Resection of positive tissue on methionine-PET is associated with improved survival in glioblastomas.

BACKGROUND AND PURPOSE: The volume of excised tumor in contrast-enhanced areas evaluated via magnetic resonance imaging is known to have a strong influence on the survival of patients with glioblastoma (GBM). In this study, we investigated the effect of tumor resection on the survival of patients with GBM in the 11 C-methionine (MET) accumulation area using MET-positron emission tomography (MET-PET). METHODS: A total of 26 patients (median age, 69 years; 15 males) who had undergone tumor resection and MET-PET before and after surgery, after being newly diagnosed with GBM, were included in the study. MET-PET before and after tumor resection were compared. The association between the decrease in the maximum standardized uptake value (SUV) of the tumor divided by the normal cortical mean SUV (%; ΔT/N), the MET extent of resection (MET-EOR) from the % reduction in the MET accumulation area (%), and residual MET accumulation area (in cm3 ; MET-residual tumor volume [RTV]), as well as the survival time of patients with GBM, were evaluated via univariate analysis. RESULTS: ΔT/N were positively associated with survival (hazard ratio [HR], 0.98 [95% confidence interval (CI), 0.97-0.99], p = .02). MET-RTV revealed a negative association with survival (HR, 1.02 [95% CI, 1.01-1.04], p = .04). Additionally, MET-EOR showed a strong trend with survival (HR, 0.99 [95% CI, 0.97-1.01], p = .06). CONCLUSIONS: Surgical resection of MET-accumulated areas in GBM significantly prolongs the survival of patients with GBM. However, a prospective large-scale multicenter study is needed to confirm our findings.

Differentiation of astrocytoma between grades II and III using a combination of methionine positron emission tomography and magnetic resonance spectroscopy.

Objective: This study aimed to establish a method for differentiating between grades II and III astrocytomas using preoperative imaging. Methods: We retrospectively analyzed astrocytic tumors, including 18 grade II astrocytomas (isocitrate dehydrogenase (IDH)-mutant: IDH-wildtype = 8:10) and 56 grade III anaplastic astrocytomas (37:19). We recorded the maximum methionine (MET) uptake ratios (tumor-to-normal: T/N) on positron emission tomography (PET) and three MRS peak ratios: choline (Cho)/creatine (Cr), N-acetyl aspartate (NAA)/Cr, and Cho/NAA, between June 2015 and June 2020. We then evaluated the cut-off values to differentiate between grades II and III. We compared the grading results between contrast enhancement effects on MR and combinational diagnostic methods (CDM) on a scatter chart using the cutoff values of the T/N ratio and MRS parameters. Results: The IDH-mutant group showed significant differences in the Cho/NAA ratio between grades II and III using univariate analysis; however, multiple regression analysis results negated this. The IDH-wildtype group showed no significant differences between the groups. Contrast enhancement effects also showed no significant differences in IDH status. Accordingly, regardless of the IDH status, no statistically independent factors differentiated between grades II and III. However, CDMs showed higher sensitivity and negative predictive value in distinguishing them than MRI contrast examinations for both IDH statuses. We demonstrated a significantly higher diagnostic rate of grade III than of grade II with CDM, which was more striking in the IDH-mutant group than in the wild-type group. Conclusions: CDM could be valuable in differentiating between grade II and III astrocytic tumors.

Radiological Prediction of Isocitrate Dehydrogenase (IDH) Mutational Status and Pathological Verification for Lower-Grade Astrocytomas.

