technetium-tc-99m-tetrofosmin and Glioma

Treatment induced necrosis is a relatively frequent finding in patients treated for high-grade glioma. Differentiation by imaging modalities between glioma recurrence and treatment induced necrosis is not always straightforward. This is a comparative study of diffusion tensor imaging (DTI), dynamic susceptibility contrast MRI and (99m)Tc-Tetrofosmin brain single-photon emission computed tomography (SPECT) for differentiation of recurrent glioma from treatment induced necrosis.. A prospective study was made of 30 patients treated for high-grade glioma who had suspected recurrent tumor on follow-up MRI. All had been treated by surgical resection of the tumor followed by standard postoperative radiotherapy with chemotherapy. No residual tumor had been found on brain imaging immediately after the initial treatment. All the patients were studied with dynamic susceptibility contrast brain MRI and, within a week, (99m)Tc-Tetrofosmin brain SPECT.. Both (99m)Tc-Tetrofosmin brain SPECT and dynamic susceptibility contrast MRI could discriminate between tumor recurrence and treatment induced necrosis with 100% sensitivity and 100% specificity. An apparent diffusion coefficient (ADC) ratio cut-off value of 1.27 could differentiate recurrence from treatment induced necrosis with 65% sensitivity and 100% specificity and a fractional anisotropy (FA) ratio cut-off value of 0.47 could differentiate recurrence from treatment induced necrosis with 57% sensitivity and 100% specificity. A significant correlation was demonstrated between (99m)Tc-Tetrofosmin uptake ratio and rCBV (P=0.003).. Dynamic susceptibility contrast MRI and brain SPECT with (99m)Tc-Tetrofosmin had the same accuracy and may be used to detect recurrent tumor following treatment for glioma. DTI also showed promise for the detection of recurrent tumor, but was inferior to both dynamic susceptibility contrast MRI and brain SPECT.

Topics: Brain; Brain Neoplasms; Chemoradiotherapy; Contrast Media; Diagnosis, Differential; Diffusion Tensor Imaging; Female; Glioma; Humans; Male; Middle Aged; Necrosis; Neoplasm Recurrence, Local; Organophosphorus Compounds; Organotechnetium Compounds; Radiation Injuries; Radiopharmaceuticals; Tomography, Emission-Computed, Single-Photon; Treatment Outcome

Assessment of the grade and type of glioma is of paramount importance for prognosis. Tumour proliferative potentials may provide additional information on the behaviour of the tumour, its response to treatment and prognosis. The purpose of this study was to investigate the correlation between diffusion tensor imaging (DTI), dynamic susceptibility contrast (DSC) magnetic resonance imaging (MRI) and (99m)Tc-Tetrofosmin brain single-photon emission computed tomography (SPECT), and the tumour grade and Ki-67 labelling index in newly diagnosed gliomas.. Study was made of patients with suspected glioma on brain MRI between December 2010 and January 2012, by DTI, DSC MRI and (99m)Tc-Tetrofosmin brain SPECT. The proliferative activity of each tumour was measured by deriving the Ki-67 proliferation index from immunohistochemical staining of tumour specimens.. Glioma was newly diagnosed in 25 patients (17 men, 8 women, aged 19-79 years, median 55 years). The Ki-67 index ranged from 1% to 80% (mean 19.4%). On evaluation of the relationship between the (99m)Tc-Tetrofosmin tumour uptake by gliomas was found to be significantly correlated with cellular proliferation (rho=0.924, p<0.0001). Regarding DTI, significant negative correlation was demonstrated between the apparent diffusion coefficient (ADC) ratio and the Ki-67 index (rho=-0.545, p=0.0087). Significant correlation was also observed between the fractional anisotropy (FA) ratio and the Ki-67 index (rho=0.489, p=0.02). Strong correlation was found between relative cerebral blood volume (rCBV) and Ki-67 index (rho=0.853, p<0.0001), and between the (99m)Tc-Tetrofosmin lesion-to-normal (L/N) uptake ratio and rCBV (rho=0.808, p ≤ 0.0001). Significant negative correlation was demonstrated between the (99m)Tc-Tetrofosmin L/N ratio and ADC ratio (rho=-0.513, p=0.014). These imaging techniques were able to distinguish between low-grade and high-grade gliomas.. Findings on DSC MRI and brain SPECT with (99m)Tc-Tetrofosmin metrics were more closely correlated with glioma cellular proliferation.

