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Masaaki Yamamoto, Atsuya Akabane, Yuji Matsumaru, Yoshinori Higuchi, Hidetoshi Kasuya and Yoichi Urakawa

Object

Little information is available on staged Gamma Knife surgery (GKS) with an interval of 3 years or more when used to treat arteriovenous malformations (AVMs) with volumes larger than 10 cm3. The goal of this study was to increase knowledge in this area by reporting the authors' experience.

Methods

The authors describe an institutional review board–approved retrospective study in which they examined databases including information on 250 patients who consecutively underwent GKS for cerebral AVMs during a 16-year period (1988–2004). Among the 250 patients the authors identified 31 patients (12.4%, 15 female and 16 male patients with a mean age of 29 years [range 10–63 years]) in whom 2-stage GKS was intentionally planned at the time of initial treatment because the volume of the AVM nidus was larger than 10 cm3. The most common presentation was bleeding (14 patients), followed by seizures (9 patients), incidental findings (7 patients), and headache with scintillation (1 patient). One patient underwent GKS for the treatment of 2 AVMs simultaneously, and thus 32 AVMs are included in this study. The mean nidus volume was 16.2 cm3 (maximum 55.8 cm3). In all 31 patients, relatively low radiation doses (12–16 Gy directed at the periphery of the lesion) were intentionally used for the first GKS. The second GKS was scheduled for at least 36 months after the first.

Results

Complete nidus obliteration was obtained after the first GKS in 1 patient. To date, 26 patients have undergone a second procedure with a post-GKS mean interval of 41 months (range 24–83 months); 2 other patients refused to undergo the second GKS, and no further treatment was given because of severe morbidity in 1 case and death due to bleeding in the other case. Among the 26 patients who did undergo a second procedure, 3 patients refused follow-up digital subtraction (DS) angiography, another is scheduled for follow-up DS angiography, and 2 patients died, one of bleeding and the other of an unknown cause. The remaining 20 patients underwent follow-up DS angiography. Complete nidus obliteration was confirmed in 13 patients (65.0%) and remarkable nidus shrinkage in the other 7 patients (35.0%). In 2 of these 7 patients, a third GKS achieved complete nidus obliteration. Therefore, the cumulative complete obliteration rate in this series was 76.2% (16 of 21 eligible patients). Seven patients (22.6%) experienced bleeding. The bleeding rates were 9.7%, 16.1%, 16.1%, and 26.1%, respectively, at 1, 2, 5, and 10 years post-GKS. There were 2 deaths and 3 cases of morbidity (persistent coma, mild hemimotor weakness, and hemianopsia in 1 patient each). Hemorrhage did not produce neurological deficits in the other 2 patients. During the mean post-GKS follow-up period of 105 months (range 42–229 months) to date, mild symptomatic GKS-related complications occurred in 2 patients (6.5%); these were classified as Radiation Oncology Group Neurotoxicity Grade 1 in 1 patient and Grade 2 in the other. Among various pre-GKS clinical factors, univariate analysis showed only patient age to impact complications (hazard ratio 0.675, 95% CI 0.306–0.942, p = 0.0085). The rate of complications in the pediatric cases was 33.3%, whereas that in the adolescent and adult cases was 0% (p = 0.0323).

Conclusions

Although a final conclusion awaits further studies and patient follow-up, these results suggest 2-stage GKS to be beneficial even for relatively large AVMs.

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Hiroshi Hasegawa, Shoji Bitoh, Hideo Otsuki, Masaaki Fujiwara, Tomio Yamamoto and Yasushi Kobayashi

✓ A case is reported of malignant schwannomatosis (malignant transformation of von Recklinghausen's disease) with catecholamine production in a patient with multiple intracranial aneurysms. The patient had a history of episodic hypertension and elevated levels of catecholamines in the serum and 24-hour urinary excretion. Postmortem examination revealed diffuse central nervous sytem (CNS) dissemination of the tumor from the thoracolumbar spinal malignant schwannoma. A high concentration of catecholamines was demonstrated in the tumor tissue, and histochemical and electron microscopy studies suggested the presence of catecholamines in the cytoplasm of some of the tumor cells. This patient's clinical and radiological features, including severe headache, vomiting, stiff neck, ptosis of the eye ipsilateral to the internal carotid-posterior communicating artery aneurysms, and local arterial narrowing, mimicked those of subarachnoid hemorrhage from a ruptured aneurysm. However, the clinical picture was caused by diffuse CNS dissemination of the tumor, another primary malignant schwannoma of the oculomotor nerve, and intimal fibrous thickening of the arterial wall.

