Yoshiko Okita

11C-methionine uptake correlates with tumor cell density rather than with microvessel density in glioma: A stereotactic image-histology comparison

(11)C-methionine positron emission tomography ((11)C-methionine PET) provides accurate detection of brain tumors. Several reports have analyzed the correlation between uptake of (11)C-methionine and Ki-67 index or microvessel density non-stereotactically and suggested that (11)C-methionine uptake reflects both proliferation potential and angiogenic capability in gliomas. As gliomas possess heterogeneous histological architecture, non-stereotactic comparison of the histology and (11)C-methionine PET image may not be accurate. In the present study, the correlation between (11)C-methionine uptake and cell or microvessel density was analyzed using histological specimens obtained by stereotactic biopsy, and an exact local comparison of (11)C-methionine PET image and histological specimens was conducted. The tumor/normal tissue (T/N) ratio of (11)C-methionine positron emission tomography was found to correlate better with cell density (R=0.747, p=0.000042) and Ki-67 index (R=0.675, p=0.00041) than with microvessel density (R=0.467, p=0.025) in a histological comparison using a stereotactic image. Furthermore, multiple linear regression analysis revealed that cell density was the key determinant for predicting (11)C-methionine level while microvessel density was not. These results suggest that cell density contributes more to (11)C-methionine uptake than microvessel density in glioma tissues and that the previously reported correlation of (11)C-methionine uptake and microvessel density in glioma patients requires reevaluation.

Diffusion tensor-based tumor infiltration index cannot discriminate vasogenic edema from tumor-infiltrated edema

Diffusion tensor imaging (DTI) by magnetic resonance imaging (MRI) is now used not only for delineating white matter fiber tracts, but also for assessing the histological characteristics of pathological tissues. Among these uses, predicting the extent or existence of tumor cell invasion into white matter by DTI is under extensive investigation. The previously reported tumor infiltration index (TII) holds great potential for the discrimination of pure vasogenic edema from tumor-infiltrated edema. However, conflicting data are being reported questioning the clinical value of TII. The present investigation reevaluated the utility of TII in patients with meningioma or glioma. We found that TII was unable to discriminate vasogenic from tumor-infiltrated edema. Conversely, detailed voxel-by-voxel comparison of TII and 11C-methionie PET in the T2-hyperintense area of gliomas showed that TII and 11C-methionie PET has a positive correlation, suggesting that, although TII is unable to discriminate the cause of edema, the extent of tumor cell invasion into white matter is depicted in gliomas by TII. These data suggest that TII involves both vasogenic and tumor-infiltrated factors, rather than only a single factor. A more intensive investigation is required to reach a complete understanding of TII.

IDH1/2 mutation is a prognostic marker for survival and predicts response to chemotherapy for grade II gliomas concomitantly treated with radiation therapy

Reliable prognostic biomarkers of grade II gliomas remain unclear. This study aimed to examine the role of mutations of isocitrate dehydrogenase (IDH1/2), 1p/19q co-deletion, and clinicopathological factors in patients with grade II glioma who were primarily treated with radiotherapy or chemoradiotherapy after surgery. Seventy-two consecutive patients, including 49 cases of diffuse astrocytomas (DA), 4 oligodendrogliomas (OL) and 19 oligoastrocytomas (OA), who underwent treatment from 1991 to 2010 at a single institution were examined. The overall survival (OS) of the DA patients (8.3 years) was significantly shorter than that of the OL and OA patients (11.7 years). IDH1/2 mutations were found in 46.9% of the DA patients and 82.6% of the OL and OA patients. The progression-free survival (PFS) and OS of the patients with IDH1/2 mutations (8.4 and 16.3 years) were significantly longer than those of the patients without IDH1/2 mutations (3.3 and 4.5 years). Among the patients with IDH1/2 mutations, those who were initially treated with chemoradiotherapy including nimustine hydrochloride (ACNU), had significantly longer PFS than those treated with radiotherapy alone, whereas no significant difference in PFS was observed between the chemoradiotherapy and radiotherapy groups in the patients without IDH1/2 mutations. Oligodendroglial tumors, age <40 years, initial Karnofsky performance status (KPS) ≥80, and IDH1/2 mutations were favorable prognostic factors regarding PFS and OS. IDH1/2 mutation was a predictive factor of response to chemoradiotherapy in grade II gliomas. Patients with IDH1/2 mutations may benefit more from chemoraiotherapy than those without IDH1/2 mutations.

