Category: Oncology

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Management of Atypical Cranial Meningiomas, Part 1: Predictors of Recurrence and the Role of Adjuvant Radiation After Gross Total Resection

Meningioma_-_brain_invasion_-_high_mag

Neurosurgery 75:347–355, 2014

Indications for external beam radiation therapy (EBRT) for atypical meningiomas (AMs) remain unclear.

OBJECTIVE: To analyze features associated with recurrence in AM patients after gross total resection (GTR) and to assess the relative benefit of EBRT in a retrospective cohort study.

METHODS: One hundred fifty-one primary AMs after GTR (88 female patients; median follow-up, 45.0 months) were examined for possible predictors of recurrence (age, sex, location, volume, bone involvement, brain invasion). The Fisher exact and Wilcoxon rank-sum tests were used to analyze the association between these predictors and use of EBRT. The impact on recurrence for these predictors and EBRT was analyzed with Kaplan-Meier and Cox regression.

RESULTS: Of 151 patients, 13 (8.6%) experienced recurrence after GTR (median, 47.0 months). Multivariate analysis identified elevated mitotic index (P = .007) and brain invasion (P = .002) as predictors of recurrence. Larger volume (P = .96) was not associated with recurrence but was more likely to prompt EBRT (P = .001). Recurrences occurred in 11 of 112 with GTR (9.8%; median, 44 months) and 2 of 39 with GTR/EBRT (5.1%; median, 133 months). The 2-, 5-, and 10-year progression-free survival rates after GTR vs GTR/ EBRT were 97%, 86%, and 68% vs 100%, 100%, and 78%. Kaplan-Meier analysis demonstrated no difference in progression-free survival or overall survival after GTR vs GTR/ EBRT (P = .8, P . .99).

CONCLUSION: Brain invasion and high mitotic rates may predict recurrence. After GTR of AMs, EBRT appears not to affect progression-free survival and overall survival, suggesting that observation rather than EBRT may be indicated after GTR.

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Successful treatment of multiple intracranial meningiomas with the antiprogesterone receptor agent mifepristone (RU486)

RU486

Acta Neurochir (2014) 156:1831–1835

Meningiomas are the most frequent primary brain tumor in adults. Evidence suggests that female sex hormones play a role in the meningioma tumorigenesis. In particular, progesterone, has a receptor (PR) that is highly expressed in the majority of grade I meningiomas. Multiple meningiomas (diffuse meningiomatosis) are less frequent, but have a higher female predominance and a higher PR expression. They are, therefore, attractive candidates for anti-PR therapy.

Methods We treated three consecutive women with multiple meningiomas with mifepristone (RU 486). It is a synthetic steroid with high affinity for both progesterone and glucocorticoid receptors. Results The treatment was well tolerated, and we observed an important and long-lasting clinical (3/3) and radiological response (2/3) or stabilisation. All the three patients are now stable after five to nine years of treatment.

Conclusions These encouraging results strongly support a prospective clinical trial in this preselected population.

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Outcomes After Surgery and Radiotherapy for Spinal Myxopapillary Ependymoma

Spinal Myxopapillary Ependymoma

Neurosurgery 75:205–214, 2014

The role of radiotherapy after surgery for myxopapillary ependymoma (MPE) is unclear.

OBJECTIVE: To review long-term outcomes after surgery, with or without radiation, for spinal MPE.

METHODS: Fifty-one patients with spinal MPE treated from 1968 to 2007 were included. Associations between clinical variables and overall survival (OS), progressionfree survival (PFS), and local control (LC) were tested with Cox regression analysis.