Background and objective The isocitrate dehydrogenase (IDH) status of patients with World Health Organization (WHO) grade II or III astrocytoma is essential for understanding its biological features and determining therapeutic strategies. This study aimed to use radiological analysis to predict the IDH status of patients with lower-grade astrocytomas and to verify the pathological implications. Methods In this study, 47 patients with grade II (17 cases) or III astrocytomas (30 cases), based on 2016 WHO Classification, underwent methionine (MET) positron emission tomography (PET) and magnetic resonance spectroscopy (MRS) on the same day between January 2013 and June 2020. The patients were retrospectively assessed. Immunohistochemistry showed 23 cases of IDH-mutant and 24 of IDH-wildtype. Based on fluid-attenuated recovery inversion (FLAIR)/T2 imaging, three doctors blinded to clinical data independently allocated 18 patients to the clear boundary group between the tumor and the normal brain and 29 to the unclear boundary group. The peak ratios of N-acetylaspartate (NAA)/creatine (Cr), choline (Cho)/Cr, and Cho/NAA and the tumor-to-normal region (T/N) ratio for maximum accumulation in MET-PET were calculated. For statistical analysis, Fisher's exact test was used to assess associations between two variables, and the Mann-Whitney U test to compare the values between the IDH-wildtype and IDH-mutant groups. The optimal cut-off values of MET T/N ratio and MRS parameters for discriminating IDH-wildtype from IDH-mutant were obtained using receiver operating characteristics curves. Results The unclear boundary group had significantly more IDH-wildtype cases than the clear boundary group (P<0.001). The IDH-wildtype group had significantly lower Cho/Cr (<1.84) and Cho/NAA (<1.62) ratios (P=0.02 and P=0.047, respectively) and a higher MET T/N ratio (>1.44, P=0.02) than the IDH-mutant group. The odds for the IDH-wildtype were 0.22 for patients who fulfilled none of the four criteria, including boundary status and three ratios, and 0.9 for all four criteria. Conclusions These results suggest that the combination of MRI, MRS, and MET-PET examination could be helpful for the prediction of IDH status in WHO grade II/III gliomas.

Image preprocessing to improve the accuracy and robustness of mutual-information-based automatic image registration in proton therapy.

PURPOSE: We propose a method that potentially improves the outcome of mutual-information-based automatic image registration by using the contrast enhancement filter (CEF). METHODS: Seventy-six pairs of two-dimensional X-ray images and digitally reconstructed radiographs for 20 head and neck and nine lung cancer patients were analyzed retrospectively. Automatic image registration was performed using the mutual-information-based algorithm in VeriSuite®. Images were preprocessed using the CEF in VeriSuite®. The correction vector for translation and rotation error was calculated and manual image registration was compared with automatic image registration, with and without CEF. In addition, the normalized mutual information (NMI) distribution between two-dimensional images was compared, with and without CEF. RESULTS: In the correction vector comparison between manual and automatic image registration, the average differences in translation error were < 1 mm in most cases in the head and neck region. The average differences in rotation error were 0.71 and 0.16 degrees without and with CEF, respectively, in the head and neck region; they were 2.67 and 1.64 degrees, respectively, in the chest region. When used with oblique projection, the average rotation error was 0.39 degrees with CEF. CEF improved the NMI by 17.9 % in head and neck images and 18.2 % in chest images. CONCLUSIONS: CEF preprocessing improved the NMI and registration accuracy of mutual-information-based automatic image registration on the medical images. The proposed method achieved accuracy equivalent to that achieved by experienced therapists and it will significantly contribute to the standardization of image registration quality.

Plan Quality Comparison Between Hippocampus-Sparing Whole-Brain Radiotherapy Treated With Halcyon and Tomotherapy Intensity-Modulated Radiotherapy.

Objective: Hippocampus-sparing whole-brain radiotherapy using Halcyon, an instrument dedicated to volumetric modulated arc therapy, has not been studied till date; hence, we aimed to examine whether it can meet the RTOG0933 criteria. Based on this, we compared Halcyon to Tomotherapy, which also uses an O-ring-type linear accelerator. Methods: This exploratory, experimental, and retrospective study used 5 sets of computed tomography images in the head area to investigate the planning target volume, hippocampal doses, and irradiation time. Calculations were performed from 1 to 4 arcs to determine the optimal number of arcs in the Halcyon plan, which were compared to those of Tomotherapy. Results: The Radiation Therapy Oncology Group 0933 criteria could not be satisfied in Halcyon with 1 arc. With 2 arcs, the condition Dmax<16 Gy was not satisfied for 1 case in the hippocampus. Since there were no significant differences between 3 and 4 arcs, including the irradiation time, 3 arcs were considered the best. We compared Halcyon at 3 arcs with tomotherapy and found that tomotherapy was inferior to Halcyon at D98%; however, it was superior to Halcyon in other dose parameters. In contrast, the irradiation time in Halcyon was overwhelmingly superior, with the irradiation time for Halcyon being 1/ninth the time for Tomotherapy. Conclusion: Halcyon was effective in handling hippocampus-sparing whole-brain radiotherapy. We believe that 3-arc radiation is best suited for this procedure. Although Halcyon was inferior to Tomotherapy in terms of dose distribution excluding D98%, it was overwhelmingly superior in terms of irradiation time.

