Long-term outcome of a tailored embolization strategy with Gamma Knife radiosurgery for high-grade brain arteriovenous malformations: a single-center experience.

OBJECTIVE: The safety and efficacy of embolization with Gamma Knife radiosurgery (GKRS) for high-grade brain arteriovenous malformations (bAVMs) are uncertain. The purpose of this study was to elucidate the long-term outcome of a tailored embolization strategy with GKRS and identify the independent factors associated with bAVM obliteration. METHODS: Between January 2014 and January 2017, a consecutive cohort of 159 patients with high-grade bAVMs who underwent embolization with GKRS was enrolled in this prospective single-center cohort study. All patients received a tailored embolization strategy with GKRS. The primary outcome was defined as bAVM obliteration. Secondary outcomes were neurological function and complications. RESULTS: After a mean follow-up of 40.4 months, 5 patients were lost to follow-up. One hundred eighteen of the remaining 154 patients had favorable neurological outcomes with complete bAVM obliteration. A decrease in bAVM nidus size was observed in 36 patients. Five patients developed intracranial hemorrhage during the latency period, and 2 patients died. The Kaplan-Meier analysis showed that the obliteration rate increased each year and reached the peak point at approximately 3 years. The multivariate Cox regression analysis of factors affecting bAVM obliteration revealed that postembolization bAVM volume < 10 cm3 (p = 0.02), supratentorial location (p < 0.01), staged embolization prior to GKRS (p < 0.01), and mean Spetzler-Martin (SM) grade (p < 0.01) were independent factors associated with a high obliteration rate. CONCLUSIONS: These data suggested that high-grade bAVMs treated using a tailored embolization strategy with GKRS were associated with a favorable clinical outcome and obliteration rate. Postembolization bAVM volume < 10 cm3, supratentorial location, staged embolization prior to GKRS, and low mean SM grade were associated with a high obliteration rate.

Dose-staged Gamma Knife radiosurgery for meningiomas: A retrospective study in a single center.

Objective: This study aimed to study the efficiency and safety of a dose-staged Gamma Knife radiosurgery strategy for large meningiomas or meningiomas close to important nerve structures. Methods: This study evaluates the outcome of a prospectively accrued series of 71 consecutive patients with meningiomas treated with staged dose-fractionated Gamma Knife radiosurgery. The average peripheral doses for the first and second fractions were 9.0 ± 0.9 Gy (8-12 Gy) and 8.6 ± 0.7 Gy (range, 7-10 Gy), respectively. The interval between fractions was 6.1 ± 1.9 months (range, 3-12 months). The median follow-up time was 36 months (12-96 months). Results: During the follow-up period after the second fraction, 97.2% achieved tumor control in our series. A total of 2 patients exhibited local recurrence at 30 and 60 months after the second fraction, respectively. No treatment-related complications or new long-term neurological dysfunctions were reported. MRIs observed slightly or moderately increased peritumoral edema in six patients, but no specific neurological complaints are attributed to this finding. Conclusion: This study investigates the efficiency and safety of dose-staged Gamma Knife radiosurgery as an alternative option for meningiomas that were large in volume, adjacent to crucial structures, or in patients with contraindications to craniotomy.

Deep learning-based detection and segmentation-assisted management of brain metastases.

