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

Circulating serum oncologic miRNA in pediatric juvenile pilocytic astrocytoma patients predicts mural nodule volume

Acta Neurochirurgica (2018) 160:1571–1581

Juvenile pilocytic astrocytomas represent the largest group of pediatric brain tumors. The ideal management for these tumors is early, total surgical resection. To detect and track treatment response, a screening tool is needed to identify patients for surgical evaluation and assess the quality of treatment. The identification of aberrant miRNA profiles in the sera of juvenile pilocytic astrocytoma patients could provide such a screening tool.

Methods The authors reviewed the serum profiles of 84 oncologically relevant miRNAs in pediatric juvenile pilocytic astrocytoma patients via qPCR screening.

Results miR-21, miR-15b, miR-23a, and miR-146b were significantly elevated in the sera of JPA patients as compared to nononcologic controls, oncologic controls, and post-JPA resection samples (p < 0.001, 0.022, 0.034, 0.044). miR-21 had the highest AUC on ROC analysis (AUC > 0.99, sensitivity 75%, specificity 100%). All four miRNAs also correlated well with tumor mural nodule size, though they only poorly correlated with total tumor size, including cystic components (Spearman’s R2: miR-21 91.7 vs 6.9%, miR-15b 86.3 vs 23.1%, miR-23a 85.8 vs 23.0%, miR-146b 59.8 vs 11.9%).

Conclusion In this small pilot study, pediatric juvenile pilocytic astrocytoma patients had significant elevations in serum miR-21, miR-15b, miR-23a, and miR-146b levels that do not appear to be driven by hydrocephalus or local distortion of the intracranial contents. These alterations correlate with solid tumor component volume and reverse with complete tumor resection, suggesting that this serum miRNA profile may delineate biomarkers for screening and tracking juvenile pilocytic astrocytoma patients. Additional studies, with a larger cohort, are needed to verify these results.

Outcomes of stereotactic radiosurgery for foramen magnum meningiomas: an international multicenter study

J Neurosurg 129:383–389, 2018

Meningiomas are the most common benign extramedullary lesions of the foramen magnum; however, their optimal management remains undefined. Given their location, foramen magnum meningiomas (FMMs) can cause significant morbidity, and complete microsurgical removal can be challenging. Anterior and anterolateral FMMs carry greater risks with surgery, but they comprise the majority of these lesions. As an alternative to resection, stereotactic radiosurgery (SRS) has been used to treat FMMs in small case series. To more clearly define the outcomes of SRS and to delineate a rational management paradigm for these lesions, the authors analyzed the safety and efficacy of SRS for FMM in an international multicenter trial.

METHODS Seven medical centers participating in the International Gamma Knife Research Foundation (IGKRF) provided data for this retrospective cohort study. Patients who were treated with Gamma Knife radiosurgery and whose clinical and radiological follow-up was longer than 6 months were eligible for study inclusion. Data from pre- and post- SRS radiological and clinical evaluations were analyzed. Stereotactic radiosurgery treatment variables were recorded.

RESULTS Fifty-seven patients (39 females and 18 males, with a median age of 64 years) met the study inclusion criteria. Thirty-two percent had undergone prior microsurgical resection. Patients most frequently presented with cranial neuropathy (39%), headache (35%), numbness (32%), and ataxia (30%). Median pre-SRS tumor volume was 2.9 cm3. Median SRS margin dose was 12.5 Gy (range 10–16 Gy). At the last follow-up after SRS, 49% of tumors were stable, 44% had regressed, and 7% had progressed. Progression-free survival rates at 5 and 10 years were each 92%. A greater margin dose was associated with a significantly increased likelihood of tumor regression, with 53% of tumors treated with > 12 Gy regressing. Fifty-two percent of symptomatic patients noted some clinical improvement. Adverse radiation effects were limited to hearing loss and numbness in 1 patient (2%).

CONCLUSIONS Stereotactic radiosurgery for FMM frequently results in tumor control or tumor regression, as well as symptom improvement. Margin doses > 12 Gy were associated with increased rates of tumor regression. Stereotactic radiosurgery was generally safe and well tolerated. Given its risk-benefit profile, SRS may be particularly useful in the management of small- to moderate-volume anterior and anterolateral FMMs.

 

Volumetric tumor growth rates of meningiomas involving the intracranial venous sinuses

Acta Neurochirurgica (2018) 160:1531–1538

There is currently no consensus as to whether meningiomas located inside the venous sinuses should be aggressively or conservatively treated. The goals of this study were to identify how sinus-invading meningiomas grow, report and compare growth rates of tumor components inside and outside the different venous sinuses, identify risk factors associated with increased tumor growth, and determine the effects of the extent of tumor resection on recurrence for meningiomas that invade the dural venous sinuses.

Methods Adult patients who underwent primary, non-biopsy resection of a WHO grade 1 meningioma invading the dural venous sinuses at a tertiary care institution between 2007 and 2015 were retrospectively reviewed. Rates of tumor growth were fit to several growth models to evaluate the most accurate model. Cohen’s d analysis was used to identify associations with increased growth of tumor in the venous sinuses. Logistic regression was used to compare extent of resection with recurrence.

