Neuroradiology Review Research Articles

Guidelines for the diagnosis and management of primary central nervous system diffuse large B-cell lymphoma.

Guidelines for the diagnosis and management of primary central nervous system diffuse large B-cell lymphoma.

CNS Response to Osimertinib Versus Standard Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors in Patients With Untreated EGFR-Mutated Advanced Non-Small-Cell Lung Cancer.

Purpose We report CNS efficacy of osimertinib versus standard epidermal growth factor receptor ( EGFR) tyrosine kinase inhibitors (TKIs) in patients with untreated EGFR-mutated advanced non-small-cell lung cancer from the phase III FLAURA study. Patients and Methods Patients (N = 556) were randomly assigned to osimertinib or standard EGFR-TKIs (gefitinib or erlotinib); brain scans were not mandated unless clinically indicated. Patients with asymptomatic or stable CNS metastases were included. In patients with symptomatic CNS metastases, neurologic status was required to be stable for ≥ 2 weeks after completion of definitive therapy and corticosteroids. A preplanned subgroup analysis with CNS progression-free survival as primary objective was conducted in patients with measurable and/or nonmeasurable CNS lesions on baseline brain scan by blinded independent central neuroradiologic review. The CNS evaluable-for-response set included patients with ≥ one measurable CNS lesion. Results Of 200 patients with available brain scans at baseline, 128 (osimertinib, n = 61; standard EGFR-TKIs, n = 67) had measurable and/or nonmeasurable CNS lesions, including 41 patients (osimertinib, n = 22; standard EGFR-TKIs, n = 19) with ≥ one measurable CNS lesion. Median CNS progression-free survival in patients with measurable and/or nonmeasurable CNS lesions was not reached with osimertinib (95% CI, 16.5 months to not calculable) and 13.9 months (95% CI, 8.3 months to not calculable) with standard EGFR-TKIs (hazard ratio, 0.48; 95% CI, 0.26 to 0.86; P = .014 [nominally statistically significant]). CNS objective response rates were 91% and 68% in patients with ≥ one measurable CNS lesion (odds ratio, 4.6; 95% CI, 0.9 to 34.9; P = .066) and 66% and 43% in patients with measurable and/or nonmeasurable CNS lesions (odds ratio, 2.5; 95% CI, 1.2 to 5.2; P = .011) treated with osimertinib and standard EGFR-TKIs, respectively. Probability of experiencing a CNS progression event was consistently lower with osimertinib versus standard EGFR-TKIs. Conclusion Osimertinib has CNS efficacy in patients with untreated EGFR-mutated non-small-cell lung cancer. These results suggest a reduced risk of CNS progression with osimertinib versus standard EGFR-TKIs.

CNS Efficacy of Osimertinib in Patients With T790M-Positive Advanced Non–Small-Cell Lung Cancer: Data From a Randomized Phase III Trial (AURA3)

Purpose In patients with epidermal growth factor receptor ( EGFR) mutation-positive advanced non-small-cell lung cancer (NSCLC), there is an unmet need for EGFR-tyrosine kinase inhibitors with improved CNS penetration and activity against CNS metastases, either at initial diagnosis or time of progression. We report the first comparative evidence of osimertinib CNS efficacy versus platinum-pemetrexed from a phase III study (AURA3; ClinicalTrials.gov identifier: NCT02151981) in patients with EGFR T790M-positive advanced NSCLC who experience disease progression with prior EGFR-tyrosine kinase inhibitor treatment. Methods Patients with asymptomatic, stable CNS metastases were eligible for enrollment and were randomly assigned 2:1 to osimertinib 80 mg once daily or platinum-pemetrexed. A preplanned subgroup analysis was conducted in patients with measurable and/or nonmeasurable CNS lesions on baseline brain scan by blinded independent central neuroradiological review. The CNS evaluable for response set included only patients with one or more measurable CNS lesions. The primary objective for this analysis was CNS objective response rate (ORR). Results Of 419 patients randomly assigned to treatment, 116 had measurable and/or nonmeasurable CNS lesions, including 46 patients with measurable CNS lesions. At data cutoff (April 15, 2016), CNS ORR in patients with one or more measurable CNS lesions was 70% (21 of 30; 95% CI, 51% to 85%) with osimertinib and 31% (5 of 16; 95% CI, 11% to 59%) with platinum-pemetrexed (odds ratio, 5.13; 95% CI, 1.44 to 20.64; P = .015); the ORR was 40% (30 of 75; 95% CI, 29% to 52%) and 17% (7 of 41; 95% CI, 7% to 32%), respectively, in patients with measurable and/or nonmeasurable CNS lesions (odds ratio, 3.24; 95% CI, 1.33 to 8.81; P = .014). Median CNS duration of response in patients with measurable and/or nonmeasurable CNS lesions was 8.9 months (95% CI, 4.3 months to not calculable) for osimertinib and 5.7 months (95% CI, 4.4 to 5.7 months) for platinum-pemetrexed; median CNS progression-free survival was 11.7 months and 5.6 months, respectively (hazard ratio, 0.32; 95% CI, 0.15 to 0.69; P = .004). Conclusion Osimertinib demonstrated superior CNS efficacy versus platinum-pemetrexed in T790M-positive advanced NSCLC.

