Category: Oncology

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Anaplastic astrocytomas: survival and prognostic factors in a surgical series

AA

Acta Neurochir (2014) 156:1053–1061

To study patient characteristics, prognostic factors and overall survival (OS) in a consecutive, surgical series of WHO grade III anaplastic astrocytomas (AA).

Methods Patients were identified from a prospective tumor database at Oslo University Hospital, Norway, and patients undergoing surgery for an AA from 2005–2012 were included. Patients’ medical charts were retrospectively reviewed for data collection.

Results A total of 99 adult patients with histologically verified AA were included. Median age was 52 years (20–81). Biopsy was conducted in 33 % and resection in 67 %. Adjuvant treatment with radiation therapy + temozolomide or radiation therapy only was given in 63 % and 26 %, respectively. The thirty-day mortality rate was 3 %. Median OS was 19 months (95 % CI 11–27 months). Age≥65 years, KPS<70, biopsy as opposed to resection, and no adjuvant treatment were confirmed negative prognostic factors in multivariate analysis. For patients undergoing resection, presence of postoperative contrast-enhanced tumor, not volume of residual tumor, had significant impact on OS in adjusted analysis.

Conclusions Median OS following surgery was 19 months, though much variable outcome was observed among subgroups of AA (95 % CI 11–27 months). Age ≥65 years, KPS<70, biopsy as opposed to resection, and no adjuvant treatment were confirmed negative prognostic factors for OS.

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Use of intraoperative fluorescein sodium fluorescence to improve the accuracy of tissue diagnosis during stereotactic needle biopsy of high-grade gliomas

stereotactic biopsy specimen obtained under the YELLOW560

Acta Neurochir (2014) 156:1071–1075

Stereotactic needle biopsy is valuable for tissue diagnosis of suspected high-grade gliomas, but limited by a sampling error that can lead to inappropriate grading of the tumor or failure to provide diagnosis. Increasing the number of biopsy attempts can increase morbidity. The authors designed a protocol to increase safety and efficiency of the procedure.

Methods Six consecutive patients with suspected high-grade gliomas who were not candidates for cytoreductive surgery underwent fluorescein-guided stereotactic needle biopsy. All received an injection of 3 mg/kg fluorescein sodium during anesthesia induction. Samples were obtained and observed under a microscope-integrated fluorescent module. If the initial specimens were fluorescent, the procedure was complete if the pathologist confirmed diagnostic tissue. Additional specimens were obtained only at the pathologist’s request. An independent neuropathologist later analyzed and graded samples for diagnostic value, tumor, and necrosis. This information was correlated to the degree of intraoperative fluorescent signal in biopsy samples.

Results During six biopsy procedures, 26 specimens were obtained: 15 (58 %) fluorescent and 11 (42%) nonfluorescent. All fluorescent specimens contained diagnostic tissue appropriate for tumor grading. Of 11 nonfluorescent specimens, four (36 %) did not contain tumor, three (27 %) contained minor hypercellularity or gliosis, and four (36 %) contained tumor with a high proportion of necrosis. All six tumors were diagnosed as glioblastoma multiforme. The sensitivity and specificity for fluorescein fluorescence was 79 % and 100 %, respectively.

Conclusions Fluorescein fluorescence may improve diagnostic accuracy and expedite stereotactic biopsy procedures.

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Intraoperative Contrast-Enhanced Ultrasound for Brain Tumor Surgery

INTRAOPERATIVE CEUS FOR BRAIN SURGERY

Neurosurgery 74:542–552, 2014 

Contrast-enhanced ultrasound (CEUS) is a dynamic and continuous modality that offers a real-time, direct view of vascularization patterns and tissue resistance for many organs. Thanks to newer ultrasound contrast agents, CEUS has become a wellestablished, live-imaging technique in many contexts, but it has never been used extensively for brain imaging. The use of intraoperative CEUS (iCEUS) imaging in neurosurgery is limited.

OBJECTIVE: To provide the first dynamic and continuous iCEUS evaluation of a variety of brain lesions.

METHODS: We evaluated 71 patients undergoing iCEUS imaging in an off-label setting while being operated on for different brain lesions; iCEUS imaging was obtained before resecting each lesion, after intravenous injection of ultrasound contrast agent. A semiquantitative, offline interobserver analysis was performed to visualize each brain lesion and to characterize its perfusion features, correlated with histopathology.

RESULTS: In all cases, the brain lesion was visualized intraoperatively with iCEUS. The afferent and efferent blood vessels were identified, allowing evaluation of the time and features of the arterial and venous phases and facilitating the surgical strategy. iCEUS also proved to be useful in highlighting the lesion compared with standard B-mode imaging and showing its perfusion patterns. No adverse effects were observed.