Results Of the 68 patients included in the study, 34 patients had postoperative residual tumors in the venous sinuses that were measured over time. The growth model that best fit the growth of intrasinus meningiomas was the Gompertzian growth model (r2 = 0.93). The annual growth rate of meningiomas inside the sinuses was 7.3%, compared to extrasinus tumors with 13.6% growth per year. The only factor significantly associated with increased tumor growth in sinuses was preoperative embolization (effect sizes (ES) [95% CI], 1.874 [7.633–46.735], p = 0.008).

Conclusions This study shows that meningiomas involving the venous sinuses have a Gompertzian-type growth with early exponential growth followed by a slower growth rate that plateaus when they reach a certain size. Overall, the growth rate of the intrasinus portion is low (7.3%), which is half of the reported growth rates for other studies involving primarily extrasinus tumors.

Meningiomas in pregnancy: timing of surgery and clinical outcomes as observed in 104 cases and establishment of a best management strategy

Acta Neurochir (2018) 160:1521–1529

There is a strong correlation between the level of circulating female sex hormones and the parturient growth of meningiomas. As a result, rapid changes in meningioma size occur during pregnancy, putting both the mother and fetus at risk. Large, symptomatic meningiomas require surgical resection, regardless of the status of pregnancy. However, the preferred timing of such complex intervention is a matter of debate. The rarity of this clinical scenario and the absence of prospective trials make it difficult to reach evidence-based conclusions. The aim of this study was to create evidencebased management guidelines for timing of surgery for pregnancy-related intracranial meningiomas.

Method The English literature from 1990 to 2016 was systematically reviewed according to PRISMA guidelines for all surgical cases of pregnancy–related intracranial meningiomas. Cases were divided into two groups: patients who have had surgery during pregnancy and delivered thereafter (group A) and patients who delivered first (group B). Groups were compared for demographic, clinical and radiological features, as well as for neurosurgical, obstetrical and neonatological outcomes. Statistical analysis was performed to assess differences.

Results A total of 104 surgical cases were identified and reviewed, of which 86 were suitable for comparison and statistical analysis. Thirty-five patients (40%) underwent craniotomy for resection during pregnancy or at delivery (group A) and 51 patients (60%) underwent surgery after delivery (group B). Groups showed no significant differences in characteristics such as age at diagnosis, number of gestations, presenting symptoms, tumor site and tumor size. Despite a comparable distribution over the gestational trimesters, group A had significantly more patients diagnosed prior to the 27th gestational week (46 vs 17.5%, p = 0.0075). Group Awas also associated with a significantly higher rate of both emergent craniotomies (40 vs 19.6%, p = 0.0048) and emergent Caesarian deliveries (47 vs 17.8%, p = 0.00481). The time from diagnosis to surgery was significantly longer in group B (11 weeks vs 1 week in group A, p = 0.0013). The rate of premature delivery was high but similar in both groups (∼70%). Risks of maternal mortality or fetal mortality were associated with group A (odds ratio = 14.7), but did not reach statistical significance.

Conclusions While surgical resection of meningioma during pregnancy may be associated with increased maternal and fetal mortalities, the overall neurosurgical, obstetrical and neonatological outcomes, as well as many clinical characteristics, are similar to patients undergoing resection postpartum. We believe that fetal survival chances have a significant impact on decision-making, as patients diagnosed at a later stage in pregnancy (≥27th week of gestation) were more likely to undergo delivery first. This complicated clinical scenario requires the close cooperation of multiple disciplines. While the mother’s health and well-being should always be paramount in guiding management, we hope that the overall good outcomes observed by this systematic review will encourage colleagues to aim for term pregnancies whenever possible in order to reduce prematurity-related problems.

Staged Stereotactic Radiosurgery for Large Brain Metastases

Neurosurgery 83:114–121, 2018

Treatment options are limited for large, unresectable brain metastases.

OBJECTIVE: To report a single institution series of staged stereotactic radiosurgery (SRS) that allows for tumor response between treatments in order to optimize the therapeutic ratio.

METHODS: Patients were treated with staged SRS separated by 1 mo with a median dose at first SRS of 15 Gy (range 10-21 Gy) and a median dose at second SRS of 14 Gy (range 10-18 Gy). Overall survival was evaluated using the Kaplan-Meier method. Cumulative incidences were estimated for neurological death, radiation necrosis, local failure (marginal or central), and distant brain failure. Absolute cumulative dose–volume histogram was created for each treated lesion. Logistic regression and competing risks regression were performed for each discrete dose received by a certain volume.

RESULTS: Thirty-three patients with 39 lesions were treated with staged radiosurgery. Overall survival at 6 and 12mowas 65.0% and 60.0%, respectively. Cumulative incidence of local failure at 6 and 12 mo was 3.2% and 13.3%, respectively. Of the patients who received staged therapy, 4 of 33 experienced local failure. Radiation necrosis was seen in 4 of 39 lesions. Two of 33 patients experienced a Radiation Therapy Oncology Group toxicity grade >2 (2 patients had grade 4 toxicities). Dosimetric analysis revealed that dose (Gy) received by volume of brain (ie, VDose(Gy))was associated with radiation necrosis, including the range V44.5Gy to V87.8Gy.

CONCLUSION: Staged radiosurgery is a safe and effective option for large, unresectable brain metastases. Prospective studies are required to validate the findings in this study.

