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Takero Hirata, Manabu Kinoshita, Keisuke Tamari, Yuji Seo, Osamu Suzuki, Nobuhide Wakai, Takamune Achiha, Toru Umehara, Hideyuki Arita, Naoki Kagawa, Yonehiro Kanemura, Eku Shimosegawa, Naoya Hashimoto, Jun Hatazawa, Haruhiko Kishima, Teruki Teshima and Kazuhiko Ogawa

OBJECTIVE

It is important to correctly and precisely define the target volume for radiotherapy (RT) of malignant glioma. 11C-methionine (MET) positron emission tomography (PET) holds promise for detecting areas of glioma cell infiltration: the authors’ previous research showed that the magnitude of disruption of MET and 18F-fluorodeoxyglucose (FDG) uptake correlation (decoupling score [DS]) precisely reflects glioma cell invasion. The purpose of the present study was to analyze volumetric and geometrical properties of RT target delineation based on DS and compare them with those based on MRI.

METHODS

Twenty-five patients with a diagnosis of malignant glioma were included in this study. Three target volumes were compared: 1) contrast-enhancing core lesions identified by contrast-enhanced T1-weighted images (T1Gd), 2) high-intensity lesions on T2-weighted images, and 3) lesions showing high DS (DS ≥ 3; hDS). The geometrical differences of these target volumes were assessed by calculating the probabilities of overlap and one encompassing the other. The correlation of geometrical features of RT planning and recurrence patterns was further analyzed.

RESULTS

The analysis revealed that T1Gd with a 2.0-cm margin was able to cover the entire high DS area only in 6 (24%) patients, which indicates that microscopic invasion of glioma cells often extended more than 2.0 cm beyond a Gd-enhanced core lesion. Insufficient coverage of high DS regions with RT target volumes was suggested to be a risk for out-of-field recurrence. Higher coverage of hDS by T1Gd with a 2-cm margin (i.e., higher values of “[T1Gd + 2 cm]/hDS”) had a trend to positively impact overall and progression-free survival. Cox regression analysis demonstrated that low coverage of hDS by T1Gd with a 2-cm margin was predictive of disease recurrence outside the Gd-enhanced core lesion, indicative of out-of-field reoccurrence.

CONCLUSIONS

The findings of this study indicate that MRI is inadequate for target delineation for RT in malignant glioma treatment. Expanding the treated margins substantially beyond the MRI-based target volume may reduce the risk of undertreatment, but it may also result in unnecessary irradiation of uninvolved regions. As MET/FDG PET-DS seems to provide more accurate information for target delineation than MRI in malignant glioma treatment, this method should be further evaluated on a larger scale.

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Ryuichi Hirayama, Manabu Kinoshita, Hideyuki Arita, Naoki Kagawa, Haruhiko Kishima, Naoya Hashimoto, Yasunori Fujimoto and Toshiki Yoshimine

OBJECTIVE

In the present study the authors aimed to determine preferred locations of meningiomas by avoiding descriptive analysis and instead using voxel-based lesion mapping and 3D image-rendering techniques.

METHODS

Magnetic resonance images obtained in 248 treatment-naïve meningioma patients with 260 lesions were retrospectively and consecutively collected. All images were registered to a 1-mm isotropic, high-resolution, T1-weighted brain atlas provided by the Montreal Neurological Institute (the MNI152), and a lesion frequency map was created, followed by 3D volume rendering to visualize the preferred locations of meningiomas in 3D.

RESULTS

The 3D lesion frequency map clearly showed that skull base structures such as parasellar, sphenoid wing, and petroclival regions were commonly affected by the tumor. The middle one-third of the superior sagittal sinus was most commonly affected in parasagittal tumors. Substantial lesion accumulation was observed around the leptomeninges covering the central sulcus and the sylvian fissure, with very few lesions observed at the frontal, parietal, and occipital convexities.

