Aya Shinomiya

Usefulness of FDG, MET and FLT-PET Studies for the Management of Human Gliomas

The use of positron imaging agents such as FDG, MET, and FLT is expected to lead the way for novel applications toward efficient malignancy grading and treatment of gliomas. In this study, the usefulness of FDG, MET and FLT-PET images was retrospectively reviewed by comparing their histopathological findings. FDG, MET, and FLT-PET were performed in 27 patients with WHO grade IV, 15 patients with WHO grade III, and 12 patients with WHO grade II during 5.5 years. The resulting PET images were compared by measuring SUVs and T/N ratios (tumor to normal tissue ratios). Although there were no significant differences in FDG-PET, there were significant differences in the T/N ratios in the MET-PET between WHO grades II and IV and in the FLT-PET between the WHO grades III and IV. In glioblastoma patients, the SUVs of the areas depicted by MRI in the MET-PET were different from those SUVs in the FLT-PET. Importantly, the areas with high SUVs in both MET-PET and FLT-PET were also high in Ki-67 index and were histologically highly malignant. PET imaging is a noninvasive modality that is useful in determining a tumor area for removal as well as improving preoperative diagnosis for gliomas.

Evaluation of 3'-deoxy-3'-[18F]-fluorothymidine (18F-FLT) kinetics correlated with thymidine kinase-1 expression and cell proliferation in newly diagnosed gliomas.

PurposeThe thymidine analog 3′-deoxy-3′-[18F]fluorothymidine (18F-FLT) has been developed as a positron emission tomography (PET) tracer to assess the proliferation activity of tumors in vivo. The present study investigated the relationship between the kinetic parameters of 18F-FLT in vivo and thymidine kinase-1 (TK-1) expression and cell proliferation rate in vitro, and blood–brain barrier (BBB) breakdown in human brain gliomas.MethodsA total of 21 patients with newly diagnosed gliomas were examined by 18F-FLT PET kinetic analysis. Maximum standardized uptake value (SUVmax) and tumor-to-normal (T/N) ratio of 18F-FLT in the tumor and 18F-FLT kinetic parameters in the corresponding contralateral region were determined. The expression levels of TK-1 protein and mRNA were determined by immunohistochemistry (IHC) and real-time polymerase chain reaction (PCR), respectively, using surgical specimens. The cell proliferation rate of the tumor was determined in terms of the Ki-67 labeling index. BBB breakdown was evaluated on MR images with contrast enhancement.Results18F-FLT SUVmax and T/N ratio were significantly correlated with the influx rate constant (K1; P = 0.001 and P < 0.001, respectively), but not with the phosphorylation rate constant (k3). IHC and real-time PCR studies demonstrated a significant correlation between K1 and TK-1 mRNA expression (P = 0.001), but not between k3 and TK-1 protein and mRNA expression. Linear regression analysis revealed a significant correlation between K1 and the Ki-67 index (P = 0.003), but not between k3 and the Ki-67 index. TK-1 mRNA expression was significantly correlated with the Ki-67 index (P = 0.009). 18F-FLT SUVmax and T/N ratio were significantly correlated with BBB breakdown evaluated by contrast enhancement in MR images (P = 0.003 and P = 0.011, respectively).ConclusionThese results indicate that 18F-FLT uptake in the tumor is significantly related to transport through the disrupted BBB, but not through phosphorylation activity. Although the tissue TK-1 expression reflects tumor proliferation activity, the phosphorylation rate constant k3 determined by 18F-FLT PET kinetic analysis does not accurately reflect TK-1 expression in the tissue and should not be used as a surrogate biomarker of cell proliferation activity in human brain gliomas.

Ameliorative effects of yokukansan on behavioral deficits in a gerbil model of global cerebral ischemia

The aim of this study was to investigate the neuroprotective effects of yokukansan, a traditional Kampo medicine, on the behavioral dysfunction induced by cerebral ischemia/reperfusion injury in gerbils. Gerbils were treated with yokukasan by oral gavage for 30 days, once per day, until the day before induction of ischemia, which was induced by occluding the bilateral common carotid artery for 5 min. The effects of yokukansan (50, 100 and 300 mg/kg) were examined by measuring neuronal damage and behavioral deficits (locomotor activity, 8-arm radial maze task). The anti-inflammatory and anti-oxidant properties of yokukansan were also examined. Administration of yokukansan at 300 mg/kg significantly reduced hippocampal neuronal death after brain ischemia, inhibited the ischemia-induced inflammatory response and DNA oxidative damage. Yokukansan also reduced ischemia-induced locomotor hyperactivity and improved memory impairment. These findings suggest that yokukansan can inhibit the inflammatory response, oxidative damage and subsequent neuronal death induced by cerebral ischemia/reperfusion injury, and also can contribute to improvement in neurological deficits following such injury.