Surgical management of incidentally discovered diffusely infiltrating low-grade glioma

J Neurosurg 129:19–26, 2018

Occasionally, diffusely infiltrating low-grade gliomas (LGGs) are identified as incidental findings in patients who have no signs or symptoms that can be ascribed to the tumors. The diagnosis of incidental, asymptomatic LGGs has become more frequent due to the vast increase in access to medical imaging technology. While management of these lesions remains controversial, early surgery has been suggested to improve outcome. The authors set out to identify and review the characteristics and surgical outcomes of patients who underwent surgical intervention for incidental LGG.

METHODS All cases of LGG surgically treated between 2004 and 2016 at the authors’ institution were analyzed to identify those that were discovered incidentally. Patients with incidentally discovered LGGs were identified, and their cases were retrospectively reviewed. An “incidental” finding was defined as an abnormality on imaging that was obtained for a reason not attributable to the glioma, such as trauma, headache, screening, or research participation. Kaplan-Meier analysis was performed to determine actuarial rates of overall survival, progression-free survival, and malignant progression– free survival.

RESULTS In 34 (6.8%) of 501 adult patients who underwent surgery for LGG, the tumors were discovered incidentally. Headache (26%, n = 9) and screening (21%, n = 7) were the most common indications for brain imaging in this group. Four of these 34 patients had initial biopsy after the tumor was identified on imaging. In 5 cases, the patients opted for immediate resection; the remaining cases were managed with a “watch-and-wait” approach, with intervention undertaken only after radiological or clinical evidence of disease progression. The mean duration of follow-up for all 34 cases was 5 years. Twelve patients (35.3%) had disease progression, with an average time to progression of 43.8 months (range 3–105 months). There were 5 cases (14.7%) of malignant progression and 4 deaths (11.8%). Oligodendroglioma was diagnosed in 16 cases (47%) and astrocytoma in 15 (44%). Twenty-five patients (74%) had IDH1 mutation and demonstrated prolonged survival. Only 2 patients had mild surgery-related complications, and 16 patients (47%) developed epilepsy during the course of the disease.

CONCLUSIONS In this retrospective analysis of cases of incidentally discovered LGGs, the tumors were surgically removed with minimal surgical risk. In patients with incidental LGGs there is improved overall survival relative to median survival for patients with symptomatic LGGS, which is likely attributable to the underlying favorable biology of the disease indicated by the presence of IDH1 mutation in 74% of the cases.

Thalamic Glioblastoma: Clinical Presentation, Management Strategies, and Outcomes

Neurosurgery 83:76–85, 2018

Thalamic glioblastomas (GBMs) represent a significant neurosurgical challenge. In view of the low incidence of these tumors, outcome data and management strategies are not well defined.

OBJECTIVE: To identify the natural history and factors associated with survival in patients with thalamic glioblastoma.

METHODS: A retrospective review of all patients with thalamic glioblastoma over a 10-yr period was performed. Presenting clinical, radiological, and outcome data were collected. Chi-squared and Fisher’s exact tests were used to compare clinical characteristics across tumor groups. Cox proportional hazard models were utilized to investigate variables of interest with regard to overall survival.

RESULTS: Fifty-seven patients met inclusion criteria, with a median age of 53 and median Karnofsky Performance Scale (KPS) score of 80. The most common presenting symptoms were weakness, confusion, and headache. Hydrocephalus was present in 47% of patients preoperatively. Stereotactic biopsy was performed in 47 cases, and 10 patients underwent craniotomy. The median overall survival was 12.2 mo. Higher KPS, younger age, and cerebrospinal fluid (CSF) diversionwere correlatedwith better overall survival univariately, respectively, while the presence of language deficits at initial presentation was associated with poorer survival. In multivariate analysis, the only significant predictor of survival was presenting KPS.

CONCLUSION: The overall survival of patients with thalamic glioblastoma is comparable to unresectable lobar supratentorial GBMs. Younger patients and those with good presenting functional status had improved survival. Midbrain involvement by the tumor is not a negative prognostic factor. Improved therapies are needed, and patients should be considered for early trial involvement and aggressive upfront therapy.

 

Anaplastic meningioma: an analysis of the National Cancer Database from 2004 to 2012

J Neurosurg 128:1684–1689, 2018

Anaplastic meningiomas represent 1%–2% of meningioma diagnoses and portend a poor prognosis. Limited information is available on practice patterns and optimal management. The purpose of this study was to define treatment patterns and outcomes by treatment modality using a large national cancer registry.

METHODS The National Cancer Database was used to identify patients diagnosed with anaplastic meningioma from 2004 to 2012. Log-rank statistics were used to compare survival outcomes by extent of resection, use of adjuvant radiotherapy (RT), and use of adjuvant chemotherapy. Least-squares linear regression was used to evaluate the utilization of RT over time. Logistic regression modeling was used to identify predictors of receipt of RT. Cox proportional hazards modeling was used to evaluate the effect of RT, gross-total resection (GTR), and chemotherapy on survival.