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Shinya Watanabe, Masaaki Yamamoto, Takuya Kawabe, Takao Koiso, Tetsuya Yamamoto, Akira Matsumura and Hidetoshi Kasuya

OBJECTIVE

The aim of this study was to reappraise long-term treatment outcomes of stereotactic radiosurgery (SRS) for vestibular schwannomas (VSs). The authors used a database that included patients who underwent SRS with a unique dose-planning technique, i.e., partial tumor coverage designed to avoid excess irradiation of the facial and cochlear nerves, focusing on tumor control and hearing preservation. Clinical factors associated with post-SRS tumor control and long-term hearing preservation were also analyzed.

METHODS

This institutional review board–approved, retrospective cohort study used the authors' prospectively accumulated database. Among 207 patients who underwent Gamma Knife SRS for VSs between 1990 and 2005, 183 (who were followed up for at least 36 post-SRS months) were studied. The median tumor volume was 2.0 cm3 (range 0.05–26.2 cm3). The median prescribed dose at the tumor periphery was 12.0 Gy (range 8.8–15.0 Gy; 12.0 Gy was used in 171 patients [93%]), whereas tumor portions facing the facial and cochlear nerves were irradiated with 10.0 Gy. As a result, 72%–99% of each tumor was irradiated with the prescribed dose. The mean cochlear doses ranged from 2.3 to 5.7 Gy (median 4.1 Gy).

RESULTS

The median durations of imaging and audiometric follow-up were 114 months (interquartile range 73–144 months) and 59 months (interquartile range 33–109 months), respectively. Tumor shrinkage was documented in 110 (61%), no change in 48 (27%), and enlargement in the other 22 (12%) patients. A further procedure (FP) was required in 15 (8%) patients. Thus, the tumor growth control rate was 88% and the clinical control rate (i.e., no need for an FP) was 92%. The cumulative FP-free rates were 96%, 93%, and 87% at the 60th, 120th, and 180th post-SRS month, respectively. Six (3%) patients experienced facial pain, and 2 developed transient facial palsy. Serviceable hearing was defined as a pure tone audiogram result better than 50 dB. Among the 66 patients with serviceable hearing before SRS who were followed up, hearing acuity was preserved in 23 (35%). Actuarial serviceable hearing preservation rates were 49%, 24%, and 12% at the 60th, 120th, and 180th post-SRS month, respectively. On univariable analysis, only cystic-type tumor (HR 3.36, 95% CI 1.18–9.36; p = 0.02) was shown to have a significantly unfavorable association with FP. Multivariable analysis followed by univariable analysis revealed that higher age (≥ 65 years: HR 2.66, 95% CI 1.16–5.92; p = 0.02), larger tumor volume (≥ 8 cm3: HR 5.36, 95% CI 1.20–17.4; p = 0.03), and higher cochlear dose (mean cochlear dose > 4.2 Gy: HR 2.22, 95% CI 1.07–4.77; p = 0.03) were unfavorable factors for hearing preservation.

CONCLUSIONS

Stereotactic radiosurgery achieved good long-term results in this series. Tumor control was acceptable, and there were few serious complications in patients with small- to medium-sized VSs. Unfortunately, hearing preservation was not satisfactory. However, the longer the observation period, the more important it becomes to compare post-SRS hearing decreases with the natural decline in untreated cases.

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Masaaki Yamamoto, Takuya Kawabe, Yasunori Sato, Yoshinori Higuchi, Tadashi Nariai, Shinya Watanabe and Hidetoshi Kasuya

Object

Although 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.

Methods

This 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.

Results

Post-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).

Conclusions

Post-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.

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Bengt Karlsson, Hidefumi Jokura, Masaaki Yamamoto, Michael Söderman and Ingmar Lax

Object

The results of a novel radiosurgical approach to treat large arteriovenous malformations (AVMs) with repeated radiosurgery are presented and discussed.