CONCLUSION: Our study is the first large-scale implementation of iCEUS in neurosurgery as a dynamic and continuous real-time imaging tool for brain surgery and provides the first iCEUS characterization of different brain neoplasms. The ability of CEUS to highlight and characterize brain tumor will possibly provide the neurosurgeon with important information anytime during a surgical procedure.

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Continuous dynamic mapping of the corticospinal tract during surgery of motor eloquent brain tumors

Continuous dynamic subcortical mapping

J Neurosurg 120:1015–1024, 2014

The authors developed a new mapping technique to overcome the temporal and spatial limitations of classic subcortical mapping of the corticospinal tract (CST). The feasibility and safety of continuous (0.4–2 Hz) and dynamic (at the site of and synchronized with tissue resection) subcortical motor mapping was evaluated.

Methods. The authors prospectively studied 69 patients who underwent tumor surgery adjacent to the CST (< 1 cm using diffusion tensor imaging and fiber tracking) with simultaneous subcortical monopolar motor mapping (short train, interstimulus interval 4 msec, pulse duration 500 μsec) and a new acoustic motor evoked potential alarm. Continuous (temporal coverage) and dynamic (spatial coverage) mapping was technically realized by integrating the mapping probe at the tip of a new suction device, with the concept that this device will be in contact with the tissue where the resection is performed. Motor function was assessed 1 day after surgery, at discharge, and at 3 months.

Results. All procedures were technically successful. There was a 1:1 correlation of motor thresholds for stimulation sites simultaneously mapped with the new suction mapping device and the classic fingerstick probe (24 patients, 74 stimulation points; r2 = 0.98, p < 0.001). The lowest individual motor thresholds were as follows: > 20 mA, 7 patients; 11–20 mA, 13 patients; 6–10 mA, 8 patients; 4–5 mA, 17 patients; and 1–3 mA, 24 patients. At 3 months, 2 patients (3%) had a persistent postoperative motor deficit, both of which were caused by a vascular injury. No patient had a permanent motor deficit caused by a mechanical injury of the CST.

Conclusions. Continuous dynamic mapping was found to be a feasible and ergonomic technique for localizing the exact site of the CST and distance to the motor fibers. The acoustic feedback and the ability to stimulate the tissue continuously and exactly at the site of tissue removal improves the accuracy of mapping, especially at low (< 5 mA) stimulation intensities. This new technique may increase the safety of motor eloquent tumor surgery.

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Predictive value of intraoperative 5-aminolevulinic acid–induced fluorescence for detecting bone invasion in meningioma surgery

Predictive value of intraoperative 5-aminolevulinic

J Neurosurg 120:840–845, 2014

Bone invasion is a major concern in meningioma surgery, since it is predictive of the recurrence of cranial involvement, morbidity, and mortality. Bone invasion has been reported in 20%–68% of studies with histopathologically confirmed data. Unfortunately, radical resection of bone invasion remains challenging. The aim of this study was to assess the role of 5-aminolevulinic acid (5-ALA) fluorescence in guiding the resection of bone-invading meningiomas. To this purpose, the sensitivity, specificity, and positive and negative predictive values of 5-ALA in detecting meningioma bone invasion were evaluated.

Methods. Data from 12 patients affected by bone-invading meningiomas (7 with skull base and 5 with convexity meningiomas) who had undergone surgery with the assistance of 5-ALA fluorescence and neuronavigation between July 2012 and March 2013 at the Department of Neurosurgery of Padua were retrospectively analyzed. To evaluate the sensitivity and specificity of 5-ALA fluorescence in detecting meningioma tissue, a pathologist analyzed 98 surgical bone samples under blue light, according to different fluorescence patterns. Magnetic resonance images and CT scans were obtained pre- and postoperatively to determine the extent of bone invasion resection.

Results. The rate of 5-ALA–induced fluorescence of both tumor and bone invasion was 100%. Based on the pathological examination of bone specimens, 5-ALA presented a sensitivity of 89.06% (95% CI 81.41%–96.71%) and a specificity of 100% in detecting meningioma bone invasion, while the positive and negative predictive values were 100% and 82.93% (95% CI 71.41%–94.45%), respectively. At the postoperative stage, MRI did not detect cases of meningioma bone invasion, whereas CT scans revealed residual hyperostosis in 2 cases.

Conclusions. In summary, 5-ALA fluorescence represents a suitable and reliable technique for identifying and removing bone infiltration by meningiomas. However, further studies are needed to prove the clinical consequences of this promising technique in a larger population.

