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Goro Otsuka, Shigeru Miyachi, Takashi Handa, Makoto Negoro, Takeshi Okamoto, Osamu Suzuki and Jun Yoshida

✓ Giant serpentine aneurysms (GSAs) are defined as partially thrombosed giant aneurysms with persistent serpentine vascular channels. Surgical management of these rare lesions is difficult because of their large size, complex structure, and unique hemodynamics. The authors report two cases of patients harboring GSAs with mass effect, which were managed effectively with endovascular treatment. The first patient was a 48-year-old man who presented with left homonymous hemianopsia caused by a GSA involving the terminal portion of the right internal carotid artery. The second patient, a 10-year-old boy, presented with tetraparesis from compression of the cervicomedullary junction by a GSA of the right vertebral artery. In each case, after confirming collateral flow by temporarily occluding the proximal artery, the aneurysm was trapped by placement of Guglielmi detachable coils at the sites at which the serpentine channels entered and exited the aneurysm. The midportion of each channel was isolated completely without packing, to maximize resorption of the devascularized mass. Mass effect and clinical symptoms rapidly improved in both cases, with no associated morbidity. We recommend endovascular trapping as a safe and effective therapeutic option for GSAs.

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Ai Namioka, Takahiro Namioka, Masanori Sasaki, Yuko Kataoka-Sasaki, Shinichi Oka, Masahito Nakazaki, Rie Onodera, Junpei Suzuki, Yuichi Sasaki, Hiroshi Nagahama, Jeffery D. Kocsis and Osamu Honmou

OBJECTIVE

Morbidity and mortality in patients with posterior circulation stroke remains an issue despite advances in acute stroke therapies. The intravenous infusion of mesenchymal stem cells (MSCs) elicits therapeutic efficacy in experimental supratentorial stroke models. However, since there are few reliable animal models of ischemia in the posterior circulation, the therapeutic approach with intravenous MSC infusion has not been tested. The objective of this study was to test the hypothesis that intravenously infused MSCs provide functional recovery in a newly developed model of brainstem infarction in rats.

METHODS

Basilar artery (BA) occlusion (BAO) was established in rats by selectively ligating 4 points of the proximal BA with 10-0 nylon monofilament suture. The intravenous infusion of MSCs was performed 1 day after BAO induction. MRI and histological examinations were performed to assess ischemic lesion volume, while multiple behavioral tests were performed to evaluate functional recovery.

RESULTS

The MSC-treated group exhibited a greater reduction in ischemic lesion volume, while behavioral testing indicated that the MSC-infused group had greater improvement than the vehicle group 28 days after the MSC infusion. Accumulated infused MSCs were observed in the ischemic brainstem lesion.

CONCLUSIONS

Infused MSCs may provide neuroprotection to facilitate functional outcomes and reduce ischemic lesion volume as evaluated in a newly developed rat model of persistent BAO.

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Takahiro Namioka, Ai Namioka, Masanori Sasaki, Yuko Kataoka-Sasaki, Shinichi Oka, Masahito Nakazaki, Rie Onodera, Junpei Suzuki, Yuichi Sasaki, Hiroshi Nagahama, Jeffery D. Kocsis and Osamu Honmou

OBJECTIVE

Intravenous infusion of mesenchymal stem cells (MSCs) derived from adult bone marrow improves behavioral function in rat models of cerebral infarction. Although clinical studies are ongoing, most studies have focused on the acute or subacute phase of stroke. In the present study, MSCs derived from bone marrow of rats were intravenously infused 8 weeks after the induction of a middle cerebral artery occlusion (MCAO) to investigate whether delayed systemic injection of MSCs improves functional outcome in the chronic phase of stroke in rats.

METHODS

Eight weeks after induction of the MCAO, the rats were randomized and intravenously infused with either MSCs or vehicle. Ischemic volume and behavioral performance were examined. Blood-brain barrier (BBB) integrity was assessed by quantifying the leakage of Evans blue into the brain parenchyma after intravenous infusion. Immunohistochemical analysis was also performed to evaluate the stability of the BBB.

RESULTS

Motor recovery was better in the MSC-treated group than in the vehicle-treated group, with rapid improvement (evident at 1 week post-infusion). In MSC-treated rats, reduced BBB leakage and increased microvasculature/repair and neovascularization were observed.

CONCLUSIONS

These results indicate that the systemic infusion of MSCs results in functional improvement, which is associated with structural changes in the chronic phase of cerebral infarction, including in the stabilization of the BBB.