BACKGROUND: Three-dimensional T1 magnetization prepared rapid acquisition gradient echo (3D-T1-MPRAGE) is preferred in detecting brain metastases (BM) among MRI. We developed an automatic deep learning-based detection and segmentation method for BM (named BMDS net) on 3D-T1-MPRAGE images and evaluated its performance. METHODS: The BMDS net is a cascaded 3D fully convolution network (FCN) to automatically detect and segment BM. In total, 1652 patients with 3D-T1-MPRAGE images from 3 hospitals (n = 1201, 231, and 220, respectively) were retrospectively included. Manual segmentations were obtained by a neuroradiologist and a radiation oncologist in a consensus reading in 3D-T1-MPRAGE images. Sensitivity, specificity, and dice ratio of the segmentation were evaluated. Specificity and sensitivity measure the fractions of relevant segmented voxels. Dice ratio was used to quantitatively measure the overlap between automatic and manual segmentation results. Paired samples t-tests and analysis of variance were employed for statistical analysis. RESULTS: The BMDS net can detect all BM, providing a detection result with an accuracy of 100%. Automatic segmentations correlated strongly with manual segmentations through 4-fold cross-validation of the dataset with 1201 patients: the sensitivity was 0.96 ±â€…0.03 (range, 0.84-0.99), the specificity was 0.99 ±â€…0.0002 (range, 0.99-1.00), and the dice ratio was 0.85 ±â€…0.08 (range, 0.62-0.95) for total tumor volume. Similar performances on the other 2 datasets also demonstrate the robustness of BMDS net in correctly detecting and segmenting BM in various settings. CONCLUSIONS: The BMDS net yields accurate detection and segmentation of BM automatically and could assist stereotactic radiotherapy management for diagnosis, therapy planning, and follow-up.

Salvage Therapy for Brain Arteriovenous Malformations After Failure of Gamma Knife Stereotactic Radiosurgery.

OBJECTIVE: The aim of this study was to investigate delayed complications in patients with brain arteriovenous malformation (BAVM) after Gamma Knife stereotactic radiosurgery and to present the salvage therapy experiences of patients with BAVM with radiation-induced changes (RICs) or intracranial hemorrhage (ICH). METHODS: This cohort consisted of 44 patients with BAVM who underwent failed GKRS between 2000 and 2015. These patients were further divided into an RIC group (23 patients) and an ICH group (21 patients) based on their post-GKRS complications. The patients' characteristics, treatment strategies, and long-term outcomes were analyzed. The modified Rankin Scale was used to assess the neurologic status of each patient. RESULTS: In our study, the marginal dose and radiosurgery-based arteriovenous malformation score were not significantly different between the 2 groups. Craniotomy was performed in 26 patients (9 patients with ICH and 17 patients with RICs), and histologic examination showed cavernous angioma changes in 6 patients. In addition, 6 patients underwent repeat radiosurgery in the ICH group, and 7 patients used bevacizumab in the RIC group. Thirty patients showed good outcomes at the last follow-up (modified Rankin Scale score <3). CONCLUSIONS: Salvage therapy for patients with BAVM should be performed based on the latency period and lesion characteristics of each individual. Prompt treatment and a longer follow-up are recommended to achieve good clinical outcomes.

A new classification and clinical results of Gamma Knife radiosurgery for cavernous sinus hemangiomas: a report of 53 cases.

BACKGROUND: Cavernous sinus hemangiomas (CaSHs) are rare vascular lesions in the cavernous sinus(CS). Gamma Knife radiosurgery (GKS) provides a treatment modality alternative to microsurgery. This study was conducted to describe a new classification of CaSHs based on their magnetic resonance (MR) imaging findings and determine the efficacy and safety of GKS in a large series of CaSH patients. METHODS: From April 2007 to November 2012, 53 patients harboring CaSHs were treated using Leksell Gamma Knife model C (before April 2012) or Perfexion (from May 2012 ) at the Gamma Knife Center of Huashan Hospital. Of the 53 patients, 15 with definitive histopathologic diagnoses after surgery, 38 were diagnosed based on their MR imaging findings. There were 15 male and 38 female patients with a mean age of 52 (range, 25-76) years old. The characteristics of MR images of CaSHs were their extremely high homogeneous intensity on T2-weighted and FLAIR images: as bright as cerebrospinal fluid signal. According to the relationship between the carotid line and their location, CaSHs were classified into three types: the intrasellar, parasellar and mixed type. The mean volume of the tumors was 13.2 ± 8.2 cm(3) (range, 1-41 cm(3)). A mean marginal dose of 13.3 Gy (range, 8-15 Gy) was directed to the 49%-64% isodose line (mean 53%). RESULTS: Of the 53 tumors, 6 (11%) were classified as intrasellar type. Eight (15%) were parasellar type and the other 39 cases(74%) mixed type. The mean radiological and clinical follow-up time of this study was 24 (range, 2-67 months) and 34 months (range, 2-73 months), respectively. The tumor control rate was 100%. The mean tumor volume reduction was 79.5% (range, 16.5%-100%) compared with the pre-GKS volume. Six months after GKS, MR imaging revealed an average of 60.2% tumor volume reduction (range, 16.5%-89.2%). Twenty-nine cases (55%) showed a >80% tumor volume decrease. Neurologically, only two of these patients showed clinical deterioration, and 33 patients demonstrated an obvious improvement in ocular or endocrine disorders. At last follow-up, there were no more complications related to GKS, and none of the tumors progressed. CONCLUSIONS: Our study showed that GKS is a useful and safe therapeutic method for CaSHs as both a primary and adjuvant treatment. The new classification of CaSHs may help predict their clinical course during tumor development and treatment response after GKS. Further studies with long-term follow-up and larger numbers of cases are necessary to optimize the treatment conditions and verify the benefit of this treatment.