A combination of TERT promoter mutation and MGMT methylation status predicts clinically relevant subgroups of newly diagnosed glioblastomas

The prognostic impact of TERT mutations has been controversial in IDH-wild tumors, particularly in glioblastomas (GBM). The controversy may be attributable to presence of potential confounding factors such as MGMT methylation status or patients’ treatment. This study aimed to evaluate the impact of TERT status on patient outcome in association with various factors in a large series of adult diffuse gliomas. We analyzed a total of 951 adult diffuse gliomas from two cohorts (Cohort 1, n = 758; Cohort 2, n = 193) for IDH1/2, 1p/19q, and TERT promoter status. The combined IDH/TERT classification divided Cohort 1 into four molecular groups with distinct outcomes. The overall survival (OS) was the shortest in IDH wild-type/TERT mutated groups, which mostly consisted of GBMs (P < 0.0001). To investigate the association between TERT mutations and MGMT methylation on survival of patients with GBM, samples from a combined cohort of 453 IDH-wild-type GBM cases treated with radiation and temozolomide were analyzed. A multivariate Cox regression model revealed that the interaction between TERT and MGMT was significant for OS (P = 0.0064). Compared with TERT mutant-MGMT unmethylated GBMs, the hazard ratio (HR) for OS incorporating the interaction was the lowest in the TERT mutant-MGMT methylated GBM (HR, 0.266), followed by the TERT wild-type-MGMT methylated (HR, 0.317) and the TERT wild-type-MGMT unmethylated GBMs (HR, 0.542). Thus, patients with TERT mutant-MGMT unmethylated GBM have the poorest prognosis. Our findings suggest that a combination of IDH, TERT, and MGMT refines the classification of grade II-IV diffuse gliomas.

MR molecular imaging of HER-2 in a murine tumor xenograft by SPIO labeling of anti-HER-2 affibody.

In vivo molecular imaging is a rapidly growing research area both for basic and clinical science. Non-invasive imaging of in vivo conditions at the molecular level increases understanding of the biological characteristics of normal and diseased tissues without the need for invasive surgical procedures. Among the various imaging modalities, magnetic resonance imaging (MRI) has garnered interest as a molecular imaging modality due to its high spatial resolution. Here, we have demonstrated that the combined use of HER-2 targeting affibody, a small 7 kDa molecule that behaves similarly to antibodies, and superparamagnetic iron oxide (SPIO) can non-invasively image HER-2 expressing cells or tissues both in vitro and in vivo by MRI. This preliminary study demonstrates that affibody-SPIO is a feasible, target-specific contrast agent for in vivo MR molecular imaging.

Use of fractional anisotropy for determination of the cut-off value in 11C-methionine positron emission tomography for glioma.

Multimodal imaging is one of the necessary steps in the treatment of malignant brain tumors, and use of magnetic resonance imaging (MRI) and positron emission tomography (PET) are the current gold standard technique for the morphological and biological assessment of malignant brain tumors. In addition, fractional anisotropy (FA) obtained from diffusion tensor imaging (DTI) and 11C-methionine PET are useful to determine the tumor border at the tumor and white matter interface. Although there is no question of their value, a universally accepted cut-off value to discriminate normal and abnormal tissue has not been established. In this study we attempted to calculate and determine the cut-off values in FA and 11C-methionine PET that will allow delineation of the tumor border at the tumor and white matter interface by combining these two modalities. We were able to determine individual cut-off values for 11 patients, and then found an average cut-off value in the T/N ratio of 11C-methionine PET of 1.27 and in FA of 0.26, values similar to those previously confirmed by histological study. Moreover, reconstructing images delineating the tumor border was possible combining these two imaging modalities. We propose that the combined analysis of DTI and 11C-methionine PET has the potential to improve tumor border imaging in glioma patients, providing important information for establishing neurosurgical strategies.

A Novel PET Index, 18F-FDG–11C-Methionine Uptake Decoupling Score, Reflects Glioma Cell Infiltration

The linear correlation between 11C-methionine PET and tumor cell density is not well conserved at the tumor border in glioma. A novel imaging analysis method, voxelwise 18F-FDG–11C-methionine PET decoupling analysis (decoupling score), was evaluated to determine whether it could be used to quantitatively assess glioma cell infiltration in MRI-nonenhancing T2 hyperintense lesions. Methods: Data collection was performed in a prospective fashion. Fifty-four MRI-nonenhancing T2 hyperintense specimens were stereotactically obtained from 23 glioma patients by intraoperative navigation guidance. The decoupling score and tumor–to–normal tissue (T/N) ratio of 11C-methionine PET were calculated at each location. Correlations between the tumor cell density at these lesions, decoupling score, and T/N ratio of 11C-methionine PET were then evaluated. Results: Both the decoupling score and the T/N ratio showed a linear correlation with tumor cell density at these specimens (R2 = 0.52 and 0.53, respectively). Use of the decoupling score (cutoff = 3.0) allowed the detection of specimens with a tumor cell density of more than 1,000/mm2, with a sensitivity and specificity of 93.5% and 87.5%, respectively, whereas conventional 11C-methionine PET (cutoff = 1.2 in T/N ratio) was able to detect with a sensitivity and specificity of 87.0% and 87.5%, respectively. Reconstructed images (decoupling map) using the decoupling score enabled the visualization of glioma lesions that were difficult to visualize by 11C-methionine PET alone. Conclusion: The decoupling score showed better performance in detecting glioma cell infiltration than 11C-methionine uptake alone, thus suggesting that 18F-FDG–11C-methionine uptake decoupling analysis is a powerful imaging modality for assessing glioma invasion.

