Spyridon Voulgaris

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.

Evaluation of meningioma aggressiveness by 99mTc-Tetrofosmin SPECT

OBJECTIVES Although meningiomas usually have a benign clinical course, atypical and malignant types of this brain tumor are associated with high recurrence rates and poor outcome; thus, DNA ploidy and S-phase -- as determined by DNA flow cytometry -- are useful indicators of their biological behavior. Brain single-photon emission computed tomography (SPECT) has been suggested as a potentially useful modality for the metabolic assessment of various brain tumors. This study evaluated whether (99m)Tc-Tetrofosmin ((99m)Tc-TF) uptake correlates with meningioma proliferative activity, as assessed by flow cytometry analysis. PATIENTS AND METHODS Ten consecutive patients (3 males, 7 females, mean age 64.6 years) with a diagnosis of a symptomatic intracranial meningioma, planned to undergo surgery, were studied. Brain SPECT by (99m)Tc-TF was performed within a week prior to surgical excision and flow cytometric analysis was performed in the excised tissue. Tumoral radiotracer accumulation was first assessed visually. Semiquantitative image analysis was also performed, by calculating the lesion-to-normal (L/N) uptake ratio. RESULTS Benign meningiomas were diagnosed in 8/10 cases, the remaining 2/10 patients had anaplastic lesions. DNA aneuploidy was found in 2 lesions, the remaining tumors were diploid. There was a significant correlation between tracer uptake and the percentage of the cell fraction on S-phase (r=0.733, P=0.05). There was also a positive correlation between tracer uptake and the level of aneuploidy and tumor grade. CONCLUSION These results imply that (99m)Tc-TF brain SPECT may have the ability to discriminate benign meningiomas from malignant meningiomas pre-operatively, the tracer uptake being a likely indicator of their proliferative activity.

Frequent abnormalities of the immune system in gliomas and correlation with the WHO grading system of malignancy

AIM To investigate the cellular and humoral immunity status of gliomas, and their association with the WHO grading system. MATERIAL AND METHODS We have conducted a case-control study of 49 patients with gliomas and 30 healthy controls. We used ELISA assays, radial immunodiffusion, indirect immunofluorescence, latex test and flow cytometry assays to estimate preoperative in serum the immunological profile. RESULTS Patients with glioma had significantly reduced amounts of IL2 (p=0.000), TNF-a (p=0.033), IgG (p=0.011), IgA (p=0.027),C4 (p=0.026) ,CD3+ (p=0.001), CD4+ (p=0.000), CD8+ (p=0.002), ratio CD4/CD8 (p=0.000), CD19+ (p=0.04) and elevated IL10 (p=0.05) compared with healthy controls. No statistically significant differences were observed concerning viral agents, total NK cells, IgM, IgE, IL16, granzyme-b, RF, ANA, ENA, anti-dsDNA and anti-cardiolipin antibodies. A higher WHO grade, after controlling for age and gender, was associated with decreased number of CD3+ (p=0.011), CD4+ (p=0.015), CD8+ (p=0.048) and ratio CD4/CD8 (p=0.027), as well as with decreased IL2 (p=0.018), C4 (p=0.02), and IgG (p=0.05). IL2 and CD4+ counts were significant predictors of grade. CONCLUSIONS A shift from Th1 to Th2, a CD3+ and CD19+ lymphocytopenia, a diminished fraction CD4/CD8 and a reduced amount of immunoglobulins and complement were observed in the patients with gliomas. A higher WHO grade of the tumor was associated with greater impairments of immunity. Since defects of both humoral and cellular immunity were equally observed and significant predictors of grade were assessed, a preoperative evaluation of the immune system of patients with gliomas is being proposed.

Correlation of matrix metalloproteinases-1 and -3 with patient age and grade of lumbar disc herniation.

