Application of 82Sr/82Rb generator in neurooncology

Abstract Introduction The applicability of “Rubidium Chloride, 82Rb from Generator” radiopharmaceutical for brain tumors (BT) diagnostics is demonstrated on the basis of the application experience of the radiopharmaceutical in neurooncology. Experimental A total of 21 patients with various brain tumors and nonneoplastic abnormal brain masses were investigated. Results and Discussions The results of the imaging and differential diagnostics of malignant and benign tumors, nonneoplastic abnormal brain masses and lesions revealed the prevalence of high uptake of the radiopharmaceutical in the malignant tumors in comparison with benign glioma and arteriovenous malformations in which 82Rb‐chloride accumulates in the vascular phase but does not linger further. The ultra‐short half‐life of radionuclide 82Rb (76 s) along with a low absorbed radiation dose with 82Rb‐chloride by intravenous administration create a new possibility of successive use of two or more radiopharmaceuticals for the examination of the same patient. For instance, PET examination with 18F‐FDG, 11C‐methionine, 11C‐choline, or any other radiopharmaceutical can be carried out in just 7–15 min. after 82Rb‐chloride injection. Conclusion Research demonstrated an effectiveness of 82Rb‐chloride application as a diagnostic agent in neurooncology. A method of dosing and administration of the generator‐produced radiopharmaceutical has been worked out. It is possible to do up to 600 PET sessions using one Russian 82Rb generator GR‐01. The generator is proved to be reliable and easy to use. The interest in 82Rb‐chloride as a tumor‐seeking radiopharmaceutical rose due to the active application of the modern devices PET/CT in the routine clinical practice.

Due to a short half-life of 82 Rb (76 s), the absorbed dose of radiation is low for a patient. It gives the opportunity to repeat testing many times as well as to use several radiopharmaceuticals successively within one day for the same patient.
Earlier the generator was used almost in cardiology only (Chatal et al., 2015). The first study of brain tumors perfusion of using PET with 82 Rb-chloride was carried out in 1980-90 s (Brooks et al., 1984;Roelcke et al., 1996;Yen et al., 1982). The attention was paid to 82 Rb + property to penetrate the blood-brain barrier (BBB).
In particular, some authors studied 82 Rb-chloride diagnostic capabilities during the estimation of blood-brain barrier permeability in patients with glial tumors and metastatic brain lesions (Brooks et al., 1984). The obtained results showed the capacity of 82 Rb-chloride to higher uptake in the areas with a damaged blood-brain barrier. The diagnostic accuracy of the method was similar to the data of the perfusion X-ray computed tomography (PCT) and magnetic resonance perfusion imaging (MRI).
Advantages and disadvantages of MRI and PET in perfusion study are not yet well investigated. At perfusion investigation with MRI, the extent of analyzed zone of interest is limited by the size of the field of view of the tomograph. This makes difficult to scan necessary volume of human brain in some cases.
Susceptibility artifacts, especially in zones of the frontal sinus and ethmoid labyrinth may appear (Jarnum et al., 2010) at MRI investigation. The results of measurement are very sensitive to technical parameters of the scanner. The proposed method of PET investigation with 82 Rb-chloride is free from these disadvantages.
An information obtained with 82 Rb-chloride PET investigations is especially effective in combination with contrast-enhanced MRI using PET/MRI fusion technique. In this case, a final conclusion on the role and advantage of PET with 82 Rb-chloride in brain tumor studies may be drawn (Nensa, Beiderwellen, Heusch, & Wetter, 2014).
This approach is simple, reproducible, and provides obtaining exact information on tumor perfusion. Short period of 82 Rb half-life provides low radiation doses. The authors set protocols for the PET data acquisition and mathematical models to calculate a constant, which shows the rate of intracellular transportation of rubidium-82 cations into the brain tumor cells (Brooks et al., 1984).
The comparison of 82 Rb-chloride diagnostic capability with those of 18 F-FDG is considered highly important, since the two radiopharmaceuticals provide mutually complementary data concerning properties of the malignant tissue under examination. This gives the opportunity to estimate both tumor perfusion ( 82 Rb-chloride) and tumor metabolism ( 18 F-FDG).
The study of 82 Rb accumulation/elimination in/out of the tumor based on the analysis of the activity/time curves above the tumor is also of significant interest for diagnostic purposes. Such an attempt was made in (Roelcke et al., 1995) using 82 Rb-chloride, 11 C-methionine, and 18 FDG as well as (Valk et al., 1988) using 82 Rb-chloride and 18 FDG. But detailed analysis of the obtained activity/time curves has not been carried out by the authors probably due to too long time of 82 Rb-chloride injection and short time of PET scanning.
The application of diagnostics with 82 Rb-chloride may be an important independent method in PET investigation of brain, or, in particular, a complementary method to ordinary approaches (Bell et al., 2015;Herholz, 2017) using compounds with 18 F, 11 C, and 13 N, especially in combination with cardiological application of the same generator.
The goal of the current research is obtaining more data with 82 Rb PET in combination with FDG PET and different diagnostic methods (CT, MRI and angiography). The present study is a pilot study, and more data need to be accumulated.