Differential proliferative index of cancer stem-like cells in primary and recurrent medulloblastoma in human.

PURPOSE: Medulloblastoma is the most common malignant primitive neuroectodermal tumor found in children. It has a tendency to recur at a primary or distant site. The mechanism underlying the regulation of the recurrence of medulloblastoma remains largely unknown. Recently, several reports have described that cancer stem-like cells (CSCs) can be identified and isolated in medulloblastoma. The authors therefore attempted to demonstrate the correlation between the biological features of medulloblastoma's CSCs and its recurrence. METHODS: The data used were obtained in five consecutive patients with medulloblastomas who subsequently experienced tumor recurrence from 2004 to 2007. The authors performed the immunohistochemical assays to analyze the expression of CSC markers, proliferation features, and proliferative status of CSCs in primary and recurrent medulloblastoma. RESULTS: Of the five patients, two had recurrence at the primary site and three had a distant recurrence. CSC markers such as CD133(Prominin-1), DCX, PSA-NCAM, TUC-4, and nestin were expressed regardless of primary or recurrent medulloblastoma. All the five tumor specimens had a high proliferation index (PI). The PI was even higher in the group of patients after recurrence at a distant site (p<0.05), while the PI remained almost the same after primary recurrence. The Ki67/nestin-, Ki67/DCX-, and Ki67/TUC-4-positive cells were significantly increased in recurrent medulloblastoma at both the primary and distant sites, whereas CSCs in primary medulloblastoma showed much lower proliferative features (p<0.05). CONCLUSIONS: Our data suggest that tumorigenesis of medulloblastomas and their recurrence might be related to CSCs. More proliferating CSCs in medulloblastomas denote worse prognosis.

Identification of tumorigenic cells and implication of their aberrant differentiation in human hemangioblastomas.

The cytological origin of hemangioblastomas (HBs) is controversial possibly owing to limitation in the framework of normal vascular development. Our previous study reported that SSEA1 (stage-specific embryonic antigen-1) cells had the potential of HB-like structure formation in vitro cellular models. Here, we characterized primary proliferating tumor-initiating cells (TICs) and their neoplasmtic transformation. Neural stem cell marker SSEA1 and its lineage-related genes were demonstrated; no embryonic and mesenchymal stem cell markers were detected whereas their lineage-related genes in part were activated. Immunohistochemistry showed that the proliferating marker was preferentially expressed in SSEA1 cells. There was significant difference in the percentage of SSEA1 cells (SSEA1+/Ki67+ cells) between inherited and sporadic HBs although the tumor proliferative index (Ki67+ cells/ all cells) did not reach statistical significance between the two groups. Further, corresponding to the morphological changes of nucleolus in number and size, these highly proliferating SSEA1 cells demonstrated coexpression of either D2-40 or the mesodermal marker Scl (stem cell leukemia), brachyury, and Flk-1 (vascular endothelial growth factor-2), respectively, indicative of the neoplasmtic transformation into the stromal or vascular cells. The present data suggest that HBs might derive from neoplastic transformation of neural stem cells/progenitors. Such findings also provide new insights into the biology of HBs and the definition of TICs in situ, as well as the mechanisms of tumor neovascularization.

