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Mikhail Chernov, Yoshihiro Muragaki and Hiroshi Iseki

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Mikhail Chernov, Yoshihiro Muragaki and Hiroshi Iseki

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Takahiro Shioyama, Yoshihiro Muragaki, Takashi Maruyama, Takashi Komori and Hiroshi Iseki

Object

Intraoperative histopathological investigation plays an important role during surgery for gliomas. To facilitate the rapid characterization of resected tissue, an original technique of intraoperative flow cytometry (iFC) was established. The objective in this study was evaluation of this technique's efficacy for rapidly determining tumor presence in the surgical biopsy sample and WHO histopathological grade of the neoplasm.

Methods

In total, 328 separate biopsy specimens obtained during the resection of 81 intracranial gliomas were analyzed with iFC. The evaluated malignancy index (MI) was defined as the ratio of the number of cells with greater than normal DNA content to the total number of cells. The duration of iFC in all cases was approximately 10 minutes. Each sample was additionally investigated histopathologically on frozen and permanent formalin-fixed paraffin-embedded tissue sections. The latter process was used as a “gold standard” control for evaluation of the diagnostic efficacy of iFC analysis.

Results

The MI differed significantly between neoplastic and perilesional brain tissue (25.3% ± 22.0% vs 4.6% ± 2.6%, p < 0.01). Receiver operating characteristic curve analysis revealed a corresponding area under the curve value of 0.941. The optimal cutoff level of the MI for identification of tumor in the biopsy specimen was 6.8%, which provided 0.88 sensitivity, 0.88 specificity, 0.97 positive predictive value, 0.60 negative predictive value, and 0.88 diagnostic accuracy. Additionally, the MI showed a significant association with WHO histopathological grades of glioma (p < 0.01), but its values in Grade II, III, and IV tumors overlapped prominently and were on average 13.3% ± 11.0%, 35.0% ± 21.8%, and 46.6% ± 23.1%, respectively.

Conclusions

Results of this study demonstrate that iFC with the determination of the MI may be feasible for rapidly determining glioma presence in a surgical biopsy sample.

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Editorial

Our failure to advance new treatments for glioma to market

John H. Sampson, Thomas J. Kaminski and Kevin A. Schulman

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Yoshihiro Muragaki, Ken Masamune, Miyuki Uematsu, Mitsuo Umezu, Hiroshi Iseki and Mikhail Chernov

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Masayuki Nitta, Yoshihiro Muragaki, Takashi Maruyama, Hiroshi Iseki, Takashi Komori, Soko Ikuta, Taiichi Saito, Takayuki Yasuda, Junji Hosono, Saori Okamoto, Shunichi Koriyama and Takakazu Kawamata

OBJECTIVE

In this study on the effectiveness and safety of photodynamic therapy (PDT) using talaporfin sodium and a semiconductor laser, the long-term follow-up results of 11 patients with glioblastoma enrolled in the authors’ previous phase II clinical trial (March 2009–2012) and the clinical results of 19 consecutive patients with newly diagnosed glioblastoma prospectively enrolled in a postmarket surveillance (March 2014–December 2016) were analyzed and compared with those of 164 patients treated without PDT during the same period.

METHODS

The main outcome measures were the median overall survival (OS) and progression-free survival (PFS) times. Moreover, the adverse events and radiological changes after PDT, as well as the patterns of recurrence, were analyzed and compared between the groups. Kaplan-Meier curves were created to assess the differences in OS and PFS between the groups. Univariate and multivariate analyses were performed to identify the prognostic factors, including PDT, among patients with newly diagnosed glioblastoma.

RESULTS

The median PFS times of the PDT and control groups were 19.6 and 9.0 months, with 6-month PFS rates of 86.3% and 64.9%, respectively (p = 0.016). The median OS times were 27.4 and 22.1 months, with 1-year OS rates of 95.7% and 72.5%, respectively (p = 0.0327). Multivariate analyses found PDT, preoperative Karnofsky Performance Scale score, and IDH mutation to be significant independent prognostic factors for both OS and PFS. Eighteen of 30 patients in the PDT group experienced tumor recurrence, including local recurrence, distant recurrence, and dissemination in 10, 3, and 4 patients, respectively. Conversely, 141 of 164 patients in the control group experienced tumor recurrence, including 101 cases of local recurrence. The rate of local recurrence tended to be lower in the PDT group (p = 0.06).