CONCLUSIONS

Using an objective visualization method, meningiomas were shown to be located around the middle third of the superior sagittal sinus, the perisylvian convexity, and the skull base. These observations, which are in line with previous descriptive analyses, justify further use of voxel-based lesion mapping techniques to help understand the biological nature of this disease.

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Yukihiro Goto, Yuichi Furuno, Takuya Kawabe, Kei Ohwada, Kazunori Tatsuzawa, Hiroyasu Sasajima and Naoya Hashimoto

A 34-year-old man with a 1-week history of diplopia was referred to the authors' hospital. Neurological examination revealed left abducens nerve palsy. Computed tomography showed a lesion in the left sphenoid sinus involving the medial wall of the left internal carotid artery (ICA) and osteolytic change at the clivus bordering the lesion. Magnetic resonance imaging demonstrated an extensive soft-tissue mass occupying the left sphenoid sinus. Surgical intervention by the endoscopic transnasal method allowed most of the lesion to be removed. Only the portion attached to the medial wall of the ICA was not removed. Postoperatively, the lesion was diagnosed as a giant cell tumor (GCT) and the patient received 120 mg of subcutaneous denosumab every 4 weeks, with additional doses on Days 8 and 15 during the first month of therapy. MRI a week after starting denosumab revealed shrinkage of the initially fast-growing residual tumor. The patient was discharged upon completion of the third denosumab administration. GCT is an aggressive stromal tumor developing mainly in young adults. Complete resection is recommended for GCT in the literature. However, size and location of the CGT often limit this approach. Various adjuvant treatments for skull base GCTs have been reported, including radiation and chemotherapy. However, the roles of adjuvant therapies have yet to be clearly defined. Denosumab, a monoclonal antibody, was recently approved for GCT in several countries. Denosumab may permit less invasive treatments for patients with GCTs while avoiding deleterious outcomes, and may also limit disease progression and recurrence.

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Takuya Kawabe, Masaaki Yamamoto, Yasunori Sato, Shoji Yomo, Takeshi Kondoh, Osamu Nagano, Toru Serizawa, Takahiko Tsugawa, Hisayo Okamoto, Atsuya Akabane, Kazuyasu Aita, Manabu Sato, Hidefumi Jokura, Jun Kawagishi, Takashi Shuto, Hideya Kawai, Akihito Moriki, Hiroyuki Kenai, Yoshiyasu Iwai, Masazumi Gondo, Toshinori Hasegawa, Soichiro Yasuda, Yasuhiro Kikuchi, Yasushi Nagatomo, Shinya Watanabe and Naoya Hashimoto

OBJECTIVE

In 1999, the World Health Organization categorized large cell neuroendocrine carcinoma (LCNEC) of the lung as a variant of large cell carcinoma, and LCNEC now accounts for 3% of all lung cancers. Although LCNEC is categorized among the non–small cell lung cancers, its biological behavior has recently been suggested to be very similar to that of a small cell pulmonary malignancy. The clinical outcome for patients with LCNEC is generally poor, and the optimal treatment for this malignancy has not yet been established. Little information is available regarding management of LCNEC patients with brain metastases (METs). This study aimed to evaluate the efficacy of Gamma Knife radiosurgery (GKRS) for patients with brain METs from LCNEC.

METHODS

The Japanese Leksell Gamma Knife Society planned this retrospective study in which 21 Gamma Knife centers in Japan participated. Data from 101 patients were reviewed for this study. Most of the patients with LCNEC were men (80%), and the mean age was 67 years (range 39–84 years). Primary lung tumors were reported as well controlled in one-third of the patients. More than half of the patients had extracranial METs. Brain metastasis and lung cancer had been detected simultaneously in 25% of the patients. Before GKRS, brain METs had manifested with neurological symptoms in 37 patients. Additionally, prior to GKRS, resection was performed in 17 patients and radiation therapy in 10. A small cell lung carcinoma–based chemotherapy regimen was chosen for 48 patients. The median lesion number was 3 (range 1–33). The median cumulative tumor volume was 3.5 cm3, and the median radiation dose was 20.0 Gy. For statistical analysis, the standard Kaplan-Meier method was used to determine post-GKRS survival. Competing risk analysis was applied to estimate GKRS cumulative incidences of maintenance of neurological function and death, local recurrence, appearance of new lesions, and complications.

