 has been successfully utilized in spinal discitis and vertebral osteomyelitis. Mediastinal infections in

In patients with the clinical diagnosis of FUO, anatomical imaging is less helpful as functional changes occur prior to anatomical alteration at a suspected site resulting in

acute inflammation, returning to normal as the disease process resolves.

immunocompromised patients have been detected by Ga-67.

even after days post injection.

imaging.

**2.2 Gallium-67: Imaging protocols and pre-requisites** 

**2.3 Gallium-67: Clinical utilities and applications** 

normal anatomical imaging. FUO has numerous causes and neoplasms including lymphoma account for up to 25% of these cases. Although PET/CT and labelled leukocytes are more frequently employed for FUO but Ga-67 can still be helpful with good detection rates where these formal are not available (Figure 1).

Fig. 1. A 40-year-old male with FUO. Ga-67 scintigraphy shows intense tracer accumulation in the left side of abdomen. SPECT/CT images localize the abnormal uptake to the thickened gastric wall measuring over 50mm. SPECT/CT report raised the suspicion of lymphoma and suggested subsequent endoscopic biopsy; the report of which showed findings consistent with gastric lymphoma.

Sarcoidosis is a systemic disorder that involves the lungs in up to 90% of the cases. Hilar lymph nodal involvement is evident in over 80% of the cases. Pulmonary accumulation of Ga-67 in these patients parallels active disease and there exists a good concordance between the Ga-67 intensity of uptake and the disease severity. Ga-67 scintigraphy has a sensitivity of 70% for detecting pulmonary parenchymal disease and a 95% for hilar adenopathy. The overall sensitivity is about 90%. If these patients are further subjected to a Thallium scintigraphic exam, it is usually negative. A characteristic Ga-67 scintigraphic pattern seen in patients with sarcoidosis is termed as the "Panda sign" (due to typically increased and

Radionuclide Infection Imaging: Conventional to Hybrid 77

list of differentials that can give rise to a similar scintigraphic picture the specificity can be increased by considering the intensity and distribution of the tracer as well as the comparison of activity either with the liver uptake or the sternum. Diffuse heterogeneous pulmonary activity which is more intense than the liver has specificity for PCP between 95-

In cases of drug-induced pulmonary toxicity (Bleomycin, Cyclophosphamide, Methotrexate, Nitrofurantoin, Amiodarone) radiologically the abnormalities are not evident at early stages of the toxicity. In such a scenario, Ga-67 provides early detection with usually moderate increased uptake seen in the lungs on the scan. More recently, Ga-67 scintigraphy (Figure 3) as well as PET/CT has been used to evaluate malignant otitis externa. These modalities are also used to evaluate the response to therapy in such cases. Vertebral osteomyelitis has been detected and evaluated by Ga-67, however, the specificity can be increased if the interpretation is done in conjunction with the bone scan. An accepted criterion in such a clinical scenario is to have Ga-67 uptake greater than uptake seen on the bone scan with incongruent tracer distribution. Labelled leukocytes, however, are more accurate for the

Fig. 3. A 46-year-old female with clinical diagnosis of right malignant otitis externa referred for Ga-67 scintigraphy. Transverse and coronal SPECT images show intense tracer uptake in the right auricular region. SPECT/CT images localize the abnormal uptake to right external

auditory meatus without evidence of any underlying bony cortical breech.

100%.

evaluation of vertebral osteomyelitis.

more prominent lacrimal, parotid and nasopharyngeal activity). This can be seen in up to 80% of patients with stage I disease. Moreover the pre-tracheal and bilateral hilar adenopathy gives rise to an inverted "Y" which is termed as a "Lambda sign" (Figure 2). It is important, however, to remember that the panda sign can be seen in cases of Mikulicz syndrome (uveoparotid fever), lymphoma, Sjogren's syndrome and HIV. Some Pulmonologist believe that a panda sign on Ga-67 scintigraphy even without a lambda sign, but with hilar adenopathy on CXR or CT is still suggestive of sarcoidosis and do not opt for a biopsy.

Fig. 2. A 28-year-old male with suspicion of sarcoidosis. Ga-67 scintigraphy shows typical "Panda" and "Lambda" signs.

The sensitivity of Ga-67 scintigraphy for PCP in HIV patients has been reported to be as high as 90-95%. The scintigraphic pattern is that of diffuse increased pulmonary uptake which is disproportionate to the clinical and radiological findings. However, due to a long

more prominent lacrimal, parotid and nasopharyngeal activity). This can be seen in up to 80% of patients with stage I disease. Moreover the pre-tracheal and bilateral hilar adenopathy gives rise to an inverted "Y" which is termed as a "Lambda sign" (Figure 2). It is important, however, to remember that the panda sign can be seen in cases of Mikulicz syndrome (uveoparotid fever), lymphoma, Sjogren's syndrome and HIV. Some Pulmonologist believe that a panda sign on Ga-67 scintigraphy even without a lambda sign, but with hilar adenopathy on CXR or CT is still suggestive of sarcoidosis and do not opt for

Fig. 2. A 28-year-old male with suspicion of sarcoidosis. Ga-67 scintigraphy shows typical

The sensitivity of Ga-67 scintigraphy for PCP in HIV patients has been reported to be as high as 90-95%. The scintigraphic pattern is that of diffuse increased pulmonary uptake which is disproportionate to the clinical and radiological findings. However, due to a long

"Panda" and "Lambda" signs.

a biopsy.

list of differentials that can give rise to a similar scintigraphic picture the specificity can be increased by considering the intensity and distribution of the tracer as well as the comparison of activity either with the liver uptake or the sternum. Diffuse heterogeneous pulmonary activity which is more intense than the liver has specificity for PCP between 95- 100%.

