Category: Oncology

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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.

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Combined use of 18 F-FDG PET and corticosteroid for diagnosis of deep-seated primary central nervous system lymphoma without histopathological confirmation

Combined use of 18 F-FDG PET and corticosteroid for diagnosis of deep-seated primary central nervous system lymphoma without histopathological confirmation

Acta Neurochir (2015) 157:187–194

Although histological diagnosis is indispensable in treating primary central nervous system lymphoma (PCNSL), we sometimes face an intractable situation in which tissue can be obtained only from a deep-seated brain lesion. In place of a histological diagnosis, the diagnostic adequacy of the combined use of 18 F-FDG PET and corticosteroid administration for PCNSL located in a deep-seated brain structure is reported.

Methods Patients with a deep-seated tumor were treated as having PCNSL without histological confirmation, based on the following criteria: (1) there was no evidence of systemic malignancy; (2) the tumor showed an extremely high FDG uptake relative to normal gray matter on pretreatment 18 FFDG PET;

(3) the tumor decreased in size 1 week after diagnostic therapy by corticosteroid administration on contrast-enhanced T1-weighted magnetic resonance imaging (MRI). FDG uptake of the lesion was evaluated by the maximum of standardized uptake values (SUVmax) and tumor-tonormal ratio of the SUV (T/N ratio). The extent of the tumor reduction was calculated by volumetric analysis for the treatment response to corticosteroid administration.

Results Ten patients (4 males and 6 females) matched these criteria. On pretreatment 18 F-FDG PET, mean SUVmax in the tumor was 24.8 (8.75–60.75), and mean T/N ratio was 3.24 (2.17–5.12). The extent of tumor volume reduction was shown to be 21 to 68 % 1 week after diagnostic therapy by corticosteroids. Mean total dose and duration of corticosteroids were 719 mg as prednisolone and 6.5 days, respectively. Nine patients achieved complete response and one patient achieved partial response on MRI after standard treatment for PCNSL with high-dose methotrexate and/or whole-brain irradiation.

Conclusion Although the value of biopsy is universal, combining 18 F-FDG PET and corticosteroid administration is an important alternative method that may lead to the diagnosis of deep-seated PCNSLs in cases with intractable histopathological confirmations.

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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.

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True aqueductal tumors: a unique entity

True aqueductal tumors-a unique entity

Acta Neurochir (2015) 157:169–177

Pure aqueductal tumors (ATs) differ from pineal region and tectal/tegmental tumors in that they are epicentered within the aqueduct. Nevertheless, these tumors are rarely described as a separate type of tumor, and are often grouped with other lesions located in the same vicinity. The present multicenter study focuses on our experience treating patients with pure ATs.

Methods Data from three large tertiary centers was collected retrospectively, including presenting symptoms, treatment paradigm, surgical approaches, pathology, and outcome.

Results Between 1999 and 2013, 16 patients with AT were diagnosed and treated at the three tertiary centers. Ages at presentation ranged from 5.5 to 57 years. Thirteen patients presented with hydrocephalus-related symptoms, and two were identified incidentally. Thirteen patients underwent an endoscopic third ventriculostomy, and two of these underwent a simultaneous endoscopic biopsy (one grade II ependymoma, one non-specified low-grade glioma). Two others underwent shunt placement. Three patients underwent resection due to tumor progression. Pathologies included glioblastoma multiforme, glioneural tumor, and ependymoma grade II. All non-resected tumors remained stable or grew only minimally.

Conclusions ATs are a rare entities that usually present with obstructive hydrocephalus. Treatment includes primarily cerebrospinal fluid drainage (preferably via an endoscopic third ventriculostomy). Simultaneous endoscopic biopsy may be done in selected cases. Tumor resection should be reserved for growing tumors; the trans-fourth ventricular or transchoroidal approaches are probably safer than other approaches used to reach the tectal region.

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Mapping p53 Mutations in Low-Grade Glioma: A Voxel-Based Neuroimaging Analysis

Mapping p53 Mutations in Low-Grade Glioma

AJNR Am J Neuroradiol 36:70–76

Brain tumor location has proved to be a prognostic factor that may be associated with features of neoplastic origin. Mutation of p53 is an atypical genetic change that occurs during tumorigenesis. Thus, a potential correlation may exist between tumor location and p53 status. The purpose of the current study was to identify anatomic characteristics of mutant p53 expression by using quantitative neuroimaging analyses.

MATERIALS AND METHODS: Preoperative MR images from 182 patients with histologically confirmed low-grade gliomas were retrospectively analyzed. All tumors were manually marked and registered to the standard space. Using a voxel-based lesion-symptom mapping analysis, we located brain regions associated with a high occurrence of p53 mutation and corrected them by using a permutation test. The acquired clusters were further included as a factor in survival analyses.

RESULTS: Statistical analysis demonstrated that the left medial temporal lobe and right anterior temporal lobe were specifically associated with high expression of mutant p53. Kaplan-Meier curves showed that tumors located in these regions were associated with significantly worse progression-free survival compared with tumors occurring elsewhere.

