Yukito Maeda

Correlation of biological aggressiveness assessed by 11C-methionine PET and hypoxic burden assessed by 18F-fluoromisonidazole PET in newly diagnosed glioblastoma.

PurposeGlioblastoma multiforme (GBM) is characterized by tissue hypoxia associated with resistance to radiotherapy and chemotherapy. To clarify the biological link between hypoxia and tumour-induced neovascularization and tumour aggressiveness, we analysed detailed volumetric and spatial information of viable hypoxic tissue assessed by 18F-fluoromisonidazole (FMISO) PET relative to neovascularization in Gd-enhanced MRI and tumour aggressiveness by L-methyl-11C-methionine (MET) PET in newly diagnosed GBMs.MethodsTen patients with newly diagnosed GBMs were investigated with FMISO PET, MET PET and Gd-enhanced MRI before surgery. Tumour volumes were calculated by performing a three-dimensional threshold-based volume of interest (VOI) analysis for metabolically active volume on MET PET (MET uptake indices of ≥1.3 and ≥1.5) and Gd-enhanced volume on MRI. FMISO PET was scaled to the blood FMISO activity to create tumour to blood (T/B) images. The hypoxic volume (HV) was defined as the region with T/B greater than 1.2. PET and MR images of each patient were coregistered to analyse the spatial location of viable hypoxic tissue relative to neovascularization and active tumour extension.ResultsMetabolically active tumour volumes defined using MET uptake indices of ≥1.3 and ≥1.5 and the volumes of Gd enhancement showed a strong correlation (r = 0.86, p < 0.01 for an index of ≥1.3 and r = 0.77, p < 0.05 for an index of ≥1.5). The HVs were also excellently correlated with the volumes of Gd enhancement (r = 0.94, p < 0.01). The metabolically active tumour volumes as defined by a MET uptake index of ≥1.3 and the HVs exhibited a strong correlation (r = 0.87, p < 0.01). On superimposed images, the metabolically active area on MET PET defined by a MET uptake index of ≥1.3 was usually larger than the area of the Gd enhancement and about 20–30% of the MET area extended outside the area of the enhancement. On the other hand, the surface area of viable hypoxic tissue with a T/B cutoff of ≥1.2 on FMISO PET did not substantially differ from the area of the Gd enhancement.ConclusionThe volumetric analysis demonstrates that the viable hypoxic tissue assessed by FMISO PET is related to the neovascularization in Gd-enhanced MRI and the tumour aggressiveness by MET PET in newly diagnosed GBMs. The spatial analysis shows that the metabolically active tumour may be substantially underestimated by Gd-enhanced MRI. Complementary use of MET and FMISO to Gd-enhanced MRI may improve the understanding of tumour biology and lead to the most efficient delineation of tumour volume and treatment strategy.

Correlation between 18F-fluoromisonidazole PET and expression of HIF-1α and VEGF in newly diagnosed and recurrent malignant gliomas

PurposeHypoxia and its consequences at the molecular level promote tumour progression and affect patient prognosis. One of the main early cellular events evoked by hypoxia is induction of hypoxia-inducible factor 1 (HIF-1) and subsequent upregulation of vascular endothelial growth factor (VEGF). In this study we sought to determine whether hypoxia detected by 18F-fluoromisonidazole (FMISO) PET accurately reflects the expression of HIF-1α and VEGF in the tumour and can be used as a biomarker of antiangiogenic treatment and as a prognostic factor in newly diagnosed and recurrent malignant gliomas.MethodsEnrolled in this study were 32 patients with newly diagnosed glioma and 16 with recurrent glioma of grade III or grade IV. All the patients had undergone FMISO PET preoperatively. The maximum tumour-to-blood FMISO activity ratio (T/Bmax) was used to evaluate the degree of tumour hypoxia and the hypoxic volume (HV) was calculated using a tumour-to-blood FMISO uptake ratio of ≥1.2. Immunohistochemical expressions of HIF-1α and VEGF were evaluated semiquantitatively using the immunoreactivity score (IRS, scores 0 to 12) and the correlation was examined between IRS of HIF-1α or VEGF and FMISO uptake of the tumour (SUVtumour) using navigation-based sampling. Survival was estimated using the Kaplan-Meier method in relation to the T/Bmax and the HV.ResultsThe T/Bmax and the HV in grade IV gliomas were significantly higher than in grade III gliomas (P < 0.01 and P < 0.01, respectively). Moderate to strong HIF-1α and VEGF expression was observed in the majority of malignant gliomas. The IRS of HIF-1α and VEGF in the tumour were not significantly different between grade III and grade IV gliomas. The IRS of HIF-1α in the tumour did not correlate with the SUVtumour of FMISO in either newly diagnosed or recurrent glioma. There was a significant but weak correlation between the IRS of VEGF and the SUVtumour of FMISO in newly diagnosed glioma, but not in recurrent glioma. The overall survival time in patients with a small HV and a low FMISO T/Bmax was significantly longer than in those with a large HV and a high FMISO T/Bmax (P < 0.01 and P < 0.05, respectively).ConclusionPreoperative FMISO uptake is significantly correlated with the expression of VEGF in the tumour and might be used as a biomarker of antiangiogenic treatment in newly diagnosed malignant gliomas. However, caution is required because the correlation was weak and there was a large overlap of FMISO uptake between glioma with high and low VEGF expression. In addition, hypoxia determined by FMISO PET appears to be a suitable biomarker for predicting a highly malignant tumour and a poor prognosis in patients with malignant glioma.