RESULTS A total of 755 adults with anaplastic meningioma were identified. The 5-year overall survival rate was 41.4%. Fifty-two percent of patients received RT, 7% received chemotherapy, and 58% underwent GTR. Older patients were less likely to receive RT (OR 0.98, p < 0.01). Older age (HR 1.04, p < 0.01), high comorbidity score (HR 1.33, p = 0.02), and subtotal resection (HR 1.57, p = 0.02) were associated with increased risk of death on multivariate modeling, while RT receipt was associated with decreased risk of death (HR 0.79, p = 0.04). Chemotherapy did not have a demonstrable effect on survival (HR 1.33, p = 0.18).

CONCLUSIONS Anaplastic meningioma portends a poor prognosis. Gross-total resection and RT are associated with improved survival, but utilization of RT is low. Unless medically contraindicated, patients with anaplastic meningioma should be offered RT.

Neurosurgical treatment of gangliogliomas in children and adolescents

Acta Neurochirurgica (2018) 160:1207–1214

The object of this study was to delineate long-term results of the surgical treatment of pediatric tumors classified as ganglioglioma or gangliocytoma.

Methods A cohort of consecutive patients 19 years or younger who had undergone primary resection of CNS tumors during the years 1980–2016 at a single institution were reviewed in this retrospective study of surgical morbidity, mortality, and academic achievement and/or work participation. Grossmotor function and activities of daily living were scored using the Barthel Index (BI).

Results Patient records for 32 consecutive children and adolescents who had undergone resection for a ganglioglioma were included in this study. Of the 32 patients, 13 were in the first decade at the first surgery, whereas 19 were in the second decade. The male/female ratio was 1.0 (16/16). No patient was lost to follow-up. The tumor was localized to the supratentorial compartment in 26 patients, to the posterior fossa in 5 patients, and to the spinal cord in 1 patient. Only two of the tumors were classified as anaplastic. Of the 30 low-grade tumors, 2 were classified as gangliocytomas, 6 were desmoplastic infantile gangliogliomas, and 22 were ordinary gangliogliomas. The aim of primary surgery was gross-total resection (GTR) and was achieved in 23 patients (71.9%). Altogether, 43 tumor resections were performed. Eight patients underwent a second resection from 1 to 10 years after primary surgery and three of these also had a third resection from 2 to 24 years after initial surgery. The reason for further resection was clinical (seizure control failure/recurrence of epilepsy or progressive neurological deficit) and/or residual tumor progression/recurrence. There was no operative mortality in this series and all 32 patients are alive with follow-up periods from 0.5 to 36 years (median 14 years). Observed 14-year survival is thus 100%. One out of two children with primary anaplastic tumor received local radiotherapy (proton) postoperatively. The other 31 patients did not have any kind of non-surgical adjuvant therapy. Twenty-one out of 26 children with supratentorial tumor had epilepsy as one of their presenting symptoms. Nineteen of these became seizure-free after initial surgery (18 of them after GTR), but 3 patients experienced recurrence of seizures within some years. Functional outcome in terms ofADL, schooling, and work participation was gratifying in most patients. Five patients have persistent hydrocephalus (HC), treated with ventriculoperitoneal (VP) shunts.

Conclusion Low-grade gangliogliomas (GGs) can be surgically treated with good long-term results including seizure and tumor control as well as school and working participation.

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State of the Art Treatment of Spinal Metastatic Disease

Neurosurgery 82:757–769, 2018

Treatment paradigms for patients with spine metastases have evolved significantly over the past decade. Incorporating stereotactic radiosurgery into these paradigms has been particularly transformative, offering precise delivery of tumoricidal radiation doses with sparing of adjacent tissues. Evidence supports the safety and efficacy of radiosurgery as it currently offers durable local tumor control with low complication rates even for tumors previously considered radioresistant to conventional radiation.

The role for surgical intervention remains consistent, but a trend has been observed toward less aggressive, often minimally invasive, techniques. Using modern technologies and improved instrumentation, surgical outcomes continue to improve with reduced morbidity.

Additionally, targeted agents such as biologics and checkpoint inhibitors have revolutionized cancer care, improving both local control and patient survivals. These advances have brought forth a need for new prognostication tools and a more critical review of long-term outcomes. The complex nature of current treatment schemes necessitates a multidisciplinary approach including surgeons, medical oncologists, radiation oncologists, interventionalists, and pain specialists.

This review recapitulates the current state-of-the-art, evidence-based data on the treatment of spinal metastases, integrating these data into a decision framework, NOMS, which integrates the 4 sentinel decision points in metastatic spine tumors: Neurologic, Oncologic, Mechanical stability, and Systemic disease and medical co-morbidities.

Spinal ependymoma in adults: a multicenter investigation of surgical outcome and progression-free survival

J Neurosurg Spine 28:654–662, 2018

Spinal ependymomas are rare glial neoplasms. Because their incidence is low, only a few larger studies have investigated this condition. There are no clear data concerning prognosis and therapy. The aim of the study was to describe the natural history, perioperative clinical course, and local tumor control of adult patients with spinal ependymomas who were surgically treated under modern treatment standards.

METHODS The authors performed a multicenter retrospective study. They identified 158 adult patients with spinal ependymomas who had received surgical treatment between January 2006 and June 2013. The authors analyzed the clinical and histological aspects of these cases to identify the predictive factors for postoperative morbidity, tumor resectability, and recurrence.