Use of 11C-methionine PET parametric response map for monitoring WT1 immunotherapy response in recurrent malignant glioma

OBJECT Immunotherapy targeting the Wilms tumor 1 (WT1) gene product is a promising treatment modality for patients with malignant gliomas, and there have been reports of encouraging results. It has become clear, however, that Gd-enhanced MR imaging does not reflect prognosis, thereby necessitating a more robust imaging evaluation system for monitoring response to WT1 immunotherapy. To meet this demand, the authors performed a voxel-wise parametric response map (PRM) analysis of (11)C-methionine PET (MET-PET) in WT1 immunotherapy and compared the data with the overall survival after initiation of WT1 immunotherapy (OS(WT1)). METHODS Fourteen patients with recurrent malignant glioma were included in the study, and OS(WT1) was compared with: 1) volume and length change in the contrast area of the tumor on Gd-enhanced MR images; 2) change in maximum uptake of (11)C-methionine; and 3) a more detailed voxel-wise PRM analysis of MET-PET pre- and post-WT1 immunotherapy. RESULTS The PRM analysis was able to identify the following 3 areas within the tumor core: 1) area with no change in (11)C-methionine uptake pre- and posttreatment; 2) area with increased (11)C-methionine uptake posttreatment (PRM(+MET)); and 3) area with decreased (11)C-methionine uptake posttreatment. While the results of Gd-enhanced MR imaging volumetric and conventional MET-PET analysis did not correlate with OS(WT1) (p = 0.270 for Gd-enhanced MR imaging length, p = 0.960 for Gd-enhanced MR imaging volume, and p = 0.110 for MET-PET), the percentage of PRM(+MET) area showed excellent correlation (p = 0.008) with OS(WT1). CONCLUSIONS This study describes the limited value of Gd-enhanced MR imaging and highlights the potential of voxel-wise PRM analysis of MET-PET for monitoring treatment response in immunotherapy for malignant gliomas. Clinical trial registration no.: UMIN000002001.

Long-term follow-up of vanishing tumors in the brain: How should a lesion mimicking primary CNS lymphoma be managed?

OBJECTIVES The spontaneous disappearance of a tumor is referred to as a vanishing tumor. Most vanishing tumors in the brain are eventually diagnosed as malignant tumors or multiple sclerosis. However, their long-term clinical course remains unclear. This study aims to elucidate the management of vanishing tumors in the brain. PATIENTS AND METHODS We defined a vanishing tumor as a case in which the tumor spontaneously disappeared or decreased to less than 70% of the initial tumor volume before definitive diagnosis and treatment (other than steroid treatment). Ten cases of vanishing tumors are reviewed. RESULTS Nine patients underwent biopsy at least once. Five patients, all of whom had malignant tumors (primary central nervous system lymphoma: 4, germinoma: 1) that recurred in 4-45 months (median: 7 months), underwent a second biopsy after the reappearance of the tumors. Five patients (tumefactive demyelinating lesion: 1, undiagnosed: 4) who had no relapse are alive, and their median follow-up time is 44 months. No cases have yet been reported of malignant brain tumors that recurred more than 5 years after spontaneous regression. CONCLUSIONS Patients with vanishing tumors should be followed up carefully by magnetic resonance imaging for at least 5 years, even after the disappearance of an enhancing lesion.

11C-methinine uptake correlates with MGMT promoter methylation in nonenhancing gliomas

OBJECTIVES Several studies have aimed to detect biomarkers in glioma using noninvasive imaging techniques. However, few studies have been able to image 1p/19q deletion by (11)C-methionine positron emission tomography ((11)C-methionine PET) or 2-hydroxyglutarate (2HG) by proton magnetic resonance spectroscopy (MRS). This study examines the correlation between (11)C-methionine uptake and MGMT promoter methylation in grade II and grade III nonenhancing gliomas. PATIENTS AND METHODS Data was collected from 20 patients with grade II and III nonenhancing gliomas who underwent both MRI and (11)C-methionine PET as part of their pre-surgical examination. We examined MGMT promoter methylation by quantitative methylation-specific PCR. RESULTS The mean MGMT promoter methylation for tumors with T/N ratios ≥1.6 was 28.0±26.3, and that for tumors with T/N ratios <1.6 was 0.68±0.89. The MGMT promoter methylation for tumors with T/N ratios ≥1.6 was significantly higher than that for tumors with T/N ratios <1.6 (P<0.05). CONCLUSIONS A higher uptake in (11)C-methionine PET may reflect increased MGMT promoter methylation. (11)C-methionine PET could be a useful tool to detect MGMT promoter methylation in nonenhancing glioma.