Focal Neuronal Damage in Patients with Neuropsychological Impairment after Diffuse Traumatic Brain Injury: Evaluation Using 11C-Flumazenil Positron Emission Tomography with Statistical Image Analysis

This study was conducted to identify the regional neuronal damage occurring in patients with neuropsychological impairment following diffuse traumatic brain injury (TBI) compared with normal control subjects. In addition, measures of the neuropsychological tests were correlated with regional ¹¹C-flumazenil (FMZ) binding potential (BP) reductions to clarify the relationship between cognitive impairment and regional neuronal damage. We performed ¹¹C-flumazenil positron emission tomography (FMZ-PET) studies using three-dimensional stereotactic surface projection (3D-SSP) statistical image analysis in eight diffuse axonal injury (DAI) patients (mean age 29.1 ± 11.1 years, range 19-46 years). All patients underwent assessment with the Wechsler Adult Intellectual Scale-Third Edition (WAIS-III) to evaluate general intelligence. Twenty healthy control subjects (mean age 24.4 ± 2.8 years, range 22-30 years) were also studied to obtain a normal database for 3D-SSP. Group comparisons showed significant regional low FMZ uptake in the bilateral medial frontal gyri, the anterior cingulate gyri, and the thalamus. Individual analysis also showed decreased FMZ uptake in these regions; however, the distribution and extent of low FMZ uptake were different in each individual patient. Full-scale IQ (FIQ) and performance IQ (PIQ) negatively correlated with the degree of FMZ BP reduction (BZR index) in the right thalamus. FIQ, verbal IQ (VIQ), and PIQ also negatively correlated with the BZR index in the left medial frontal gyrus. DAI uniformly induced neuronal damage in the medial frontal cortex and the thalamus, which may be related to underlying cognitive impairments in diffuse TBI patients. Future studies to confirm a common area of focal neuronal damage and a direct correlation with neuropsychological testing may validate the use of FMZ-PET for the functional diagnosis of neuropsychological impairments after TBI.

Detection of brain amyloid β deposition in patients with neuropsychological impairment after traumatic brain injury: PET evaluation using Pittsburgh Compound-B

Abstract Objective: Traumatic brain injury (TBI) is an epigenetic risk factor for Alzheimer’s disease (AD) and amyloid β (Aβ) deposition is observed histopathologically in the traumatized brain. This study was conducted to detect cerebral Aβ deposition using amyloid positron emission tomography (PET) in patients with neuropsychological impairment after TBI. Methods: Twelve patients with post-traumatic neuropsychological impairment (11 men and one woman, age range = 21–78 years) were examined using Pittsburgh Compound B (11C-PIB) PET at the chronic stage after TBI (range = 5–129 months). Results: 11C-PIB was positive in three patients and negative in the other nine patients. There was no correlation between 11C-PIB deposition and the severity of injury; initial CT findings; elapsed time from the injury; and neuropsychological test scores. Conclusions: The absence of Aβ deposition in many patients with chronic neuropsychological impairment after TBI does not support the premise that Aβ pathology progresses over time in the traumatized brain. Early and sequential 11C-PIB PET examination may clarify the time course of Aβ deposition in the traumatized brain and the relationship between traumatic brain insult and subsequent neuropsychological impairment.