RESULTS Gross-total resection (GTR) was achieved in 80% of cases. At discharge, 37% of the patients showed a neurological decline. During follow-up the majority recovered, whereas 76% showed at least preoperative status. Permanent functional deterioration remained in 2% of the patients. Transient deficits were more frequent in patients with cervically located ependymomas (p = 0.004) and in older patients (p = 0.002). Permanent deficits were independently predicted only by older age (p = 0.026). Tumor progression was observed in 15 cases. The 5-year progression-free survival (PFS) rate was 80%, and GTR (p = 0.037), WHO grade II (p = 0.009), and low Ki-67 index (p = 0.005) were independent prognostic factors for PFS. Adjuvant radiation therapy was performed in 15 cases. No statistically relevant effects of radiation therapy were observed among patients with incompletely resected ependymomas (p = 0.079).

CONCLUSIONS Due to its beneficial value for PFS, GTR is important in the treatment of spinal ependymoma. Grosstotal resection is feasible in the majority of cases, with acceptable rates of permanent deficits. Also, Ki-67 appears to be an important prognostic factor and should be included in a grading scheme for spinal ependymomas.

Intraoperative perception and estimates on extent of resection during awake glioma surgery: overcoming the learning curve

J Neurosurg 128:1410–1418, 2018

There is ample evidence that extent of resection (EOR) is associated with improved outcomes for glioma surgery. However, it is often difficult to accurately estimate EOR intraoperatively, and surgeon accuracy has yet to be reviewed. In this study, the authors quantitatively assessed the accuracy of intraoperative perception of EOR during awake craniotomy for tumor resection.

METHODS A single-surgeon experience of performing awake craniotomies for tumor resection over a 17-year period was examined. Retrospective review of operative reports for quantitative estimation of EOR was recorded. Definitive EOR was based on postoperative MRI. Analysis of accuracy of EOR estimation was examined both as a general outcome (gross-total resection [GTR] or subtotal resection [STR]), and quantitatively (5% within EOR on postoperative MRI). Patient demographics, tumor characteristics, and surgeon experience were examined. The effects of accuracy on motor and language outcomes were assessed.

RESULTS A total of 451 patients were included in the study. Overall accuracy of intraoperative perception of whether GTR or STR was achieved was 79.6%, and overall accuracy of quantitative perception of resection (within 5% of postoperative MRI) was 81.4%. There was a significant difference (p = 0.049) in accuracy for gross perception over the 17- year period, with improvement over the later years: 1997–2000 (72.6%), 2001–2004 (78.5%), 2005–2008 (80.7%), and 2009–2013 (84.4%). Similarly, there was a significant improvement (p = 0.015) in accuracy of quantitative perception of EOR over the 17-year period: 1997–2000 (72.2%), 2001–2004 (69.8%), 2005–2008 (84.8%), and 2009–2013 (93.4%). This improvement in accuracy is demonstrated by the significantly higher odds of correctly estimating quantitative EOR in the later years of the series on multivariate logistic regression. Insular tumors were associated with the highest accuracy of gross perception (89.3%; p = 0.034), but lowest accuracy of quantitative perception (61.1% correct; p < 0.001) compared with tumors in other locations. Even after adjusting for surgeon experience, this particular trend for insular tumors remained true. The absence of 1p19q co-deletion was associated with higher quantitative perception accuracy (96.9% vs 81.5%; p = 0.051). Tumor grade, recurrence, diagnosis, and isocitrate dehydrogenase-1 (IDH-1) status were not associated with accurate perception of EOR. Overall, new neurological deficits occurred in 8.4% of cases, and 42.1% of those new neurological deficits persisted after the 3-month follow-up. Correct quantitative perception was associated with lower postoperative motor deficits (2.4%) compared with incorrect perceptions (8.0%; p = 0.029). There were no detectable differences in language outcomes based on perception of EOR.

CONCLUSIONS The findings from this study suggest that there is a learning curve associated with the ability to accurately assess intraoperative EOR during glioma surgery, and it may take more than a decade to be truly proficient. Understanding the factors associated with this ability to accurately assess EOR will provide safer surgeries while maximizing tumor resection.

Sodium Fluorescein Facilitates Guided Sampling of Diagnostic Tumor Tissue in Nonenhancing Gliomas

Neurosurgery 82:719–727, 2018

Accurate tissue sampling in nonenhancing (NE) gliomas is a unique surgical challenge due to their intratumoral histological heterogeneity and absence of contrast enhancement as a guide for intraoperative stereotactic guidance. Instead, T2/fluid-attenuated inversion-recovery (FLAIR) hyperintensity on MRI is commonly used as an imaging surrogate for pathological tissue, but sampling from this region can yield nondiagnostic or underdiagnostic brain tissue. Sodium fluorescein is an intraoperative fluorescent dye that has a high predictive value for tumor identification in areas of contrast enhancement and NE in glioblastomas. However, the underlying histopathological alterations in fluorescent regions of NE gliomas remain undefined.

OBJECTIVE: To evaluate whether fluorescein can identify diagnostic tissue and differentiate regions with higher malignant potential during surgery for NE gliomas, thus improving sampling accuracy.