RESULTS

The overall median survival time (MST) was 9.6 months. MSTs for patients classified according to the modified recursive partitioning analysis (RPA) system were 25.7, 11.0, and 5.9 months for Class 1+2a (20 patients), Class 2b (28), and Class 3 (46), respectively. At 12 months after GKRS, neurological death–free and deterioration–free survival rates were 93% and 87%, respectively. Follow-up imaging studies were available in 78 patients. The tumor control rate was 86% at 12 months after GKRS.

CONCLUSIONS

The present study suggests that GKRS is an effective treatment for LCNEC patients with brain METs, particularly in terms of maintaining neurological status.

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Manabu Kinoshita, Hideyuki Arita, Yoshiko Okita, Naoki Kagawa, Haruhiko Kishima, Naoya Hashimoto, Hisashi Tanaka, Yoshiyuki Watanabe, Eku Shimosegawa, Jun Hatazawa, Yasunori Fujimoto and Toshiki Yoshimine

OBJECTIVE

Diffusion MRI is attracting increasing interest for tissue characterization of gliomas, especially after the introduction of antiangiogenic therapy to treat malignant gliomas. The goal of the current study is to elucidate the actual magnitude of the correlation between diffusion MRI and cell density within the tissue. The obtained results were further extended and compared with metabolic imaging with 11C-methionine (MET) PET.

METHODS

Ninety-eight tissue samples from 37 patients were stereotactically obtained via an intraoperative neuronavigation system. Diffusion tensor imaging (DTI) and MET PET were performed as routine presurgical imaging studies for these patients. DTI was converted into fractional anisotropy (FA) and apparent diffusion coefficient (ADC) maps, and MET PET images were registered to Gd-administered T1-weighted images that were used for navigation. Metrics of FA, ADC, and tumor-to-normal tissue ratio of MET PET along with relative values of FA (rFA) and ADC (rADC) compared with normal-appearing white matter were correlated with cell density of the stereotactically obtained tissues.

RESULTS

rADC was significantly lower in lesions obtained from Gd-enhancing lesions than from nonenhancing lesions. Although rADC showed a moderate but statistically significant negative correlation with cell density (p = 0.010), MET PET showed a superb positive correlation with cell density (p < 0.0001). On the other hand, rFA showed little correlation with cell density.

CONCLUSIONS

The presented data validated the use of rADC for estimating the treatment response of gliomas but also caution against overestimating its limited accuracy compared with MET PET.

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Manabu Kinoshita, Mai Taniguchi, Masatoshi Takagaki, Nobuhisa Seike, Naoya Hashimoto and Toshiki Yoshimine

Neurosurgical patties are the most frequently used instruments during neurosurgical procedures, and their high performance is required to ensure safe operations. They must offer cushioning, water-absorbing, water-retaining, and non–tissue adherent characteristics. Here, the authors describe a revised neurosurgical patty that is superior in all respects to the conventional patty available in Japan. Patty characteristics were critically and scientifically evaluated using various in vitro assays. Moreover, a novel ex vivo evaluation system focusing on the adherent characteristics of the neurosurgical patty was developed. The proposed assay could provide benchmark data for comparing different neurosurgical patties, offering neurosurgeons objective data on the performance of patties. The newly developed patty was also evaluated in real neurosurgical settings and showed superb performance during various neurosurgical procedures.

