Myocardial perfusion SPECT as a potential mediator on circulating chromogranin A in patients with old myocardial infarction.

OBJECTIVE: Chromogranin A (CgA) is a soluble polypeptide stored within and released from secretory granules of endocrine and other cell types (including cardiomyocytes); CgA appears to be a marker of the overall neuroendocrine activity. Increased levels of serum CgA have been found not only in patients with neuroendocrine neoplasms but also with other malignancies, hypertension, myocardial infarction, heart, or renal failure. SUBJECTS AND METHODS: A population of 307 patients (202 males, 105 females) was enrolled. The study group consisted of 118 individuals (38.4%) with myocardial infarction more than one year old (MI group); the remaining 189 (61.6%) had no known heart disease (control group). All patients underwent myocardial perfusion scintigraphy (MPS) after blood withdrawal for serum CgA measurement. To test whether a possible effect of old infarction on serum CgA is mediated by MPS findings, we employed analysis of covariance for three distinct categories of left ventricular (LV) perfusion deficits as dichotomous predictors: (1) any-type deficits (abnormal MPS); (2) reversible deficits (ischemia); and (3) fixed deficits (scar). RESULTS: In all three MPS conditions, the effect of age, gender, and LV ejection fraction (EFLV) on serum CgA was statistically significant: women exhibited higher CgA levels than men (P=0.008-0.023), whereas increasing age and decreasing EFLV were associated with increasing CgA (all P<0.001). Conversely, no statistically significant differences in mean CgA levels were found between MI patients and normal controls with either abnormal MPS, scar, or ischemia, or their degree and extent. CONCLUSION: Although serum CgA is significantly associated with age, gender, and EFLV in patients with an old MI, no association was found between CgA levels and either old MI history or MPS findings. The verified involvement of circulating CgA in the acute/subacute phase of infarction appears to be blunted in infarctions older than a year.

Performance of 18F-FDG, 11C-Methionine, and 18F-FET PET for Glioma Grading: A Meta-analysis.

PURPOSE: Gliomas constitute the most frequent primary brain tumors. Glioblastoma, the most common and malignant glioma in adults, has dismal prognosis with any current therapy. On the other hand, low-grade gliomas, the second most common type of gliomas, are potentially curative with appropriate treatment. METHODS: We conducted a meta-analysis to assess the performance of PET tracers with the best available evidence, namely, fluorodeoxyglucose (FDG), C-methionine (MET), and F-fluoroethyltyrosine (FET), in differentiating low- from high-grade gliomas. RESULTS: Twenty-three studies with a total of 994 participants were included in this meta-analysis. The pooled sensitivities of both MET PET and FET PET were found to be significantly higher than of FDG PET (94%, 88%, and 63% respectively, P < 0.001). The pooled specificity of FDG PET was found to be significantly greater compared with both MET PET and FET PET (89%, 55%, and 57%, respectively; P = 0.002). Fluorodeoxyglucose PET was superior in terms of higher positive likelihood ratio values compared with both FET PET and MET PET. CONCLUSIONS: This meta-analysis indicated that both MET and FET were superior to FDG in terms of sensitivity for identifying glioma grade.

99mTc-Tetrofosmin Uptake Correlates with the Sensitivity of Glioblastoma Cell Lines to Temozolomide.

99mTc-tetrofosmin (99mTc-TF) is a single-photon emission computed tomography tracer that has been used for brain tumor imaging. The aim of the study was to assess if 99mTc-TF uptake by glioblastoma cells correlates with their response to temozolomide (TMZ). We investigated the correlation of TMZ antitumor effect with the 99mTc-TF uptake in two glioblastoma cell lines. The U251MG cell line is sensitive to TMZ, whereas T98G is resistant. Viability and proliferation of the cells were examined by trypan blue exclusion assay and xCELLigence system. Cell cycle was analyzed with flow cytometry. The radioactivity in the cellular lysate was measured with a gamma scintillation counter. TMZ induced G2/M cell cycle arrest in U251MG cells, whereas there was no effect on cell cycle in T98G cells. Lower 99mTc-TF uptake was observed in U251MG cells that were exposed to TMZ compared to control (P = 0.0159). No significant difference in respect to 99mTc-TF uptake was found in T98G cells when exposed to TMZ compared to control (P = 0.8). With 99mTc-TF, it was possible to distinguish between TMZ-sensitive and resistant glioblastoma cells within 6 h of treatment initiation. Thus, 99mTc-TF uptake may consist a novel approach to assess an early response of glioblastoma to chemotherapy and deserves further investigation.

Comparison of (99m)tc-tetrofosmin and (99m)tc-sestamibi uptake in glioma cell lines: the role of p-glycoprotein expression.