CONCLUSIONS

The results of the present study suggest that PDT with talaporfin sodium and a semiconductor laser provides excellent local control, with few adverse effects even in cases of multiple laser irradiations, as well as potential survival benefits for patients with newly diagnosed glioblastoma.

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George Vartholomatos, George A. Alexiou, Anna Batistatou, Athanassios P. Kyritsis and Spyridon Voulgaris

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Noriko Tamura, Motohiro Hayashi, Mikhail Chernov, Manabu Tamura, Ayako Horiba, Yoshiyuki Konishi, Yoshihiro Muragaki, Hiroshi Iseki and Yoshikazu Okada

Object

The focus of the present study was the evaluation of outcomes after unstaged and staged-volume Gamma Knife surgery (GKS) in children harboring intracranial arteriovenous malformations (AVMs).

Methods

Twenty-two children (median age 9.5 years) underwent GKS for AVMs and were followed up for at least 2 years thereafter. The disease manifested with intracranial hemorrhage in 77% of cases. In 68% of patients the lesion affected eloquent brain structures. The volume of the nidus ranged from 0.1 to 6.7 cm3. Gamma Knife surgery was guided mainly by data from dynamic contrast-enhanced CT scans, with preferential targeting of the junction between the nidus and draining vein. The total prescribed isodose volume was kept below 4.0 cm3, and the median margin dose was 22 Gy (range 20–25 Gy). If the volume of the nidus was larger than 4.0 cm3, a second radiosurgical session was planned for 3–4 years after the first one. Nine patients in the present series underwent unstaged radiosurgery, whereas staged-volume treatment was scheduled in 13 patients.

Results

Complete obliteration of the AVM was noted in 17 (77%) of 22 patients within a median period of 47 months after the last radiosurgical session. Complete obliteration of the lesion occurred in 89% of patients after unstaged treatment and in 62.5% after staged GKS. Four (67%) of 6 high-grade AVMs were completely obliterated. Complications included 3 bleeding episodes, the appearance of a region of hyperintensity on T2-weighted MR images in 2 patients who had no symptoms, and reappearance of the nidus in the vicinity of the completely obliterated AVM in 1 patient.

Conclusions

Radiosurgery is a highly effective management option for intracranial AVMs in children. For larger lesions, staged GKS may be applied successfully. Initial targeting of the nidus adjacent to the draining vein and application of a sufficient radiation dose to a relatively small volume (≤ 4 cm3) provides a good balance between a high probability of obliteration and a low risk of treatment-related complications.

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Yu Fujii, Yoshihiro Muragaki, Takashi Maruyama, Masayuki Nitta, Taiichi Saito, Soko Ikuta, Hiroshi Iseki, Kazuhiro Hongo and Takakazu Kawamata

OBJECTIVE

WHO Grade III gliomas are relatively rare and treated with multiple modalities such as surgery, chemotherapy, and radiotherapy. The impact of the extent of resection (EOR) on improving survival in patients with this tumor type is unclear. Moreover, because of the heterogeneous radiological appearance of Grade III gliomas, the MRI sequence that best correlates with tumor volume is unknown. In the present retrospective study, the authors evaluated the prognostic significance of EOR.

METHODS

Clinical and radiological data from 122 patients with newly diagnosed WHO Grade III gliomas who had undergone intraoperative MRI–guided resection at a single institution between March 2000 and December 2011 were analyzed retrospectively. Patients were divided into 2 groups by histological subtype: 81 patients had anaplastic astrocytoma (AA) or anaplastic oligoastrocytoma (AOA), and 41 patients had anaplastic oligodendroglioma (AO). EOR was calculated using pre- and postoperative T2-weighted and contrast-enhanced T1-weighted MR images. Univariate and multivariate analyses were performed to evaluate the prognostic significance of EOR on overall survival (OS).