Usefulness of positron emission tomography for differentiating gliomas according to the 2016 World Health Organization classification of tumors of the central nervous system.

OBJECTIVE: Positron emission tomography (PET) is important in the noninvasive diagnostic imaging of gliomas. There are many PET studies on glioma diagnosis based on the 2007 WHO classification; however, there are no studies on glioma diagnosis using the new classification (the 2016 WHO classification). Here, the authors investigated the relationship between uptake of 11C-methionine (MET), 11C-choline (CHO), and 18F-fluorodeoxyglucose (FDG) on PET imaging and isocitrate dehydrogenase (IDH) status (wild-type [IDH-wt] or mutant [IDH-mut]) in astrocytic and oligodendroglial tumors according to the 2016 WHO classification. METHODS: In total, 105 patients with newly diagnosed cerebral gliomas (6 diffuse astrocytomas [DAs] with IDH-wt, 6 DAs with IDH-mut, 7 anaplastic astrocytomas [AAs] with IDH-wt, 24 AAs with IDH-mut, 26 glioblastomas [GBMs] with IDH-wt, 5 GBMs with IDH-mut, 19 oligodendrogliomas [ODs], and 12 anaplastic oligodendrogliomas [AOs]) were included. All OD and AO patients had both IDH-mut and 1p/19q codeletion. The maximum standardized uptake value (SUV) of the tumor/mean SUV of normal cortex (T/N) ratios for MET, CHO, and FDG were calculated, and the mean T/N ratios of DA, AA, and GBM with IDH-wt and IDH-mut were compared. The diagnostic accuracy for distinguishing gliomas with IDH-wt from those with IDH-mut was assessed using receiver operating characteristic (ROC) curve analysis of the mean T/N ratios for the 3 PET tracers. RESULTS: There were significant differences in the mean T/N ratios for all 3 PET tracers between the IDH-wt and IDH-mut groups of all histological classifications (p < 0.001). Among the 27 gliomas with mean T/N ratios higher than the cutoff values for all 3 PET tracers, 23 (85.2%) were classified into the IDH-wt group using ROC analysis. In DA, there were no significant differences in the T/N ratios for MET, CHO, and FDG between the IDH-wt and IDH-mut groups. In AA, the mean T/N ratios of all 3 PET tracers in the IDH-wt group were significantly higher than those in the IDH-mut group (p < 0.01). In GBM, the mean T/N ratio in the IDH-wt group was significantly higher than that in the IDH-mut group for both MET (p = 0.034) and CHO (p = 0.01). However, there was no significant difference in the ratio for FDG. CONCLUSIONS: PET imaging using MET, CHO, and FDG was suggested to be informative for preoperatively differentiating gliomas according to the 2016 WHO classification, particularly for differentiating IDH-wt and IDH-mut tumors.

Dissociation Between 11C-Methionine-Positron Emission Tomography and Gadolinium-Enhanced Magnetic Resonance Imaging in Longitudinal Features of Glioblastoma After Postoperative Radiotherapy.

The aims of the present study were to compare the longitudinal changes of glioblastoma multiforme after radiotherapy (RT) between 11C-methionine positron emission tomography (MET-PET) and gadolinium (Gd)-enhanced magnetic resonance imaging (MRI) and to clarify whether these changes were predictive of survival. We included 30 patients, who had undergone MET-PET and Gd-MRI before and every 3 months after RT. The lesion/normal brain uptake (L/N) ratio and contrast-enhancing lesion volume were examined. The L/N ratio was decreased until 9 months after RT with significance until 3 months. The contrast-enhancing lesion volume was decreased until 3 months and thereafter increased until 9 months with significance. The variation rates of the L/N ratio between pre-RT and 3 months differentiated survival of >23 months from ≤23 months. A dissociation could exist in the longitudinal changes of GBM after RT between MET-PET and Gd-MRI. The variation rate of the L/N ratio could be related to survival.

Application of an In Vitro Dissolution/Permeation System to Early Screening of Oral Formulations of Poorly Soluble, Weakly Basic Drugs Containing an Acidic pH-Modifier.