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Using Higher Isodose Lines for Gamma Knife Treatment of 1 to 3 Brain Metastases Is Safe and Effective

Motor function after stereotactic radiosurgery for brain metastases in the region of the motor cortex

Neurosurgery 74:360–366, 2014

Higher isodose lines (IDLs) in Gamma Knife (GK) Perfexion treatment of brain metastases (BMet) could result in lower local control (LC) or higher radiation necrosis (RN) rates, but reduce treatment time.

OBJECTIVE: To assess the impact of the heterogeneity index (HI) and conformality index (CFI) on local failure (LF) for patients treated with GK for 1 to 3 BMet.

METHODS: From an institutional review board—approved database, 320 patients with 496 BMet were identified, treated for 1 to 3 BMet from July 2007 to April 2011 on GK Perfexion. Cox proportional hazards regression was used to analyze significance of HI, CFI, IDL, dose, tumor diameter, recursive partitioning analysis class, tumor radioresistance, primary, smoking history, metastasis location, and whole-brain radiation therapy (WBRT) history with LF and RN.

RESULTS: Median follow-up by lesion was 6.8 months (range, 0-49.6). The series median survival was 14.2 months. Per RECIST, 9.5% of lesions failed, 33.9% were stable, 38.3% partially responded, 17.1% responded completely, and 1.2% could not be assessed. The 12-month LC rate was 87.3%. On univariate analysis, a dose less than 20 Gy (hazard ratio [HR]: 2.940, P , .001); tumor size (HR: 1.674, P , .001); and cerebellum/brainstem location vs other (HR: 1.891, P = .043) were significant for LF. Non-small cell lung cancer (HR: 0.333, P = .0097) was associated with better LC. On multivariate analysis, tumor size (HR: 1.696, P , .001) and cerebellum/brainstem location vs other (HR: 1.959, P = .033) remained significant for LF. Variables not significant for LF included CI, IDL, and HI.

CONCLUSION: Our study of patients with 1 to 3 BMet treated with GK demonstrated no difference in LC or RN with varying HI, indicating that physicians can treat to IDL at 70% or higher IDL to reduce treatment time without increased LF or RN.

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Use of High-Field Intraoperative Magnetic Resonance Imaging to Enhance the Extent of Resection of Enhancing and Nonenhancing Gliomas

Use_of_High_Field_Intraoperative_Magnetic

Neurosurgery 74:339–350, 2014

Intraoperative magnetic resonance imaging (IoMRI) is used to improve the extent of resection of brain tumors. Most previous studies evaluating the utility of IoMRI have focused on enhancing tumors.

OBJECTIVE: To report our experience with the use of high-field IoMRI (1.5 T) for both enhancing and nonenhancing gliomas.

METHODS: An institutional review board–approved retrospective review was performed of 102 consecutive glioma patients (104 surgeries, 2010-2012). Pre-, intra-, and postoperative tumor volumes were assessed. Analysis was performed with the use of volumetric T2 images in 43 nonenhancing and 13 minimally enhancing tumors and with postcontrast volumetric magnetization-prepared rapid gradient-echo images in 48 enhancing tumors.

RESULTS: In 58 cases, preoperative imaging showed tumors likely to be amenable to complete resection. Intraoperative electrocorticography was performed in 32 surgeries, and 14 cases resulted in intended subtotal resection of tumors due to involvement of deep functional structures. No further resection (complete resection before IoMRI) was required in 25 surgeries, and IoMRI showed residual tumor in 79 patients. Of these, 25 surgeries did not proceed to further resection (9 due to electrocorticography findings, 14 due to tumor in deep functional areas, and 2 due to surgeon choice). Additional resection that was performed in 54 patients resulted in a final median residual tumor volume of 0.21 mL (0.6%). In 79 patients amenable to complete resection, the intraoperative median residual tumor volume for the T2 group was higher than for the magnetization-prepared rapid gradient-echo group (1.088 mL vs 0.437 mL; P = .049), whereas the postoperative median residual tumor volume was not statistically significantly different between groups.

CONCLUSION: IoMRI enhances the extent of resection, particularly for nonenhancing gliomas.

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5-Aminolevulinic Acid-derived Tumor Fluorescence: The Diagnostic Accuracy of Visible Fluorescence Qualities as Corroborated by Spectrometry and Histology and Postoperative Imaging

5_Aminolevulinic_Acid_derived_Tumor_Fluorescence__

Neurosurgery 74:310–320, 2014

5-Aminolevulinic acid is used for fluorescence-guided resections. During resection, different macroscopic fluorescence qualities (“strong,” “weak”) can be distinguished that help guide resections.