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Ryuichi Hirayama, Yasunori Fujimoto, Masao Umegaki, Naoki Kagawa, Manabu Kinoshita, Naoya Hashimoto and Toshiki Yoshimine

Object

Existing training methods for neuroendoscopic surgery have mainly emphasized the acquisition of anatomical knowledge and procedures for operating an endoscope and instruments. For laparoscopic surgery, various training systems have been developed to teach handling of an endoscope as well as the manipulation of instruments for speedy and precise endoscopic performance using both hands. In endoscopic endonasal surgery (EES), especially using a binostril approach to the skull base and intradural lesions, the learning of more meticulous manipulation of instruments is mandatory, and it may be necessary to develop another type of training method for acquiring psychomotor skills for EES. Authors of the present study developed an inexpensive, portable personal trainer using a webcam and objectively evaluated its utility.

Methods

Twenty-five neurosurgeons volunteered for this study and were divided into 2 groups, a novice group (19 neurosurgeons) and an experienced group (6 neurosurgeons). Before and after the exercises of set tasks with a webcam box trainer, the basic endoscopic skills of each participant were objectively assessed using the virtual reality simulator (LapSim) while executing 2 virtual tasks: grasping and instrument navigation. Scores for the following 11 performance variables were recorded: instrument time, instrument misses, instrument path length, and instrument angular path (all of which were measured in both hands), as well as tissue damage, max damage, and finally overall score. Instrument time was indicated as movement speed; instrument path length and instrument angular path as movement efficiency; and instrument misses, tissue damage, and max damage as movement precision.

Results

In the novice group, movement speed and efficiency were significantly improved after the training. In the experienced group, significant improvement was not shown in the majority of virtual tasks. Before the training, significantly greater movement speed and efficiency were demonstrated in the experienced group, but no difference in movement precision was shown between the 2 groups. After the training, no significant differences were shown between the 2 groups in the majority of the virtual tasks. Analysis revealed that the webcam trainer improved the basic skills of the novices, increasing movement speed and efficiency without sacrificing movement precision.

Conclusions

Novices using this unique webcam trainer showed improvement in psychomotor skills for EES. The authors believe that training in terms of basic endoscopic skills is meaningful and that the webcam training system can play a role in daily off-the-job training for EES.

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Yasuyoshi Chiba, Manabu Kinoshita, Yoshiko Okita, Akihiro Tsuboi, Kayako Isohashi, Naoki Kagawa, Yasunori Fujimoto, Yusuke Oji, Yoshihiro Oka, Eku Shimosegawa, Satoshi Morita, Jun Hatazawa, Haruo Sugiyama, Naoya Hashimoto and Toshiki Yoshimine

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 11C-methionine PET (MET-PET) in WT1 immunotherapy and compared the data with the overall survival after initiation of WT1 immunotherapy (OSWT1).

Methods

Fourteen patients with recurrent malignant glioma were included in the study, and OSWT1 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 11C-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 11C-methionine uptake pre- and posttreatment; 2) area with increased 11C-methionine uptake posttreatment (PRM+MET); and 3) area with decreased 11C-methionine uptake posttreatment. While the results of Gd-enhanced MR imaging volumetric and conventional MET-PET analysis did not correlate with OSWT1 (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 OSWT1.

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.

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Naoya Hashimoto, Carter S. Rabo, Yoshiko Okita, Manabu Kinoshita, Naoki Kagawa, Yasunori Fujimoto, Eiichi Morii, Haruhiko Kishima, Motohiko Maruno, Amami Kato and Toshiki Yoshimine

Object

The precise natural history of incidentally discovered meningiomas (IDMs) remains unknown. It has been reported that for symptomatic meningiomas, tumor location can be used to predict growth. As to whether the same is true for IDMs has not been reported. This study aims to answer this question and provide biological evidence for this assumption by extending the study to involve symptomatic cases.

Methods

A total of 113 IDMs were analyzed by fine volumetry. A comparison of growth rates and patterns between skull base and non–skull base IDMs was made. Subsequently, materials obtained from 210 patients with symptomatic meningiomas who were treated in the authors' hospital during the same period were included for a biological comparison between skull base and non–skull base tumors using the MIB-1 index.