This study aimed to evaluate the usefulness of the dissolution/permeation system (D/P system) as an in vitro tool for early screening of oral formulations of weakly basic drugs containing an acidic pH-modifier. Dipyridamole, having a prominent pH-dependent solubility, was used as a model drug, and various granules containing different amounts of fumaric acid were prepared. Prepared granules were administered orally to hypochlorhydria model rats. It was confirmed that fumaric acid improved the absorption of dipyridamole depending on its amount in the granules. Separately, dissolution and permeation of dipyridamole were observed in vitro in the D/P system. When using a medium with a low buffer capacity which mimicked the human intestinal fluid, rank order of the permeated amount of dipyridamole from various granules in the D/P system did not correlate with its absorption in hypochlorhydric rats. In contrast, when applying a medium with high buffer capacity, the permeated amount in the D/P system well reflected the effects of fumaric acid on the in vivo absorption of dipyridamole. In conclusion, by setting appropriate experimental protocols according to the properties of test compounds and formulations, D/P system can be a potent in vitro tool to predict in vivo performance of oral formulations.

Intracranial subarachnoid hemorrhage following cervical laminoplasty: a report of two cases.

Intracranial hemorrhage is a rare complication of spinal surgery. Case 1 was a 58-year-old man who underwent cervical laminoplasty. No apparent iatrogenic dural rupture or cerebrospinal fluid leakage was observed. An hour after the surgery, the patient had convulsions and became restless thereafter. CT revealed an intracranial subarachnoid hemorrhage (SAH). The patient recovered normal consciousness the next morning. Case 2 was a 68-year-old woman who underwent cervical laminoplasty without postoperative cerebrospinal fluid leakage. Six days after the surgery, the patient continued to complain of nausea and headache. By 13 days, the patient reported relief from her symptoms. There was no evidence of cerebral aneurysm, or vascular malformation in both cases. Patients undergoing cervical laminoplasty might be at risk for developing SAH. Careful attention to intraoperative neck positioning, strict monitoring and control of perioperative blood pressure, and complete dural repair are essential measures for preventing SAH.

Re-irradiation of recurrent glioblastoma multiforme using 11C-methionine PET/CT/MRI image fusion for hypofractionated stereotactic radiotherapy by intensity modulated radiation therapy.

BACKGROUND: This research paper presents a valid treatment strategy for recurrent glioblastoma multiforme (GBM) using hypofractionated stereotactic radiotherapy by intensity modulated radiation therapy (HS-IMRT) planned with 11C-methionine positron emission tomography (MET-PET)/computed tomography (CT)/magnetic resonance imaging (MRI) fusion. METHODS: Twenty-one patients with recurrent GBM received HS-IMRT planned by MET-PET/CT/MRI. The region of increased amino acid tracer uptake on MET-PET was defined as the gross tumor volume (GTV). The planning target volume encompassed the GTV by a 3-mm margin. Treatment was performed with a total dose of 25- to 35-Gy, given as 5- to 7-Gy daily for 5 days. RESULTS: With a median follow-up of 12 months, median overall survival time (OS) was 11 months from the start of HS-IMRT, with a 6-month and 1-year survival rate of 71.4% and 38.1%, respectively. Karnofsky performance status was a significant prognostic factor of OS as tested by univariate and multivariate analysis. Re-operation rate was 4.8% for radiation necrosis. No other acute or late toxicity Grade 3 or higher was observed. CONCLUSIONS: This is the first prospective study of biologic imaging optimized HS-IMRT in recurrent GBM. HS-IMRT with PET data seems to be well tolerated and resulted in a median survival time of 11 months after HS-IMRT.

Hypofractionated high-dose irradiation with positron emission tomography data for the treatment of glioblastoma multiforme.

This research paper presents clinical outcomes of hypofractionated high-dose irradiation by intensity-modulated radiation therapy (Hypo-IMRT) with (11)C-methionine positron emission tomography (MET-PET) data for the treatment of glioblastoma multiforme (GBM). A total of 45 patients with GBM were treated with Hypo-IMRT after surgery. Gross tumor volume (GTV) was defined as the area of enhanced lesion on MRI, including MET-PET avid region; clinical target volume (CTV) was the area with 5 mm margin surrounding the GTV; planning target volume (PTV) was the area with 15 mm margin surrounding the CTV, including MET-PET moderate region. Hypo-IMRT was performed in 8 fractions; planning the dose for GTV was escalated to 68 Gy and that for CTV was escalated to 56 Gy, while keeping the dose delivered to the PTV at 40 Gy. Concomitant and adjuvant TMZ chemotherapy was administered. At a median follow-up of 18.7 months, median overall survival (OS) was 20.0 months, and median progression-free survival was 13.0 months. The 1- and 2-year OS rates were 71.2% and 26.3%, respectively. Adjuvant TMZ chemotherapy was significantly predictive of OS on multivariate analysis. Late toxicity included 7 cases of Grade 3-4 radiation necrosis. Hypo-IMRT with MET-PET data appeared to result in favorable survival outcomes for patients with GBM.

