Tadashi Nariai

Changes in cerebral blood flow during steady-state cycling exercise: a study using oxygen-15-labeled water with PET

Cerebral blood flow (CBF) during dynamic exercise has never been examined quantitatively using positron emission tomography (PET). This study investigated changes in CBF that occur over the course of a moderate, steady-state cycling exercise. Global and regional CBF (gCBF and rCBF, respectively) were measured using oxygen-15-labeled water (H215O) and PET in 10 healthy human subjects at rest (Rest), at the onset of exercise (Ex1) and at a later phase in the exercise (Ex2). At Ex1, gCBF was significantly (P<0.01) higher (27.9%) than at Rest, and rCBF was significantly higher than at Rest in the sensorimotor cortex for the bilateral legs (M1Leg and S1Leg), supplementary motor area (SMA), cerebellar vermis, cerebellar hemispheres, and left insular cortex, with relative increases ranging from 37.6% to 70.5%. At Ex2, gCBF did not differ from Rest, and rCBF was significantly higher (25.9% to 39.7%) than at Rest in only the M1Leg, S1Leg, and vermis. The areas showing increased rCBF at Ex1 were consistent with the central command network and the anatomic pathway for interoceptive stimuli. Our results suggest that CBF increases at Ex1 in parallel with cardiovascular responses then recovers to the resting level as the steady-state exercise continues.

Direct comparison of radiation dosimetry of six PET tracers using human whole-body imaging and murine biodistribution studies

ObjectiveWe investigated the whole-body biodistributions and radiation dosimetry of five 11C-labeled and one 18F-labeled radiotracers in human subjects, and compared the results to those obtained from murine biodistribution studies.MethodsThe radiotracers investigated were 11C-SA4503, 11C-MPDX, 11C-TMSX, 11C-CHIBA-1001, 11C-4DST, and 18F-FBPA. Dynamic whole-body positron emission tomography (PET) was performed in three human subjects after a single bolus injection of each radiotracer. Emission scans were collected in two-dimensional mode in five bed positions. Regions of interest were placed over organs identified in reconstructed PET images. The OLINDA program was used to estimate radiation doses from the number of disintegrations of these source organs. These results were compared with the predicted human radiation doses on the basis of biodistribution data obtained from mice by dissection.ResultsThe ratios of estimated effective doses from the human-derived data to those from the mouse-derived data ranged from 0.86 to 1.88. The critical organs that received the highest absorbed doses in the human- and mouse-derived studies differed for two of the six radiotracers. The differences between the human- and mouse-derived dosimetry involved not only the species differences, including faster systemic circulation of mice and differences in the metabolism, but also measurement methodologies.ConclusionsAlthough the mouse-derived effective doses were roughly comparable to the human-derived doses in most cases, considerable differences were found for critical organ dose estimates and pharmacokinetics in certain cases. Whole-body imaging for investigation of radiation dosimetry is desirable for the initial clinical evaluation of new PET probes prior to their application in subsequent clinical investigations.

The status of Tsukuba BNCT trial: BPA-based boron neutron capture therapy combined with X-ray irradiation.

The phase II trial has been prepared to assess the effectiveness of BPA (250 mg/kg)-based NCT combined with X-ray irradiation and temozolomide (75 mg/m(2)) for the treatment of newly diagnosed GBM. BPA uptake is determined by (18)F-BPA-PET and/or (11)C-MET-PET, and a tumor with the lesion to normal ratio of 2 or more is indicated for BNCT. The maximum normal brain point dose prescribed was limited to 13.0 Gy or less. Primary end point is overall survival.

