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Naoki Ikegaya, Akio Takahashi, Takanobu Kaido, Yuu Kaneko, Masaki Iwasaki, Nobutaka Kawahara and Taisuke Otsuki

Surgical treatment of the insula is notorious for its high probability of motor complications, particularly when resecting the superoposterior part. Ischemic damage to the pyramidal tract in the corona radiata has been regarded as the cause of these complications, resulting from occlusion of the perforating arteries to the pyramidal tract through the insular cortex. The authors describe a strategy in which a small piece of gray matter is spared at the bottom of the periinsular sulcus, where the perforating arteries pass en route to the pyramidal tract, in order to avoid these complications. This method was successfully applied in 3 patients harboring focal cortical dysplasia in the posterior insula and frontoparietal operculum surrounding the periinsular sulcus. None of the patients developed permanent postoperative motor deficits, and seizure control was achieved in all 3 cases. The method described in this paper can be adopted for functional preservation of the pyramidal tract in the corona radiata when resecting epileptogenic pathologies involving insular and opercular regions.

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Douglas Kondziolka

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Shigeo Matsunaga, Takashi Shuto, Nobutaka Kawahara, Jun Suenaga, Shigeo Inomori and Hideyo Fujino

Object

The outcomes after Gamma Knife surgery (GKS) were retrospectively analyzed in patients with brain metastases from radioresistant primary colorectal cancer to evaluate the efficacy of GKS and the prognostic factors for local tumor control and overall survival.

Methods

The authors reviewed the medical records of 152 patients with 616 tumors. The group included 102 men and 50 women aged 35–85 years (mean age 64.4 years), who underwent GKS for metastatic brain tumors from colorectal cancer between April 1992 and September 2008 at Yokohama Rosai Hospital.

Results

The mean prescription dose to the tumor margin was 18.5 Gy (range 8–30 Gy). The mean tumor volume at GKS was 2.0 cm3 (range 0.004–10.0 cm3). The primary tumors were located in the colon in 88 patients and the rectum in 64. The median interval between the diagnosis of primary lesions and the diagnosis of brain metastases was 27 months (range 0–180 months). The median neuroradiological follow-up period after GKS was 3 months (mean 6.4 months, range 1–93 months). The local tumor growth control rate, based on MR imaging, was 91.2%. The significant factors for unfavorable local tumor growth control, based on multivariate analysis, were larger tumor volume (p = 0.001) and lower margin dose (p = 0.016). The median overall survival time was 6 months. Lower Karnofsky Performance Scale (KPS) score (p = 0.026) and the presence of extracranial metastases (p = 0.004) at first GKS were significantly correlated with poor overall survival period in multivariate analysis. The cause of death was systemic disease in 112 patients and neurological disease in 13 patients. Leptomeningeal carcinomatosis was significantly correlated with a shorter duration of neurological survival in multivariate analysis (p < 0.0001).

Conclusions

Gamma Knife surgery is effective for suppression of local tumor growth in patients with brain metastases from radioresistant colorectal primary cancer. Therefore, clinical and radiological screening of intracranial metastases for patients with lower KPS scores and/or the presence of extracranial metastases as well as follow-up examinations after GKS for brain metastases should be performed periodically in patients with colorectal cancer, because the neurological prognosis is improved by initial and repeat GKS for newly diagnosed or recurrent tumors leading to a prolonged high-quality survival period.

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Shigeo Matsunaga, Takashi Shuto, Nobutaka Kawahara, Jun Suenaga, Shigeo Inomori and Hideyo Fujino

Object

The goal of this study was to analyze prognostic factors for local tumor control and survival and indications for initial treatment with the Gamma Knife in patients with up to 10 metastatic brain tumors from primary breast cancer.

Methods

Outcomes were retrospectively reviewed in 101 women with a total of 600 tumors, who underwent Gamma Knife surgery (GKS) for metastatic brain tumors between April 1992 and December 2008 at 1 institution. The inclusion criteria were up to 10 brain metastases, maximum diameter of tumor < 3 cm, and total tumor volume < 15 cm3. The exclusion criteria were poor systemic condition, presence of carcinomatous meningitis, and previous whole brain radiation treatment and/or craniotomy.