Use of PET in the diagnosis of primary CNS lymphoma in patients with atypical MR findings

ObjectiveThe diagnosis of primary central nervous system lymphoma (PCNSL) in immunocompetent patients with atypical magnetic resonance (MR) findings such as disseminated lesions or no (non-enhancing) lesion is sometimes difficult because of mimicking other tumorous and non-tumorous diseases. Positron emission tomography (PET) with 18F-fluorodeoxyglucose (FDG) and 11C-methionine (MET) can measure the glucose and amino acid metabolism in the lesions and may provide useful information for diagnosing PCNSL in patients with such subtle MR findings.MethodsWe performed PET studies with FDG and MET in 17 histologically proven PCNSL and compared the uptake of FDG and MET qualitatively and quantitatively in the tumors between 12 typical and 5 atypical MR findings.ResultsAll typical PCNSL showed strong uptake of FDG and MET; however, visual analysis of FDG and MET uptake in atypical PCNSL was not very useful for finding lesions in the brain. Semiquantitative FDG and MET uptake values (SUVmax) and quantitative FDG influx rate constant (Ki) in the tumors are significantly lower in atypical PCNSL compared with those in typical PCNSL. These values obtained in the lesions with atypical MR findings were also not useful for differentiating PCNSL from other tumorous and non-tumorous diseases. The k3 values evaluated by FDG kinetic analysis in atypical PCNSL were similar to those obtained in typical PCNSL.ConclusionsVisual analysis of FDG and MET uptake in atypical PCNSL was not useful for finding the lesions in the brain. Semiquantitative and quantitative values obtained in the lesions with atypical MR findings were also not useful for differentiating PCNSL from other tumorous and non-tumorous diseases. The k3 values evaluated by FDG kinetic analysis in atypical PCNSL may provide valuable information in the diagnosis of PCNSL.

Hypoxia assessed by 18F-fluoromisonidazole positron emission tomography in newly diagnosed gliomas:

Objective The aim of this study was to evaluate the degree of hypoxia in newly diagnosed gliomas using 18F-fluoromisonidazole (FMISO) PET and to compare the results with tumor grade. Methods A total of 30 patients with newly diagnosed gliomas were examined using FMISO PET. Grading of the tumor was performed according to the WHO classification. The FMISO PET images were scaled to the venous blood concentration of FMISO activity to produce tumor-to-blood (T/B) values. Hypoxia was defined as a region with a T/B ratio of at least 1.2, and the maximum T/B (T/Bmax) value was calculated by region-of-interest analysis. Results There was a correlation between FMISO uptake and glioma grade, with all low-grade gliomas (grades I and II) demonstrating no hypoxia and all high-grade gliomas (grades III and IV) showing hypoxia. The mean T/Bmax in grade IV gliomas was significantly higher than that in grade III gliomas (P<0.02). Conclusion FMISO PET is a potential tracer in the assessment of noninvasive tumor grading in newly diagnosed gliomas.

Correlation of (18)F-fluoromisonidazole PET findings with HIF-1α and p53 expressions in head and neck cancer: comparison with (18)F-FDG PET.

ObjectiveWe evaluated tumor hypoxia using 18F-fluoromisonidazole (18F-FMISO) PET in relation to the expression of hypoxia-inducible factor-1&agr; (HIF-1&agr;) and p53 in patients with head and neck cancer and compared the results with those obtained using 2-deoxy-2-18F-fluoro-D-glucose (18F-FDG) PET. Materials and methodsA total of 28 tumors (23 primary tumors and five metastatic lymph nodes) from 24 patients with newly diagnosed head and neck cancer were examined with 18F-FMISO PET and 18F-FDG PET. The 18F-FMISO PET images were scaled to the venous blood concentration of 18F-FMISO activity to produce tumor-to-blood (T/B) values. Hypoxia was defined as a region with a T/B ratio greater than or equal to 1.2. The maximum T/B (T/Bmax) and hypoxic volumes were calculated by region-of-interest analysis. For 18F-FDG PET, the maximum standardized uptake value (SUVmax) and hypermetabolic volume were calculated by region-of-interest analysis. The expressions of HIF-1&agr; and p53 using immunohistochemistry were estimated in tumor tissue samples. ResultsA weak correlation was observed between hypoxic volume and T/Bmax (r=0.53, P=0.003) on using 18F-FMISO PET and between hypermetabolic volume and SUVmax (r=0.38, P=0.046) on using 18F-FDG PET. The hypoxic volume using 18F-FMISO PET and hypermetabolic volume using 18F-FDG PET also showed a weak correlation (r=0.44, P=0.020). The values of 18F-FMISO hypoxic volume showed a weak correlation with HIF-1&agr; (r=0.40, P=0.037) and p53 (r=0.47, P=0.012) obtained on immunohistochemical examination. ConclusionThis study demonstrates a weak correlation between hypoxic volume measured by 18F-FMISO PET and expressions of HIF-1&agr; and p53 in head and neck cancer.