Stereotactic radiosurgery for patients with multiple brain metastases: a case-matched study comparing treatment results for patients with 2–9 versus 10 or more tumors

OBJECTnAlthough stereotactic radiosurgery (SRS) alone is not a standard treatment for patients with 4-5 tumors or more, a recent trend has been for patients with 5 or more, or even 10 or more, tumors to undergo SRS alone. The aim of this study was to reappraise whether the treatment results for SRS alone for patients with 10 or more tumors differ from those for patients with 2-9 tumors.nnnMETHODSnThis was an institutional review board-approved, retrospective cohort study that gathered data from the Katsuta Hospital Mito GammaHouse prospectively accumulated database. Data were collected for 2553 patients who consecutively had undergone Gamma Knife SRS alone, without whole-brain radiotherapy (WBRT), for newly diagnosed (mostly) or recurrent (uncommonly) brain metastases during 1998-2011. Of these 2553 patients, 739 (28.9%) with a single tumor were excluded, leaving 1814 with multiple metastases in the study. These 1814 patients were divided into 2 groups: those with 2-9 tumors (Group A, 1254 patients) and those with 10 or more tumors (Group B, 560 patients). Because of considerable bias in pre-SRS clinical factors between groups A and B, a case-matched study, which used the propensity score matching method, was conducted for clinical factors (i.e., age, sex, primary tumor state, extracerebral metastases, Karnofsky Performance Status, neurological symptoms, prior procedures [surgery and WBRT], volume of the largest tumor, and peripheral doses). Ultimately, 720 patients (360 in each group) were selected. The standard Kaplan-Meier method was used to determine post-SRS survival times and post-SRS neurological death-free survival times. Competing risk analysis was applied to estimate cumulative incidence for local recurrence, repeat SRS for new lesions, neurological deterioration, and SRS-induced complications.nnnRESULTSnPost-SRS median survival times did not differ significantly between the 2 groups (6.8 months for Group A vs 6.0 months for Group B; hazard ratio [HR] 1.133, 95% CI 0.974-1.319, p = 0.10). Furthermore, rates of neurological death were very similar: 10.0% for group A and 9.4% for group B (p = 0.89); neurological death-free survival times did not differ significantly between the 2 groups (HR 1.073, 95% CI 0.649-1.771, p = 0.78). The cumulative incidence of local recurrence (HR 0.425, 95% CI 0.0.181-0.990, p = 0.04) and repeat SRS for new lesions (HR 0.732, 95% CI 0.554-0.870, p = 0.03) were significantly lower for Group B than for Group A patients. No significant differences between the groups were found for cumulative incidence for neurological deterioration (HR 0.994, 95% CI 0.607-1.469, p = 0.80) or SRS-related complications (HR 0.541, 95% CI 0.138-2.112, p = 0.38).nnnCONCLUSIONSnPost-SRS treatment results (i.e., median survival time; neurological death-free survival times; and cumulative incidence for local recurrence, repeat SRS for new lesions, neurological deterioration, and SRS-related complications) were not inferior (neither less effective nor less safe) for patients in Group B than for those in Group A. We conclude that carefully selected patients with 10 or more tumors are not unfavorable candidates for SRS alone. A randomized controlled trial should be conducted to test this hypothesis.

Long-term follow-up of surgically treated juvenile patients with moyamoya disease

OBJECTnSurgical revascularization is considered an effective treatment for juvenile patients with moyamoya disease (MMD). Yet the long-term outcome in surgically treated patients still needs to be clarified. More than 30 years have passed since the authors department started intensively treating pediatric patients with MMD using indirect anastomosis techniques. In this study the authors surveyed the current status of these patients.nnnMETHODSnActivities of daily living (ADLs) were surveyed and present clinical status was assessed based on the modified Rankin scale (mRS). Cerebrovascular events subsequent to surgical treatment were also recorded.nnnRESULTSnSince 1979, 208 patients younger than 19 years of age with MMD were surgically treated and followed up for > 3 years. Data were available on 172 patients (83%), who had been followed up for a mean of 14.3 years (range 3-32 years). Activity of daily living outcomes were as follows: 138 patients (80.2%) had mRS scores of 0-2, 29 (16.9%) a score of 3, 1 (0.6%) a score of 4, 1 (0.6%) a score of 5, and 3 (1.7%) a score of 6. Cerebrovascular events occurred 8 or more years after surgery in 6 patients (3.4%), that is, 6 hemorrhages and 3 infarctions. The cumulative risk of late-onset stroke at 10, 20, and 30 years after surgical intervention was 0.8%, 6.3%, and 10.0%, respectively.nnnCONCLUSIONSnThis long-term survey demonstrated that most surgically treated pediatric patients with MMD maintain good ADL outcomes. However, a significant number of new cerebrovascular events occurred more than 10 years after the initial surgery. Additional follow-up will help to identify which events may occur during the adult years of patients treated as children.

