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Daily bibliographic review of the Neurosurgery Department. La Fe University Hospital. Valencia, Spain

Awake Craniotomy vs Craniotomy Under General Anesthesia for Perirolandic Gliomas

Neurosurgery 81:481–489, 2017

A craniotomy with direct cortical/subcortical stimulation either awake or under general anesthesia (GA) present 2 approaches for removing eloquent region tumors. With a reported higher prevalence of intraoperative seizures occurring during awake resections of perirolandic lesions, oftentimes, surgery under GA is chosen for these lesions.

OBJECTIVE: To evaluate a single-surgeon’s experience with awake craniotomies (AC) vs surgery under GA for resecting perirolandic, eloquent, motor-region gliomas.

METHODS: Between 2005 and 2015, a retrospective analysis of 27 patients with perirolandic, eloquent, motor-area gliomas that underwent an AC were case-control matched with 31 patients who underwent surgery under GA for gliomas in the same location. All patients underwent direct brain stimulation with neuromonitoring and perioperative risk factors, extent of resection, complications, and discharge status were assessed.

RESULTS: The postoperative Karnofsky Performance Score (KPS) was significantly lower for theGApatients at 81.1 compared to theACpatients at 93.3 (P=.040). The extent of resection for GA patients was 79.6% while the AC patients had an 86.3% resection (P = .136). There were significantly more 100% total resections in the AC patients 25.9% compared to the GA group (6.5%; P=.041). Patients in theGAgroup had a longer mean length of hospitalization of 7.9 days compared to the AC group at 4.2 days (P = .049).

CONCLUSION: We show that AC can be performed with more frequent total resections, better postoperative KPS, shorter hospitalizations, as well as similar perioperative complication rates compared to surgery under GA for perirolandic, eloquent motor-region glioma.

A method for safely resecting anterior butterfly gliomas

J Neurosurg 126:1795–1811, 2017

Gliomas invading the anterior corpus callosum are commonly deemed unresectable due to an unacceptable risk/benefit ratio, including the risk of abulia. In this study, the authors investigated the anatomy of the cingulum and its connectivity within the default mode network (DMN). A technique is described involving awake subcortical mapping with higher attention tasks to preserve the cingulum and reduce the incidence of postoperative abulia for patients with so-called butterfly gliomas.

METHODS The authors reviewed clinical data on all patients undergoing glioma surgery performed by the senior author during a 4-year period at the University of Oklahoma Health Sciences Center. Forty patients were identified who underwent surgery for butterfly gliomas. Each patient was designated as having undergone surgery either with or without the use of awake subcortical mapping and preservation of the cingulum. Data recorded on these patients included the incidence of abulia/akinetic mutism. In the context of the study findings, the authors conducted a detailed anatomical study of the cingulum and its role within the DMN using postmortem fiber tract dissections of 10 cerebral hemispheres and in vivo diffusion tractography of 10 healthy subjects.

RESULTS Forty patients with butterfly gliomas were treated, 25 (62%) with standard surgical methods and 15 (38%) with awake subcortical mapping and preservation of the cingulum. One patient (1/15, 7%) experienced postoperative abulia following surgery with the cingulum-sparing technique. Greater than 90% resection was achieved in 13/15 (87%) of these patients.

CONCLUSIONS This study presents evidence that anterior butterfly gliomas can be safely removed using a novel, attention-task based, awake brain surgery technique that focuses on preserving the anatomical connectivity of the cingulum and relevant aspects of the cingulate gyrus.

 

Maximizing safe resection of low- and high-grade glioma

dti-gliomas

J Neurooncol (2016) 130:269–282

Surgical resection plays a central role in the management of gliomas. In this study, we review the evidence in support of extent of resection to improve survival, symptom management, and time to malignant transformation in low- and high-grade gliomas, and summarize the findings from our literature search regarding the role of extent of resection and intraoperative practices to maximize safety.

There is a growing body of evidence supporting improved overall survival, improved progression-free survival, and superior quality of life with greater extent of resection.

Additionally, a better understanding of central nervous system plasticity allows for a staged approach to the surgical management of low- and intermediate-grade gliomas.

A number of intraoperative techniques have been utilized to offer safer glioma surgery with greater extent of resection. Approaches such as awake brain tumor surgery can be safely performed with low failure rates and excellent long-term functional outcomes.