Low concordance between surgical and radiological assessment of degree of resection and treatment-related hypothalamic damage: results of KRANIOPHARYNGEOM 2007.

Assessment of presurgical hypothalamic involvement (psHI) and treatment-related hypothalamic damage (trHD) is relevant for the decision on risk-adapted treatment and rehabilitation strategies in craniopharyngioma. 129 surgical reports of childhood-onset craniopharyngioma patients recruited 2007-2014 in KRANIOPHARYNGEOM 2007 were analyzed. Data on psHI were available based on surgeon's (63%), reference neuroradiologist's (95%), and local radiologist's (23%) assessment. The surgical degree of resection (DoR) was assessed by neurosurgeon (95%), reference neuroradiologist (73%), and local radiologist (61%). TrHD was assessed by neurosurgeon (33%), by reference neuroradiologist (95%), and by local radiologist (2%). Neurosurgical center size was categorized based on patient load. Surgical assessments on psHI (n = 78), DoR (n = 89) and trHD (n = 42) as documented in surgical reports could be compared with the assessment of respective parameters by reference neuroradiologist. Differences with regard to DoR (p = 0.0001) and trHD (p < 0.0001) were detectable between surgeon's and reference neuroradiologist's assessment, whereas psHI was assessed similarly. Concordance for DoR and trHD was observed in 48 and 62%, respectively. Surgeons estimated a higher rate of complete resections and a lower rate of trHD. Neuroradiological reference assessment of trHD had higher predictive value for hypothalamic sequelae then surgical assessment. Observed differences were not related to neurosurgical center size. Observed differences between surgical and neuroradiological estimation of risk factors in craniopharyngioma support the necessity of neuroradiological reference review to assure standards of quality. This could be established by central internet-based neuroradiological review in KRANIOPHARYNGEOM 2007. Standardization of surgical reports including specific assessment of tumor/damage location is recommended.

CNS response to osimertinib in patients with T790M-positive advanced NSCLC: pooled data from two phase II trials

BackgroundCentral nervous system (CNS) metastases are common in patients with non-small-cell lung cancer (NSCLC). Osimertinib has shown systemic efficacy in patients with CNS metastases, and early clinical evidence shows efficacy in the CNS. To evaluate osimertinib activity further, we present a pre-specified subgroup analysis of CNS response using pooled data from two phase II studies: AURA extension (NCT01802632) and AURA2 (NCT02094261). Patients and methodsPatients with T790M-positive advanced NSCLC, who had progressed following prior epidermal growth factor receptor-tyrosine kinase inhibitor treatment, received osimertinib 80mg od (n=411). Patients with stable, asymptomatic CNS metastases were eligible for enrolment; prior CNS treatment was allowed. Patients with≥1 measurable CNS lesion (per RECIST 1.1) on baseline brain scan by blinded independent central neuroradiology review (BICR) were included in the evaluable for CNS response set (cEFR). The primary outcome for this CNS analysis was CNS objective response rate (ORR) by BICR; secondary outcomes included CNS duration of response, disease control rate (DCR) and progression-free survival (PFS). ResultsOf 128 patients with CNS metastases on baseline brain scans, 50 were included in the cEFR. Confirmed CNS ORR and DCR were 54% [27/50; 95% confidence interval (CI) 39–68] and 92% (46/50; 95% CI 81–98), respectively. CNS response was observed regardless of prior radiotherapy to the brain. Median CNS duration of response (22% maturity) was not reached (range, 1–15months); at 9months, 75% (95% CI 53–88) of patients were estimated to remain in response. Median follow-up for CNS PFS was 11months; median CNS PFS was not reached (95% CI, 7, not calculable). The safety profile observed in the cEFR was consistent with the overall patient population. ConclusionsOsimertinib demonstrated clinically meaningful efficacy against CNS metastases, with a high DCR, encouraging ORR, and safety profile consistent with that reported previously. ClinicalTrials.gov numberNCT01802632; NCT02094261