Topics: Adult; Aged; Brain; Brain Neoplasms; Diffusion Tensor Imaging; Ethylenediamines; Female; Glioma; Humans; Immunohistochemistry; Ki-67 Antigen; Magnetic Resonance Imaging; Male; Middle Aged; Neoplasm Grading; Organophosphorus Compounds; Organotechnetium Compounds; Tomography, Emission-Computed, Single-Photon; Young Adult

Multidrug resistance (MDR) remains a major obstacle to successful chemotherapeutic treatment of cancer. Several chemotherapeutic and radiopharmaceutical agents are substrates of the pumps encoded by the MDR genes, and therefore, their accumulation is prevented. We evaluated in vivo whether [(99m)Tc]tetrofosmin ((99m)Tc-TF) uptake is influenced by the MDR profile of gliomas.. Eighteen patients with histologically confirmed glioma were included in the study. Brain single-photon emission computed tomography by (99m)Tc-TF was performed within a week prior to surgical excision, and the expression of MRP5 was assessed by immunohistochemistry. Radiotracer accumulation was assessed by a semiquantitative method, calculating the lesion-to-normal uptake ratio.. Using Spearman's ρ analysis, we found no correlation between tracer uptake expressed as lesion-to-normal and MRP5 expression. There was a significant correlation between glioma aggressiveness as assessed by Ki-67/MIB-1 and MRP5 expression.. The present data suggest that (99m)Tc-TF uptake is not influenced by glioma's MDR phenotype. Thus, (99m)Tc-TF constitutes a suitable radiotracer for imaging gliomas.

Topics: Adult; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Female; Glioma; Humans; Male; Middle Aged; Organophosphorus Compounds; Organotechnetium Compounds; Phenotype; Tomography, Emission-Computed, Single-Photon

Brain single-photon emission computed tomography (SPECT) has been proposed as a potentially useful modality for the metabolic assessment of various brain tumors.. In a 10-patient prospective pilot study we evaluated whether (99m)Tc-Tetrofosmin ((99m)Tc-TF) uptake correlates with glioma proliferative activity assessed by flow cytometric analysis. (99m)Tc-TF brain SPECT was performed shortly before surgical tumor excision.. Eight patients were diagnosed with glioblastoma multiform and 2 with anaplastic astrocytoma. All tumors were aneuploid. We found a significant positive linear correlation between (99m)Tc-TF uptake and percentage of tumor cells on the S-phase of the cell cycle (r=0.92, P=0.001).. Initial evidence suggests that (99m)Tc-TF could provide a non-invasive indicator of glioma proliferative activity.

Topics: Aged; Aneuploidy; Brain Neoplasms; Cell Proliferation; DNA; Female; Flow Cytometry; Gamma Cameras; Glioblastoma; Glioma; Humans; Image Processing, Computer-Assisted; Male; Middle Aged; Organophosphorus Compounds; Organotechnetium Compounds; Pilot Projects; Prospective Studies; Radiopharmaceuticals; Tomography, Emission-Computed, Single-Photon

Topics: Brain Neoplasms; Glioma; Humans; Image Processing, Computer-Assisted; Magnetic Resonance Imaging; Organophosphorus Compounds; Organotechnetium Compounds; Radiotherapy Planning, Computer-Assisted; Sensitivity and Specificity; Technetium Tc 99m Sestamibi; Tomography, Emission-Computed, Single-Photon