Reoperation for Recurrent Glioblastoma and Its Association With Survival Benefit

multifocal glioblastoma

Neurosurgery 79:678–689, 2016

Glioblastoma is the most common and aggressive primary brain tumor. Despite current treatment, recurrence is inevitable. There are no clear guidelines for treatment of recurrent glioblastoma.

OBJECTIVE: To investigate factors at initial surgery predictive of reoperation, and the prognostic variables associated with survival, including reoperation for recurrence.

METHODS: A retrospective cohort study was performed, including adult patients diagnosed with glioblastoma between January 2010 and December 2013. Student t test and Fisher exact test compared continuous and categorical variables between reoperation and nonreoperation groups. Univariable and Cox regression multivariable analysis was performed.

RESULTS: In a cohort of 204 patients with de novo glioblastoma, 49 (24%) received reoperation at recurrence. The median overall survival in the reoperation group was 20.1 months compared with 9.0 months in the nonreoperation group (P = .001). Reoperation was associated with longer overall survival in our total population (hazard ratio, 0.646; 95% confidence interval, 0.543-0.922; P = .016) but subject to selection bias. Subgroup analyses excluding patients unlikely to be considered for reoperation suggested a much less significant effect of reoperation on survival, which warrants further study with larger cohorts. Factors at initial surgery predictive for reoperation were younger age, smaller tumor size, initial extent of resection $50%, shorter inpatient stay, and maximal initial adjuvant therapy. When unfavorable patient characteristics are excluded, reoperation is not an independent predictor of survival.

CONCLUSION: Patients undergoing reoperation have favorable prognostic characteristics, which may be responsible for the survival difference observed. We recommend that a large clinical registry be developed to better aid consistent and homogenous data collection.

A prospective Phase II clinical trial of 5-aminolevulinic acid to assess the correlation of intraoperative fluorescence intensity and degree of histologic cellularity during resection of high-grade gliomas

Combining 5-Aminolevulinic Acid Fluorescence and Intraoperative Magnetic Resonance Imaging in Glioblastoma Surgery

J Neurosurg 124:1300–1309, 2016

There is evidence that 5-aminolevulinic acid (ALA) facilitates greater extent of resection and improves 6-month progression-free survival in patients with high-grade gliomas. But there remains a paucity of studies that have examined whether the intensity of ALA fluorescence correlates with tumor cellularity. Therefore, a Phase II clinical trial was undertaken to examine the correlation of intensity of ALA fluorescence with the degree of tumor cellularity.

Methods A single-center, prospective, single-arm, open-label Phase II clinical trial of ALA fluorescence-guided resection of high-grade gliomas (Grade III and IV) was held over a 43-month period (August 2010 to February 2014). ALA was administered at a dose of 20 mg/kg body weight. Intraoperative biopsies from resection cavities were collected. The biopsies were graded on a 4-point scale (0 to 3) based on ALA fluorescence intensity by the surgeon and independently based on tumor cellularity by a neuropathologist. The primary outcome of interest was the correlation of ALA fluorescence intensity to tumor cellularity. The secondary outcome of interest was ALA adverse events. Sensitivities, specificities, positive predictive values (PPVs), negative predictive values (NPVs), and Spearman correlation coefficients were calculated.

Results A total of 211 biopsies from 59 patients were included. Mean age was 53.3 years and 59.5% were male. The majority of biopsies were glioblastoma (GBM) (79.7%). Slightly more than half (52.5%) of all tumors were recurrent. ALA intensity of 3 correlated with presence of tumor 97.4% (PPV) of the time. However, absence of ALA fluorescence (intensity 0) correlated with the absence of tumor only 37.7% (NPV) of the time. For all tumor types, GBM, Grade III gliomas, and recurrent tumors, ALA intensity 3 correlated strongly with cellularity Grade 3; Spearman correlation coefficients (r) were 0.65, 0.66, 0.65, and 0.62, respectively. The specificity and PPV of ALA intensity 3 correlating with cellularity Grade 3 ranged from 95% to 100% and 86% to 100%, respectively. In biopsies without tumor (cellularity Grade 0), 35.4% still demonstrated ALA fluorescence. Of those biopsies, 90.9% contained abnormal brain tissue, characterized by reactive astrocytes, scattered atypical cells, or inflammation, and 8.1% had normal brain. In nonfluorescent (ALA intensity 0) biopsies, 62.3% had tumor cells present. The ALA-associated complication rate among the study cohort was 3.4%.