| E XPERIMENTAL
The procedures followed were performed in accordance with the Rbchloride radiopharmaceutical elution system scheme: Programmable syringe pump-1; 3-way stopcock-2; sterilizing filter-3; saline supply-4; plastic extender (tubing with Luer edges)-5; adapter (from Swagelok to Luer)-6; one-way valve-7; syringe with saline for air removal from the system-8; peripheral venous catheter-9; 82 Sr/ 82 Rb generator-10 There are three possible elution types of radiopharmaceutical administration: constant-flow elution, constant-activity elution, and constant-time elution. For the administration of the generator-produced radiopharmaceutical 82 Rb-chloride, we use the constant-time elution as the most preferable one. As a rule, a stream infusion of the radiopharmaceutical lasts 14 s (the period from 11 to 16 s is acceptable). The volume of eluate per infusion ranges from 5 to 25 ml, and the infusion rate ranges from 3 to 90 ml/min (the usual range is 40-80 ml/min). Provided service conditions, the entire period of the generator operation ranks over all known analogs and certified for in tissue phase. The uptake index (UI) and vascularization degree F I G U R E 2 (a-d), Female patient g. Diagnosis: glioblastoma multiforme recurrence growth of the right parietal lobe. (a) At MRI (T2-weighted image), the tumor is well visible, and perifocal edema is defined. (b) 18 F-FDG PET image demonstrates heterogeneous unsharp mass with the high glycolytic rate glycolysis (UI = 1.0). The lesion is partially visible due to its location in the white matter as well as to edema and ischemization of the adjacent brain cortex. (c) 82 Rb-chloride PET image demonstrates a sharp homogeneous hypervascular focus with high radiopharmaceutical uptake in the tissue phase (UI = 17) (position 1). Contralateral brain cortex is shown in position 2. (d) Activity/ Time curve of the lesion (1) shows that the tumor has the high vascularization degree (VD = 2.1). Vascular permeability is impaired. Within the tissue phase, high radiopharmaceutical uptake in tumor exceeds the radiopharmaceutical uptake in the contralateral brain cortex (2) in 17 times. A typical for malignant tumors slow monotonic radiopharmaceutical uptake in the tumor within the tissue phase is observed 1 2 1.
(VD) were estimated, and activity/time curves for tumors and normal brain cortex areas were plotted. UI is a ratio between maximal activity value accumulated in zone of interest of the tumor and maximal activity value in the zone of interest of the intact brain tissue.

VD is a ratio between maximal activity value accumulated in zone of
interest of the tumor and maximal activity value in the normal cortex of the vascular phase.
A total of 21 patients at the age of 18-76 with different brain tumors were examined. All the patients underwent PET examination with 82 Rb-chloride along with MRT with contrast agent, and some patients underwent PET examination with 18 F-FDG, CT along with brain X-ray angiography.

| RE SULTS AND D ISCUSS I ON S
In 14 of total amount, 21 patients (67%) brain tumors were diagnosed. In 10 of 14 patients, malignant tumors (8 glioblastoma and 2 meningioma) were diagnosed. In other 4 of 14 patients, the benign brain tumors (3 astrocytoma and 1 meningioma) were diagnosed. In

of 21 patients, postsurgical cysts and in 4 patients arteriovenous
malformations were diagnosed.