Delayed Complications in Patients Surviving at Least 3 Years After Stereotactic Radiosurgery for Brain Metastases

PURPOSEnLittle is known about delayed complications after stereotactic radiosurgery in long-surviving patients with brain metastases. We studied the actual incidence and predictors of delayed complications.nnnPATIENTS AND METHODSnThis was an institutional review board-approved, retrospective cohort study that used our database. Among our consecutive series of 2000 patients with brain metastases who underwent Gamma Knife radiosurgery (GKRS) from 1991-2008, 167 patients (8.4%, 89 women, 78 men, mean age 62 years [range, 19-88 years]) who survived at least 3 years after GKRS were studied.nnnRESULTSnAmong the 167 patients, 17 (10.2%, 18 lesions) experienced delayed complications (mass lesions with or without cyst in 8, cyst alone in 8, edema in 2) occurring 24.0-121.0 months (median, 57.5 months) after GKRS. The actuarial incidences of delayed complications estimated by competing risk analysis were 4.2% and 21.2% at the 60th month and 120th month, respectively, after GKRS. Among various pre-GKRS clinical factors, univariate analysis demonstrated tumor volume-related factors: largest tumor volume (hazard ratio [HR], 1.091; 95% confidence interval [CI], 1.018-1.154; P=.0174) and tumor volume≤10 cc vs >10 cc (HR, 4.343; 95% CI, 1.444-12.14; P=.0108) to be the only significant predictors of delayed complications. Univariate analysis revealed no correlations between delayed complications and radiosurgical parameters (ie, radiosurgical doses, conformity and gradient indexes, and brain volumes receiving >5 Gy and >12 Gy). After GKRS, an area of prolonged enhancement at the irradiated lesion was shown to be a possible risk factor for the development of delayed complications (HR, 8.751; 95% CI, 1.785-157.9; P=.0037). Neurosurgical interventions were performed in 13 patients (14 lesions) and mass removal for 6 lesions and Ommaya reservoir placement for the other 8. The results were favorable.nnnCONCLUSIONSnLong-term follow-up is crucial for patients with brain metastases treated with GKRS because the risk of complications long after treatment is not insignificant. However, even when delayed complications occur, favorable outcomes can be expected with timely neurosurgical intervention.

A clinical trial protocol for second line treatment of malignant brain tumors with BNCT at University of Tsukuba

We have evaluated the efficacy and safety of boron neutron capture therapy (BNCT) for recurrent glioma and malignant brain tumor using a new protocol. One of the two patients enrolled in this trial is a man with recurrent glioblastoma and the other is a woman with anaplastic meningioma. Both are still alive and no severe adverse events have been observed. Our findings suggest that NCT will be safe as a palliative therapy for malignant brain tumors.

Clinical benefit of 11C methionine PET imaging as a planning modality for radiosurgery of previously irradiated recurrent brain metastases.