3′-Deoxy-3′-[ 18 F]-fluorothymidine ([ 18 F]-FLT) transport in newly diagnosed glioma: correlation with nucleoside transporter expression, vascularization, and blood–brain barrier permeability

Abstract3′-Deoxy-3′-[18F]-fluorothymidine ([18F]-FLT), a marker of cellular proliferation, has been used in positron emission tomography (PET) examination of gliomas. The aim of this study was to investigate whether the uptake of [18F]-FLT in glioma correlates with messenger RNA (mRNA) levels of the equilibrative nucleoside transporter 1 (ENT1), microvascular density (assessed by CD34 immunohistochemistry), and the blood–brain barrier (BBB) breakdown. A total of 21 patients with newly diagnosed glioma were examined with [18F]-FLT PET. Tumor lesions were identified as areas of focally increased [18F]-FLT uptake, exceeding that of surrounding normal tissue. Dynamic analysis of [18F]-FLT PET revealed correlations between the phosphorylation rate constant k3 and ENT1 expression; however there was no correlation between the kinetic parameters and CD34 score. There was a good correlation between the gadolinium (Gd) enhancement score (evaluating BBB breakdown) and ENT1 expression, CD34 score, and Ki-67 index. This preliminary study suggests that ENT1 expression might not reflect accumulation of [18F]-FLT in vivo due to BBB permeability in glioma.

The effects of d-allose on transient ischemic neuronal death and analysis of its mechanism

The present study investigates the neuroprotective effects of d-allose, a rare sugar, against ischemia/reperfusion injury in a gerbil model. Transient forebrain ischemia was induced by occlusion of the bilateral common carotid arteries for 5 min. D-Allose was intravenously injected before and after ischemia (200 mg/kg). Extracellular glutamate and lactate release from the gerbil brain, and PO₂ profiles were monitored during ischemia and reperfusion. We also examined neuronal death and oxidative damage in the hippocampus one week after ischemia reperfusion, and investigated functional outcome. D-Allose administration suppressed glutamate and lactate release compared to vehicle controls. Brain damage, 8-OHdG levels (a marker of oxidative stress) and locomotor activities were significantly decreased by D-allose treatment. The present results suggest that d-allose reduces delayed neuronal death and behavioral deficits after transient ischemia by changing cerebral metabolism and inhibiting oxidative stress.

Neuroprotection of granulocyte colony-stimulating factor during the acute phase of transient forebrain ischemia in gerbils.

The present study investigates the potential protective effects of granulocyte colony-stimulating factor (G-CSF) and underlying mechanisms in a gerbil model of global cerebral ischemia. We examined neuronal death, inflammatory reaction and neurogenesis in hippocampus 72 h after transient forebrain ischemia and investigated functional deficits. G-CSF was administered intraperitoneally 24 h before ischemia and then daily. Treatment with G-CSF at 25-50 μg/kg significantly reduced neuronal loss in the hippocampus CA1 area but not at 10 ug/kg. G-CSF at 50 μg/kg significantly decreased the level of TNF-α, the number of Iba1 (microglia marker) positive cells and reduced locomotor activity 72 h after transient forebrain ischemia. Furthermore, the number of DCX-positive cells in the hippocampal dentate gyrus increased in with G-CSF treatment. Our findings indicate that G-CSF reduces hippocampal neuronal cell death dose-dependently and attenuates sensorimotor deficits after transient forebrain ischemia. These neuroprotective effects of G-CSF may be linked to inhibition of inflammation and possibly increased neurogenesis in the hippocampus.

Relapse of herpes encephalitis induced by temozolomide-based chemoradiation in a patient with malignant glioma

The authors report on a case of concurrent herpes simplex encephalitis (HSE) and malignant glioma. The co-occurrence of HSE and malignant glioma is very rare, but it can occur during glioma treatment. Both radiotherapy and chemoradiation with temozolomide can induce viral reactivation, leading to HSE relapse. Careful observation for HSE is necessary when administering chemoradiation to patients with a history of HSE. Antiviral therapy for HSE must be initiated immediately, and the chemoradiation for glioma should be stopped; however, it is not clear what antitumor therapy is optimal when HSE co-occurs during the treatment of glioma.