Conclusions The PPV of utilizing the most robust ALA fluorescence intensity (lava-like orange) as a predictor of tumor presence is high. However, the NPV of utilizing the absence of fluorescence as an indicator of no tumor is poor. ALA intensity is a strong predictor for degree of tumor cellularity for the most fluorescent areas but less so for lower ALA intensities. Even in the absence of tumor cells, reactive changes may lead to ALA fluorescence.

Combining 5-Aminolevulinic Acid Fluorescence and Intraoperative Magnetic Resonance Imaging in Glioblastoma Surgery

Combining 5-Aminolevulinic Acid Fluorescence and Intraoperative Magnetic Resonance Imaging in Glioblastoma Surgery

Neurosurgery 78:475–483, 2016

Glioblastoma resection guided by 5-aminolevulinic acid (5-ALA) fluorescence and intraoperative magnetic resonance imaging (iMRI) may improve surgical results and prolong survival.

OBJECTIVE: To evaluate 5-ALA fluorescence combined with subsequent low-field iMRI for resection control in glioblastoma surgery.

METHODS: Fourteen patients with suspected glioblastoma suitable for complete resection of contrast-enhancing portions were enrolled. The surgery was carried out using 5-ALA–induced fluorescence and frameless navigation. Areas suspicious for tumor underwent biopsy. After complete resection of fluorescent tissue, low-field iMRI was performed. Areas suspicious for tumor remnant underwent biopsy under navigation guidance and were resected. The histological analysis was blinded.

RESULTS: In 13 of 14 cases, the diagnosis was glioblastoma multiforme. One lymphoma and 1 case without fluorescence were excluded. In 11 of 12 operations, residual contrast enhancement on iMRI was found after complete resection of 5-ALA fluorescent tissue. In 1 case, the iMRI enhancement was in an eloquent area and did not undergo a biopsy. The 28 biopsies of areas suspicious for tumor on iMRI in the remaining 10 cases showed tumor in 39.3%, infiltration zone in 25%, reactive central nervous system tissue in 32.1%, and normal brain in 3.6%. Ninety-three fluorescent and 24 non-fluorescent tissue samples collected before iMRI contained tumor in 95.7% and 87.5%, respectively.

CONCLUSION: 5-ALA fluorescence–guided resection may leave some glioblastoma tissue undetected. MRI might detect areas suspicious for tumor even after complete resection of all fluorescent tissue; however, due to the limited accuracy of iMRI in predicting tumor remnant (64.3%), resection of this tissue has to be considered with caution in eloquent regions.

The Value of 5-Aminolevulinic Acid in Low-grade Gliomas and High-grade Gliomas Lacking Glioblastoma Imaging Features

The Value of 5-Aminolevulinic Acid in Low-grade Gliomas and High-grade Gliomas Lacking Glioblastoma Imaging Features

Neurosurgery 78:401–411, 2016

Approximately 20% of grade II and most grade III gliomas fluoresce after 5-aminolevulinic acid (5-ALA) application. Conversely, approximately 30% of nonenhancing gliomas are actually high grade.

OBJECTIVE: The aim of this study was to identify preoperative factors (ie, age, enhancement, 18F-fluoroethyl tyrosine positron emission tomography [18F-FET PET] uptake ratios) for predicting fluorescence in gliomas without typical glioblastomas imaging features and to determine whether fluorescence will allow prediction of tumor grade or molecular characteristics.

METHODS: Patients harboring gliomas without typical glioblastoma imaging features were given 5-ALA. Fluorescence was recorded intraoperatively, and biopsy specimens collected from fluorescing tissue. World Health Organization (WHO) grade, Ki-67/MIB-1 index, IDH1 (R132H) mutation status, O6-methylguanine DNA methyltransferase (MGMT) promoter methylation status, and 1p/19q co-deletion status were assessed. Predictive factors for fluorescence were derived from preoperative magnetic resonance imaging and 18F-FET PET. Classification and regression tree analysis and receiver-operatingcharacteristic curves were generated for defining predictors.