RESULTS: The median age at diagnosis was 35 years (range, 8-63 years). Twenty patients (39%) had surgery alone, 30 (59%) had surgery plus radiotherapy (RT), and 1 (2%) had RT only. At a median follow-up of 11 years (range, 0.2-37 years), 10-year OS, PFS, and LC for the entire group were 93%, 63%, and 67%, respectively. Nineteen patients (37%) had disease recurrence, and the recurrence was mostly local (79%). Twenty-eight of 50 patients who had surgery (56%) had gross total resection; 10-year LC was 56% after surgery vs 92% after surgery and RT (log-rank P = .14); the median time of LC was 10.5 years for patients receiving gross total resection plus RT, and 4.75 years for gross total resection only (P = .03). Among 16 patients with subtotal resection and follow-up data, 10-year LC was 0% after surgery vs 65% for surgery plus RT (log-rank P = .008). On multivariate analyses adjusting for resection type, age older that 35 years at diagnosis and receipt of adjuvant radiation were associated with improved PFS (hazard ratio [HR]: 0.14, P = .003 and HR: 0.45, P = .009) and LC (HR: 0.22, P = .02 and HR: 0.45, P = .009).

CONCLUSION: Postoperative radiotherapy after resection of MPE was associated with improved PFS and LC.

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Retrosigmoid removal of small acoustic neuroma: curative tumor removal with preservation of function

Retrosigmoid removal of small acoustic neuroma

J Neurosurg 121:554–563, 2014

Management of small acoustic neuromas (ANs) consists of 3 options: observation with imaging followup, radiosurgery, and/or tumor removal. The authors report the long-term outcomes and preservation of function after retrosigmoid tumor removal in 44 patients and clarify the management paradigm for small ANs.

Methods. A total of 44 consecutively enrolled patients with small ANs and preserved hearing underwent retrosigmoid tumor removal in an attempt to preserve hearing and facial function by use of intraoperative auditory monitoring of auditory brainstem responses (ABRs) and cochlear nerve compound action potentials (CNAPs). All patients were younger than 70 years of age, had a small AN (purely intracanalicular/cerebellopontine angle tumor ≤ 15 mm), and had serviceable hearing preoperatively. According to the guidelines of the Committee on Hearing and Equilibrium of the American Academy of Otolaryngology–Head and Neck Surgery Foundation, preoperative hearing levels of the 44 patients were as follows: Class A, 19 patients; Class B, 17; and Class C, 8. The surgical technique for curative tumor removal with preservation of hearing and facial function included sharp dissection and debulking of the tumor, reconstruction of the internal auditory canal, and wide removal of internal auditory canal dura.

Results. For all patients, tumors were totally removed without incidence of facial palsy, death, or other complications. Total tumor removal was confirmed by the first postoperative Gd-enhanced MRI performed 12 months after surgery. Postoperative hearing levels were Class A, 5 patients; Class B, 21; Class C, 11; and Class D, 7. Postoperatively, serviceable (Class A, B, or C) and useful (Class A or B) levels of hearing were preserved for 84% and 72% of patients, respectively. Better preoperative hearing resulted in higher rates of postoperative hearing preservation (p = 0.01); preservation rates were 95% among patients with preoperative Class A hearing, 88% among Class B, and 50% among Class C. Reliable monitoring was more frequently provided by CNAPs than by ABRs (66% vs 32%, p < 0.01), and consistently reliable auditory monitoring was significantly associated with better rates of preservation of useful hearing. Long-term follow-up by MRI with Gd administration (81 ± 43 months [range 5–181 months]; median 7 years) showed no tumor recurrence, and although the preserved hearing declined minimally over the long-term postoperative follow-up period (from 39 ± 15 dB to 45 ± 11 dB in 5.1 ± 3.1 years), 80% of useful hearing and 100% of serviceable hearing remained at the same level.

Conclusions. As a result of a surgical technique that involved sharp dissection and internal auditory canal reconstruction with intraoperative auditory monitoring, retrosigmoid removal of small ANs can lead to successful curative tumor removal without long-term recurrence and with excellent functional outcome. Thus, the authors suggest that tumor removal should be the first-line management strategy for younger patients with small ANs and preserved hearing.

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Volumetric MRI assessment of glioblastoma

Volumetric MRI assessment of GBM.jpg

J Neurosurg 121:536–542, 2014

Robust methodology that allows objective, automated, and observer-independent measurements of brain tumor volume, especially after resection, is lacking. Thus, determination of tumor response and progression in neurooncology is unreliable. The objective of this study was to determine if a semi-automated volumetric method for quantifying enhancing tissue would perform with high reproducibility and low interobserver variability.