OBJECT The authors studied the histological alterations and the expression of matrix metalloproteinase (MMP)-1 and MMP-3 in disc specimens of patients who had undergone operations for lumbar disc herniation. METHODS Forty-three lumbar disc specimens were evaluated histopathologically for degenerative changes and immunohistochemical expression of MMP-1 and MMP-3. The observed degenerative changes provided a degenerative score that was applied in each patient. Sections of disc immunostained for MMP-1 and MMP-3 were evaluated semiquantitatively. Patients were categorized in 3 age groups: < 30 years, between 30 and 60 years, and > 60 years of age. The expression of MMP-1 and MMP-3 were correlated to patients age, degenerative score, and grade of lumbar disc herniation. RESULTS There was no statistically significant difference in the degenerative score between the age groups. Degenerative changes were more pronounced in greater grades of herniation (p < 0.0001). In the group of patients < 30 years of age there was a significant correlation between MMP-1 and MMP-3 expression and both degenerative score and herniation grade. For the group of patients 30-60 years of age, there was no significant difference between MMP-1 expression and degenerative score, but the correlation between MMP-1 expression and grade of herniation was significant. There was a significant correlation between MMP-3 expression and both degenerative score and herniation grade. Regarding the patients > 60 years of age, there was a significant correlation between MMP-1 and MMP-3 expression and both degenerative score and herniation grade. There was a significantly lower expression of both MMP-1 and MMP-3 in the group < 30 years of age compared with the other ages. No significant correlation was found in MMP-1 and MMP-3 expression between the groups of patients who were 30-60 and > 60 years of age. Interestingly, in age groups > 30 years, there were no statistically significant differences between the expression of MMP-1 and MMP-3, whereas in patients < 30 years of age the expression of MMP-3 was significantly lower than the expression of MMP-1. CONCLUSIONS The expression of MMP-1 and MMP-3 were strongly correlated to the age of the patients and the grade of herniation. An important finding in this study is the differential expression of MMP-1 and MMP-3 between the age groups. In the young age group it appears that deregulation of MMP-1 expression is higher than that of MMP-3 in the pathogenesis of lumbar disc herniation.

Descriptive Epidemiology of Cerebral Gliomas in Northwest Greece and Study of Potential Predisposing Factors, 2005–2007

Background: To investigate the epidemiologic and clinical characteristics (age, sex, tumor location, socioeconomic status) and potential predisposing factors (alcohol, tobacco, mobile phone use, severe head trauma) of cerebral gliomas in a defined area of Northwest Greece. Methods: The prospective study was conducted in patients with gliomas referred to all 7 hospitals of a study area with a population of 488,435 inhabitants, from June 1, 2005, to May 31, 2007. Incidence rates (IR) were calculated as new cases diagnosed among residents of the study area during the study period per 100,000 inhabitants. A case-control study was carried out in order to study the possible association of the risk of glioma with smoking, alcohol, use of mobile phone, and severe cranial trauma. Results: A total of 56 glioma incident cases were identified with IRs of glioma and glioblastoma (GBM) at 5.73/105/year and 3.69/105/year, respectively. A male to female ratio of 1.25 was obtained in the GBM group. IRs of glioma and GBM for both males and females were higher in the age group 60–79. The most frequent anatomic location was the frontal lobe. 46.5% of the patients originated from the low, 25% from the middle and 28.5% from the high socioeconomic class. There was no significant association between glioma and alcohol consumption, smoking and mobile phone use. A trend for a positive association between the risk of glioma and a history of severe cranial trauma was observed, but this association was not statistically significant. Conclusion: The estimated IR of glioma and GBM in this study was higher compared with data from other studies carried out on European, Asian and US populations. Further studies may be needed to assess the possible association of genetic, environmental and lifestyle factors with the high occurrence of gliomas observed in this study.

Fast cell cycle analysis for intraoperative characterization of brain tumor margins and malignancy