In all 10 cases, malignant tumors (glioblastoma and meningioma)
were exactly visualized at PET examination with 82 Rb-chloride. In all the cases, abnormal focuses of radiopharmaceutical high uptake were detected in the image of a tumor node (Figures 2, 3). Activity/ time curves plotted over malignant tumors images (Figure 2) show for high vascularization of the malignant tumors along with pathological permeability of cell membranes of the tumor blood vessels as compared to intact brain cortex. It is noteworthy that as a rule, monotonic increase in radiopharmaceutical's uptake in malignant glioma and meningioma was detected during the whole scan session (11 min) (Figures 2, 3).
Earlier in (Granov et al., 1997(Granov et al., , 2011(Granov et al., , 2012, we demonstrated that optimal time for PET scanning with 82 Rb-chloride is 11 min. Along with this, in order to obtain correct activity/time curves the radiopharmaceutical should be administrated during 11-16 s which is faster than in (Roelcke et al., 1995) (30-60 s when scanning time is 6 min).
Radiopharmaceutical uptake in the tumor node appeared to be low in 3 patients with astrocytoma of a low malignant potential ( Figure 4). Tumor imaging in such cases became possible entirely due to the far lower uptake of 82 Rb-chloride in intact brain cortex, and due to this fact, tumors were partially seen ( Figure 4). As a rule, within the tissue phase monotonic radiopharmaceutical elimination was observed or radiopharmaceutical content remained at low level.
At the same time, high radiopharmaceutical uptake in the tumor was

R4 R3
Radiopharmaceutical uptake in postsurgical cysts after tumor eradication was close to its background absorption. Cysts were not visualized on the background of radiopharmaceutical low uptake in the brain cortex.
In patients with arteriovenous malformation (AVM), high 82 Rbchloride uptake was detected only in the vascular phase and it was low in the tissue phase ( Figure 5).
An uptake index UI (ratio 82 Rb-uptake in tumor/ 82 Rb-uptake in normal brain tissue) was estimated in order to carry out the quantification of obtained data. Obtained results of the radiopharmaceutical uptake level in the examined masses are shown in Table 1.
The data represented in Table 1 show that the high 82 Rb-chloride uptake (in UI units) was observed in malignant tumors. On average, UI found in malignant tumors was 19.2 ± 5.8, while in benign glioma and postsurgical cysts the radiopharmaceutical uptake was signifi-   TA B L E 1 Radiopharmaceutical 82 Rb-chloride uptake level in the brain lesions (21 patients in total)

Number of patients
Uptake index (UI) for brain lesions, tissue phase (observed range and average) Vascularization degree (VD) for brain lesions, of vascular phase (observed range and average) Note. UI is a ratio between maximal activity value accumulated in zone of interest of the tumor and maximal activity value in the zone of interest of the intact brain tissue. VD is a ratio between activity value accumulated in region of interest in the tumor and activity value in the intact brain tissue of vascular phase.
tumor and nontumor lesions, such as AVM, in human brain with low radiation effective doses (1.0-1.9 mSv).
2. Uptake index and activity/time curve analysis in constant-elution time mode with short-lived 82 Rb (T 1/2 = 76 s) provide evaluation of vascularization in tumors and malignancy of gliomas.

A low diagnostic dose acceptable in neurooncological studies (up
to 820 MBq with 2D-scanner) makes it possible to use 82 Sr/ 82 Rb generator during a long period (60 days certified for generator GR-01), in particular, after cardiological studies with the same generator.

ACK N OWLED G M ENTS
We want warmly to acknowledge all patients with different brain tumors participated in the studies.

CO N FLI C T O F I NTE R E S T S
The authors have no conflict of interests to declare.