Methods. Fifty-seven MR images from 13 patients with glioblastoma were assessed using our method, by 2 neuroradiologists, 1 neurosurgeon, 1 neurosurgical resident, 1 nurse practitioner, and 1 medical student. The 2 neuroradiologists also performed traditional 1-dimensional (1D) and 2-dimensional (2D) measurements. Intraclass correlation coefficients (ICCs) assessed interobserver variability between measurements. Radiological response was determined using Response Evaluation Criteria In Solid Tumors (RECIST) guidelines and Macdonald criteria. Kappa statistics described interobserver variability of volumetric radiological response determinations.

Results. There was strong agreement for 1D (RECIST) and 2D (Macdonald) measurements between neuroradiologists (ICC = 0.42 and 0.61, respectively), but the agreement using the authors’ novel automated approach was significantly stronger (ICC = 0.97). The volumetric method had the strongest agreement with regard to radiological response (k = 0.96) when compared with 2D (k = 0.54) or 1D (k = 0.46) methods. Despite diverse levels of experience of the users of the volumetric method, measurements using the volumetric program remained remarkably consistent in all users (0.94).

Conclusions. Interobserver variability using this new semi-automated method is less than the variability with traditional methods of tumor measurement. This new method is objective, quick, and highly reproducible among operators with varying levels of expertise. This approach should be further evaluated as a potential standard for response assessment based on contrast enhancement in brain tumors.

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Molecular stereotactic biopsy technique improves diagnostic accuracy and enables personalized treatment strategies in glioma patients

Molecular stereotactic biopsy technique

Acta Neurochir (2014) 156:1427–1440

In gliomas molecular biomarkers are increasingly gaining diagnostic, prognostic and predictive significance. Determination of biomarker status after biopsy is important as not all patients are eligible for open tumor resection.We developed and validated prospectively (6/10–12/11) a protocol allowing for both reliable determination of multiple biomarkers and representative histological diagnoses from small-sized biopsies.

Methods All molecular stereotactic biopsies were performed according to a detailed workflow. The selection of specimens best suited for molecular analyses was intra-operatively guided by the attending neuropathologist. Postoperative screening was done by methylation specific PCR using two distinct cryopreserved specimens to test for reproducibility of the findings and to rule out contamination. The DNA of a single best-suited specimen (1 mm3) was subjected to detailed molecular analysis (MGMT promoter methylation, IDH1/2 mutational status, LOH 1p and/or 19q).

Results 159 consecutively enrolled untreated gliomas were analyzed (94 glioblastomas, 2 gliosarcomas, 24 anaplastic astrocytomas, 10 oligo-tumors grade II/III, 20 grade II astrocytomas and 9 pilocytic astrocytomas). Transient morbidity was 2 %. Overall, the drop-out rate due to tissue contamination was 0.4 %. Median time from biopsy to histological and molecular genetic analyses was 3 and 5 days, respectively. Distributions of the respective biomarker status for tumor subgroups were consistent with the literature. The final histological diagnosis was changed/modified in 5/159 patients according to molecular findings. Treatment after molecular biopsy was highly personalized.

Conclusions Molecular stereotactic biopsy is feasible and safe, can be implemented in daily clinical practice, improves diagnostic precision and enables personalized treatment. Keywords

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Proteomic analysis of cerebrospinal fluid: toward the identification of biomarkers for gliomas

Proteomics

Neurosurg Rev (2014) 37:367–380

Gliomas are the most common primary brain tumors in adults and, despite advances in the understandings of glioma pathogenesis in the genetic era, they are still ineradicable, justifying the need to develop more reliable diagnostic and prognostic biomarkers for this malignancy. Because changes in cerebrospinal fluid (CSF) are suggested to be capable of sensitively reflecting pathological processes, e.g., neoplastic conditions, in the central nervous system, CSF has been deemed a valuable source for potential biomarkers screening in this era of proteomics.