METHODS: Thirteen patients who presented with NE, T2/FLAIR hyperintense lesions suspicious for glioma received fluorescein (10%, 3 mg/kg intravenously) during surgical resection.

RESULTS: Patchy fluorescence was identified within the T2/FLAIR hyperintense area in 10 of 13 (77%) patients. Samples taken from fluorescent regions were more likely to demonstrate diagnostic glioma tissue and cytologic atypia (P < .05). Fluorescein demonstrated a 95% positive predictive value for the presence of diagnostic tissue. Samples from areas of fluorescence also demonstrated greater total cell density and higher Ki-67 labeling than nonfluorescent biopsies (P < .05).

CONCLUSION: Fluorescence in NE gliomas is highly predictive of diagnostic tumor tissue and regions of higher cell density and proliferative activity.

Risk assessment of motor function using nTMS-based tractography

J Neurosurg 128:800–810, 2018

Navigated transcranial magnetic stimulation (nTMS) and diffusion tensor imaging fiber tracking (DTI FT) based on nTMS data are increasingly used for preoperative planning and resection guidance in patients suffering from motor-eloquent brain tumors. The present study explores whether nTMS-based DTI FT can also be used for individual preoperative risk assessment regarding surgery-related motor impairment.

METHODS Data derived from preoperative nTMS motor mapping and subsequent nTMS-based tractography in 86 patients were analyzed. All patients suffered from high-grade glioma (HGG), low-grade glioma (LGG), or intracranial metastasis (MET). In this context, nTMS-based DTI FT of the corticospinal tract (CST) was performed at a range of fractional anisotropy (FA) levels based on an individualized FA threshold ([FAT]; tracking with 50%, 75%, and 100% FAT), which was defined as the highest FA value allowing for visualization of fibers (100% FAT). Minimum lesion-to-CST distances were measured, and fiber numbers of the reconstructed CST were assessed. These data were then correlated with the preoperative, postoperative, and follow-up status of motor function and the resting motor threshold (rMT).

RESULTS At certain FA levels, a statistically significant difference in lesion-to-CST distances was observed between patients with HGG who had no impairment and those who developed surgery-related transient or permanent motor deficits (75% FAT: p = 0.0149; 100% FAT: p = 0.0233). In this context, no patient with a lesion-to-CST distance ≥ 12 mm suffered from any new surgery-related permanent paresis (50% FAT and 75% FAT). Furthermore, comparatively strong negative correlations were observed between the rMT and lesion-to-CST distances of patients with surgery-related transient paresis (Spearman correlation coefficient [rs]; 50% FAT: rs = –0.8660; 75% FAT: rs = –0.8660) or surgery-related permanent paresis (50% FAT: rs = –0.7656; 75% FAT: rs = –0.6763).

CONCLUSIONS This is one of the first studies to show a direct correlation between imaging, clinical status, and neurophysiological markers for the integrity of the motor system in patients with brain tumors. The findings suggest that nTMSbased DTI FT might be suitable for individual risk assessment in patients with HGG, in addition to being a surgery-planning tool. Importantly, necessary data for risk assessment were obtained without significant additional efforts, making this approach potentially valuable for direct clinical use.

Navigated 3D–ultrasound versus conventional neuronavigation during awake resections of eloquent low-grade gliomas

Acta Neurochir (2018) 160:331–342

The data showing usefulness of navigated 3D– ultrasound (3DUS) during awake resections of eloquent gliomas are sparse. Results of surgeries performed using 3DUS were never compared to procedures guided by standard neuronavigation. The aim of this work is to assess the effectiveness of 3DUS during awake resections of eloquent low-grade gliomas (LGGs) by comparing surgical results of two series of patients operated on using conventional neuronavigation and using 3DUS. To our knowledge, a similar study is lacking in the literature.

Methods During a 4-year period (September 2006 to August 2010) 21 awake resections of LGGs guided by neuronavigation (series 1, S1) were consecutively performed in Department of Neurosurgery in Bratislava. During another 4-year period (August 2010 to July 2014) 28 awake resections of LGGs guided by 3DUS (series 2, S2) were consecutively conducted. In both patients series, the eloquent cortical and subcortical structures were intraoperatively detected by direct electrical stimulation. Extent of tumor resection (EOR) and functional outcome in both series were compared.

Results EOR was significantly greater (p = 0.022) in S2 (median = 93.25%; mean = 86.79%), as compared to S1 (median 87.1%; mean = 75.85%). One permanent minor deficit in S1 and 2 minor deficits in S2 occurred, the difference was not significant (p = 0.999).

Conclusions Our work represents the first study comparing results of surgeries guided by 3DUS versus conventional navigation. The extent of awake resections of eloquent LGG guided by 3DUS was greater comparing to awake resections guided by standard neuronavigation; use of 3DUS had no impact on the number of new permanent deficits.

The surgical treatment of tumors of the fourth ventricle

J Neurosurg 128:339–351, 2018

Fourth ventricle tumors are rare, and surgical series are typically small, comprising a single pathology, or focused exclusively on pediatric populations. This study investigated surgical outcome and complications following fourth ventricle tumor resection in a diverse patient population. This is the largest cohort of fourth ventricle tumors described in the literature to date.