OBJECTIVE: This prospective study was designed to assess the reliability of visible fluorescence qualities by spectrometry, pathology, and imaging.

METHODS: Thirty-three patients with malignant gliomas received 5-aminolevulinic acid (20 mg/kg). After debulking surgery, standardized biopsies were obtained from tissues with “weak” and “strong” fluorescence and from nonfluorescing near and distant brain for blinded assessment of cell density and tissue type (necrosis, solid or infiltrating tumor, normal tissue). The positive predictive value was calculated. Unresected fluorescing tissue was navigated for blinded correlation to postoperative magnetic resonance imaging (MRI). Receiver operating characteristic curves were generated for assessing the classification efficiency of spectrometry.

RESULTS: “Strong” fluorescence corresponded to greater spectrometric fluorescence, solidly proliferating tumor, and high cell densities, whereas “weak” fluorescence corresponded to lower spectrometric fluorescence, infiltrating tumor, and medium cell densities. The positive predictive value was 100% in strongly fluorescing tissue and 95% in weakly fluorescing tissue. Spectrometric fluorescence was detected in marginal tissue without macroscopic fluorescence. Depending on the threshold, spectrometry displayed greater sensitivity but lower specificity (accuracy 88.4%). Residual MRI enhancement in the tumor bed was detected in 15 of 23 (65%) patients with residual fluorescence, but in none of the patients without residual fluorescence.

CONCLUSION: Macroscopic fluorescence qualities predict solid and infiltrating tumor, providing useful information during resection. Fluorescence appears superior to contrast enhancement on MRI for indicating residual tumor. Spectrometry, on the other hand, is more sensitive but less specific, depending on threshold definition.

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Impact of therapeutic regimen and clinical presentation on overall survival in CNS lymphoma

Primary LymphomaActa Neurochir (2014) 156:355–365

The authors present a retrospective analysis of 45 patients who underwent treatment of CNS lymphoma (both primary and secondary) at a single institution between 2005 and 2012. Methods This study involves 21 female and 24 male patients with a mean age of 59.2 years. All medical records and pathology reports were reviewed for each patient. Univariate and multivariate analyses of overall survival were performed.

Results Presentation with altered mental status was a significant risk factor for worse overall survival. An HIV infection, deep lesion location, and age over 60 did not impact survival. A survival benefit was demonstrated with the use of systemic therapy, specifically rituximab, and radiation. The CNS Lymphoma Score was derived from this cohort, which proved a powerful predictive tool for overall survival. The surgical complication rate in this series was 17.8 %.

Conclusions This study highlights the prognostic importance of presentingmental status on outcomes in CNS lymphoma and demonstrates a summative benefit of rituximab and whole brain radiation therapy. Considering these factors together provides an easily applicable andmeaningful stratification for this patient population. The surgical complication rate in this patient population is not negligible. The high percentage of wound-related surgical complications suggests the need for a waiting period between surgery and initiation of chemotherapy to allow for wound healing.

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Near-infrared imaging of brain tumors using the Tumor Paint BLZ-100 to achieve near-complete resection of brain tumors

Near-infrared imaging of brain tumors using the Tumor Paint BLZ-100 to achieve near-complete resection of brain tumors

Neurosurg Focus 36 (2):E1, 2014

The intraoperative clear delineation between brain tumor and normal tissue in real time is required to ensure near-complete resection without damaging the nearby eloquent brain. Tumor Paint BLZ-100, a tumor ligand chlorotoxin (CTX) conjugated to indocyanine green (ICG), has shown potential to be a targeted contrast agent. There are many infrared imaging systems in use, but they are not optimized to the low concentration and amount of ICG. The authors present a novel proof-of-concept near-infrared (NIR) imaging system using a standard charge-coupled device (CCD) camera for visualizing low levels of ICG attached to the tumors. This system is small, inexpensive, and sensitive. The imaging system uses a narrow-band laser at 785 nm and a notch filter in front of the sensor at the band. The camera is a 2-CCD camera, which uses identical CCDs for both visible and NIR light.

Methods. The NIR system is tested with serial dilution of BLZ-100 from 1 μM to 50 pM in 5% Intralipid solution while the excitation energy is varied from 5 to 40 mW/cm2. The analog gain of the CCD was changed from 0, 6, and 12 dB to determine the signal-to-noise ratio. In addition to the Intralipid solution, BLZ-100 was injected 48 hours before euthanizing the mice that were implanted with the human glioma cell line. The brain was removed and imaged using the NIR imaging system.