Results

The 110 patients with IDMs included 93 females and 17 males, with a mean follow-up period of 46.9 months. There were 38 skull base (34%) and 75 non–skull base (66%) meningiomas. Forty-two (37%) did not exhibit growth of more than 15% of the volume, whereas 71 (63%) showed growth. Only 15 (39.5%) of 38 skull base meningiomas showed growth, whereas 56 (74.7%) of 75 non–skull base meningiomas showed growth (p = 0.0004). In the 71 IDMs (15 skull base and 56 non–skull base), there was no statistical difference between the 2 groups in terms of mean age, sex, follow-up period, or initial tumor volume. However, the percentage of growth (p = 0.002) was significantly lower and the doubling time (p = 0.008) was significantly higher in the skull base than in the non–skull base tumor group. In subsequently analyzed materials from 94 skull base and 116 non–skull base symptomatic meningiomas, the mean MIB-1 index for skull base tumors was markedly low (2.09%), compared with that for non–skull base tumors (2.74%; p = 0.013).

Conclusions

Skull base IDMs tend not to grow, which is different from non–skull base tumors. Even when IDMs grow, the rate of growth is significantly lower than that of non–skull base tumors. The same conclusion with regard to biological behavior was confirmed in symptomatic cases based on MIB-1 index analyses. The authors' findings may impact the understanding of the natural history of IDMs, as well as strategies for management and treatment of IDMs and symptomatic meningiomas.

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Masayuki Hirata, Tetsu Goto, Gareth Barnes, Yuka Umekawa, Takufumi Yanagisawa, Amami Kato, Satoru Oshino, Haruhiko Kishima, Naoya Hashimoto, Youichi Saitoh, Naoki Tani, Shiro Yorifuji and Toshiki Yoshimine

Object

Event-related cerebral oscillatory changes reflect regional brain activation. In a previous study, the authors proposed a new method to determine language dominance: examine frontal oscillatory changes during silent reading by using synthetic aperture magnetometry (SAM). The authors' aims in the present study were to establish a normal template for this method, to confirm the results of their previous study with a larger patient population, and to evaluate their method with respect to language localization.

Methods

A statistical group analysis of 14 healthy volunteers was conducted to establish a normal control. Language dominance and localization were then evaluated in a larger population of 123 consecutive patients. Study participants were instructed to silently read 100 visually presented words. Using SAM, the spatial distribution of the oscillatory changes was obtained as the Student t statistic by comparing the current density for each voxel between 1 second before and 1 second after each word presentation. Group analyses of the healthy volunteers were performed using statistical nonparametric mapping. Language dominance in the patients was determined according to the laterality index (LI) calculated using peak t values of the left and right frontal desynchronizations. Language dominance was prospectively assessed, and the results were compared with those of the Wada test (63 patients). Language localization results were quantitatively compared with those of stimulation mapping (17 patients).

Results

Group analysis of the healthy volunteers indicated β to low γ band desynchronization in the left frontal area and α to β desynchronization in the left parietotemporal areas. In patients, the frontal language areas were detected in 118 persons (95.9%). Lateralization of β or low γ desynchronization in the inferior or middle frontal gyri corresponded well with language dominance. The introduction of the LI resulted in a quantitative evaluation of language dominance, whose results were concordant with those of the Wada test in 51 (85.0%) of 60 cases. The distance between the estimated frontal language areas and stimulation-positive sites was 6.0 ± 7.1 mm (mean ± SD).

Conclusions

This study is the first in which magnetoencephalography (MEG) was used to determine language dominance in a large population, and the results were compared with those of the Wada test. Moreover, language localization results obtained using MEG were compared with those obtained by invasive mapping. The authors' method, which is based on neuromagnetic oscillatory changes, is a new approach for noninvasively evaluating the frontal language areas, a procedure that has been problematic using MEG dipole methods. Synthetic aperture magnetometry is a noninvasive alternative to Wada testing for language dominance and helps to determine stimulation sites for invasive mapping.