Hemangioblastomas might derive from neoplastic transformation of neural stem cells/progenitors in the specific niche.

The cytological origin of central nervous system hemangioblastoma (HB) remains unclear and controversial, largely owing to a lack of in-depth characterization of tumorigenic cells and their progeny tracking. We have now detected a cell subpopulation by stage-specific embryonic antigen-1 expression, which were defined as tumor-initiating cells (TICs) in both sporadic and familial HBs. These TICs subpopulations had universal neural stem cell characteristics. Nevertheless, the freshly sorted TICs endowed with potential of multi-progeny derivatives, including HB components and non-HB ingredients, depended on environmental induction in vitro. Importantly, the freshly harvested TICs formed malignant tumors by injection into conventional mice model, while did redevelop the characteristic HB-like structures within a special mice model with HB-microenvironment, indicating HB niche dependency for the TICs derivative specification. Taken together, the data of the present study suggested that HBs might derive from neoplastic transformation of neural stem cells/progenitors in the specific niche.

[Surgical treatment for the giant aneurysms of middle cerebral artery].

OBJECTIVE: To discuss the surgical treatment of the giant aneurysms of middle cerebral artery. METHODS: Clinical data, surgical methods and outcomes were analyzed in 17 giant aneurysms of middle cerebral artery treated from January 2001 to March 2008. CT scan, CTA, MRA, DSA and 3D-DSA were performed before operations so that we could comprehend the location, size, and shape of aneurysms and compensatory circulation of collateral branches to design the individualized treatment options. All patients had been surgically treated mostly by modified pterional approach, of which, direct clipping of the aneurysms was accomplished in 4 patients, aneurysms trapping or removal after trapping in 4, aneurysms excision or trapping combined with vessels reconstruction in 7, and aneurysms wrapping in 2 cases. RESULTS: CT and MRI revealed the shape and size of aneurysms clearly, while DSA and 3D-DSA could demonstrate the aneurysm's neck and relationship with the adjacent structure. Postoperative neurological function was evaluated according to Glasgow Outcome Scale when patients were discharged. Twelve patients had excellent neurological outcomes. However 4 patients were moderately disabled and one were severely disabled. No patient was dead postoperatively. CONCLUSIONS: It is necessary to perform elaborate imaging before operations for individualized surgical planning. The temporary occlusion of the parent artery and elimination of intra-aneurysmal thrombus are helpful to clipping the aneurysmal neck. Vessels reconstruction is a new and effective method of treating the giant aneurysms of middle cerebral artery.

Brain tumor stem cells: view from cell proliferation.

A small population of TSCs, which form neurospheres and possess the capacity for self-renewal, has been recently identified in adult and pediatric brain tumors. They differentiate into phenotypically diverse populations, including neuronal, astrocytic, and oligodendroglial cells in vitro and recapitulate original tumors in vivo. The understanding of brain TSCs has been greatly advanced by the knowledge of cell proliferation, which contributes to initiate and sustain the malignant phenotype. In this article, the authors summarized the evidence of the presence of TSCs in human brain tumors and emphasized the significance of the proliferative status of TSCs. By analyzing the data, the authors found that CD133(+) cell-initiated glioblastomas have a higher proliferation index when compared to CD133(-) cells-induced glioblastomas. Furthermore, the relationship and difference of cell proliferation between TSCs and normal NSCs were reviewed. Finally, the preliminary evidence that TSCs in malignant brain tumors have more proliferative capacity than stem/progenitor cells in benign brain tumors was discussed.