(99m)Tc-Tetrofosmin ((99m)Tc-TF) and (99m)Tc-Sestamibi ((99m)Tc-MIBI) are SPECT tracers that have been used for brain tumor imaging. Tumor's multidrug resistance phenotype, namely, P-glycoprotein (p-gp), and the multidrug resistance related proteins (MRPs) expression have been suggested to influence both tracers' uptake. In the present study we set out to compare (99m)Tc-TF and (99m)Tc-MIBI uptake in high-grade glioma cell lines and to investigate the influence of gliomas p-gp expression on both tracers' uptake. We used four glioma cell lines (U251MG, A172, U87MG, and T98G). The expression of p-gp protein was evaluated by flow cytometry. Twenty µCi (7.4·10(5) Bq) of (99m)Tc-TF and (99m)Tc-MIBI were used. The radioactivity in the cellular lysate was measured with a dose calibrator. P-gp was significantly expressed only in the U251MG cell line (P < 0.001). In all gliomas cell lines (U251MG, U87MG, A172, and T98G) the (99m)Tc-TF uptake was significantly higher than (99m)Tc-sestamibi. The U251MG cell line, in which significant p-gp expression was documented, exhibited the strongest uptake difference. (99m)Tc-TF uptake was higher than (99m)Tc-MIBI in all studied high-grade glioma cell lines. Thus, (99m)Tc-TF may be superior to (99m)Tc-MIBI for glioma imaging in vivo.

Comparison of diffusion tensor, dynamic susceptibility contrast MRI and (99m)Tc-Tetrofosmin brain SPECT for the detection of recurrent high-grade glioma.

INTRODUCTION: 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. METHODS: 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. RESULTS: 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). CONCLUSIONS: 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.

Correlation of diffusion tensor, dynamic susceptibility contrast MRI and (99m)Tc-Tetrofosmin brain SPECT with tumour grade and Ki-67 immunohistochemistry in glioma.

OBJECTIVE: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: Findings on DSC MRI and brain SPECT with (99m)Tc-Tetrofosmin metrics were more closely correlated with glioma cellular proliferation.

Is there still a place for SPET in the era of PET brain imaging?

Although positron emission tomography (PET) may be credited with providing the impetus for the new clinical interest in functional neuroimaging and currently is an increasingly important imaging tool for noninvasive assessment of brain tumors, single-photon emission tomography (SPET) has offered an alternative technique with the relative advantages of lower price and wide availability. Brain SPET has been proven useful in the differentiation of tumor recurrence from radiation necrosis, in the non-invasive assessment of gliomas and meningiomas aggressiveness, in differentiating neoplastic from non neoplastic intracerebral haemorrhage, in monitoring treatment response and estimating patients' prognosis. Thus, SPET may still have a role in the diagnosis and characterization of brain tumors. Future comparative studies between SPET and PET or latest magnetic resonance based neuroimaging techniques are warranted.

Glioblastoma multiforme imaging: the role of nuclear medicine.

Glioblastoma multiforme (GBM) is the most common and most malignant primary brain tumor occurring during adulthood. The incidence of GBM is nearly 5 cases per 100,000 population per year. The standard of care for newly diagnosed GBM includes surgical resection when possible, followed by radiotherapy and concomitant and adjuvant chemotherapy with temozolomide. Imaging modalities used in nuclear medicine, namely positron emission tomography (PET) and single-photon emission computed tomography (SPECT) have been employed towards the evaluation of brain tumors. Herewith, we discuss the value of the above imaging techniques in the assessment of GBM aggressiveness, in the distinction of treatment induced necrosis from glioma recurrence, in the estimation of overall prognosis and in the evaluation of treatment response in patients with GBM.

Prognostic significance of MRP5 immunohistochemical expression in glioblastoma.

INTRODUCTION: Glioblastoma multiforme (GBM) is the most frequent malignant primary brain tumor in adults, exhibiting poor survival. The efficacy of chemotherapy is often limited by the development of multidrug resistance by the tumor cells. In the current study, we investigated the prognostic significance of the multidrug resistance protein 5 (MRP5) in patients with GBM. MATERIALS AND METHODS: We retrospectively studied 33 patients with GBM treated with a combination of surgery, postoperative radiotherapy and adjuvant temozolomide chemotherapy. MRP5 protein expression was determined immunohistochemically and correlated with other prognostic factors and survival. RESULTS: The immunohistochemical expression of MRP5 was observed in 0-45% of tumor cells. Patients with MRP5 index >11% exhibited significantly worse survival compared to those with MRP5 index ≤ 11 (10.5 vs. 18 months, p = 0.0002). Patients with Ki-67 index lower than 30% had longer survival (15 vs. 11 months, p = 0.0084). Furthermore, patients with a gross total tumor excision had better survival (p = 0.016). No significant difference was observed between preoperative Karnofsky performance score, age, gender and survival. In multivariate analysis, MRP5 index and the extent of tumor resection were identified as factors with independent prognostic power. CONCLUSION: The present results imply that MRP5 index may hold a prognostic role in patients with GBM.

Influence of glioma's multidrug resistance phenotype on (99m)Tc-tetrofosmin uptake.

PURPOSE: 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. PROCEDURES: 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. RESULTS: 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. CONCLUSION: 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.

Characterization of intracranial space-occupying lesions by 99(m)Tc-Tetrofosmin SPECT.