CONCLUSIONS: Our voxel-level imaging analysis provides new evidence that genetic changes during cancer may have anatomic specificity. Additionally, the current study suggests that tumor location identified on structural MR images could potentially be used for customized presurgical outcome prediction.

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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.

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Surgery of Intradural Extramedullary Tumors: Retrospective Analysis of 107 Cases

Intradural extramedullary tumors

Neurosurgery 75:509–514, 2014

Intradural extramedullary tumors (IDEMTs) are uncommon lesions that cause pain and neurological deficits.

OBJECTIVE: To evaluate the effects of surgery for IDEMTs.

METHODS: This cohort study recruited all patients operated on for IDEMTs at the Department of Neurology and Psychiatry of Sapienza University of Rome from January 2003 to January 2013. The analysis was conducted on clinical records evaluation over a 1-year follow-up. The Graphic Rating Scale was used to assess pain. Neurological deficits were detected through neurological examination. Quality of life was evaluated with the EuroQol (EQ-5D). Statistical interpretation of the data was performed with SPSS version 19 software.

RESULTS: One hundred seven patients were recruited. Three were lost to follow-up. Patients reported lower level of pain 1 year after surgery (before surgery, 6.05; after surgery, 3.65). Mean comparison showed a significant decrease of 22.400 (P , .001). Ninety-two patients (88.5%) were neurologically asymptomatic 1 year after surgery. Only 12 patients (11.5%) presented with a deficit, with a global decrease of 39% (x2 = 27.6; P, .005). The quality of life in patients was middle to high (mean rating of EQ-5D visual analog score, 61.78%). The lowest levels of quality of life were found in patients with sphincter dysfunctions (mean, 33.4).

CONCLUSION: Surgery for IDEMTs has a good outcome. Patients reported lower levels of pain and a drastic reduction in neurological symptoms 1 year after surgery. The quality of life is middle to high. It is influenced mainly by the neurological outcome.

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Practical surgical indicators to identify candidates for radical resection of insulo-opercular gliomas

Surgical indicators insular gliomas

J Neurosurg 121:1124–1132, 2014

Maximum resection of gliomas with minimum surgical complications usually leads to optimum outcomes for patients. Radical resection of insulo-opercular gliomas is still challenging, and selection of ideal patients can reduce risk and obtain better outcomes.

Methods. This retrospective study included 83 consecutively treated patients with newly diagnosed gliomas located at the insulo-opercular region and extending to the sylvian fissure around the primary motor and somatosensory cortices. The authors selected 4 characteristics as surgical indicators: clear tumor boundaries, negative enhancement, intact lenticulostriate arteries, and intact superior extremity of the central insular sulcus.

Results. Univariate analysis showed that tumors with clear boundaries were associated with higher rates of gross-total resection than were tumors with ambiguous boundaries (75.7% vs 19.6%). Tumors with negative enhancement compared with enhanced tumors were associated with lower frequency of tumor progression (32.0% vs 81.8%, respectively) and lower rates of surgical complications (14.0% vs 45.5%, respectively). Tumors with intact lenticulostriate arteries were associated with higher rates of gross-total resection than were tumors with involved lenticulostriate arteries (67.3% vs 11.8%, respectively). Tumors with intact superior extremity of the central insular sulcus were associated with higher rates of gross-total resection (57.4% vs 20.7%, respectively) and lower rates of surgical complications (18.5% vs 41.4%, respectively) than were tumors with involved anatomical structures. Multivariate analysis showed that clear tumor boundaries were independently associated with gross-total resection (p < 0.001). Negative enhancement was found to be independently associated with surgical complications (p = 0.005), overall survival times (p < 0.001), and progression-free survival times (p = 0.004). Independent associations were also found between intact lenticulostriate arteries and gross-total resection (p < 0.001), between intact lenticulostriate arteries and progression-free survival times (p = 0.026), and between intact superior extremity of the central insular sulcus and gross-total resection (p = 0.043). Among patients in whom all 4 indicators were present, prognosis was good (5- year survival rate 93.3%), resection rate was maximal (gross-total resection 100%), and surgical complication rate was minimal (6.7%). Also among these patients, overall rates of survival (p = 0.003) and progression-free survival (p = 0.005) were significantly higher than among patients in whom fewer indicators were present.

Conclusions. The authors propose 4 simple indicators that can be used to identify ideal candidates for radical resection of insulo-opercular gliomas, improve the outcomes, and promote maximum resection without introducing neurological complications. The indicators are clear tumor boundaries, negative enhancement, intact lenticulostriate arteries, and intact superior extremity of the central insular sulcus.

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Management of Atypical Cranial Meningiomas, Part 2: Predictors of Progression and the Role of Adjuvant Radiation After Subtotal Resection

Meningioma_-_brain_invasion_-_high_mag

Neurosurgery 75:356–363, 2014

The efficacies of adjuvant stereotactic radiosurgery (SRS) and external beam radiation therapy (EBRT) for atypical meningiomas (AMs) after subtotal resection (STR) remain unclear.

OBJECTIVE: To analyze the clinical, histopathological, and radiographic features associated with progression in AM patients after STR.