1353P - CNS response to osimertinib in Asian-Pacific patients (pts) with T790M-positive advanced NSCLC: data from an open-label Phase II trial (AURA17)

Background: Osimertinib has shown CNS efficacy in a pooled analysis of two Phase II trials (AURA extension: NCT01802632, AURA2: NCT02094261) in pts with T790M-positive advanced NSCLC. We report osimertinib efficacy in CNS metastases (mets) from a Phase II, open-label, single-arm trial (AURA17: NCT02442349) in Asia-Pacific pts with T790M-positive advanced NSCLC who had progressed on prior EGFR-TKI therapy, with or without additional anti-cancer regimens. Methods: Pts with stable, asymptomatic, CNS mets were eligible for enrolment and received osimertinib 80 mg once daily. This prespecified subgroup analysis was conducted in pts with CNS mets present on baseline brain scan as assessed by blinded independent central neuroradiology review (BICR). Endpoints included CNS objective response rate (ORR), duration of response (DoR) and progression-free survival (PFS) by RECIST 1.1. The CNS full analysis set (cFAS) comprised pts with ≥1 measurable and/or non-measurable CNS lesion present on baseline brain scan by BICR; the CNS evaluable for response set (cEFR) comprised pts with ≥1 measurable CNS lesion. Results: At the data cut-off of 4 November 2016, 59/171 pts (35%) were included in the cFAS. In the cFAS and cEFR (n = 23), 3 and 0 pts had brain radiotherapy ≤6 months prior to study entry, respectively. CNS ORR was 42% (25/59; 95% CI 30, 56) for the cFAS and 70% (16/23; 95% CI 47, 87) for the cEFR. Median CNS DoR was not reached (95% CI 9.2, not calculable [NC]) for the cFAS and 11.1 months (95% CI 8.2, NC) for the cEFR. CNS DCR was 85% (95% CI 73, 93) for the cFAS and 91% (95% CI 72, 99) for the cEFR. Median CNS PFS was not reached in both cFAS (95% CI 12.4, NC) and cEFR groups (95% CI 9.4, NC), with a median follow-up for CNS PFS of 7.1 and 8.2 months, respectively. At 12 months, 70% (95% CI 53, 82) of pts in the cFAS and 61% (95% CI 31, 81) of pts in the cEFR were estimated to remain on study, alive and CNS progression-free. Conclusions: These data are consistent with previous reports of CNS response to osimertinib in pts with T790M-positive advanced NSCLC in global studies, and demonstrate clinically meaningful efficacy in Asian-Pacific pts with CNS mets. Clinical trial identification: NCT02442349 Legal entity responsible for the study: AstraZeneca Funding: AstraZeneca Disclosure: C. Zhou: Lecture honorarium: Eli Lily, AZ, Roche, Pfizer, Sanofi, BI, Henrui Advisory board: Roche, BI, AZ. Y. Lu: Consulting or Advisory Role: AstraZeneca, Hoffmann-La Roche, Eli Lilly, Pfizer, Elekta, Varian Medical Systems. J. Wang, Y. Chen: Employee of AstraZeneca. Y-L. Wu: Speaker fees from AstraZeneca, Roche, Eli Lilly, Sanofi, Pfizer. All other authors have declared no conflicts of interest.

CNS response to osimertinib in patients (pts) with T790M-positive advanced NSCLC: Data from a randomized phase III trial (AURA3).