Hypertrophic cranial pachymeningitis with IgG4-positive plasma cells detected by C-11 methionine PET.

A 53-year-old man who presented with mild headache and ophthalmodynia underwent carbon-11 methionine (MET) positron emission tomography (PET). MET PET images demonstrated intense uptake in the periphery of the brain, significantly higher than the physiological uptake in the brain. Biopsy specimens f

A comparative study of F-18 FDG PET and 201Tl scintigraphy for detection of primary malignant bone and soft-tissue tumors.

Purpose: The purpose of this study was to compare 2-[F-18]fluoro-2-deoxy-D-glucose (FDG) positron emission tomography (PET) and Tl-201 chloride (Tl) scintigraphy for detection of primary malignant bone and soft-tissue tumors. Materials and Methods: A total of 40 patients with suspicion of malignant bone and soft-tissue tumors were examined. FDG PET imaging was performed at 1-hour post-FDG injection. Tl planar and single photon emission computed tomography images were acquired 10 minutes (early) and 2 hours (delayed) after injection of Tl. We evaluated FDG and Tl uptake visually and semiquantitatively using standardized uptake value and tumor to contralateral normal tissue ratio on planar images, respectively. Results: Of the 33 patients with malignant tumors, all but 2 liposarcomas showed positive accumulation on FDG PET. However, all 7 benign lesions were also positive on FDG PET. Both early and delayed Tl images were positive for 27 of the 33 malignant tumors. Of the 6 false-negative cases on Tl images, 5 were liposarcomas. Both early and delayed Tl images were negative for 5 of the 7 benign lesions. The sensitivity of FDG PET for detection of primary malignant bone and soft-tissue tumors was 94% and the specificity, 0%. The corresponding values for Tl scintigraphy were 82% and 71%. The mean FDG standardized uptake value in malignant tumors was higher than that in benign lesions, but this difference was not statistically significant. Statistically significant differences were observed between malignant and benign lesions for both early and delayed tumor to contralateral normal tissue ratios. Conclusions: FDG PET was found to be more sensitive than Tl scintigraphy for primary malignant bone and soft-tissue tumors, although it was less specific.

Use of 11C-methionine positron emission tomography in basal germinoma: assessment of treatment response and residual tumor

IntroductionPrognosis of germinoma arising in the basal ganglia or thalamus is worse compared to that in the pineal or suprasellar region. One of the reasons for poor prognosis is the difficulty in evaluating the efficacy of treatment by conventional neuroimaging tools.PET studiesThe usefulness of 11C-methionine (MET) positron emission tomography (PET) in monitoring the biological nature of brain tumors has been proved in glioma patients.Case reportsHerein, we describe MET-PET findings in three cases of germinomas in the basal ganglia or thalamus and discuss the use of MET-PET in the assessment of treatment response and residual tumor for the next treatment strategy. The patients showed transient increase of MET uptake in the lesions after the initial treatment. Although we did not perform histological verification, MET- PET findings suggested that active tumor cells were still alive in the lesions after the initial treatment. MET uptake gradually decreased during the course of intensive therapy in these patients. MET-PET also revealed germinoma invasion in the brain before discernible signal abnormality or mass lesion in conventional magnetic resonance images in two patients.DiscussionFurther studies including histological verification and long-term follow-up might validate the use of MET-PET in monitoring the treatment efficacy and evaluation of active residual tumor after the treatment.ConclusionUntil we understand what MET uptake truly represents, treatment strategy based on MET uptake must be carefully designed to prevent overtreatment and resultant complications.