[Development of quality assurance/quality control web system in radiotherapy].

Our purpose is to develop a QA/QC (quality assurance/quality control) web system using a server-side script language such as HTML (HyperText Markup Language) and PHP (Hypertext Preprocessor), which can be useful as a tool to share information about QA/QC in radiotherapy. The system proposed in this study can be easily built in one's own institute, because HTML can be easily handled. There are two desired functions in a QA/QC web system: (i) To review the results of QA/QC for a radiotherapy machine, manuals, and reports necessary for routinely performing radiotherapy through this system. By disclosing the results, transparency can be maintained, (ii) To reveal a protocol for QA/QC in one's own institute using pictures and movies relating to QA/QC for simplicity's sake, which can also be used as an educational tool for junior radiation technologists and medical physicists. By using this system, not only administrators, but also all staff involved in radiotherapy, can obtain information about the conditions and accuracy of treatment machines through the QA/QC web system.

Epilepsy surgery of dysembryoplastic neuroepithelial tumors using advanced multitechnologies with combined neuroimaging and electrophysiological examinations.

PURPOSE: We report three cases of dysembryoplastic neuroepithelial tumor (DNT) with intractable epilepsy which were successfully treated with surgery. METHODS: In all cases, technology beyond the routine workup was critical to success. Preoperative magnetic resonance imaging, (18)F-fluorodeoxyglucose positron emission tomography (PET), (11)C-methionine-PET, interictal electroencephalography, and intraoperative electrocorticography were utilized in all patients. In individual cases, however, additional procedures such as preoperative magnetoencephalography (Case 1), diffusion tensor fiber tractography, a neuronavigation system, and intraoperative somatosensory-evoked potential (Case 2), and fiber tractography and the neuronavigation-guided fence-post tube technique (Case 3) were instrumental. RESULTS: In all the cases, the objectives of total tumor resection, resection of the epileptogenic zone, and complete postoperative seizure control and the avoidance of surgical complications were achieved. CONCLUSIONS: Dysembryoplastic neuroepithelial tumor is commonly associated with medically intractable epilepsy, and surgery is frequently utilized. As DNT may arise in any supratentorial and intracortical locations within or near the critical area of the brain, meticulous surgical strategies are necessary to avoid neurological deficits. We demonstrate in the following three cases how adjunct procedures using advanced multitechnologies with neuroimaging and electrophysiological examinations may be utilized to ensure success in DNT surgery.

Clinical value of [¹¹C]methionine PET for stereotactic radiation therapy with intensity modulated radiation therapy to metastatic brain tumors.

PURPOSE: This study investigated the clinical impact of (11)C-labeled methionine-positron emission tomography (MET-PET) for stereotactic radiation therapy with intensity modulated radiation therapy (SRT-IMRT) in metastatic brain tumors. METHODS AND MATERIALS: Forty-two metastatic brain tumors were examined. All tumors were treated with SRT-IMRT using a helical tomotherapy system. Gross tumor volume (GTV) was defined and drawn on the stereotactic magnetic resonance (MR) image, taking into account the respective contributions of MR imaging and MET-PET. Planning target volume (PTV) encompassed the GTV-PET plus a 2-mm margin. SRT-IMRT was performed, keeping the dose for PTV at 25-35 Gy in 5 fractions. The ratio of the mean value of MET uptake to the contralateral normal brain (L/N ratio) was plotted for the PTV prior to SRT-IMRT, at 3 months following SRT-IMRT, and at 6 months following SRT-IMRT. Tumor characteristic changes of MET uptake before and after SRT-IMRT were evaluated quantitatively, comparing them with MRI examination. RESULTS: Mean ± SD L/N ratios were 1.95 ± 0.83, 1.18 ± 0.21, and 1.12 ± 0.25 in the pre-SRT-IMRT group, in the 3 months post-SRT-IMRT group, and in the 6 months post-SRT-IMRT group, respectively. Differences in the mean L/N ratio between the pre-SRT-IMRT group and the 3-month post-SRT-IMRT group and between the pre-SRT-IMRT group and the 6 month post-SRT-IMRT group were statistically significant, irrespective of MRI examination. CONCLUSIONS: We showed examples of metastatic lesions demonstrating significant decreases in MET uptake following SRT-IMRT. MET-PET seems to have a potential role in providing additional information, although MRI remains the gold standard for diagnosis and follow-up after SRT-IMRT. The present study is a preliminary approach, but to more clearly define the impact of PET-based radiosurgical assessment, further experimental and clinical analyses are required.