Topics: Brain Neoplasms; Glioma; Humans; Organophosphorus Compounds; Organotechnetium Compounds; Radiopharmaceuticals; Tomography, Emission-Computed, Single-Photon

Topics: Brain Neoplasms; Clinical Trials as Topic; Glioma; Humans; Necrosis; Neoplasm Recurrence, Local; Organophosphorus Compounds; Organotechnetium Compounds; Prognosis; Radionuclide Imaging; Reproducibility of Results; Thallium Radioisotopes; Tomography, Emission-Computed, Single-Photon

Topics: Brain Neoplasms; Cell Proliferation; Female; Glioma; Humans; Ki-67 Antigen; Male; Middle Aged; Organophosphorus Compounds; Organotechnetium Compounds; Radiopharmaceuticals; Tomography, Emission-Computed, Single-Photon

Topics: Brain Neoplasms; Glioblastoma; Glioma; Humans; Neoplasm Staging; Organophosphorus Compounds; Organotechnetium Compounds; Prognosis; Radiopharmaceuticals; Tomography, Emission-Computed, Single-Photon

The differentiation between brain tumor recurrence and post-irradiation injury remains an imaging challenge. Computed tomography (CT) and magnetic resonance imaging (MRI) cannot always distinguish between the two. Although glioma cell line studies substantiated a plausible imaging superiority of (99m)Tc-tetrofosmin ((99m)Tc-TF) over other radiopharmaceuticals, little has been reported on its in vivo imaging properties. We assessed (99m)Tc-TF single-photon emission CT (SPECT) in cases where morphologic brain imaging was inconclusive between recurrence and radionecrosis.. A total of 11 patients (7 men, 4 women) were evaluated. The initial diagnosis was glioblastoma multiforme (4), anaplastic astrocytoma (1), anaplastic oligodendroglioma (3), grade-II astrocytoma (2), and low-grade oligodendroglioma (1). All patients had been operated on and then received adjuvant external-beam radiotherapy. After a mean follow-up period of 25 months, there was clinical suspicion of recurrence, for which (99m)Tc-TF SPECT was performed.. In 8/11 cases, an abnormally increased tracer uptake appeared in the region that CT and/or MRI indicated as suspicious; in half of these cases, recurrence was confirmed histologically after surgery and in the other four by growth of the lesion over a 6-month follow-up period, and clinical deterioration. The remaining 3/11 patients had faint tracer uptake in the suspicious region, compatible with radiation injury; these lesions remained morphologically unaltered in a mean 12-month follow-up period, with no clinical deterioration in the patient's condition, a course strongly favoring the diagnosis of radiation injury.. Metabolic brain imaging by (99m)Tc-TF could offer useful information in the workup of treated brain tumors, where radiomorphologic findings between recurrence and radionecrosis are inconclusive.

Topics: Adult; Brain; Brain Neoplasms; Cell Line, Tumor; Female; Glioma; Humans; Magnetic Resonance Imaging; Male; Middle Aged; Organophosphorus Compounds; Organotechnetium Compounds; Pilot Projects; Radiopharmaceuticals; Recurrence; Tomography, Emission-Computed, Single-Photon; Tomography, X-Ray Computed

Topics: Brain; Brain Neoplasms; Diagnosis, Differential; Diffusion Magnetic Resonance Imaging; Glioma; Humans; Neoplasm Recurrence, Local; Organophosphorus Compounds; Organotechnetium Compounds; Positron-Emission Tomography; Radiation Injuries; Radiopharmaceuticals; Tomography, Emission-Computed, Single-Photon