RESULTS

The 5-, 8-, and 10-year OS rates for all patients were 74.28%, 70.59%, and 65.88%, respectively. The 5- and 8-year OS rates for patients with AA and AOA were 72.2% and 67.2%, respectively, and the 10-year OS rate was 62.0%. On the other hand, the 5- and 8-year OS rates for patients with AO were 79.0% and 79.0%; the 10-year OS rate is not yet available. The median pre- and postoperative T2-weighted high–signal intensity volumes were 56.1 cm3 (range 1.3–268 cm3) and 5.9 cm3 (range 0–180 cm3), respectively. The median EOR of T2-weighted high–signal intensity lesions (T2-EOR) and contrast-enhanced T1-weighted lesions were 88.8% (range 0.3%–100%) and 100% (range 34.0%–100%), respectively. A significant survival advantage was associated with resection of 53% or more of the preoperative T2-weighted high–signal intensity volume in patients with AA and AOA, but not in patients with AO. Univariate analysis showed that preoperative Karnofsky Performance Scale score (p = 0.0019), isocitrate dehydrogenase 1 (IDH1) mutation (p = 0.0008), and T2-EOR (p = 0.0208) were significant prognostic factors for survival in patients with AA and AOA. Multivariate analysis demonstrated that T2-EOR (HR 3.28; 95% CI 1.22–8.81; p = 0.0192) and IDH1 mutation (HR 3.90; 95% CI 1.53–10.75; p = 0.0044) were predictive of survival in patients with AA and AOA.

CONCLUSIONS

T2-EOR was one of the most important prognostic factors for patients with AA and AOA. A significant survival advantage was associated with resection of 53% or more of the preoperative T2-weighted high–signal intensity volume in patients with AA and AOA.

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Masayuki Nitta, Yoshihiro Muragaki, Takashi Maruyama, Soko Ikuta, Takashi Komori, Katsuya Maebayashi, Hiroshi Iseki, Manabu Tamura, Taiichi Saito, Saori Okamoto, Mikhail Chernov, Motohiro Hayashi and Yoshikazu Okada

OBJECT

There is no standard therapeutic strategy for low-grade glioma (LGG). The authors hypothesized that adjuvant therapy might not be necessary for LGG cases in which total radiological resection was achieved. Accordingly, they established a treatment strategy based on the extent of resection (EOR) and the MIB-1 index: patients with a high EOR and low MIB-1 index were observed without postoperative treatment, whereas those with a low EOR and/or high MIB-1 index received radiotherapy (RT) and/or chemotherapy. In the present retrospective study, the authors reviewed clinical data on patients with primarily diagnosed LGGs who had been treated according to the above-mentioned strategy, and they validated the treatment policy. Given their results, they will establish a new treatment strategy for LGGs stratified by EOR, histological subtype, and molecular status.

METHODS

One hundred fifty-three patients with diagnosed LGG who had undergone resection or biopsy at Tokyo Women's Medical University between January 2000 and August 2010 were analyzed. The patients consisted of 84 men and 69 women, all with ages ≥ 15 years. A total of 146 patients underwent surgical removal of the tumor, and 7 patients underwent biopsy.

RESULTS

Postoperative RT and nitrosourea-based chemotherapy were administered in 48 and 35 patients, respectively. Extent of resection was significantly associated with both overall survival (OS; p = 0.0096) and progression-free survival (PFS; p = 0.0007) in patients with diffuse astrocytoma but not in those with oligodendroglial subtypes. Chemotherapy significantly prolonged PFS, especially in patients with oligodendroglial subtypes (p = 0.0009). Patients with a mutant IDH1 gene had significantly longer OS (p = 0.034). Multivariate analysis did not identify MIB-1 index or RT as prognostic factors, but it did identify chemotherapy as a prognostic factor for PFS and EOR as a prognostic factor for OS and PFS.

CONCLUSIONS

The findings demonstrated that EOR was significantly correlated with patient survival; thus, one should aim for maximum tumor resection. In addition, patients with a higher EOR can be safely observed without adjuvant therapy. For patients with partial resection, postoperative chemotherapy should be administered for those with oligodendroglial subtypes, and repeat resection should be considered for those with astrocytic tumors. More aggressive treatment with RT and chemotherapy may be required for patients with a poor prognosis, such as those with diffuse astrocytoma, 1p/19q nondeleted tumors, or IDH1 wild-type oligodendroglial tumors with partial resection.