In cases of drug-induced pulmonary toxicity (Bleomycin, Cyclophosphamide, Methotrexate, Nitrofurantoin, Amiodarone) radiologically the abnormalities are not evident at early stages of the toxicity. In such a scenario, Ga-67 provides early detection with usually moderate increased uptake seen in the lungs on the scan. More recently, Ga-67 scintigraphy (Figure 3) as well as PET/CT has been used to evaluate malignant otitis externa. These modalities are also used to evaluate the response to therapy in such cases. Vertebral osteomyelitis has been detected and evaluated by Ga-67, however, the specificity can be increased if the interpretation is done in conjunction with the bone scan. An accepted criterion in such a clinical scenario is to have Ga-67 uptake greater than uptake seen on the bone scan with incongruent tracer distribution. Labelled leukocytes, however, are more accurate for the evaluation of vertebral osteomyelitis.

Fig. 3. A 46-year-old female with clinical diagnosis of right malignant otitis externa referred for Ga-67 scintigraphy. Transverse and coronal SPECT images show intense tracer uptake in the right auricular region. SPECT/CT images localize the abnormal uptake to right external auditory meatus without evidence of any underlying bony cortical breech.

Radionuclide Infection Imaging: Conventional to Hybrid 79

background ratio. Approximately 50% of the injected dose is localized to the bone. The

When bone scintigraphy is performed for the evaluation of osteomyelitis, the study is done in three phases. These include a dynamic sequence termed as the flow or perfusion phase, followed by immediate static image of the area of interest termed as the blood-pool phase or soft tissue phase. The third phase is the static delayed imaging of the area of interest usually acquired 2-4 hours post injection. Some also perform a fourth phase at 24 hours which is usually a static spot view of the region of interest. The usual adult dosage is 740-925 MBq.

Three-phase bone scintigraphy is the radionuclide procedure of choice for diagnosing osteomyelitis in non-violated bone i.e. bone that is not affected by underlying conditions. It is highly sensitive for diagnosing osteomyelitis and can detect the process 7-14 days before the manifestation of radiological changes. The reported sensitivity of 90-100% and specificity of 70-95% for identification of osteomyelitis is in non-violated bone. In adults a negative bone scan essentially rules out infection. Focal hyperperfusion, focal hyperemia, and focally increased bony uptake on delayed images are the characteristic scintigraphic findings for osteomyelitis. Many times due to some underlying bone conditions the specificity of the bone scan for osteomyelitis is further compromised. In such situations, the additional images at 24 hours (4th - phase) may improve specificity. This is due to the fact that uptake in woven or immature bone present in osteomyelitis continues for several more hours than normal bone. The accuracy of 4-phase bone scan that is more specific but less sensitive than a 3-phase bone scan is approximately 85%. Further the specificity of bone scan can also be improved by addition of Ga-67 scintigraphy. The overall accuracy of bone scan/Ga-67

Three-phase bone scintigraphy and MRI are considered the modalities of choice for diagnosing osteomyelitis. Moreover, MRI can assess the associated soft tissue complications. MRI has its limitations as well. The replacement of marrow fat with edema and exudate results in a decreased signal on T1 and an increased signal on T2-weighted images. Such findings are not specific for osteomyelitis and can be seen with acute infarction, fracture or even tumour. Therefore the overall sensitivity and specificity of MRI for detection of acute osteomyelitis ranges from 92-100% and 89-100% respectively. CT is more sensitive to detect cortical destruction. On site-based analysis by (Bar-Shalom et al., 2006) scintigraphy (planar & SPECT) and SPECT/CT showed concordant results for diagnosis and localization of 50% of infection sites. SPECT/CT defined the precise anatomical localization of 44% of infectious sites that were erroneous or equivocal on scintigraphy in this study. In another preliminary report, (Horger et al., 2003) found that SPECT/CT improved the diagnostic performance of three-phase bone scan for osteomyelitis avoiding false-positive or equivocal results. In our own experience SPECT/CT has always had an incremental value to routine planar imaging and in many clinical situations in particular further characterizing the abnormalities to reach

tracer uptake is dependent upon the blood flow and the rate of new bone formation.

Patients are instructed to be well hydrated and void frequently after the injection.

**3.2 Tc-99m MDP: Imaging protocols and pre-requisites** 

**3.3 Tc-99m MDP: Clinical utilities and applications**

scintigraphy is approximately 65-80%.

definitive imaging diagnosis (Figure 5).

**3.4 Tc-99m MDP: Hybrid SPECT/CT imaging** 