The aims of this study were to assess the clinical usefulness of [Tc-99m] tetrofosmin (TF) single photon emission computed tomography (SPECT) and X-ray transmission computed tomography (CT), performed simultaneously with a hybrid imaging device for the functional anatomical mapping of brain tumors and to evaluate the additional information of SPECT/CT when compared to SPECT alone. Thirty (30) patients were studied: 20 were evaluated before undergoing surgery and 10 after surgery and before radiotherapy planning. The acquisition of both functional (SPECT) and morphologic (CT) images were obtained in a single session. SPECT images were firstly evaluated alone and then reinterpreted by adding the anatomical (CT) planes. Fusion imaging was successfully obtained in all patients with precise correspondence between SPECT and CT slices. SPECT/CT had a significant clinical impact in 13 (43.3%) of 30 cases; in particular, SPECT/CT accurately characterized eight lesions near sites of physiological uptake (i.e., four near ventricles/choroids plexus, three near venous sinuses, one near the skull) and localized viable tumor tissue in 5 patients evaluated after surgery. SPECT/CT with TF using this hybrid device represents a useful clinical tool in brain tumor imaging, both correctly categorizing focal areas near sites of physiological uptake and localizing viable tumor tissue after surgery.

Topics: Adult; Aged; Brain Mapping; Brain Neoplasms; Female; Glioma; Humans; Male; Middle Aged; Organophosphorus Compounds; Organotechnetium Compounds; Photons; Radiopharmaceuticals; Reproducibility of Results; Sensitivity and Specificity; Tomography, Emission-Computed, Single-Photon; Tomography, X-Ray Computed

The emergence of multidrug resistance (MDR) is a major obstacle to successful chemotherapy of malignant glioma tumors. Overexpression of the multidrug resistance-associated protein isoform 1 (MRP1), associated with a high level of intracellular glutathione (GSH), is a well-characterized mechanism of MDR in glioma cells. Previously, we have investigated the role of GSH and MRP1 in the accumulation of two radiopharmaceuticals classically used in nuclear medicine: (99m)Tc-sestamibi (MIBI) and (99m)Tc-tetrofosmin (TFOS), in a model of glioma cell lines. Although the involvement of GSH in MRP1-mediated transport of the two radiopharmaceuticals has been demonstrated, the exact transport mechanisms involving phase II (conjugation) and phase III (efflux) detoxification of these lipophilic cations has not been fully elucidated. To clarify the difference of release kinetics observed between MIBI and TFOS, we have studied the efficiency of formation of monogluthationyl conjugates mediated by glutathione S-transferses (GSTs). Our results clearly demonstrate that, in our model, the main efflux mechanism for radiopharmaceuticals is on monoglutathionyl-conjugates of MIBI (MIBI-SG) and TFOS (TFOS-SG). These mechanisms involving MRP1, and the phase II of detoxification is not efficient for TFOS in resistant glioma cells. A relatively slower catalytic efficiency of formation of TFOS-SG conjugate (0.006%.s(-1)) prevents its expulsion, contrary to MIBI (0.133%.s(-1)), suggesting that TFOS should be interesting in the detection and management of patients with high-grade glioma.

Topics: Catalysis; Cell Line, Tumor; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Glioma; Glutathione; Humans; Kinetics; Multidrug Resistance-Associated Proteins; Organophosphorus Compounds; Organotechnetium Compounds; Phenotype; Technetium Tc 99m Sestamibi

In our previous studies, we demonstrated a possible effect of cellular glutathione (GSH) depletion on plasma-membrane permeability and fluidity in glioma-cell lines. We therefore investigated the effect of GSH modulation on accumulation of two radiotracers, Tc-99m-sestamibi (MIBI) and Tc-99m-tetrofosmin (TFOS), and on plasma-membrane cholesterol content in sensitive U-87-MG and resistant U-87-MG-CIS and U-87-MG-MEL (MRP1 positive) human glioma-cell lines. GSH depletion was mediated by BSO pretreatment and addition of N-acetylcysteine reversed the effect. MIBI and TFOS uptakes, total cholesterol, and cholesteryl-ester contents were evaluated under each condition. In contrast with TFOS, MIBI accumulation was inversely proportional to the cell multidrug resistance phenotype. Similar cholesterol contents were observed in all cell lines, demonstrating that MRP1 did not modify lipid membrane composition. A decrease of intracellular GSH allows an increase of plasma-membrane cholesterol and a decrease of cholesteryl-ester content, which in turn results in spectacular TFOS uptake. The GSH status of the cells plays an important role in the plasma membrane cholesterol composition and TFOS uptake, which appears to be particularly sensitive to this modification. In contrast with MIBI, TFOS is not an MRP1 probe in glioma cells, and therefore appears to be a suitable tracer in this indication.