Results. The authors’ results show that the NIR imaging system using a standard CCD is able to visualize the ICG down to 50 nM of concentration with a high signal-to-noise ratio. The preliminary experiment on human glioma implanted in mouse brains demonstrated that BLZ-100 has a high affinity for glioma compared with normal brain tissue. Additionally, the results show that NIR excitation is able to penetrate deeply and has a potential to visualize metastatic lesions that are separate from the main tumor.

Conclusions. The authors have seen that BLZ-100 has a very high affinity toward human gliomas. They also describe a small, cost-effective, and sensitive NIR system for visualizing brain tumors tagged using BLZ-100. The authors hope that the use of BLZ-100 along with NIR imaging will be useful to delineate the brain tumors in real time and assist surgeons in near-complete tumor removal to increase survival and reduce neurological deficits.

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5-ALA complete resections go beyond MR contrast enhancement

5-ALA complete resections go beyond MR contrast

Acta Neurochir (2014) 156:305–312

The technique of 5-aminolevulinic acid (5-ALA) tumor fluorescence is increasingly used to improve visualization of tumor tissue and thereby to increase the rate of patients with gross total resections. In this study, we measured the resection volumes in patients who underwent 5-ALA-guided surgery for non-eloquent glioblastoma and compared them with the preoperative tumor volume.

Methods We selected 13 patients who had received a complete resection according to intraoperative 5-ALA induced fluorescence and CRET according to post-operative T1 contrast-enhanced MRI. The volumes of pre-operative contrast enhancing tissue, post-operative resection cavity and resected tissue were determined through shift-corrected volumetric analysis.

Results The mean resection cavity (29 cm3) was marginally smaller than the pre-operative contrast-enhancing tumor (39 cm3, p =0.32). However, the mean overall resection volume (84 cm3) was significantly larger than the pre-operative contrast-enhancing tumor (39 cm3, p=0.0087). This yields a mean volume of resected 5-ALA positive, but radiological non-enhancing tissue of 45 cm3. The mean calculated rim of resected tissue surpassed pre-operative tumor diameter by 6 mm(range 0–10 mm).

Conclusions Results of the current study imply that (i) the resection cavity underestimates the volume of resected tissue and (ii) 5-ALA complete resections go significantly beyond the volume of pre-operative contrast-enhancing tumor bulk on MRI, indicating that 5-ALA also stains MRI non-enhancing tumor tissue. Use of 5-ALA may thus enable extension of coalescent tumor resection beyond radiologically evident tumor. The impact of this more extended resection method on time to progression and overall survival has not been determined, and potentially puts adjacent and functionally intact tissue at risk.

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Insular low-grade glioma and postoperative seizure outcome

Surgery for insular low-grade glioma- predictors of postoperative seizure outcome

J Neurosurg 120:12–23, 2014

Although a number of recent studies on the surgical treatment of insular low-grade glioma (LGG) have demonstrated that aggressive resection leads to increased overall patient survival and decreased malignant progression, less attention has been given to the results with respect to tumor-related epilepsy. The aim of this investigation was to evaluate the impact of volumetric, histological, and intraoperative neurophysiological factors on seizure outcome in patients with insular LGG.

Methods. The authors evaluated predictors of seizure outcome with special emphasis on both the extent of tumor resection (EOR) and the tumor’s infiltrative pattern quantified by computing the difference between the preoperative T2- and T1-weighted MR images (DVT2T1) in 52 patients with preoperative drug-resistant epilepsy.

Results. The 12-month postoperative seizure outcome (Engel class) was as follows: seizure free (Class I), 67.31%; rare seizures (Class II), 7.69%; meaningful seizure improvement (Class III), 15.38%; and no improvement or worsening (Class IV), 9.62%. Poor seizure control was more common in patients with a longer preoperative seizure history (p < 0.002) and higher frequency of seizures (p = 0.008). Better seizure control was achieved in cases with EOR ≥ 90% (p < 0.001) and DVT2T1 < 30 cm3 (p < 0.001). In the final model, DVT2T1 proved to be the strongest independent predictor of seizure outcome in insular LGG patients (p < 0.0001).

Conclusions. No or little postoperative seizure improvement occurs mainly in cases with a prevalent infiltrative tumor growth pattern, expressed by high DVT2T1 values, which consequently reflects a smaller EOR.

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The silent phase of diffuse low-grade gliomas. Is it when we missed the action?

Diffuse low-grade glioma

Acta Neurochir (2013) 155:2237–2242

It is commonly believed that, before being diagnosed after onset of symptoms, diffuse low-grade glioma evolve silently for a long time. The present study aimed to estimate for the first time the exact duration of this silent phase, during which the glioma is radiologically visible but undiscovered.