9005 Background: CNS metastases (mets) are common in pts with advanced NSCLC. Preclinical studies have shown CNS penetration of osimertinib, and clinical data from a pooled analysis of 2 Phase II trials (AURA extension: NCT01802632, AURA2: NCT02094261) showed activity in the CNS. We report the first evidence of osimertinib efficacy in CNS mets from a randomized Phase III study (AURA3; NCT02151981) in pts with T790M-positive advanced NSCLC who have progressed on or after prior EGFR-TKI therapy. Methods: Pts were randomized 2:1 to osimertinib 80 mg once daily or platinum-based doublet chemotherapy every 3 wks for up to 6 cycles; maintenance pemetrexed was allowed. Pts with stable, asymptomatic CNS mets were eligible for enrolment. A prespecified subgroup analysis was conducted in pts with CNS mets present on baseline brain scan, as assessed by blinded independent central neuroradiology review (BICR), to define CNS objective response rate (ORR), duration of response (DoR) and progression-free survival (PFS) by RECIST v1.1. The CNS full analysis set (cFAS) included pts with ≥1 measurable and/or non-measurable CNS mets present on baseline brain scan by BICR; the CNS evaluable for response set (cEFR) included only pts with ≥1 measurable CNS mets. Results: As of 15 April 2016, 116/419 (28%) pts were included in the cFAS. In the cEFR (n = 46), CNS ORR was 70% (21/30; 95% CI 51, 85) with osimertinib and 31% (5/16; 95% CI 11, 59) with chemotherapy (OR, 5.13; 95% CI 1.44, 20.64; p = 0.015). In the cFAS, CNS ORR was 40% (30/75; 95% CI 29, 52) with osimertinib and 17% (7/41; 95% CI 7, 32) with chemotherapy (OR, 3.24; 95% CI 1.33, 8.81; p = 0.014). In the cEFR and cFAS, median CNS DoR was 8.9 months (m) (95% CI 4.3, NC and 4.3, NC) for osimertinib and 5.7 m (95% CI NC, NC and 4.4, 5.7; respectively) for chemotherapy. Median CNS PFS in the cFAS was significantly longer with osimertinib than with chemotherapy (11.7 vs 5.6 m; HR 0.32; 95% CI 0.15, 0.69; p = 0.004). Conclusions: Consistent with the overall response to osimertinib reported in pts with T790M-positive advanced NSCLC, osimertinib was superior to chemotherapy in the treatment of pts with CNS mets; CNS response rate was higher, responses were more durable and CNS PFS was longer. Clinical trial information: NCT02151981.

AIUM Practice Parameter for the Performance of an Ultrasound Examination of the Neonatal and Infant Spine

AIUM Practice Parameter for the Performance of an Ultrasound Examination of the Neonatal and Infant Spine

AIUM Practice Parameter for the Performance of an Ultrasound Examination of the Neonatal and Infant Spine.

AIUM Practice Parameter for the Performance of an Ultrasound Examination of the Neonatal and Infant Spine.

178 High Abbreviated Injury Scale Grade Conversion Rate Following Neuro-Spinal Scaffold Implantation in Acute Thoracic Complete Abbreviated Injury Scale A Spinal Cord Injury

Abstract In preclinical models, Neuro-Spinal Scaffold (NSS) implantation following spinal cord injury (SCI) promotes neural sparing and regeneration through internal decompression and tissue remodeling. Rather than typical postinjury cyst formation, the NSS acts through appositional healing to form neuropermissive remodeled tissue. A pilot study of the NSS enrolled 5 patients with complete thoracic SCI; 3 converted to incomplete. Neurological recovery in 2 patients was either sustained (beyond 12 months) or delayed by 6 months. Postinjury MRI scans and clinical time course suggest that reduced cyst formation and ongoing neural regeneration may contribute to these observations. Scaffolds were implanted 7 to 81 hours after injury within the intraspinal lesion. ISNCSCI examinations and MRIs were performed before implantation and through 6-month follow-up. There were no NSS-related serious safety events. On screening MRI, patients typically exhibited spinal cord compression and edema. Three of 5 patients had intraspinal hemorrhage. Based on central neuroradiology review of pre- and postoperative MRI scans through 6 months, none of the patients had definite cyst formation defined by T2 and T1 changes. By 6 months, 3 of 5 patients had converted from Abbreviated Injury Scale (AIS) A to AIS B(2) or C(1). One patient gained 10 points of hip and knee function by 6 months, with additional improvement and new ankle function at 12 months (increased motor score of 8). One patient converted from AIS A to B at 6 months, a late-occurring conversion that is extremely rare. This study represents the first use of the intraspinal NSS in patients with complete thoracic SCI. By 6 months, the low incidence of cyst formation with preservation of some intralesion internal architecture is consistent with preclinical results in which the resorbable NSS was replaced by a matrix of axon-containing remodeled tissue. The possibility of ongoing neural regeneration may contribute to the high incidence of AIS conversion and sustained period of neurological recovery.