Topics: Biological Transport; Buthionine Sulfoximine; Cell Line, Tumor; Cholesterol Esters; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Glioma; Glutathione; Humans; Membrane Lipids; Multidrug Resistance-Associated Proteins; Organophosphorus Compounds; Organotechnetium Compounds; Technetium Tc 99m Sestamibi

Our aim was to determine whether the Ca2+ ion or cell membrane Ca2+ and Na+/Ca2+ ion transport systems are involved in maintaining the cell-associated activity of technetium-99m-hexakis-methoxy-isobutyl-isonitrile (99mTc-MIBI) and technetium-99m-ethylene-bis[bis(2-ethoxyethyl)phosphin] (99mTc-tetrofosmin) in tumour cell lines. The cell-associated activities of 99mTc-MIBI and 99mTc-tetrofosmin were assessed in various buffers, with or without Na+ and/or with different concentrations of Ca2+, in Lewi's murine lung cell carcinoma and human glioma cell lines. Different Ca2+ channel modulators, such as verapamil, flunarizine and 3,4-dichlorobenzamil (DCB), were used to assess the effect of Ca2+ channels on the cell-associated activity of 99mTc-MIBI and 99mTc-tetrofosmin. Despite significant differences between cell lines, the cell-associated activity of 99mTc-MIBI was higher in buffers without extracellular Ca2+ and Na+. The cell-associated activity of 99mTc-MIBI was significantly lower in all buffers containing high concentrations of Ca2+ in both cell lines. The cell-associated activity of Tc-tetrofosmin was also significantly higher in buffers without Ca2+, and was significantly decreased in buffers with high concentrations of Ca2+. All modulators significantly increased the cell-associated activity of 99mTc-MIBI in both cell lines in all buffers. All modulators increased the cell-associated activity of 99mTc-tetrofosmin, particularly in buffers containing Ca2+. The cell-associated activities of both 99mTc-MIBI and 99mTc-tetrofosmin may be dependent on verapamil-, flunarizine- and DCB-sensitive Ca2+ channels.

Topics: Amiloride; Animals; Antineoplastic Agents; Calcium; Calcium Channels; Carcinoma, Lewis Lung; Cell Survival; Extracellular Space; Flunarizine; Glioma; Humans; Ion Channel Gating; Metabolic Clearance Rate; Mice; Organophosphorus Compounds; Organotechnetium Compounds; Radionuclide Imaging; Radiopharmaceuticals; Sodium; Technetium Tc 99m Sestamibi; Tumor Cells, Cultured; Verapamil

We have investigated the effect of glutathione (GSH) depletion on the chemosensitivity of human malignant glioma cell lines: G111, G5 and G152. All the cell lines showed a multidrug resistant (MDR) phenotype associated with MRP1 expression, high intracellular levels of GSH, and depolarized plasma membranes. Tc-99M-Sestamibi (MIBI) and Tc-99M-Tetrofosmin (Tfos) were used for monitoring the MDR mechanisms. Modulation of GSH content was performed with butoxysulfoximide (BSO) pre-treatment alone or in combination with GSH ethyl ester. MIBI and Tfos accumulation in the cells was inversely correlated to the GSH content, a higher accumulation was found after BSO pre-treatment and addition of GSH ethyl ester reversed this process. BSO could therefore play a role as a chemosensitizing drug and thus help to overcome MDR. However, higher accumulation of MIBI and Tfos was observed even in the sensitive cells suggesting another effect of BSO on the cell physiological characteristics. No sign of apoptosis has been found indicating a possible direct effect on the plasma membrane fluidity and permeability. MIBI and Tfos don't follow the expected behavior of a MDR probe in the glioma cells and given the particular morpho-physiological characteristics of these types of tumors, Tfos could be rather used as a marker of the tumor growth and proliferation.