Methods We retrospectively reviewed our French national database of diffuse low-grade glioma, searching for patients with an MRI-based assessment of their velocity of diameter growth at diagnosis and before any treatment (at least three MRIs over more than 6months). For each patient, the duration of the silent phase was estimated by the formula: duration = initial diameter / initial velocity of growth.

Results A total of 148 patients were included in the study. The mean lead-time duration (i.e., duration of the silent phase) was 14.0±7.8 years (median, 11.6 ; range, 1.6-39.4). The leadtime is statistically not correlated to the tumor volume. It is markedly decreasing with the velocity of diameter expansion.

Conclusions Diffuse low-grade glioma are radiologically detectable but clinically silent for more than a decade. Such a long period of silent evolution could explain our current failure to cure these tumors. It can also be viewed as a window of opportunity to detect these tumors earlier, suggesting the need to set up a screening program.

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Surgical strategy in grade II astrocytoma

Surgical strategy in grade II astrocytoma

Acta Neurochir (2013) 155:2227–2235

We recently demonstrated a survival benefit of early resection in unselected diffuse low-grade gliomas (LGG). However, heterogeneity within the LGG entity warrants investigation in a homogenous subgroup. Astrocytoma represents the largest subgroup of LGG, and is characterized by diffuse growth and inferior prognosis. We aimed to study the effects of early resection compared to biopsy and watchful waiting in this subgroup.

Methods Patient data was retrospectively reviewed in two neurosurgical departments with regional referral practice. In one hospital, initial diagnostic biopsies and watchful waiting was favored, while early resections guided with three-dimensional (3D) ultrasound were advocated in the other hospital. This created a natural experiment with patient management heavy influenced by residential address. In the hospitals’ histopathology databases, all adult patients diagnosed with supratentorial LGG from 1998 through 2009 were screened (n =169) and underwent blinded histopathological review. Histopathological review concluded with 117 patients with grade II astrocytomas that were included in the present study. The primary end-point was overall survival assessed by a regional comparison.

Results Early resections were performed in 51 (82 %) versus 12 (22 %) patients in the respective hospitals (p <0.001). The two patient populations were otherwise similar. Median survival was 9.7 years (95 % CI 7.5–11.9) if treated in the hospital favoring early resections compared to 5.6 years (95 % CI 3.5– 7.6) if treated at the hospital favoring biopsy and watchful waiting (p =0.047). No difference in surgical-related neurological morbidity was seen (p =0.843).

Conclusions Early 3D ultrasound guided resections improve survival, apparently without increasedmorbidity, compared to biopsy and watchful waiting in patients with diffuse World Health Organization (WHO) grade II astrocytomas.

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Management and outcome of high-grade multicentric gliomas

Management and outcome of high-grade multicentric gliomas

Acta Neurochir (2013) 155:2245–2251

Multicentric malignant gliomas are wellseparated tumours in different lobes or hemispheres, without anatomical continuity between lesions. The purpose of this study was to explore the clinical features, the pathology and the outcome according to the management strategies in a consecutive series of patients treated at a single institution. In addition, an analysis of the existing literature is presented.

Methods For the institutional analysis, a retrospective review of all patients who underwent treatment for multicentric gliomas in the last 7 years was performed. For the analysis of the literature, a MEDLINE search with no date limitations was accomplished for surgical treatment of multicentric malignant gliomas.

Results Two hundred and thirty-nine patients with glioma were treated in our department. Eighteen patients (7.5%) with a mean age of 64 years (age range, 37–78 years) presented multicentric malignant gliomas. Thirteen patients (72 %) underwent surgical resection of at least one lesion that was followed by adjuvant treatment in all but one case. Five patients (28 %) underwent stereotactic biopsy and thereafter received chemotherapy. A survival advantage was associated with resection of at least one lesion followed by adjuvant treatment (median overall survival 12 months) compared with 4 months for stereotactic biopsy followed by chemotherapy. Similar results were obtained from the review of the literature.

Conclusions Resection of at least one lesion seems to play a significant role in the management of selected patients with multicentric malignant gliomas. Multi-institutional studies on larger series are warranted to define how aggressively the patients with malignant multicentric gliomas should be treated.

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Role of intraoperative neurophysiological monitoring during fluorescence-guided resection surgery

Role of intraoperative neurophysiological monitoring during fluorescence-guided resection surgery

Acta Neurochir (2013) 155:2201–2213

Fluorescence-guided resection (FGR) using 5- aminolevulinic acid (5-ALA) exhibits a potential risk of permanent neurological deficits that can be minimized using intraoperative neurophysiological monitoring (IONM). We assessed the role of IONM in FGR surgery in patients harboring tumors in or near eloquent areas.