NTCT-08STEREOTACTIC RADIOSURGERY (SRS) FOR SPINAL METASTASES: A COMPLICATION PROFILE OF VERTEBRAL BODY FRACTURE. ANALYSIS OF 79 CASES

Radiation treatment of spinal and paraspinal tumors has been limited by the tolerance of the spinal cord. Radiosurgery uses a stereotactic approach to deliver a conformal, high radiation dose to a localized target thereby increasing the likelihood of successful tumor control while minimizing radiation damage to the spinal cord. Since the first description of LINAC-based spinal SRS, multiple centers have reported their experience with emphasis on tumor and pain control. Recently reports on side effects and complications, including myelopathy and vertebral body fractures, were published. In this study, we summarize the risk of developing vertebral body fractures after the use of SRS for spinal metastases. This is a (IRB-approved) retrospective review of patients with metastatic lesions, who were treated with SRS between November 2007 and October 2014 in our institution. We performed a neuro-radiological imaging review and compared data sets before and after the treatment. Patients were grouped for pre-existing and newly developed vertebral fracture occurring after the SRS treatment. 79 patients were treated by SRS for spinal metastases during the study period; we collected data for 67 spinal segments with sufficient follow up data. Mean age was 61 years (25-80 years). Distribution according to spinal segments: cervical (8.7%), thoracic (40.6%), lumbar (43.5%) and sacral (7.2%). Mean prescription dose: 17.52Gy (8-25Gy) in mean 1.7(1-5) fractions. Mean maximal dose was 21.56Gy and mean peripheral dose was 15.51Gy.We noted new vertebral fracture in 18 cases (26.1%), mean time for follow up imaging 5 months (±7.1months). No patient was symptomatic from the fracture or needed a spinal fixation. The overall mean survival was 25.86 months (±19.83months). Spinal SRS is an effective palliative procedure with a low morbidity profile. Yet spinal fractures occur after the radiation treatment relatively commonly and patients therefore require active surveillance for this side effect.

MTR-13EVALUATION OF p75 EXPRESSION AND PATTERNS OF RECURRENCE IN PATIENTS WITH MALIGNANT GLIOMAS TREATED WITH BEVACIZUMAB

BACKGROUND: There is no standard treatment for patients with recurrent malignant gliomas (MGs) and after antiangiogenic therapy, 15% recur in a distant location suggesting the development of VEGF independent invasive mechanisms. We hypothesized that p75NTR expression could be associated to the pattern of recurrence/progression in patients with MGs treated with bevacizumab. METHODS: Adult patients with MGs (gliomas Grade III and Glioblastoma) treated with bevacizumab who had given written consent were identified. Clinical data were extracted from the charts. Pathology was centrally reviewed by a neuropathologist (JC) who also evaluated p75NTR by immunohistochemistry using a scoring system (intensity index, prevalence index - % of positive cells- and a combination index - the product of the two). Brain MRIs underwent central neuroradiology review (JS). All researchers were blinded to others' results. RESULTS: Thirty patients were included; 83% were male; 87% had glioblastoma and 84% received bevacizumab as second line therapy. Recurrences were 42% local (n = 10), 21% diffuse (n= 5) and 12% distal (n = 3). Six patients (25%) had radiologic stability despite clinical deterioration. There was no association between p75 expression and pattern of progression. In univariate analysis, progression free survival (PFS) was associated with KPS [HR 0.94 (CI 95% 0.89–0.990; p = 0.046], prevalence index for p75 [HR 1.8 (CI 95% 1.17-1.34); p = 0.007], and combined score for p75 expression [HR 1.18 (CI 95% 1.03-1.34); p = 0.012]. Patients with >50% p75 positive cells had shorter PFS [HR 3.3 (CI 95% 1.12-8.89); p = 0.018]. Tumors with any p75 positive cell had worse PFS than p75 negative tumors [HR 3.64 (CI 95% 1.18-11.22); p = 0.024]. CONCLUSION: The expression of p75 was associated with PFS in recurrent MGs. We were not able to find an association between the pattern of recurrence/progression and the expression of p75 in patients with MGs after treatment with Bevacizumab.