Results

The mean tumor volume at GKS was 3.7 cm3 (range 0.016–14.3 cm3). The mean margin dose was 19 Gy (range 8–30 Gy). Neuroimaging showed that the local tumor growth control rate was 97%, and the tumor response rate was 82.3%. Larger tumor volume (p = 0.001) and lower margin dose (p = 0.001) were significant adverse prognostic factors for local tumor growth control according to a multivariate analysis. The number of brain metastatic lesions was 4 or fewer in 76 patients and 5 or more in 25 patients. The median overall survival time was 13 months. Multivariate analysis revealed that the presence of extracranial metastases (p = 0.041) and lesions that were not the human epidermal growth factor receptor–2 (HER2)–positive type (p = 0.001) were significant adverse prognostic factors for overall survival. The number of brain metastases was not statistically significant, except for a single metastasis. The median new lesion–free survival time after initial GKS was 9 months. Five or more lesions at initial GKS (p = 0.007) and younger patient age (p = 0.008) reduced survival significantly. The prevention of neurological death after GKS was 93.9% at 1 year, and a lower Karnofsky Performance Scale score (p = 0.009) was the only unfavorable factor. Median overall survival associated with the HER2-positive phenotype was significantly longer than survival associated with the other phenotypes (luminal and triple-negative). There were no statistically significant differences between the 3 breast cancer phenotypes for the incidence of new brain metastases after initial GKS.

Conclusions

Initial GKS resulted in excellent local tumor control rates, which were associated with prolonged survival and a low risk of neurological death for patients with up to 10 metastatic brain tumors from primary breast cancer. The authors recommend periodic clinical and neuroradiological follow-up examinations after GKS in patients with 5 or more lesions at initial GKS, because they carry a high risk of development of new brain metastases, and in patients with the HER2-positive phenotype, because they tend to have a favorable prognosis in overall survival. Last, the authors recommend additional GKS or whole-brain radiation treatment for salvage treatment if new brain metastases occur.

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Gakushi Yoshikawa, Toshihiko Momiyama, Soichi Oya, Keisuke Takai, Jun-ichi Tanaka, Shigeki Higashiyama, Nobuhito Saito, Takaaki Kirino and Nobutaka Kawahara

Object

The capacity to replace lost neurons after insults is retained by several regions of adult mammalian brains. However, it is unknown how many neurons actually replace and mature into region-specific functional neurons to restore lost brain function. In this paper, the authors asked whether neuronal regeneration could be achieved efficaciously by growth factor treatment using a global ischemia model in rats, and they analyzed neuronal long-term maturation processes.

Methods

Rat global ischemia using a modified 4-vessel occlusion model was used to induce consistent ischemic neuronal injury in the dorsolateral striatum. To potentiate the proliferative response of neural progenitors, epidermal growth factor and fibroblast growth factor–2 were infused intraventricularly for 7 days from Day 2 after ischemia. Six weeks after ischemia, the number of neurons was counted in the defined dorsolateral striatum. To label the proliferating neural progenitors for tracing studies, 5-bromo-2′-deoxyuridine (BrdU; 150 mg/kg, twice a day) was injected intraperitoneally from Days 5 to 7, and immunohistochemical studies were conducted to explore the maturation of these progenitors. Migration of the progenitors was further studied by enhanced green fluorescent protein retrovirus injection. The effect of an antimitotic drug (cytosine arabinoside) on the neuronal count was also evaluated for contribution to regeneration. To see electrophysiological changes, treated rats were subjected to slice studies by whole-cell recordings. Finally, the effect of neural regeneration was assessed by motor performance by using the staircase test.