Utility of fractional anisotropy imaging analyzed by statistical parametric mapping for detecting minute brain lesions in chronic-stage patients who had mild or moderate traumatic brain injury.

Diffusion tensor imaging (DTI) has recently evolved as valuable technique to investigate diffuse axonal injury (DAI). This study examined whether fractional anisotropy (FA) images analyzed by statistical parametric mapping (FA-SPM images) are superior to T(2)*-weighted gradient recalled echo (T2*GRE) images or fluid-attenuated inversion recovery (FLAIR) images for detecting minute lesions in traumatic brain injury (TBI) patients. DTI was performed in 25 patients with cognitive impairments in the chronic stage after mild or moderate TBI. The FA maps obtained from the DTI were individually compared with those from age-matched healthy control subjects using voxel-based analysis and FA-SPM images (p < 0.001). Abnormal low-intensity areas on T2*GRE images (T2* lesions) were found in 10 patients (40.0%), abnormal high-intensity areas on FLAIR images in 4 patients (16.0%), and areas with significantly decreased FA on FA-SPM image in 16 patients (64.0%). Nine of 10 patients with T2* lesions had FA-SPM lesions. FA-SPM lesions topographically included most T2* lesions in the white matter and the deep brain structures, but did not include T2* lesions in the cortex/near-cortex or lesions containing substantial hemosiderin regardless of location. All 4 patients with abnormal areas on FLAIR images had FA-SPM lesions. FA-SPM imaging is useful for detecting minute lesions because of DAI in the white matter and the deep brain structures, which may not be visualized on T2*GRE or FLAIR images, and may allow the detection of minute brain lesions in patients with post-traumatic cognitive impairment.

Metabolic assessment of monofocal acute inflammatory demyelination using MR spectroscopy and (11)C-methionine-, (11)C-choline-, and (18)F-fluorodeoxyglucose-PET.

Monofocal acute inflammatory demyelination (MAID), which is observable by CT and MRI as a well-enhanced mass lesion with prominent perifocal edema, is very similar to malignant gliomas radiologically, making differential diagnosis of the two pathologies difficult. The aim of this study was to assess the different metabolic activities between MAID and malignant gliomas by MRS, methionine-PET, choline-PET, and FDG-PET. Six patients with MAID underwent methionine, choline, and FDG-PET, and 4 of the patients also underwent magnetic resonance spectroscopy (MRS). The images obtained from these patients were compared with the corresponding images of 19 anaplastic astrocytomas (AA) and 21 glioblastomas (GBM). The mean choline/creatine ratio of MAID was significantly lower than that of GBM. There were no significant differences in the mean NAA/creatine and lactate/creatine ratios among these pathologies. The methionine T/N ratio of MAID was significantly lower than those of AA and GBM. The choline T/N ratio of MAID was significantly lower than that of GBM. There were no significant differences in the FDG T/N ratios among these pathologies. These results demonstrate that the metabolic activity of MAID significantly differs in part from that of malignant gliomas. Combined PET and MRS neuroimaging examinations may be useful for differential diagnosis of these pathologies.

Simultaneous integrated boost technique by helical tomotherapy for the treatment of glioblastoma multiforme with 11C-methionine PET: report of three cases.

We performed hypofractionated high-dose irradiation of a patient's residual glioblastoma multiforme using a simultaneous integrated boost (SIB) technique with helical tomotherapy system (HT) planning. The gross tumor volume (GTV)-1 was defined as the area of intensive (11)C-methionine (MET) uptake and GTV-2 was defined as the area of moderate MET uptake. The planning target volume (PTV)-1 encompassed GTV-1 plus a 5 mm margin, and PTV-2 encompassed GTV-2 plus a 2 mm margin. SIB with HT was performed in eight fractions, planning the dose for GTV-1 at 68 Gy (biologically effective dose: BED = 126 Gy), PTV-1 at 56 Gy (BED = 95 Gy), and PTV-2 at 40 Gy (BED = 60 Gy). In each of the target areas, the uptake value on (11)C-methionine positron emission tomography (MET-PET) was considerably decreased following SIB, although no remarkable changes were demonstrated on magnetic resonance imaging (MRI). These cases demonstrate that SIB with HT planning using MET-PET offers excellent target coverage and uniformity. In addition, SIB with HT planning using MET-PET is organ sparing and MET-PET has great efficacy for monitoring treatment response after SIB. To more clearly define the impact of SIB with HT planning using MET-PET, further investigations are required.