Flow cytometry, although indispensable for the characterization of hematologic malignancies, has not been extensively evaluated in solid tumors. To date intraoperative pathology evaluation of frozen sections of tissue obtained during surgery is the gold standard for intraoperative diagnosis. We investigated the value of a modified rapid protocol for cell cycle analysis for the intraoperative characterization of intracranial lesions and their surgical margins. We investigated patients who underwent surgery for an intracranial lesion suspicious for a tumor. DNA analysis and frozen sections were performed on tumor samples that were taken during surgery. Thirty-one patients met the inclusion criteria for the study. There was a significant difference in G0/G1 phase between high-grade and low-grade tumors. Receiver operating characteristic (ROC) analysis provided 75% of G0/G1 fraction as the optimal cutoff value thresholding the discrimination between low and high-grade tumors. There was a significant difference in S-phase and mitoses fraction between high-grade and low-grade tumors. ROC analysis indicated 6% of S-phase and 9.7% of mitoses as the optimal cutoff values thresholding the discrimination between these two groups. In the glioblastoma patients, we also analyzed the perilesional tissue and found significant differences between tumor mass and margins regarding the G0/G1 phase, the S-phase and mitoses fraction. In conclusion rapid cell cycle analysis is a method capable of differentiating low from high-grade tumors and delineating tumor margins in gliomas. Thus, the role of cell cycle analysis in brain tumors warrants further investigation.

Diffusion tensor and dynamic susceptibility contrast MRI in glioblastoma.

OBJECTIVE We prospectively investigated the correlation between diffusion tensor (DTI), dynamic susceptibility contrast (DSC) perfusion MRI metrics and Ki-67 labelling index in glioblastomas. METHODS We studied seventeen patients who were operated on for glioblastoma. DTI and DSC MRI were performed within a week prior to surgical excision. Lesion/normal ratios were calculated for the apparent diffusion coefficient (ADC), fractional anisotropy (FA), relative cerebral blood volume (rCBV), relative cerebral blood flow (rCBF) and relative mean transit time (rMTT) ratio. In the excised tumour specimens Ki-67 antigen expression was evaluated by the MIB-1 immunostaining method. RESULTS A significant correlation was observed between Ki-67 index and ADC ratio (r = -0.528, p = 0.029) and FA ratio (r = 0.589, p = 0.012). rCBV and rMTT presented a trend towards significant correlation with Ki-67 index (r = 0.628, p = 0.07 and r = 0.644, p = 0.06 respectively). There was a trend towards better survival for patients with gross total tumour excision and FA values lower than 0.48 (p = 0.1 and p = 0.09 respectively). No significant correlation was found between ADC ratio, rCBV, rCBF, rMTT and overall survival. CONCLUSION ADC ratio, FA ratio, rCBV and rMTT tumour/normal tissue ratios may represent indicators of glioma proliferation. FA values may hold promise for predicting survival in patients with glioblastoma.

Coagulopathy in moderate head injury. The role of early administration of low molecular weight heparin

Introduction: Abnormalities in blood coagulation are relatively common after traumatic brain injury (TBI). We prospectively studied the safety of the early antithrombotic prophylaxis with low molecular weight heparin. Methods: We prospectively evaluated 61 patients with moderate TBI. Patients requiring surgical treatment and/or with injuries in other systems were excluded. Coagulation studies included among others prothrombin time (PT), plasma fibrinogen levels and D-dimer levels. Blood samples were collected on admission and 24 h, 48 h, and 72 h later. Prophylaxis was started within 24 hours with tinzaparin. Results: In 42 of 61 patients a form of disseminated intravascular coagulation (DIC) was detected. The severity of head injury was correlated with the severity of the coagulation disorders. The PT was prolonged in the first two days. Plasma fibrinogen levels dropped initially and increased to above normal values 2-3 days later. D-dimer levels were significantly elevated and in 19 patients remained elevated throughout the study period. Clinical manifestations of DIC were not observed. Conclusions: Patients with moderate TBI are at a serious risk of developing brain intravascular microthrombosis. Our study supports the early use of low molecular weight heparin.

The role of the PTEN gene in malignant gliomas

This article focuses on the latest data about the role of the gene for phosphatase and tensin homologue located on chromosome 10 (PTEN) in malignant gliomas. PTEN acts as a tumour suppressor gene and plays a critical role in cell cycle progression, angiogenesis, migration, invasions and stem cell regulation. Furthermore, there is an interaction with other tumour suppressor genes. We discuss the role of miRNAs in modulating PTEN expression and also PTENs role in the nucleus.

Correlation of glioma proliferation assessed by flow cytometry with 99mTc-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.