METHODS: Fifty-nine primary AMs after STR were examined for predictors of progression, including the impact of SRS and EBRT, in a retrospective cohort study.

RESULTS: Twenty-seven patients (46%) progressed after STR (median, 30 months). On univariate analysis, spontaneous necrosis positively (hazard ratio = 5.2; P = .006) and adjuvant radiation negatively (hazard ratio = 0.3; P = .009) correlated with progression; on multivariate analysis, only adjuvant radiation remained independently significant (hazard ratio = 0.3; P = .006). SRS and EBRT were associated with greater local control (LC; P = .02) and progression-free survival (P = .007). The 2-, 5-, and 10-year actuarial LC rates after STR vs STR/EBRT were 60%, 34%, and 34% vs 96%, 65%, and 45%. The 2-, 5-, and 10-year actuarial progression-free survival rates after STR vs STR/EBRT were 60%, 30%, and 26% vs 96%, 65%, and 45%. Compared with STR alone, adjuvant radiation therapy significantly improved LC in AMs that lack spontaneous necrosis (P = .003) but did not improve LC in AMs with spontaneous necrosis (P = .6).

CONCLUSION: Adjuvant SRS or EBRT improved LC of AMs after STR but only for tumors without spontaneous necrosis. Spontaneous necrosis may aid in decisions to administer adjuvant SRS or EBRT after STR of AMs.

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Effect of neoadjuvant temozolomide upon volume reduction and resection of diffuse low-grade glioma

Effect of neoadjuvant temozolomide upon volume reduction and resection of diffuse low-grade glioma

J Neurooncol (2014) 120:155–161

Maximal safe resection is associated with prolonged survival in patients with low-grade glioma (LGG). It has been suggested that neoadjuvant temozolomide may provide sufficient tumor shrinkage to facilitate aggressive surgical debulking. We examined the impact of temozolomide upon volume reduction and resectability of LGG.

We retrospectively identified 20 adult patients with biopsy proven, deemed not totally resectable LGGs, treated initially with temozolomide. Volumetric 3D (calculated from serial FLAIR images) and 2D tumor measurements were obtained prior to treatment and at 3 months post-treatment. The anticipated extent of resection (EOR) at the 2 time points was measured based on anatomical limitations, calculated as: [(total tumor volume – unresectable tumor volume)/total tumor volume] x 100. Eloquent cortex, deep structures and corpus callosum were considered unresectable.

Mean tumor volume was 68.4 cm3 pre-treatment and 49.5 cm3 at 3 months post-treatment. The mean change from baseline to 3 months after treatment was -32.5 % (p\0.001). Mean 2D pre-treatment area was 28.6 and 23.3 cm2 at 3 months post-treatment. The 2D change was also significant, with mean change of -17 % (p\0.001). 5 % had partial response; 40 % minor response; 45 % stable disease; and 10 % progressive disease by RANO criteria. Mean pretreatment anticipated EOR was 67.2 and 71.5 %at 3 months post-treatment. The mean change from baseline was 4.3 % (p = 0.10).

Our findings demonstrate significant volumetric and 2D reduction of LGG with temozolomide. Although this tumor shrinkage might facilitate radical surgical resection in some cases, our data failed to show statistically significant improvement in anticipated EOR.

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Aneurysmal bone cysts of the spine: treatment options and considerations

ABC

J Neurooncol (2014) 120:171–178

Aneurysmal bone cysts (ABCs) are benign bone lesions with annual incidences ranging from 1.4 to 3.2 cases per million people. Approximately, 10–30 % of ABCs are found in the spine. Such lesions are traditionally treated with curettage or other intralesional techniques.

Because ABCs can be locally aggressive, intralesional resection can be incomplete and result in recurrence. This has led to increased use of novel techniques, including selective arterial embolization (SAE).

This study aims to: (1) compare outcomes based on extent of surgical resection, and (2) compare the efficacy of SAE versus surgical resection.

Clinical data pertaining to 71 cases of spinal ABCs were ambispectively collected from nine institutions in Europe, North America, and Australia. Twenty-two spinal ABCs were treated with surgery, 32 received preoperative embolization and surgery, and 17 were treated with SAE.

Most tumors were classified as Enneking stage 2 (n = 29, 41 %) and stage 3 (n = 29, 41 %). Local recurrence and survival were investigated and a significant difference was not observed between treatment groups. However, all three local recurrences occurred following surgical resection. Surgical resection was further categorized based on Enneking appropriateness. Recurrences only occurred following intralesional Enneking inappropriate (EI) resections (P = 0.10), a classification that characterized 47 % of all surgical resections. Furthermore, 56 % of intralesional resections were EI, compared to only 10 % of en bloc resections (P = 0.01). Although SAE treatment did not result in any local recurrences, 35 % involved more than five embolization procedures.

Spinal ABCs can be effectively treated with intralesional resection, en bloc resection, or SAE. Preoperative embolization should be considered before intralesional resection to limit intraoperative bleeding. Treatment plans must be guided by lesion characteristics and clinical presentation.

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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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