METHODS This is an 18-year (1993–2010) retrospective review of 55 cases involving patients undergoing surgery for tumors of the fourth ventricle. Data included patient demographic characteristics, pathological and radiographic tumor characteristics, and surgical factors (approach, surgical adjuncts, extent of resection, etc.). The neurological and medical complications following resection were collected and outcomes at 30 days, 90 days, 6 months, and 1 year were reviewed to determine patient recovery. Patient, tumor, and surgical factors were analyzed to determine factors associated with the frequently encountered postoperative neurological complications.

RESULTS There were no postoperative deaths. Gross-total resection was achieved in 75% of cases. Forty-five percent of patients experienced at least 1 major neurological complication, while 31% had minor complications only. New or worsening gait/focal motor disturbance (56%), speech/swallowing deficits (38%), and cranial nerve deficits (31%) were the most common neurological deficits in the immediate postoperative period. Of these, cranial nerve deficits were the least likely to resolve at follow-up. Multivariate analysis showed that patients undergoing a transvermian approach had a higher incidence of postoperative cranial nerve deficits, gait disturbance, and speech/swallowing deficits than those treated with a telovelar approach. The use of surgical adjuncts (intraoperative navigation, neurophysiological monitoring) did not significantly affect neurological outcome. Twenty-two percent of patients required postoperative CSF diversion following tumor resection. Patients who required intraoperative ventriculostomy, those undergoing a transvermian approach, and pediatric patients (< 18 years old) were all more likely to require postoperative CSF diversion. Twenty percent of patients suffered at least 1 medical complication following tumor resection. Most complications were respiratory, with the most common being postoperative respiratory failure (14%), followed by pneumonia (13%).

CONCLUSIONS The occurrence of complications after fourth ventricle tumor surgery is not rare. Postoperative neurological sequelae were frequent, but a substantial number of patients had neurological improvement at long-term followup. Of the neurological complications analyzed, postoperative cranial nerve deficits were the least likely to completely resolve at follow-up. Of all the patient, tumor, and surgical variables included in the analysis, surgical approach had the most significant impact on neurological morbidity, with the telovelar approach being associated with less morbidity.

 

Phase I Study of DNX-2401 (Delta-24-RGD) Oncolytic Adenovirus: Replication and Immunotherapeutic Effects in Recurrent Malignant Glioma

J Clin Oncol 36. © 2018

https://doi.org/10.1200/JCO.2017.75.8219

DNX-2401 (Delta-24-RGD; tasadenoturev) is a tumor-selective, replication-competent oncolytic adenovirus. Preclinical studies demonstrated antiglioma efficacy, but the effects and mechanisms of action have not been evaluated in patients.

Methods A phase I, dose-escalation, biologic-end-point clinical trial of DNX-2401 was conducted in 37 patients with recurrent malignant glioma. Patients received a single intratumoral injection of DNX-2401 into biopsy-confirmed recurrent tumor to evaluate safety and response across eight dose levels (group A). To investigate the mechanism of action, a second group of patients (group B) underwent intratumoral injection through a permanently implanted catheter, followed 14 days later by en bloc resection to acquire post-treatment specimens.

Results In group A (n = 25), 20% of patients survived > 3 years from treatment, and three patients had a ≥ 95% reduction in the enhancing tumor (12%), with all three of these dramatic responses resulting in >3 years of progression-free survival from the time of treatment. Analyses of post-treatment surgical specimens (group B, n = 12) showed that DNX-2401 replicates and spreads within the tumor, documenting direct virus-induced oncolysis in patients. In addition to radiographic signs of inflammation, histopathologic examination of immune markers in post-treatment specimens showed tumor infiltration by CD8+ and T-bet+ cells, and transmembrane immunoglobulin mucin-3 downregulation after treatment. Analyses of patient-derived cell lines for damage-associated molecular patterns revealed induction of immunogenic cell death in tumor cells after DNX-2401 administration.

Conclusion Treatment with DNX-2401 resulted in dramatic responses with long-term survival in recurrent highgrade gliomas that are probably due to direct oncolytic effects of the virus followed by elicitation of an immune-mediated antiglioma response.

Adult Pilocytic Astrocytoma: An Institutional Series and Systematic Literature Review for Extent of Resection and Recurrence

World Neurosurg. (2018) 110:276-283

Pilocytic astrocytoma is a classically benign tumor that most often affects pediatric patients. Rarely, it occurs during adulthood. We present a case series and systematic literature review of adult pilocytic astrocytoma (APA) to examine the clinical presentation, extent of resection, and recurrence rate associated with this tumor in this population.

MATERIALS AND METHODS: Our institutional records were retrospectively reviewed for cases of pilocytic astrocytoma in adults. A PubMed search identified English-language studies of pathology-proven APA. A meta-analysis was performed to determine the relationship between extent of tumor resection and recurrence.