Results

Following epidermal growth factor and fibroblast growth factor–2 infusion into the lateral ventricles for 7 days beginning on Day 2, when severe neuronal loss in the adult striatum was confirmed (2.3% of normal controls), a significant increase of striatal neurons was observed at 6 weeks (~ 15% of normal controls) compared with vehicle controls (~ 5% of normal controls). Immunohistochemical studies by BrdU and enhanced green fluorescent protein retrovirus injection disclosed proliferation of neural progenitors in the subventricular zone and their migration to the ischemic striatum. By BrdU tracing study, NeuN- and BrdU-positive new neurons significantly increased at 6 and 12 weeks following the treatment. These accounted for 4.6 and 11.0% of the total neurons present, respectively. Antimitotic treatment demonstrated an approximately 66% reduction in neurons at 6 weeks. Further long-term studies showed dynamic changes of site-specific maturation among various neuronal subtypes even after 6 weeks. Electrophysiological properties of these newly appeared neurons underwent changes that conform to neonatal development. These regenerative changes were accompanied by a functional improvement of overall behavioral performance.

Conclusions

Treatment by growth factors significantly contributed to regeneration of mature striatal neurons after ischemia by endogenous neural progenitors, which was accompanied by electrophysiological maturation and improved motor performance. Recognition and improved understanding of these underlying dynamic processes will contribute to the development of novel and efficient regenerative therapies for brain injuries.

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Nobutaka Kawahara, Tomio Sasaki, Takahiro Asakage, Kazunari Nakao, Masashi Sugasawa, Hirotaka Asato, Isao Koshima and Nobuhito Saito

Object

Primary temporal bone malignancy is a rare form of tumor for which the therapeutic strategy remains controversial. In this study, the authors reviewed their experience with radical temporal bone resection (TBR) of such lesions and analyzed the long-term results to provide treatment recommendations.

Methods

Between 1994 and 2006, 17 patients (10 men and 7 women) underwent total or subtotal TBR for primary temporal bone malignancies. Tumors were graded according to the University of Pittsburgh system. The effects of surgical margins and tumor extensions on patient survival were analyzed using the Kaplan–Meier method.

Results

All tumors, except 1, were graded T4 (most advanced). Subtotal TBR was performed in 14 patients, and total TBR was performed in 3. The surgical margin was tumor negative in 10 patients and tumor positive in 7. For large tumors extending into the infratemporal fossa or encroaching on the jugular foramen, orbitozygomatic (3 patients) and posterior transjugular (4 patients) approaches were combined with the standard approach, and en bloc resection with a negative margin was achieved in all cases but 1. The follow-up time ranged from 0.3–11.6 years (mean 3.3 years). The 5-year recurrence-free and disease-specific survival rates were 67.5 and 60.1%, respectively. When a negative surgical margin was achieved, the survival rates improved to 100 and 89%, respectively.

Conclusions

The neurosurgical skull base technique could improve the probability of en bloc resection with a tumor-free margin for extensive temporal bone malignancies, which would cure a subset of patients. The active participation of neurosurgeons would improve patient care in this field.

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Keisuke Maruyama, Masahiro Shin, Masao Tago, Hiroki Kurita, Nobutaka Kawahara, Akio Morita and Nobuhito Saito

Object

Appropriate management of hemorrhage after Gamma Knife surgery (GKS) for arteriovenous malformations (AVMs) of the brain is poorly understood, although a certain proportion of patients suffer from hemorrhage.

Methods

Among 500 patients observed for 1 to 183 months (median 70 months) after GKS, 32 patients (6.4%) suffered a hemorrhage. Hemorrhage developed even after angiographically documented obliteration of the AVM in five (2%) of 250 patients followed for 1 to 133 months (median 75 months) post-GKS. These patients had been treated according to their pathological condition. Treatment of these patients and their outcomes were retrospectively reviewed. As a management strategy in patients with preobliteration hemorrhage, the intracerebral hematoma and the AVM nidus were removed in four patients, and chronic encapsulated hematoma was removed in three. Among 11 patients who were conservatively treated, AVMs were ultimately obliterated in five, including three patients who underwent repeated GKS. Intracerebral hematoma from angiographically documented obliterated AVMs was radically resected in two patients, including one who also underwent aspiration of an accompanying symptomatic cyst. Intraoperative bleeding was easily controlled in these patients. Outcomes after hemorrhage, measured with the modified Rankin Scale, were significantly better in patients with postobliteration hemorrhage than in those with preobliteration hemorrhage (p < 0.05).