Object Stereotactic radiosurgery with gamma knife (GK-SRS) generally improves the focal control of brain metastases. Yet in cases of focal recurrence at a previous radiation site, MRI is often imperfect in differentiating between active tumor and radiation injury. We have examined whether the use of 11C methionine (MET) with PET will facilitate this differentiation and improve the outcome of GK-SRS for focally recurrent brain metastases after prior treatment. Methods Eighty-eight patients underwent GK-SRS for postirradiation recurrent brain metastases. Thirty-four patients received radiation in areas manifesting high MET uptake (PET group) in a dose-planning procedure using MET-PET/MRI fusion images. Fifty-four patients referred from other institutes received radiation based on dose planning information obtained from MRI (MRI group). Results Sex, age, and the ratio of breast cancer differed significantly between the MRI and PET groups. The total irradiation volume was significantly smaller in the PET group, and the minimal irradiation dose was significantly higher. In a multivariable statistical analysis, the use of MET-PET (P = 0.02) was independently associated with prolonged overall survival after treatment, Karnofsky performance status (P = 0.002), the number of lesions (P = 0.03), and patient’s sex (P = 0.02). The median survival time was significantly longer in the PET group (18.1 months) than in the MRI group (8.6 months) (P = 0.01). Conclusion 11C methionine-PET/MRI fusion images for dose planning lengthened survival in patients undergoing GK-SRS for focally recurrent brain metastases.

Validity of prognostic grading indices for brain metastasis patients undergoing repeat radiosurgery.

OBJECTIVESnWe tested the validity of 5 prognostic indices, Recursive Partitioning Analysis (RPA), Score Index for Radiosurgery (SIR), Basic Score for Brain Metastases (BSBM), Graded Prognostic Assessment (GPA), and Modified-RPA, for patients who underwent repeat stereotactic radiosurgery (re-SRS).nnnMETHODSnFor this study, we used our database, which included 804 patients who underwent gamma knife re-SRS during the period 1998-2013.nnnRESULTSnThere were statistically significant survival differences among patients stratified into 3 or 4 groups based on the 5 systems (P < 0.001). With RPA, SIR, BSBM, and the Modified-RPA, there were statistically significant median survival time (MST) differences between any 2 pairs within the 3/4 groups. With the GPA system, however, the MST difference between the GPA 3.5-4.0 and GPA 3.0 groups did not reach statistical significance (P = 0.48). There were large patient number discrepancies among the 3/4 groups in the RPA, SIR, BSBM, and GPA whereas patient numbers were very similar among the 3 Modified-RPA system groups. Our present results show the RPA and BSBM systems to reflect changes less well, with 86%-95% of patients remaining in the same categories between the first and second SRS procedures. However, with SIR, GPA, and the Modified-RPA, 25%-31% of patients were categorized into different subclasses, either better or worse. With the modified-RPA system, such categorical change correlated well with post-re-SRS MSTs.nnnCONCLUSIONSnAmong the 5 systems, based on patient number proportions, MST separation among the 3/4 groups, and/or detailed reflection of status changes, the Modified-RPA system was shown to be most applicable to re-SRS patients.

Increased adenosine A1 receptor levels in hemianopia patients after cerebral injury: an application of PET using 11C-8-dicyclopropylmethyl-1-methyl-3-propylxanthine.

Purpose The aim of this study was to apply positron emission tomography (PET) with 11C-8-dicyclopropylmethyl-1-methyl-3-propylxanthine (MPDX), a radioligand for adenosine A1 receptor (A1R), to patients with hemianopia caused by brain injury to study neurorepair mechanisms in the brain. Patients and Methods Four patients with homonymous hemianopia and 15 healthy subjects were examined using PET to measure cerebral glucose metabolism, 11C-flumazenil (FMZ) binding to the central benzodiazepine receptor, and MPDX binding to A1R. Left and right regions of interest (ROIs) were selected, and semiquantitative data on the 3 kinds of PET examinations were obtained. The ROIs were referenced using the data for homologous regions in the contralateral hemisphere [ipsilateral/contralateral (I/C) ratio]. Results The I/C ratios for cerebral glucose metabolism and FMZ binding were low in the primary visual cortex (PVC) and visual association cortex in all the patients, whereas MPDX binding increased in the PVC in patients 1 and 2. Patients 1 and 2 experienced improvement in their visual field after 1 year. However, the other 2 patients showed no changes. We observed an increase in MPDX binding to A1R in the injured portion of the PVC in the patients who recovered. Conclusions Evaluation of A1R by MPDX-PET may be useful for predicting prognosis and understanding the compensatory and reorganization processes in hemianopia caused by organic brain damage.