Methods IONM and FGR surgeries were performed on 34 patients (49.8±2.4 years) harbored malignant primary gliomas near eloquent cortical areas or semioval center. Different combinations of neurophysiological techniques were used depending on each patient.

Results Gross total resection (GTR) was achieved in 66.7 % of the patients, mean 90.4±3.7 % without neurological deficits. Resection in four patients was stopped by the occurrence of severe warning criteria despite the presence of fluorescence. Hemispheric transcranial electrical stimulation was safe and confident even in cortical surgery. Notably, a significant percentage of patients exhibited clinical improvement after the surgery. One week after surgery, only one patient worsened, and seven patients improved. At 3 months, 27.8 % of the patients improved, and the other patients maintained a similar status to their pre-surgery condition.Warning common criteria (amplitude reduction and/or latency increase) appeared in 68.2 and 50.0 % of patients during cortical or semioval surgery, respectively, with neither a false-negative nor a false-positive clinical outcome. Although 5-ALA exhibits phototoxicity, VEP did not induce any secondary effects in the visual system, including eyelids.

Conclusions IONM can be helpful during surgery to maximize the tumor resection, meanwhile help to avoid neurological deficits and, therefore, to improve the quality of life of these patients.

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Effect of dural detachment on long-term tumor control for meningiomas treated using Simpson Grade IV resection

Effect of dural detachment on long-term tumor control for meningiomas treated using Simpson Grade IV resection

J Neurosurg 119:1373–1379, 2013

Meningiomas treated by subtotal or partial resection are associated with significantly shorter recurrencefree survival than those treated by gross-total resection. The Simpson grading system classifies incomplete resections into a single category, namely Simpson Grade IV, with wide variations in the volume and location of residual tumors, making it complicated to evaluate the achievement of surgical goals and predict the prognosis of these tumors. Authors of the present study investigated the factors related to necessity of retreatment and tried to identify any surgical nuances achievable with the aid of modern neurosurgical techniques for meningiomas treated using Simpson Grade IV resection.

Methods. This retrospective analysis included patients with WHO Grade I meningiomas treated using Simpson Grade IV resection as the initial therapy at the University of Tokyo Hospital between January 1995 and April 2010. Retreatment was defined as reresection or stereotactic radiosurgery due to postoperative tumor growth.

Results. A total of 38 patients were included in this study. Regrowth of residual tumor was observed in 22 patients with a mean follow-up period of 6.1 years. Retreatment was performed for 20 of these 22 tumors with regrowth. Risk factors related to significantly shorter retreatment-free survival were age younger than 50 years (p = 0.006), postresection tumor volume of 4 cm3 or more (p = 0.016), no dural detachment (p = 0.001), and skull base location (p = 0.016). Multivariate analysis revealed that no dural detachment (hazard ratio [HR] 6.42, 95% CI 1.41–45.0; p = 0.02) and skull base location (HR 11.6, 95% CI 2.18–218; p = 0.002) were independent risk factors for the necessity of early retreatment, whereas postresection tumor volume of 4 cm3 or more was not a statistically significant risk factor.

Conclusions. Compared with Simpson Grade I, II, and III resections, Simpson Grade IV resection includes highly heterogeneous tumors in terms of resection rate and location of the residual mass. Despite the difficulty in analyzing such diverse data, these results draw attention to the favorable effect of dural detachment (instead of maximizing the resection rate) on long-term tumor control. Surgical strategy with an emphasis on detaching the tumor from the affected dura might be another important option in resection of high-risk meningiomas not amenable to gross-total resection.

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Recurrent high-grade glioma treated with bevacizumab: prognostic value of MGMT methylation, EGFR status and pretreatment MRI in determining response and survival

Recurrent GBM and bevacizumab

J Neurooncol (2013) 115:267–276

Although bevacizumab represented an important advance in treatment of recurrent high-grade gliomas (HGG), responses occur in fewer than half of patients. There are no validated biomarkers for anti-angiogenic therapy that are available for routine clinical use.

We assessed the prognostic values of imaging and molecular markers in this patient population. MRI scans from 191 patients with recurrent HGG obtained prior to initiating bevacizumab were reviewed for areas of enhancement, necrosis, T2/FLAIR abnormality, and ADC values. Serial MRI scans following the initiation of bevacizumab were evaluated for response and progression. Non-radiographic markers including EGFR and MGMT status were also assessed with respect to response and patient survival.