Total synthesis of buergerinin F via effective construction of the asymmetric quaternary carbons using an enantioselective aldol reaction.

An efficient method for the synthesis of (+)-buergerinin F is established via the enantioselective aldol reaction of a tetra-substituted ketene silyl acetal with crotonaldehyde, followed by intramolecular Wacker-type ketalization.

Transport of the dopamine D2 agonist pramipexole by rat organic cation transporters OCT1 and OCT2 in kidney.

We investigated the mechanism of renal tubular secretion of the dopamine D2 receptor agonist pramipexole in rats, focusing on organic cation transporters 1 and 2. The uptake of [14C]pramipexole by Xenopus oocytes injected with complementary RNA of either rat organic cation transporter (rOCT) 1 or rOCT2 was significantly higher than that by water-injected oocytes: the kinetic parameters, K(m) and V(max), of pramipexole uptake were 49.5 muM and 234 pmol/60 min/oocyte for rOCT1, and 16.9 microM and 12.8 pmol/60 min/oocyte for rOCT2. Pramipexole was taken up into kidney slices in a time- and concentration-dependent manner, and Eadie-Hofstee plots revealed the involvement of two saturable components. The kinetic parameters, K(m1) and V(max1), of the high-affinity component were 12.9 microM and 10.7 nmol/15 min/g kidney, respectively. The uptake of [14C]pramipexole by rOCT1, rOCT2, and kidney slices was inhibited by procainamide and corticosterone, which are selective inhibitors of rOCT1 and rOCT2, respectively. The IC50 values of procainamide and corticosterone for the uptake of [14C]pramipexole by rOCT1, rOCT2, and kidney slices were 7.7, 167.0, and 47.0 microM and 163.7, 10.7, and 47.7 microM, respectively. These results demonstrate that both rOCT1 and rOCT2 are involved in the renal uptake of pramipexole across the basolateral membrane of the proximal tubular epithelial cells.

Influx and efflux transport of H1-antagonist epinastine across the blood-brain barrier.

We investigated influx and efflux transporters involved in blood-brain barrier transport of the nonsedative H1-antagonist epinastine. The basal-to-apical transport of [14C]epinastine was markedly higher than that in the opposite direction in LLC-GA5-COL150 cells stably transfected with human multidrug resistance (MDR)1 gene. The brain-to-plasma concentration ratio of [14C]epinastine in mdr1a/b(-/-) mice was 3.2 times higher than that in wild-type mice. The uptake of both [3H]mepyramine and [14C]epinastine into immortalized rat brain capillary endothelial cells (RBEC)1 showed temperature and concentration dependence. The kinetic parameters, K(m), V(max), and uptake clearance (V(max)/K(m)), of the initial uptake of [3H]mepyramine and [14C]epinastine by RBEC1 were 150 microM, 41.8 nmol/min/mg protein, and 279 microl/min/mg protein for mepyramine and 10.0 mM, 339 nmol/min/mg protein, and 33.9 microl/min/mg protein for epinastine, respectively. The uptake of [3H]mepyramine and [14C]epinastine by RBEC1 was inhibited by organic cations such as quinidine, amantadine, and verapamil, but not by other organic cations, tetraethyl ammonium, guanidine, and carnitine. Organic anions such as benzoic acid, estrone-3-sulfate, taurocholate, and neutral digoxin were not inhibitory. Furthermore, some cationic H1 antagonists (chlorpheniramine, cyproheptadine, ketotifen, and desloratadine) inhibited the [3H]mepyramine and [14C]epinastine uptake into RBEC1. In conclusion, the present study demonstrated that the combination of efficient efflux transport by P-glycoprotein and poor uptake by the influx transporter, which is identical with that responsible for the uptake of mepyramine, account for the low brain distribution of epinastine.