This systematic review focused on the proteomic analysis of glioma CSF that has been published to date and identified a total of 19 differentially expressed proteins. Further functional and protein-protein interaction assessments were performed by using Protein Analysis Through Evolutionary Relationships (PANTHER) website and Ingenuity Pathway Analysis (IPA) software, which revealed several important protein networks (e.g., IL- 6/STAT-3) and four novel focus proteins (IL-6, galanin (GAL), HSPA5, andWNT4) that might be involved in glioma pathogenesis.

The concentrations of these focus proteins were subsequently determined by enzyme-linked immunosorbent assay (ELISA) in an independent set of CSF and tumor cyst fluid (CF) samples. Specifically, glioblastoma (GBM) CF had significantly lower GAL, HSPA5, andWNT4 levels than CSF from different grades of glioma. In contrast, IL-6 level was significantly higher in GBM CF when compared with CSF and, among different CSF groups, was highest in GBM CSF.

Therefore, these candidate protein biomarkers, identified from both the literatures and in silico analysis, may have potentials in clinical diagnosis, prognosis evaluation, treatment response monitoring, and novel therapeutic targets identification for patients with glioma.

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Trends in Fluorescence Image-Guided Surgery for Gliomas

Trends in Fluorescence Image-Guided Surgery for Gliomas

Neurosurgery 75:61–71, 2014

Mounting evidence suggests that a more extensive surgical resection is associated with an improved life expectancy for both low-grade and high-grade glioma patients. However, radiographically complete resections are not often achieved in many cases because of the lack of sensitivity and specificity of current neurosurgical guidance techniques at the margins of diffuse infiltrative gliomas.

Intraoperative fluorescence imaging offers the potential to improve the extent of resection and to investigate the possible benefits of resecting beyond the radiographic margins.

Here, we provide a review of wide-field and high-resolution fluorescence-imaging strategies that are being developed for neurosurgical guidance, with a focus on emerging imaging technologies and clinically viable contrast agents. The strengths and weaknesses of these approaches will be discussed, as well as issues that are being addressed to translate these technologies into the standard of care.

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Preoperative Imaging to Predict Intraoperative Changes in Tumor-to-Corticospinal Tract Distance

Preoperative Imaging to Predict Intraoperative Changes in Tumor-to-Corticospinal Tract Distance

Neurosurgery 75:23–30, 2014

Preoperative diffusion tensor imaging (DTI) is used to demonstrate corticospinal tract (CST) position. Intraoperative brain shifts may limit preoperative DTI value, and studies characterizing such shifts are lacking.

OBJECTIVE: To examine tumor characteristics that could predict intraoperative shift in tumor-to-CST distance using high-field intraoperative magnetic resonance imaging.

METHODS: We retrospectively evaluated preoperative and intraoperative DTIs, tumor pathology, and imaging characteristics of patients who underwent resection of an intraaxial tumor adjacent to the CST to identify covariates that significantly affected shift in tumor-to-CST distance. For validation, we analyzed data from a separate, 20-patient cohort.

RESULTS: In the first cohort, the mean intraoperative shift in the tumor-to-CST distance was 3.18 6 3.58 mm. The mean shift for the 20 patients with contrast and the 5 patients with non–contrast-enhancing tumors was 3.93 6 3.64 and 0.18 6 0.18 mm, respectively (P , .001). No association was found between intraoperative shift in tumor-to-CST distance and tumor pathology, tumor volume, edema volume, preoperative tumor-to- CST distance, or extent of resection. According to receiver-operating characteristic analysis, nonenhancement predicted a tumor-to-CST distance shift of #0.5 mm, with a sensitivity of 100% and a specificity of 75%. We validated these findings using the second cohort.

CONCLUSION: For nonenhancing intra-axial tumors, preoperative DTI is a reliable method for assessing intraoperative tumor-to-CST distance because of minimal intraoperative shift, a finding that is important in the interpretation of subcortical motor evoked potential to maximize extent of resection and to preserve motor function. In resection of intra-axial enhancing tumors, intraoperative imaging studies are crucial to compensate for brain shift.

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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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