65 of 191 patients (34 %) showed complete or partial response at the time of their best response MRI and demonstrated longer progression free survival (PFS) and overall survival (OS) compared to the group without response (PFS: 6.9 vs 3.5 months, OS: 10.9 vs 6.1 months). Minimum ADC values within enhancing and non-enhancing regions were lower in responders compared to those of nonresponders (1,099 vs 984 x 10-6 mm2/s, p = 0.006). Smaller enhancing area was associated with longer OS (HR = 1.99, p = 0.017). The ratio of T2/FLAIR to enhancing area was prognostic of OS for only the Grade III HGG subgroup (HR = 0.14, p = 0.004).

Area of enhancing tumor at baseline can stratify survival in patients with recurrent HGG treated with bevacizumab. The extent of edema relative to enhancing area may have a prognostic role specific to Grade III HGG.

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Glioma Spheroids Obtained via Ultrasonic Aspiration Are Viable and Express Stem Cell Markers

Glioma, Immunohistochemistry, Organotypic, Spheroids, Tumor-initiating cells, Ultrasonic aspiration

Neurosurgery 73:868–886, 2013

Ultrasonic aspirators allow safe, rapid, and accurate removal of brain tumors. However, the tissue fragments removed are used surprisingly little in research.

OBJECTIVE: To investigate whether such tissue fragments could be cultured as organotypic multicellular spheroids because access to biopsy tissue is often limited.

METHODS: Tissue fragments obtained by ultrasonic aspiration from 10 glioblastomas and tumor biopsy tissue from 7 of these tumors were cultured in serum-containing and serum-free medium. On culturing, the fragments formed spheroids, which were prepared for histology. Two glioblastoma cell lines from ultrasonic fragments and biopsy tissue were established as well.

RESULTS: Hematoxylin and eosin staining showed viable glioma spheroids obtained from both ultrasonic and biopsy tissue in both types of medium. Endothelial growth factor receptor and PTEN/chromosome 10 status was found to be preserved in most spheroids (7-8 of 10 tumors), together with the level of glial fibrillary acidic protein, von Willebrand factor, and Ki-67. The levels of stem cell markers CD133, Bmi-1, nestin, and Sox2 also were preserved. The ultrasonic spheroids had higher levels of glial fibrillary acidic protein and von Willebrand factor and lower levels of Bmi-1, nestin, Sox2, and Olig2 compared with conventional biopsy spheroids. For both types of spheroids, the stem cell medium seemed to favor expression of stem cell markers. The established cell lines were capable of both spheroid formation at clonal density and tumor formation in vivo.

CONCLUSION: Viable organotypic and proliferating spheroids were easily obtained from ultrasonic tissue fragments. The preservation of markers and the establishment of cell lines with tumor-initiating cell properties suggest ultrasonic spheroids as a new tissue resource for glioma research.

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The preoperative use of navigated transcranial magnetic stimulation facilitates early resection of suspected low-grade gliomas in the motor cortex

The preoperative use of navigated transcranial magnetic stimulation facilitates early resection of suspected low-grade gliomas in the motor cortex

Acta Neurochir (2013) 155:1813–1821

Resection is recommended for low-grade gliomas, but often it is not performed if the tumor is suspected of invading the primary motor cortex. The study aim is to assess what influence preoperative navigated transcranial magnetic stimulation (nTMS) has on the treatment strategy and clinical outcome for suspected low-grade gliomas in presumed motor eloquent location.

Methods This paper reports on all our patients with gliomas in the primary motor cortex that were non-enhancing on MRI, since we began using nTMS (n=11). For the comparison group, we identified the 11 most recent such patients just before we started using nTMS.

Results Exact delineation of motor functional versus nonfunctional cortical tissue was provided by nTMS in all cases, also within the area of altered FLAIR signal. In 6 out of 11 cases, the nTMS mapping result changed the treatment plan towards early and more extensive resection. Only one nTMS patient had another seizure within the follow-up period, whereas four patients in the comparison group had further seizures. In the nTMS group, 1 of 4 patients with pre-op neurological deficits improved by one year; whereas the comparison group had increased neurological deficits in 3 of the 8 patients not having surgery. The median (range) change of tumor volume from baseline to 1 year was −83 % (−67 % to −100 %) in the nTMS group, but +12 % (+40 % to −56 %) in the comparison group (p<0.001).

Conclusions nTMS provides accurate motor mapping results also in infiltrative gliomas and enables more frequent and more extensive surgical resection of non-enhancing gliomas in or near the primary motor cortex. The substantial differences observed here in neurological and oncological outcomes suggest that further comparative research is warranted.

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