RESULTS: Of 166 tumors, 82 were diagnosed as WHO grade II, 76 as grade III, and 8 as glioblastomas grade IV. Contrast enhancement, tumor volume, and 18F-FET PET uptake ratio .1.85 predicted fluorescence. Fluorescence correlated with WHO grade (P , .001) and Ki-67/MIB-1 index (P , .001), but not with MGMT promoter methylation status, IDH1 mutation status, or 1p19q co-deletion status. The Ki-67/MIB-1 index in fluorescing grade III gliomas was higher than in nonfluorescing tumors, whereas in fluorescing and nonfluorescing grade II tumors, no differences were noted.

CONCLUSION: Age, tumor volume, and 18F-FET PET uptake are factors predicting 5-ALA-induced fluorescence in gliomas without typical glioblastoma imaging features. Fluorescence was associated with an increased Ki-67/MIB-1 index and high-grade pathology. Whether fluorescence in grade II gliomas identifies a subtype with worse prognosis remains to be determined.

Awake craniotomy to maximize glioma resection: methods and technical nuances over a 27-year period

awake craniotomy

J Neurosurg 123:325–339, 2015

Awake craniotomy is currently a useful surgical approach to help identify and preserve functional areas during cortical and subcortical tumor resections. Methodologies have evolved over time to maximize patient safety and minimize morbidity using this technique. The goal of this study is to analyze a single surgeon’s experience and the evolving methodology of awake language and sensorimotor mapping for glioma surgery.

Methods The authors retrospectively studied patients undergoing awake brain tumor surgery between 1986 and 2014. Operations for the initial 248 patients (1986–1997) were completed at the University of Washington, and the subsequent surgeries in 611 patients (1997–2014) were completed at the University of California, San Francisco. Perioperative risk factors and complications were assessed using the latter 611 cases.

Results The median patient age was 42 years (range 13–84 years). Sixty percent of patients had Karnofsky Performance Status (KPS) scores of 90–100, and 40% had KPS scores less than 80. Fifty-five percent of patients underwent surgery for high-grade gliomas, 42% for low-grade gliomas, 1% for metastatic lesions, and 2% for other lesions (cortical dysplasia, encephalitis, necrosis, abscess, and hemangioma). The majority of patients were in American Society of Anesthesiologists (ASA) Class 1 or 2 (mild systemic disease); however, patients with severe systemic disease were not excluded from awake brain tumor surgery and represented 15% of study participants. Laryngeal mask airway was used in 8 patients (1%) and was most commonly used for large vascular tumors with more than 2 cm of mass effect. The most common sedation regimen was propofol plus remifentanil (54%); however, 42% of patients required an adjustment to the initial sedation regimen before skin incision due to patient intolerance. Mannitol was used in 54% of cases. Twelve percent of patients were active smokers at the time of surgery, which did not impact completion of the intraoperative mapping procedure. Stimulation-induced seizures occurred in 3% of patients and were rapidly terminated with ice-cold Ringer’s solution. Preoperative seizure history and tumor location were associated with an increased incidence of stimulation- induced seizures. Mapping was aborted in 3 cases (0.5%) due to intraoperative seizures (2 cases) and patient emotional intolerance (1 case). The overall perioperative complication rate was 10%.

Conclusions Based on the current best practice described here and developed from multiple regimens used over a 27-year period, it is concluded that awake brain tumor surgery can be safely performed with extremely low complication and failure rates regardless of ASA classification; body mass index; smoking status; psychiatric or emotional history; seizure frequency and duration; and tumor site, size, and pathology.

The Effect of Timing of Concurrent Chemoradiation in Patients With Newly Diagnosed Glioblastoma

Relationship of glioblastoma multiforme to the subventricular zone is associated with survival

Neurosurgery 77:248–253, 2015

The effect of timing of initiation of concurrent radiation and chemotherapy after surgery on outcome of patients with glioblastoma (GBM) remains unclear.

OBJECTIVE: To further explore this issue, we analyzed 4 clinical trials for patients newly diagnosed with GBM receiving concurrent and adjuvant temozolomide.

METHODS: The cohort study included 198 adult patients with newly diagnosed supratentorial GBM who were enrolled from 2004 to 2010 in 4 clinical trials consisting of radiation plus temozolomide and an experimental agent. The interval to initiation of therapy was determined from the time of surgical resection. The partitioning deletion/ substitution/addition algorithm was used to determine the cutoff points for timing of chemoradiation at which there was a significant difference in overall survival (OS) and progression-free survival (PFS).