DIAGNOSING FRONTOTEMPORAL DEMENTIA IN OUTPATIENTS: AN AUDIT OF RADIOLOGICAL REPORTS AND REVIEW OF DIAGNOSTIC CRITERIA

ObjectiveThe Frontotemporal Dementias (FTDs) comprise a clinically and pathologically heterogeneous group of disorders which usually have in common selective degeneration of the frontal and temporal lobes. They account for 10–20%...

CLIPPERS among patients diagnosed with non-specific CNS neuroinflammatory diseases

Chronic Lymphocytic Inflammation with Pontine Perivascular Enhancement Responsive to Steroids (CLIPPERS) is an inflammatory CNS disorder characterized by 1) subacute onset of cerebellar and brainstem symptoms, 2) peripontine contrast-enhancing perivascular lesions with a “salt-and-pepper” appearance on MRI, and 3) angiocentric, predominantly T-lymphocytic infiltration as revealed by brain biopsy. Inflammatory diseases including neuroinfections, CNS lymphoma and neurosarcoidosis must be excluded. Since CLIPPERS was described in 2010, many patients might have been misdiagnosed in the past. We therefore searched medical records from a large tertiary neurological center, the Department of Neurology at Rigshospitalet, Copenhagen University Hospital, for patients discharged between 1999 and 2013 with a diagnosis of “sarcoidosis with other localization”, “other acute disseminating demyelination”, “other demyelinating disease in the CNS” or “encephalitis, myelitis or encephalomyelitis”. Of 206 identified patients, 24 had been examined by brain biopsy and were included for further evaluation. Following clinical, neuroradiological and neuropathological review, 3 patients (12.5%) were reclassified as having CLIPPERS. Median long-term follow-up was 75months. The present results suggest that clinical re-evaluation of patients previously diagnosed with unspecified inflammatory demyelinating CNS disease or atypical neurosarcoidosis may increase the detection rate of CLIPPERS. Further, potentially severe neurological deficits and progressive parenchymal atrophy on MRI may suggest neurodegenerative features, which emphasizes the need for early immunomodulatory treatment.

Neurological phenotypes in Niemann-Pick disease type C (NPC): clinical, biochemical and neuroradiological retrospective review of 48 Brazilian patients

Previous published literature examining the impact of Fabry disease for female heterozygotes has alluded to the idea that women with this disease have aunique clinical relationshipwith the healthcare systemand engage in Fabry disease medical management in amanner different from their male counterparts. The past history of labeling these women as carriers for the disease and asymptomatic has been proposed as one barrier to females’ participation in evaluation and monitoring for Fabry disease (Gibas 2008). However, the health beliefs unique to females with Fabry disease have not been thoroughly addressed in the literature. We attempt to examine this issue in more detail utilizing the Health Belief Model, a mechanism to assess perceived susceptibility to and seriousness of a disease, perceived benefit of engaging in a health behavior, and perceived barriers to performing this behavior. Part one of this study explored health beliefs among ten females through qualitative interviews and is summarized in another abstract. For part two, fifty adult females diagnosed and at-risk for Fabry disease from across the United States were asked to participate in a concurrent demographic survey and written, multiple choice and open-ended health beliefs questionnaire. Themes emerging from analysis of part one of this study informed the design of the open-ended health beliefs questionnaire assessing perceived susceptibility to and seriousness of disease manifestations and perceived barriers and benefits to clinical evaluation, monitoring, and treatment for Fabry disease. Preliminary findings demonstrate subjects perceive the seriousness of Fabry disease to be similar for bothmales and females with the disease. Subjects also perceive females in general to be susceptible to a range of the manifestations of Fabry disease; however, in comparison, when asked to respond regarding personal susceptibility, there was inconsistency and a decreased response toward susceptibility to disease manifestations. Interestingly, the majority of females do not believe “carrier” is an appropriate term to describe their status due to the possibility a female could demonstrate symptoms of the disease. Of the potential barriers to engaging in clinical evaluation, monitoring, and treatment, the most commonly reported included feeling overwhelmed and anxiety. Analysis of this data is ongoing.

Bevacizumab, irinotecan, and radiotherapy versus standard temozolomide and radiotherapy in newly diagnosed, MGMT-nonmethylated glioblastoma patients: First results from the randomized multicenter GLARIUS trial.