RESULTS: Forty-six patients with APA were diagnosed at our institution (mean age 33.6  13.3; 24 [52%] female). Twenty-four patients (52%) underwent gross total resection, 11 (24%) subtotal resection, 4 (9%) near total resection, 4 (9%) observation after biopsy, and 3 (6%) radiotherapy alone. Tumors recurred or progressed in 6 (13%) patients, of whom 4 were treated by STR and 2 were treated by radiotherapy alone. Thirty-nine (95%) patients were still alive at last follow-up. A systematic literature review identified 415 patients with APA in 38 studies. Including our case series, 7 studies reported extent of resection, followup, and recurrence. Of 254 patients with a weighted mean follow-up of 77.7  49.6 (31e250) months, 129 (51%) were treated with gross total resection, and 125 (49%) underwent subtotal resection. Tumor recurred in 79 (31%) patients, 22 (27%) after gross total resection and 57 (73%) after subtotal resection (P < 0.001).

CONCLUSIONS: Pilocytic astrocytoma rarely presents during adulthood. Overall, prognosis is favorable and survival rates are high. APA recurrence is more likely after STR, and the goal of surgery should always be GTR when feasible.

Developing an Algorithm for Optimizing Care of Elderly Patients With Glioblastoma

Neurosurgery 82:64–75, 2018

Elderly patients with glioblastoma have an especially poor prognosis; optimizing their medical and surgical care remains of paramount importance.

OBJECTIVE: To investigate patient and treatment characteristics of elderly vs nonelderly patients and develop an algorithm to predict elderly patients’ survival.

METHODS: Retrospective analysis of 554 patients (mean age=60.8; 42.0% female) undergoing first glioblastoma resection or biopsy at our institution (2005-2011).

RESULTS: Of the 554 patients, 218 (39%) were elderly (≥65 yr). Compared with nonelderly, elderly patients were more likely to receive biopsy only (26% vs 16%), have ≥1 medical comorbidity (40% vs 20%), and develop postresection morbidity (eg, seizure, delirium; 25% vs 14%), and were less likely to receive temozolomide (TMZ) (78% vs 90%) and gross total resection (31% vs 45%). To predict benefit of resection in elderly patients (n = 161), we identified 5 factors known in the preoperative period that predicted survival in a multivariate analysis. We then assigned points to each (1 point: Charlson comorbidity score >0, subtotal resection, tumor >3 cm; 2 points: preoperative weakness, Charlson comorbidity score >1, tumor >5 cm, age >75 yr; 4 points: age >85 yr). Having 3 to 5 points (n = 78, 56%) was associated with decreased survival compared to 0 to 2 points (n = 41, 29%, 8.5 vs 16.9 mo; P = .001) and increased survival compared to 6 to 9 points (n = 20, 14%, 8.5 vs 4.5 mo; P < .001). Patients with 6 to 9 points did not survive significantly longer than elderly patients receiving biopsy only (n = 57, 4.5 vs 2.7 mo; P = .58).

CONCLUSION: Further optimization of the medical and surgical care of elderly glioblastoma patients may be achieved by providing more beneficial therapies while avoiding unnecessary resection in those not likely to receive benefit from this intervention.

 

Symmetry of the arcuate fasciculus and its impact on language performance of patients with brain tumors in the language-dominant hemisphere

J Neurosurg 127:1407–1416, 2017

Cerebral damage in frontal, parietal, and temporal brain areas and, probably more importantly, their interconnections can lead to deficits in language. However, neural plasticity and repair allow the brain to partly compensate for neural injury, mediated by both functional and structural changes. In this study, the authors sought to systematically investigate the relationship between language performance in brain tumor patients and structural perisylvian pathways (i.e., the arcuate fasciculus [AF]) using probabilistic fiber tracking on diffusion tensor imaging. The authors used a previously proposed model in which the AF is divided into anterior, long, and posterior segments. The authors hypothesized that right-handed patients with gliomas in the language-dominant (left) hemisphere would benefit from a more symmetrical or right-lateralized language pathway in terms of better preservation of language abilities. Furthermore, they investigated to what extent specific tumor characteristics, including proximity to the AF, affect language outcome in such patients.

METHODS Twenty-seven right-handed patients (12 males and 15 females; mean age 52 ± 16 years) with 11 low-grade and 16 high-grade gliomas of the left hemisphere underwent 3-T diffusion-weighted MRI (30 directions) and language assessment as part of presurgical planning. For a systematic quantitative evaluation of the AF, probabilistic fiber tracking with a 2 regions of interest approach was carried out. Volumes of the 3 segments of both hemispheric AFs were evaluated by quantifying normalized and thresholded pathways. Resulting values served to generate the laterality index of the AFs.

RESULTS Patients without language deficits tended to have an AF that was symmetric or lateralized to the right, whereas patients with deficits in language significantly more often demonstrated a left-lateralized posterior segment of the AF. Patients with high-grade gliomas had more severe language deficits than those with low-grade gliomas. Backward logistic regression revealed the laterality index of the posterior AF segment and tumor grade as the only independent statistically significant predictors for language deficits in this cohort.

CONCLUSIONS In addition to the well-known fact that tumor entity influences behavioral outcome, the authors’ findings suggest that the right homologs of structural language-associated pathways could be supportive for language function and facilitate compensation mechanisms after brain damage in functionally eloquent areas. This further indicates that knowledge about preoperative functional redistribution (identified by neurofunctional imaging) increases the chance for total or near-total resections of tumors in eloquent areas. In the future, longitudinal studies with larger groups are mandatory to overcome the methodological limitations of this cross-sectional study and to map neuroplastic changes associated with language performance and rehabilitation in brain tumor patients.

 

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

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