Topics: Annexin A5; Antimetabolites; Apoptosis; ATP Binding Cassette Transporter, Subfamily B; Blotting, Western; Buthionine Sulfoximine; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Glioma; Glutathione; Humans; Membrane Potentials; Mitochondria; Multidrug Resistance-Associated Proteins; Organophosphorus Compounds; Organotechnetium Compounds; Radiopharmaceuticals; Technetium Tc 99m Sestamibi; Tumor Cells, Cultured

Two radiopharmaceuticals, Tc-99m-MIBI (MIBI) and Tc-99m-Tetrofosmin (Tfos), are currently used for in vivo non-invasive monitoring of the MultiDrug Resistant (MDR) status of tumours. As gliomas are highly multidrug resistant, it is expected that the tracers would be poorly retained in those cells, but the in vivo and in vitro studies to date have shown that Tfos was highly retained in malignant gliomas. The high degree of malignancy of tumour cells is linked to alterations of physiological parameters as plasma membrane potential and intracellular pH. In order to elucidate the contribution of those parameters to Tfos and MIBI uptakes in malignant gliomas, we used several glioma cell lines--G111, G5, G152, and 42 MG-BA. These cells showed to be chemoresistant with a high level of expression and activity of the Multidrug Resistant associated Protein 1 (MRP1). They also had an alkaline intracellular pH (pHi) related to the Na+/H+ antiporter (NHE-1) expression and depolarised plasma membranes (-45 to -55 mV). In spite of their chemoresistance, we have found a high accumulation of both radiotracers in gliomas, more important for Tfos than MIBI, related to the presence and activity of NHE-1. In conjunction, the uptakes of the tracers were only partially dependent upon the plasma membrane potential of the glioma cell lines, again Tfos uptake being less dependent on this parameter than MIBI uptake. In conclusion, the evidence accumulated in this study suggests that Tfos could be a suitable glioma marker in vivo.

Topics: Glioma; Humans; Hydrogen-Ion Concentration; Membrane Potentials; Multidrug Resistance-Associated Proteins; Organophosphorus Compounds; Organotechnetium Compounds; Radionuclide Imaging; Radiopharmaceuticals; Sodium-Hydrogen Exchangers; Technetium Tc 99m Sestamibi; Tumor Cells, Cultured

The objective of this study was to compare the accumulation of Tc-99m-tetrofosmin and Tc-99m-sestamibi in four grade IV glioma cell lines and to correlate their accumulation with the multidrug resistance of the cells. Tc-99m-tetrofosmin in all glioma cell lines showed slightly higher uptake and more efficient release beyond 150 min than Tc-99m-sestamibi and the retention of both tracers in the cells was to a certain extend inversely proportional to their degree of multidrug resistance. The results obtained showed that the efflux of both tracers was carried out only in part through the MRP/GS-X pump system. Tc-99m-tetrofosmin showed good potential as a marker of recurrent malignant glioma and in vivo studies are currently underway to confirm these observations.

Topics: Antibodies, Monoclonal; ATP-Binding Cassette Transporters; Biomarkers, Tumor; Brain Neoplasms; Flow Cytometry; Genes, MDR; Glioma; Glutathione; Humans; Immunoglobulin G; Multidrug Resistance-Associated Proteins; Organophosphorus Compounds; Organotechnetium Compounds; Radiopharmaceuticals; Technetium Tc 99m Sestamibi