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Masahito Nakazaki, Masanori Sasaki, Yuko Kataoka-Sasaki, Shinichi Oka, Takahiro Namioka, Ai Namioka, Rie Onodera, Junpei Suzuki, Yuichi Sasaki, Hiroshi Nagahama, Takeshi Mikami, Masahiko Wanibuchi, Jeffery D. Kocsis and Osamu Honmou

OBJECTIVE

Reperfusion therapy with intravenous recombinant tissue plasminogen activator (rtPA) is the standard of care for acute ischemic stroke. However, hemorrhagic complications can result. Intravenous infusion of mesenchymal stem cells (MSCs) reduces stroke volume and improves behavioral function in experimental stroke models. One suggested therapeutic mechanism is inhibition of vascular endothelial dysfunction. The objective of this study was to determine whether MSCs suppress hemorrhagic events after rtPA therapy in the acute phase of transient middle cerebral artery occlusion (tMCAO) in rats.

METHODS

After induction of tMCAO, 4 groups were studied: 1) normal saline [NS]+vehicle, 2) rtPA+vehicle, 3) NS+MSCs, and 4) rtPA+MSCs. The incidence rate of intracerebral hemorrhage, both hemorrhagic and ischemic volume, and behavioral performance were examined. Matrix metalloproteinase–9 (MMP-9) levels in the brain were assessed with zymography. Quantitative analysis of regional cerebral blood flow (rCBF) was performed to assess hemodynamic change in the ischemic lesion.

RESULTS

The MSC-treated groups (Groups 3 and 4) experienced a greater reduction in the incidence rate of intracerebral hemorrhage and hemorrhagic volume 1 day after tMCAO even if rtPA was received. The application of rtPA enhanced activation of MMP-9, but MSCs inhibited MMP-9 activation. Behavioral testing indicated that both MSC-infused groups had greater improvement than non-MSC groups had, but rtPA+MSCs provided greater improvement than MSCs alone. The rCBF ratio of rtPA groups (Groups 2 and 4) was similar at 2 hours after reperfusion of tMCAO, but both were greater than that in non-rtPA groups.

CONCLUSIONS

Infused MSCs may inhibit endothelial dysfunction to suppress hemorrhagic events and facilitate functional outcome. Combined therapy of infused MSCs after rtPA therapy facilitated early behavioral recovery.

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Hideyuki Kano, Takashi Shuto, Yoshiyasu Iwai, Jason Sheehan, Masaaki Yamamoto, Heyoung L. McBride, Mitsuya Sato, Toru Serizawa, Shoji Yomo, Akihito Moriki, Yukihiko Kohda, Byron Young, Satoshi Suzuki, Hiroyuki Kenai, Christopher Duma, Yasuhiro Kikuchi, David Mathieu, Atsuya Akabane, Osamu Nagano, Douglas Kondziolka and L. Dade Lunsford

OBJECT

The purpose of this study was to evaluate the role of stereotactic radiosurgery (SRS) in the management of intracranial hemangioblastomas.

METHODS

Six participating centers of the North American Gamma Knife Consortium and 13 Japanese Gamma Knife centers identified 186 patients with 517 hemangioblastomas who underwent SRS. Eighty patients had 335 hemangioblastomas associated with von Hippel–Lindau disease (VHL) and 106 patients had 182 sporadic hemangioblastomas. The median target volume was 0.2 cm3 (median diameter 7 mm) in patients with VHL and 0.7 cm3 (median diameter 11 mm) in those with sporadic hemangioblastoma. The median margin dose was 18 Gy in VHL patients and 15 Gy in those with sporadic hemangioblastomas.

RESULTS

At a median of 5 years (range 0.5–18 years) after treatment, 20 patients had died of intracranial disease progression and 9 patients had died of other causes. The overall survival after SRS was 94% at 3 years, 90% at 5 years, and 74% at 10 years. Factors associated with longer survival included younger age, absence of neurological symptoms, fewer tumors, and higher Karnofsky Performance Status. Thirty-three (41%) of the 80 patients with VHL developed new tumors and 17 (16%) of the106 patients with sporadic hemangioblastoma had recurrences of residual tumor from the original tumor. The 5-year rate of developing a new tumor was 43% for VHL patients, and the 5-year rate of developing a recurrence of residual tumor from the original tumor was 24% for sporadic hemangioblastoma patients. Factors associated with a reduced risk of developing a new tumor or recurrences of residual tumor from the original tumor included younger age, fewer tumors, and sporadic rather than VHL-associated hemangioblastomas. The local tumor control rate for treated tumors was 92% at 3 years, 89% at 5 years, and 79% at 10 years. Factors associated with an improved local tumor control rate included VHL-associated hemangioblastoma, solid tumor, smaller tumor volume, and higher margin dose. Thirteen patients (7%) developed adverse radiation effects (ARE) after SRS, and one of these patients died due to ARE.

CONCLUSIONS

When either sporadic or VHL-associated tumors were observed to grow on serial imaging studies, SRS provided tumor control in 79%–92% of tumors.

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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.