RESULTS: The median wait time between surgery and initiation of concurrent chemoradiation was 29.5 days (range, 7-56 days). A short delay in chemoradiation administration (at 30-34 days) was predictive of prolonged OS (hazard ratio [HR]: 0.63, P = .03) and prolonged PFS (HR: 0.68, P = .06) compared with early initiation of concurrent chemoradiation (<30 days), after adjusting for protocol and baseline prognostic variables including extent of resection by multivariate analysis. A longer delay to chemoradiation beyond 34 days was not associated with improved OS or PFS compared with early initiation (HR: 0.94, P = .77 and HR: 0.91, P = .63, respectively).

CONCLUSION: A short delay in the start of concurrent chemoradiation is beyond the classic paradigm of 4 weeks post-resection and may be associated with prolonged OS and PFS.

Outcomes in Reoperated Low-Grade Gliomas

OUTCOMES IN REOPERATED LOW-GRADE GLIOMAS

Neurosurgery 77:175–184, 2015

Low-grade gliomas (LGGs) comprise a diverse set of intrinsic brain tumors that correlate strongly with survival. Data on the effect of reoperation are sparse.

OBJECTIVE: To evaluate the effect of reoperation on patients with LGG.

METHODS: Fifty-two consecutive patients with reoperated LGGs treated at the University of Washington between 1986 and 2004 were identified and evaluated in a retrospective analysis.

RESULTS: The average overall survival (OS) for this cohort was 12.95 ± 0.96 years. The overall 10-year survival rate was 57%. The absence of any residual tumor at either the first or second operation was associated with significantly increased OS. Negative prognostic variables for OS included the use of upfront radiation and pathology at recurrence. The average overall progression-free survival to the first recurrence (PFS1) was 6.23 ± 0.51 years. Positive prognostic factors for improved PFS1 included the use of upfront radiation therapy. Variables not associated with differences in PFS1 included the use of upfront chemotherapy, enhancement, pathology, extent of resection, the presence of residual tumor, and Karnofsky Performance Scale score <80. The average overall progression-free survival to the second recurrence was 2.73 ± 0.39 years. Pathology at recurrence was associated with significant differences in progression-free survival to the second recurrence, as was extent of resection at time of first recurrence, and Karnofsky Performance Scale score <80.

CONCLUSION: This is among the largest studies to assess variables associated with outcome in patients with reoperated LGG. Reresection appears to provide significant benefit, and extent of resection remains the strongest predictor of OS.

Surgical results of tumor resection using tractography-integrated navigation-guided fence-post catheter techniques and motor-evoked potentials for preservation of motor function in patients with glioblastomas near the pyramidal tracts

Surgical results of tumor resection using tractography-integrated

Neurosurg Rev (2015) 38:293–307

The current optimal surgery for glioblastomas (GBMs) near the pyramidal tract (PT) is to remove as much tumor as possible and to preserve motor function. The purpose of this study is to investigate the usefulness of tractography integrated navigation-guided fence-post catheter techniques and motor-evoked potentials (MEPs) for preserving postoperative motor function after GBM surgery.

We retrospectively examined 49 patients who underwent resection for GBM near the PT. Diffusion tensor (DT) imaging-based tractography of the PT was performed preoperatively and integrated into the navigation system. When possible, silicon catheters were used as “fence-posts” and were inserted along the tumor boundaries, avoiding the PT, before tumor removal using the navigation system (fence-post catheter techniques). Cortical and subcortical MEPs were also monitored during resection of the tumor. Fence-post catheter techniques using a tractography integrated navigation system were used in 45 of 49 patients.

This technique enabled placement of the catheters, avoided the motor pathways, and allowed easier resection of the tumors. Tumors near the PT were resected using subcortical and cortical MEPs. The amplitudes of cortical MEPs after tumor removal were maintained at over 33 % of those obtained before resection.

Thirty-six patients showed obvious responses of subcortical MEPs at ≤20 mA. The degree of resection was gross total in 21 patients, subtotal in 21, and partial in seven. One month after surgery, only one patient showed worsened motor function.