Methods

The outcome was studied following repeated Gamma Knife surgery (GKS) for large AVMs, defined as a nidus volume of 9 ml or more. The philosophy was to treat the whole AVM with a low dose of radiation (≥ 10 Gy), and to repeat the treatment if the AVM shrank but was not obliterated. The study included 133 patients with AVMs treated at one of three different institutions. Clinical information was available for all patients, and complete radiological follow-up was available in 89 patients after the first treatment, and in 19 after the second treatment.

Results

The estimated obliteration rate following repeated GKS was 62%. Four patients (3%) developed neurological deficits caused by the radiation, whereas five others (4%) developed cystic changes. The annual incidence of hemorrhage was high (7%), of which 35% occurred within the 1st year after the first treatment.

Conclusions

Repeated radiosurgery seems to be a viable option for some AVMs considered to be too large for conventional radiosurgical treatment. The incidence of posttreatment hemorrhages seems to be a larger clinical problem than radiation-induced complications.

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Takuya Kawabe, Masaaki Yamamoto, Yasunori Sato, Bierta E. Barfod, Yoichi Urakawa, Hidetoshi Kasuya and Katsuyoshi Mineura

Object

Because brainstem metastases are not deemed resectable, stereotactic radiosurgery (SRS) is the only treatment modality expected to achieve a radical cure. The authors describe their treatment results, focusing particularly on how long patients can survive without neurological deterioration following SRS for brainstem metastases.

Methods

This was an institutional review board–approved, retrospective cohort study in which the authors pulled from their database information on 2553 consecutive patients with brain metastases who underwent Gamma Knife surgery (GKS) at the Mito GammaHouse between July 1998 and July 2011. Among the 2553 patients, excluding cases in which there was meningeal dissemination, 200 cases of brainstem metastases (78 women and 122 men with a mean age of 64 years [range 36–86 years]) were identified and analyzed. The most common primary site was the lung (137 patients) followed by the gastrointestinal tract (24 patients), breast (17 patients), kidney (12 patients), and others (10 patients). Among the 200 patients, 15 patients (7.5%) harbored at least 2 tumors in the brainstem: 11 patients had 2 tumors, 2 patients had 3 tumors, and 1 patient each had 4 or 5 tumors. Therefore, a total of 222 tumors were irradiated. These 222 tumors were located in the pons (121 lesions), the midbrain (65 lesions), and the medulla oblongata (36 lesions). The mean and median tumor volumes were 1.3 and 0.2 cm3 (range 0.005–10.7 cm3), and the median peripheral radiation dose was 18.0 Gy (range 12.0–25.0 Gy).

Results

The overall median survival time (MST) was 6.0 months. Distribution of MSTs across Recursive Partitioning Analysis (RPA) classes showed that the MSTs were 9.4 months in Class I (20 patients), 6.0 months in Class II (171 patients), and 1.9 months in Class III (9 patients). Better Karnofsky Performance Scale score, single metastasis, and well-controlled primary tumor were significant predictive factors for longer survival. The neurological and qualitative survival rates were 90.8% and 89.2%, respectively, at 24 months post-GKS. Better KPS score and smaller tumor volume tended to be associated with prolonged qualitative survival. Follow-up imaging studies were available for 129 patients (64.5%). The tumor control rate was 81.8% at 24 months post-GKS. Smaller tumor volume tended to contribute to tumor control.

Conclusions

The present results indicate that GKS is effective in the treatment of brainstem metastases, particularly from the viewpoint of maintaining a good neurological condition in the patient.

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Masaaki Yamamoto, Takuya Kawabe, Yasunori Sato, Yoshinori Higuchi, Tadashi Nariai, Bierta E. Barfod, Hidetoshi Kasuya and Yoichi Urakawa

Object

Although stereotactic radiosurgery (SRS) alone for patients with 4–5 or more tumors is not a standard treatment, a trend for patients with 5 or more tumors to undergo SRS alone is already apparent. The authors' aim in the present study was to reappraise whether SRS results for ≥ 5 tumors differ from those for 1–4 tumors.