Differentiating neoplastic from non-neoplastic intracranial lesions is of paramount importance for patient management. Benign lesions can have many of the features of malignant brain tumors on both computed tomography (CT) and conventional magnetic resonance imaging (MRI). Herewith, we set out to investigate the role of (99m)Tc-Tetrofosmin (99(m)Tc-TF) brain SPECT in the differentiation of neoplastic from non-neoplastic intracranial lesions. We prospectively studied, between September 2004 and September 2009, patients with intracranial lesions suspected of being tumors on CT/MRI that were operated on. All patients with suspected tumor on CT/MRI underwent 99(m)Tc-TF brain SPECT within a week before surgery and CT/MRI studies. Radiotracer accumulation in intracranial lesions was assessed visually and then a semiquantitative method of image analysis was applied, by calculating the lesion-to-normal (L/N) uptake ratio. We compared the L/N ratios between low-grade gliomas and high-grade gliomas, low and high-grade gliomas and intra-axial non-neoplastic lesions, low and high-grade gliomas and metastases, and typical versus anaplastic meningiomas Ninety patients suffered from neoplastic lesions and 16 harboured non-neoplastic pathologies. There was a significant difference between low-grade gliomas and high-grade gliomas (P = 0.0019). ROC analysis provided 2.8 as the optimum cutoff value thresholding discrimination between these two groups, with 91.3% sensitivity and 83.3% specificity. When comparing gliomas (low and high-grade) with intra axial non-neoplastic lesions the difference was statistically significant (P < 0.0001). There was no statistically significant difference between gliomas (low and high-grade) and metastases. Regarding meningiomas, there was a statistically significant difference between typical and anaplastic meningiomas (P = 0.0002). ROC analysis provided 9.6 as the optimum cutoff value thresholding discrimination between these two groups, with 96% sensitivity and 100% specificity. (99m)Tc-TF brain SPECT may differentiate neoplastic from non-neoplastic intracranial pathologies and could prove useful for pre-surgical evaluation of intracranial lesions.

The value of 99mTc-tetrofosmin brain SPECT in predicting survival in patients with glioblastoma multiforme.

UNLABELLED: (99m)Tc-tetrofosmin brain SPECT has been reported as a useful tool for the evaluation of glioma proliferation. In the present study, we set out to investigate the prognostic value of (99m)Tc-tetrofosmin brain SPECT in patients with glioblastoma multiforme. METHODS: We prospectively studied 18 patients (13 men, 5 women; mean age ± SD, 60.8 ± 7.79 y) who were operated on for glioblastoma multiforme. All patients underwent preoperative (99m)Tc-tetrofosmin brain SPECT, and surgical excision was performed within a week after SPECT. All patients received postoperative radiotherapy and chemotherapy. RESULTS: By calculating the lesion-to-normal (L/N) (99m)Tc-tetrofosmin uptake ratio, we found that patients with an L/N ratio of more than 4.7 had significantly worse survival than did patients with an L/N ratio of 4.7 or less. Furthermore, patients with a Karnofsky Performance Score more than 90 had a significantly better survival rate. Although patients with near-total tumor resection who were younger than 60 y survived longer, the difference did not reach statistical significance. In the multivariate analysis, (99m)Tc-tetrofosmin uptake and Karnofsky Performance Score were identified as factors with independent prognostic power. CONCLUSION: (99m)Tc-tetrofosmin brain SPECT may be an independent prognostic factor in patients with glioblastoma multiforme. Further larger studies are needed to verify these results.

Assessment of glioma proliferation using imaging modalities.

The assessment of glioma proliferation rate is important to predict tumor behavior, response to therapy and prognosis. Various methods, largely involving immunohistological markers in tissue samples, have been proposed to this aim; however, they all require tissue removal through a biopsy or during a surgical procedure. Consequently, non-invasive imaging modalities that could reliably assess the proliferative potential of intracranial space-occupying lesions in vivo would be of obvious significance. In the present study we review the contribution of MRI, positron emission tomography and single-photon emission CT for the assessment of the proliferative potential of gliomas.

Correlation of glioma proliferation assessed by flow cytometry with (99m)Tc-Tetrofosmin SPECT uptake.

OBJECTIVES: Brain single-photon emission computed tomography (SPECT) has been proposed as a potentially useful modality for the metabolic assessment of various brain tumors. MATERIAL AND METHODS: 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. RESULTS: 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). CONCLUSION: Initial evidence suggests that (99m)Tc-TF could provide a non-invasive indicator of glioma proliferative activity.

Glioma recurrence versus radiation necrosis: accuracy of current imaging modalities.

Treatment for brain gliomas is a combined approach of surgery, radiation therapy and chemotherapy. Nevertheless, high-grade gliomas usually recur despite treatment. Ionizing radiation therapy to the central nervous system may cause post-radiation damage. Differentiation between post-irradiation necrosis and recurrent glioma on the basis of clinical signs and symptomatology has not been possible. Computed tomography (CT) and magnetic resonance imaging (MRI) suffer from significant limitations when applied to differentiate recurrent brain tumor from radiation necrosis. We reviewed the contribution of recent MRI techniques, single-photon emission CT and positron emission tomography to discriminate necrosis for glioma recurrence. We concluded that despite the progress being made, further research is needed to establish reliable imaging modalities that distinguish between true tumour progression and treatment-related necrosis.