Therefore, fence-post catheter techniques using a tractography-integrated navigation system and MEPs may contribute to preserving motor function after surgery for GBMs that are near the PT.

Anatomic features of glioblastoma and their potential impact on survival

Anatomic features of glioblastoma and their potential impact on survival

Acta Neurochir (2015) 157:179–186

Many reports on glioblastoma multiforme discuss the prognostic impact of anatomical features such as cysts, necrotic changes, extent of edema or subependymal spread of tumor cells. In the present study, we examined different growth patterns and their possible relations to patient survival.

Methods To analyze whether anatomical characteristics are related to prognosis, we reviewed the prospectively collected pre- and postoperative MRIs of 83 patients in the 5-ALA study, provided by the 5-ALA Glioma Study Group. Following a standardized analytic work flow, the tumor volume and site, presence of necrosis or cysts, and perifocal edema were assessed preoperatively. In the same way, postoperative MRI and the MRI at first recurrence were analyzed. In addition, survival time of the patients was documented.

Results Median survival time of all 83 patients was 15.1 months (range 1.5 to 70.1, mean 18). The site or volume of glioblastoma, as well as the presence of intratumoral necrosis or cysts, did not exert a significant effect on survival time; 96.4 % of recurrences occurred within the former resection margin. Tumors with initial contact with the subependymal zone had multifocal or ventricular recurrences significantly more often. In patients with residual tumor on early postoperative MRI, the follow-up images displayed enlargement of the remnants in 91.9 % of these cases.

Conclusions A merely anatomical analysis of the glioblastoma growth pattern cannot reliably provide prognostic information. The occurrence of most recurrences next to the resection margin and the high percentage of growing residual tumors underline the importance of complete resections.

Fluorescent Cancer-Selective Alkylphosphocholine Analogs for Intraoperative Glioma Detection

Fluorescent_Cancer_Selective_Alkylphosphocholine

Neurosurgery 76:115–124, 2015

5-Aminolevulinic acid (5-ALA)-induced tumor fluorescence aids brain tumor resections but is not approved for routine use in the United States. We developed and describe testing of 2 novel fluorescent, cancer-selective alkylphosphocholine analogs, CLR1501 (green) and CLR1502 (near infrared), in a proof-of-principle study for fluorescence-guided glioma surgery.

OBJECTIVE: To demonstrate that CLR1501 and CLR1502 are cancer cell-selective fluorescence agents in glioblastoma models and to compare tumor-to-normal brain (T:N) fluorescence ratios with 5-ALA.

METHODS: CLR1501, CLR1502, and 5-ALA were administered to mice with magnetic resonance imaging-verified orthotopic U251 glioblastoma multiforme- and glioblastoma stem cell-derived xenografts. Harvested brains were imaged with confocal microscopy (CLR1501), the IVIS Spectrum imaging system (CLR1501, CLR1502, and 5-ALA), or the Fluobeam near-infrared fluorescence imaging system (CLR1502). Imaging and quantitative analysis of T:N fluorescence ratios were performed.

RESULTS: Excitation/emission peaks are 500/517 nm for CLR1501 and 760/778 nm for CLR1502. The observed T:N ratio for CLR1502 (9.28 6 1.08) was significantly higher (P , .01) than for CLR1501 (3.51 6 0.44 on confocal imaging; 7.23 6 1.63 on IVIS imaging) and 5-ALA (4.81 6 0.92). Near-infrared Fluobeam CLR1502 imaging in a mouse xenograft model demonstrated high- contrast tumor visualization compatible with surgical applications.

CONCLUSION: CLR1501 (green) and CLR1502 (near infrared) are novel tumor-selective fluorescent agents for discriminating tumor from normal brain. CLR1501 exhibits a tumor-to-brain fluorescence ratio similar to that of 5-ALA, whereas CLR1502 has a superior tumor-to-brain fluorescence ratio. This study demonstrates the potential use of CLR1501 and CLR1502 in fluorescence-guided tumor surgery.