LBA2000 Background: In patients with MGMT-nonmethylated glioblastoma (GBM), primary chemotherapy with temozolomide (TMZ) is at best moderately effective. There is an urgent need for more effective therapies in this large subgroup of GBM. Since results of phase II trials with the antiangiogenic agent bevacizumab (BEV) +/- irinotecan (IRI) are promising in recurrent GBM, the GLARIUS trial explored the efficacy of BEV/IRI as compared to standard TMZ in the first-line therapy of MGMT-non-methylated GBM. Methods: In the randomized, multicenter, open-label GLARIUS trial, adult patients with newly diagnosed, histologically confirmed and MGMT-non-methylated GBM received local radiotherapy (RT, 30 x 2 Gy) and were randomized (2:1) for experimental therapy with BEV (10 mg/kg q2w) during RT followed by maintenance BEV (10 mg/kg q2w) + IRI (125 mg/m² q2w (without enzyme-inducing antiepileptic drugs (EIAEDs)) or 340 mg/m² (with EIAEDs)) or standard therapy with daily TMZ (75 mg/m2) during RT followed by 6 courses of TMZ (150-200 mg/m2/day for 5 days q4w). The primary endpoint was progression-free survival rate after 6 months (PFS-6) as determined by central neuroradiological review. Results: The intent-to-treat population included 170 patients (67.1% male, median age 56 years (range 25-78 years), 48.8% complete resection rate, 78.8% of patients with KPS 90% or higher); 116 patients received BEV/IRI, 54 patients had TMZ. The frequencies of adverse events in both arms of the trial were within the expected range. The PFS-6 rate was significantly higher in the BEV/IRI arm (71.1%, 95% CI 58.1-80.8%) than in the TMZ arm (26.2%, 95% CI 13.1-41.4%, p&lt;0.0001 logrank test). Conclusions: The significant and clinically meaningful increase in the primary endpoint PFS-6 upon BEV/IRI chemotherapy suggests that BEV/IRI is superior to standard TMZ therapy in newly diagnosed MGMT-nonmethylated GBM patients. Clinical trial information: 2009-010390-21.

Diagnostic Challenges of Primary Thalamic Gliomas—Identification of a Minimally Enhancing Neuroradiological Subtype with Aggressive Neuropathology and Poor Clinical Outcome

To evaluate neuropathology and neuroradiology in the diagnosis and clinical outcome of a retrospective cohort of thalamic gliomas. Neuropathological and neuroradiological review was undertaken in 25 cases of radiologically suspected thalamic glioma (excluding childhood pilocytic astrocytoma) over an 8 year period (2004-2012) at Frenchay Hospital and compared to the clinical outcome. In 12/25 (48%) there was a difference in neuropathological and suspected neuroradiological grading of the lesion of one or more grades. In 5/12 (42%) cases, the neuroradiology was lower grade than the pathology. In 4/5 (80%) of these cases, we identified a minimally enhancing subtype where the neuroradiology was predicted to be of lower grade than neuropathology. In 4/12, (33%) the suspected neuroradiology grade was higher than the final pathology. In 3/4, (75%) of these cases the suspected neuroradiology grade was higher than the neuropathology possibly because of unusual differentiation within the thalamic glioma (central neurocytoma, anaplastic oligoastrocytoma, and diffuse astrocytoma with pilocytic features). In 3/12 (25%) the biopsy was non-diagnostic. Neuropathology was a better predictor of clinical outcome than neuroradiology. 9/10 (90%) WHO Grade 4 gliomas and 8/9 (88%) Grade 3 gliomas on neuropathology were dead between 3-7 years after diagnosis. 3/3 (100%) Grade 2 gliomas on neuropathology were alive 3-7 years after diagnosis. 2/3 (67%) of the non-diagnostic cases were alive 3-7 years after biopsy. In 1/3 (33%) of the non-diagnostic cases the outcome was unknown. Diagnosis of primary thalamic glioma is challenging. We have identified that in the thalamus, a pattern of diffuse infiltration with minimal enhancement on imaging may often represent high-grade glioma. Neuropathology is overall the best predictor of clinical outcome.