Methods

This institutional review board–approved retrospective cohort study used the authors' database of prospectively accumulated data that included 2553 consecutive patients who underwent SRS, not in combination with concurrent whole-brain radiotherapy, for brain metastases (METs) between 1998 and 2011. These 2553 patients were divided into 2 groups: 1553 with tumor numbers of 1–4 (Group A) and 1000 with ≥ 5 tumors (Group B). Because there was considerable bias in pre-SRS clinical factors between Groups A and B, a case-matched study was conducted. Ultimately, 1096 patients (548 each in Groups A and B) were selected. The standard Kaplan-Meier method was used to determine post-SRS survival and the post-SRS neurological death–free survival times. Competing risk analysis was applied to estimate cumulative incidences of local recurrence, repeat SRS for new lesions, neurological deterioration, and SRS-induced complications.

Results

The post-SRS median survival time was significantly longer in the 548 Group A patients (7.9 months, 95% CI 7.0–8.9 months) than in the 548 Group B patients (7.0 months 95% [CI 6.2–7.8 months], HR 1.176 [95% CI 1.039–1.331], p = 0.01). However, incidences of neurological death were very similar: 10.6% in Group A and 8.2% in Group B (p = 0.21). There was no significant difference between the groups in neurological death–free survival intervals (HR 0.945, 95% CI 0.636–1.394, p = 0.77). Furthermore, competing risk analyses showed that there were no significant differences between the groups in cumulative incidences of local recurrence (HR 0.577, 95% CI 0.312–1.069, p = 0.08), repeat SRS (HR 1.133, 95% CI 0.910–1.409, p = 0.26), neurological deterioration (HR 1.868, 95% CI 0.608–1.240, p = 0.44), and major SRS-related complications (HR 1.105, 95% CI 0.490–2.496, p = 0.81).

In the authors' cohort, age ≤ 65 years, female sex, a Karnofsky Performance Scale score ≥ 80%, cumulative tumor volume ≤ 10 cm3, controlled primary cancer, no extracerebral METs, and neurologically asymptomatic status were significant factors favoring longer survival equally in both groups.

Conclusions

This retrospective study suggests that increased tumor number is an unfavorable factor for longer survival. However, the post-SRS median survival time difference, 0.9 months, between the two groups is not clinically meaningful. Furthermore, patients with 5 or more METs have noninferior results compared to patients with 1–4 tumors, in terms of neurological death, local recurrence, repeat SRS, maintenance of good neurological state, and SRS-related complications. A randomized controlled trial should be conducted to test this hypothesis.

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Kaoru Tamura, Masaru Aoyagi, Noboru Ando, Takahiro Ogishima, Hiroaki Wakimoto, Masaaki Yamamoto and Kikuo Ohno

Object

Recent evidence suggests that a glioma stem cell subpopulation may determine the biological behavior of tumors, including resistance to therapy. To investigate this hypothesis, the authors examined varying grades of gliomas for stem cell marker expressions and histopathological changes between primary and recurrent tumors.

Methods

Tumor samples were collected during surgery from 70 patients with varying grades of gliomas (Grade II in 12 patients, Grade III in 16, and Grade IV in 42) prior to any adjuvant treatment. The samples were subjected to immunohistochemistry for MIB-1, factor VIII, GFAP, and stem cell markers (CD133 and nestin). Histopathological changes were compared between primary and recurrent tumors in 31 patients after radiation treatment and chemotherapy, including high-dose irradiation with additional stereotactic radiosurgery.

Results

CD133 expression on glioma cells was confined to de novo glioblastomas but was not observed in lower-grade gliomas. In de novo glioblastomas, the mean percentage of CD133-positive glioma cells in sections obtained at recurrence was 12.2% ± 10.3%, which was significantly higher than that obtained at the primary surgery (1.08% ± 1.78%). CD133 and Ki 67 dual-positive glioma cells were significantly increased in recurrent de novo glioblastomas as compared with those in primary tumors (14.5% ± 6.67% vs 2.16% ± 2.60%, respectively). In contrast, secondary glioblastomas rarely expressed CD133 antigen even after malignant progression following radiotherapy and chemotherapy.

Conclusions

The authors' results indicate that CD133-positive glioma stem cells could survive, change to a proliferative cancer stem cell phenotype, and cause recurrence in cases with de novo glioblastomas after radiotherapy and chemotherapy.