The role of cancer stem cells in glioblastoma

The role of cancer stem cells in glioblastoma

Neurosurg Focus 37 (6):E6, 2014

Recurrence in glioblastoma is nearly universal, and its prognosis remains dismal despite significant advances in treatment over the past decade. Glioblastoma demonstrates considerable intratumoral phenotypic and molecular heterogeneity and contains a population of cancer stem cells that contributes to tumor propagation, maintenance, and treatment resistance. Cancer stem cells are functionally defined by their ability to self-renew and to differentiate, and they constitute the diverse hierarchy of cells composing a tumor. When xenografted into an appropriate host, they are capable of tumorigenesis.

Given the critical role of cancer stem cells in the pathogenesis of glioblastoma, research into their molecular and phenotypic characteristics is a therapeutic priority.

In this review, the authors discuss the evolution of the cancer stem cell model of tumorigenesis and describe the specific role of cancer stem cells in the pathogenesis of glioblastoma and their molecular and microenvironmental characteristics. They also discuss recent clinical investigations into targeted therapies against cancer stem cells in the treatment of glioblastoma.

Predicting the “usefulness” of 5-ALA-derived tumor fluorescence for fluorescence-guided resections in pediatric brain tumors

5-ALA in pedidatric brain tumors

Acta Neurochir (2014) 156:2315–2324

Five-aminolevulinic acid (Gliolan, medac, Wedel, Germany, 5-ALA) is approved for fluorescence-guided resections of adult malignant gliomas. Case reports indicate that 5-ALA can be used for children, yet no prospective study has been conducted as of yet. As a basis for a study, we conducted a survey among certified European Gliolan users to collect data on their experiences with children.

Methods Information on patient characteristics, MRI characteristics of tumors, histology, fluorescence qualities, and outcomes were requested. Surgeons were further asked to indicate whether fluorescence was “useful”, i.e., leading to changes in surgical strategy or identification of residual tumor. Recursive partitioning analysis (RPA) was used for defining cohorts with high or low likelihoods for useful fluorescence.

Results Data on 78 patients <18 years of age were submitted by 20 centers. Fluorescence was found useful in 12 of 14 glioblastomas (85 %), four of five anaplastic astrocytomas (60 %), and eight of ten ependymomas grades II and III (80 %). Fluorescence was found inconsistently useful in PNETs (three of seven; 43 %), gangliogliomas (two of five; 40 %), medulloblastomas (two of eight, 25 %) and pilocytic astrocytomas (two of 13; 15 %). RPA of pre-operative factors showed tumors with supratentorial location, strong contrast enhancement and first operation to have a likelihood of useful fluorescence of 64.3 %, as opposed to infratentorial tumors with first surgery (23.1 %).

Conclusions Our survey demonstrates 5-ALA as being used in pediatric brain tumors. 5-ALA may be especially useful for contrast-enhancing supratentorial tumors. These data indicate controlled studies to be necessary and also provide a basis for planning such a study.

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 Resonance Imaging to Enhance the Extent of Resection of Enhancing and Nonenhancing Gliomas

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.

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.

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.

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.

Blood-based biomarkers for malignant gliomas

Blood-based biomarkers for malignant gliomas

J Neurooncol (2013) 113:345–352

Malignant gliomas remain incurable and present unique challenges to clinicians, radiologists and clinical and translational investigators. One of the major problems in treatment of these tumors is our limited ability to reliably assess tumor response or progression.

The most frequently used neuro-imaging studies (contrast-enhanced MRI and CT) rely on changes of blood–brain barrier (BBB) integrity, providing only an indirect assessment of tumor burden. In addition, the BBB can be altered by commonly used interventions including radiation, glucocorticoids and vascular endothelial growth factor inhibitors, further complicating the interpretation of scans. Newer radiologic techniques including PET and magnetic resonance spectroscopy are theoretically promising but thus far have not meaningfully changed the assessment of patients with malignant gliomas. A tumor-specific, bloodbased biomarker would be of immediate use to clinicians and investigators if sufficiently sensitive and specific.

This review discusses the potential utility of such a biomarker, the general classes of tumor-derived blood-based biomarkers and it summarizes the currently available data on circulating tumor cells, circulating nucleic acids and circulating proteins in patients with malignant gliomas. It is unclear which marker or marker class appears to be the most promising for these tumors.

This article provides thoughts on how novel candidate blood-based markers could be discovered and tested in a more comprehensive way and why these efforts should be among the top priorities in neuro-oncologic research in the coming years.

Neurosurgery Department. “La Fe” University Hospital. Valencia, Spain

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