Editorial: Separation surgery

The management of patients with spine metastases from a functional and health-related quality of life (HRQOL) perspective is one of the most challenging issues faced by both oncologists and spine surgeons. Higher levels of evidence have been achieved over the past decade in defining the positive impact of surgery and/or conventional external beam radiation therapy (cEBRT) in these patients.1,3 More recently, stereotactic radiosurgery (SRS) has provided a successful treatment option for traditionally radioresistant tumors, but has been limited in a setting where extensive epidural disease restricts radiation dose due to the threat of cord toxicity.2 In this patient group, maximally invasive surgery to achieve gross-total resection of the tumor was often necessary to prevent local recurrence and optimize HRQOL. This surgery is resource intensive, with a not-insignificant adverse event rate, so it is not ideal in those patients who are systemically compromised and have limited life expectancy. To address this problem, Laufer et al.4 report on a treatment method of surgically removing the epidural disease (separation surgery) and then administering high-dose SRS to the remaining tumor, thus providing a means of potentially achieving local control while minimizing surgical insult and cord toxicity. The study has a strong rationale and clear purpose: to determine local recurrence rate after separation surgery and SRS. The study design is a retrospective case series involving a relatively large consecutive patient cohort treated at a specialized cancer center between 2002 and 2011. The study design is reasonable for the research question, given the complexity of the patient population and the evolution of the treatment method, but not optimal with the number of potential confounders, treatment variability, and difficulty in accurately determining the primary or dependent outcome. Unfortunately, the validity or accuracy of local recurrence determination is difficult due to changes in technology over time, reviewer variability (imaging reports were used as well as neuroradiology and neurosurgeon review), lack of technique standardization (CT myelogram and MRI), effect of spinal implant imaging artifact, lack of standardized time periods, and quantitative evaluation. With these limitations, the magnitude of the group without local recurrence (82% of the patients) is questionable; however, such an impressive effect change cannot be ignored, and the positive effect is probably a true finding. The authors use a very appropriate and robust statistical analysis to try and overcome the treatment variability and aforementioned limitations. The variability leaves the study underpowered on a number of secondary outcomes, but trends can be observed. The study does not include a patient-focused HRQOL instrument to ensure that impressive imaging outcomes are correlated with those of the patient. This omission is not critical, given the research question being asked, and using local recurrence rate as the primary outcome is a reasonable surrogate for HROQL outcome in prospective tumor research. Finally, the generalizability of the study’s findings must be considered. The breadth and variability of the cohort supports external validity, but the specialization and technology of the center and subspecialization of the surgeons and oncologists may limit it. The management of patients with symptomatic spinal metastases is difficult. Carrying out high-quality clinical research involving patients whose quality of life you are trying to optimize for their remaining time is even more demanding. The authors should be congratulated for giving us evidence for a treatment method that potentially fills a therapeutic void in this truly deserving patient population. Can we implement the findings from this study into our clinical practice despite its being at the lower level of study design hierarchy? Though the study is statistically sound and optimal within the restraints of a retrospective design, its limitations diminish its impact. The effect size, external validity within the context of large cancer centers, and the unique patient population probably support cautious implementation of this treatment method. As the technique evolves and is used by more centers, prospective evaluation will be essential. (http://thejns.org/doi/abs/10.3171/2012.10.SPINE12743)

MRI FINDINGS IN ACUTE WERNICKE'S ENCEPHALOPATHY

BackgroundWernicke's encephalopathy (WE) is a neurological emergency due to thiamine deficiency. The clinical triad of ophthalmoplegia, altered consciousness, and ataxia is uncommon. MRI is a powerful tool to help prompt...

Spinal dysraphism associated with the cutaneous lumbosacral infantile hemangioma: a neuroradiological review

Spinal dysraphism is suspected in patients with midline abnormalities, especially in those with lumbosacral cutaneous markings. A recent prospective study demonstrated that isolated cutaneous infantile hemangiomas (IH) of the lumbosacral region have one of the highest risks (relative risk of 438) of associated spinal dysraphism. The specific types of dysraphism and radiological findings associated with cutaneous IH of the lumbosacral region have not been described in detail, to the best of our knowledge. The aim of this multicenter study is to retrospectively classify types of spinal anomalies associated with the cutaneous lumbosacral IH. The radiological images of 20 cases of lumbosacral infantile hemangioma associated with spinal dysraphism were reviewed. Tethered cord was found in 60% of the 20 cases, spinal lipoma was present in 50% and 45% had intraspinal hemangiomas. Sinus tract was found in 40% of the children. A range of spinal anomalies is associated with cutaneous lumbosacral infantile hemangiomas and MRI can be used to characterize these abnormalities.