Conclusions

Various types of hemorrhagic complications after GKS for AVMs can be properly managed based on an understanding of each pathological condition. Although a small risk of bleeding remains after angiographically demonstrated obliteration, surgery for such AVMs is safe, and the patient outcomes are more favorable. Radical resection to prevent further hemorrhage is recommended for ruptured AVMs after obliteration because such AVMs can cause repeated hemorrhages.

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Takayuki Hara, Nobutaka Kawahara, Koji Tsuboi, Junji Shibahara, Tetsuo Ushiku and Takaaki Kirino

✓ Skull base chordomas containing a sarcomatous component are extremely rare. Here the authors report two new cases in which a recurrent tumor with a sarcomatous component appeared after the patient had undergone charged-particle radiotherapy. Histological examinations performed in Case 1 revealed some retention of epithelial features in the sarcomatous component, whereas no such regions were observed in Case 2. Both patients had rapidly deteriorating clinical courses and died within 6 months after diagnosis of the recurrent tumor. The authors discuss the significance of the histological subtypes of these tumors for long-term prognosis and their pathogenetic mechanisms in relation to radiotherapy. Although these sarcomatous transformations are rare in conventional chordomas, a careful histological examination and thorough follow-up imaging studies are crucial when treating patients with such lesions.

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Kazuhide Furuya, Lidong Zhu, Nobutaka Kawahara, Osamu Abe and Takaaki Kirino

Object. Although brain tissue may be protected by previous preconditioning, the temporal evolution of infarcts in such preconditioned brain tissue during focal cerebral ischemia is largely unknown. Therefore, in this study the authors engaged in long-term observation with magnetic resonance (MR) imaging to clarify the difference in lesion evolution between tolerant and nontolerant conditions.

Methods. Bacterial lipopolysaccharide (LPS; 0.9 mg/kg) was administered intravenously to induce cross-ischemic tolerance. Focal cerebral ischemia was induced 72 hours later in spontaneously hypertensive rats. Serial brain MR images were obtained 6 hours, 24 hours, 4 days, 7 days, and 14 days after ischemia by using a 7.05-tesla unit.

Lesion-reducing effects were evident 6 hours after ischemia in the LPS group. Preconditioning with LPS does not merely delay but prevents ischemic cell death by reducing lesion size. Lesion reduction was a sustained effect noted up to 14 days after ischemia. Reduction of local cerebral blood flow (lCBF) in the periinfarct area was significantly inhibited in the LPS group, which was correlated with endothelial nitric oxide synthase (eNOS) expression.

Conclusions. Significant preservation of lCBF in the periinfarct area, which is relevant to sustained upregulation of eNOS, could be a candidate for the long-term inhibiting effect on infarct evolution in the LPS-induced tolerant state.

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Masahiro Shin, Nobutaka Kawahara, Keisuke Maruyama, Masao Tago, Keisuke Ueki and Takaaki Kirino

Object. Radiosurgery has been widely adopted for the treatment of cerebral arteriovenous malformations (AVMs) in which the practical endpoint is angiographic evidence of obliteration, presumed to be consistent with elimination of the risk of hemorrhage. To test this unverified assumption, the authors followed 236 radiosurgery-treated AVMs between 1 and 133 months (median 77 months) after angiographic evidence of obliteration.

Methods. Four patients experienced hemorrhage between 16 and 51 months after angiographic confirmation of AVM obliteration, and two underwent resection. The histological findings in these patients showed occlusion of the AVM by thickening of the intimal layer with dense hyalinization as well as a small amount of residual AVM vessels and a tiny vasculature. The risks of hemorrhage from these presumaby obliterated AVMs were 0.3% for the annual bleeding risk and 2.2% for the cumulative risk over 10 years. Continuous enhancement of the nidus on computerized tomography (CT) or magnetic resonance (MR) imaging was the only significant factor positively associated with hemorrhage in the statistical analysis (p = 0.0212).

Conclusions. Because the study was based on limited follow-up data, its significance for defining predictive features of hemorrhage after angiographic evidence of obliteration is still indeterminable. Nevertheless, disappearance of the AVM on angiography after radiosurgery does not always indicate total elimination of the disease, especially when CT or MR imaging continues to demonstrate an enhancing lesion. The authors therefore recommend continual follow up even after evidence of AVM obliteration on angiography.