Prognostic Value of Preoperative MRI Metrics for Diffuse Lower-Grade Glioma Molecular Subtypes.

BACKGROUND AND PURPOSE: Despite the improved prognostic relevance of the 2016 WHO molecular-based classification of lower-grade gliomas, variability in clinical outcome persists within existing molecular subtypes. Our aim was to determine prognostically significant metrics on preoperative MR imaging for lower-grade gliomas within currently defined molecular categories. MATERIALS AND METHODS: We undertook a retrospective analysis of 306 patients with lower-grade gliomas accrued from an institutional data base and The Cancer Genome Atlas. Two neuroradiologists in consensus analyzed preoperative MRIs of each lower-grade glioma to determine the following: tumor size, tumor location, number of involved lobes, corpus callosum involvement, hydrocephalus, midline shift, eloquent cortex involvement, ependymal extension, margins, contrast enhancement, and necrosis. Adjusted hazard ratios determined the association between MR imaging metrics and overall survival per molecular subtype, after adjustment for patient age, patient sex, World Health Organization grade, and surgical resection status. RESULTS: For isocitrate dehydrogenase (IDH) wild-type lower-grade gliomas, tumor size (hazard ratio, 3.82; 95% CI, 1.94-7.75; P < .001), number of involved lobes (hazard ratio, 1.70; 95% CI, 1.28-2.27; P < .001), hydrocephalus (hazard ratio, 4.43; 95% CI, 1.12-17.54; P = .034), midline shift (hazard ratio, 1.16; 95% CI, 1.03-1.30; P = .013), margins (P = .031), and contrast enhancement (hazard ratio, 0.34; 95% CI, 0.13-0.90; P = .030) were associated with overall survival. For IDH-mutant 1p/19q-codeleted lower-grade gliomas, tumor size (hazard ratio, 2.85; 95% CI, 1.06-7.70; P = .039) and ependymal extension (hazard ratio, 6.34; 95% CI, 1.07-37.59; P = .042) were associated with overall survival. CONCLUSIONS: MR imaging metrics offers prognostic information for patients with lower-grade gliomas within molecularly defined classes, with the greatest prognostic value for IDH wild-type lower-grade gliomas.

Molecular Subtype Classification in Lower-Grade Glioma with Accelerated DTI.

BACKGROUND AND PURPOSE: Image-based classification of lower-grade glioma molecular subtypes has substantial prognostic value. Diffusion tensor imaging has shown promise in lower-grade glioma subtyping but currently requires lengthy, nonstandard acquisitions. Our goal was to investigate lower-grade glioma classification using a machine learning technique that estimates fractional anisotropy from accelerated diffusion MR imaging scans containing only 3 diffusion-encoding directions. MATERIALS AND METHODS: Patients with lower-grade gliomas (n = 41) (World Health Organization grades II and III) with known isocitrate dehydrogenase (IDH) mutation and 1p/19q codeletion status were imaged preoperatively with DTI. Whole-tumor volumes were autodelineated using conventional anatomic MR imaging sequences. In addition to conventional ADC and fractional anisotropy reconstructions, fractional anisotropy estimates were computed from 3-direction DTI subsets using DiffNet, a neural network that directly computes fractional anisotropy from raw DTI data. Differences in whole-tumor ADC, fractional anisotropy, and estimated fractional anisotropy were assessed between IDH-wild-type and IDH-mutant lower-grade gliomas with and without 1p/19q codeletion. Multivariate classification models were developed using whole-tumor histogram and texture features from ADC, ADC + fractional anisotropy, and ADC + estimated fractional anisotropy to identify the added value provided by fractional anisotropy and estimated fractional anisotropy. RESULTS: ADC (P = .008), fractional anisotropy (P < .001), and estimated fractional anisotropy (P < .001) significantly differed between IDH-wild-type and IDH-mutant lower-grade gliomas. ADC (P < .001) significantly differed between IDH-mutant gliomas with and without codeletion. ADC-only multivariate classification predicted IDH mutation status with an area under the curve of 0.81 and codeletion status with an area under the curve of 0.83. Performance improved to area under the curve = 0.90/0.94 for the ADC + fractional anisotropy classification and to area under the curve = 0.89/0.89 for the ADC + estimated fractional anisotropy classification. CONCLUSIONS: Fractional anisotropy estimates made from accelerated 3-direction DTI scans add value in classifying lower-grade glioma molecular status.

Extent of Surgical Resection in Lower-Grade Gliomas: Differential Impact Based on Molecular Subtype.

BACKGROUND AND PURPOSE: Diffuse lower-grade gliomas are classified into prognostically meaningful molecular subtypes. We aimed to determine the impact of surgical resection on overall survival in lower-grade glioma molecular subtypes. MATERIALS AND METHODS: For 172 patients with lower-grade gliomas (World Health Organization grade II or III), pre- and postsurgical glioma volumes were determined using a semiautomated segmentation software based on FLAIR or T2-weighted MR imaging sequences. The association of pre- and postsurgical glioma volume and the percentage of glioma resection with overall survival was determined for the entire cohort and separately for lower-grade glioma molecular subtypes based on isocitrate dehydrogenase (IDH) and 1p/19q status, after adjustment for age, sex, World Health Organization grade, chemotherapy administration, and radiation therapy administration. RESULTS: For the entire cohort, postsurgical glioma volume (hazard ratio, 1.80; 95% CI, 1.18-2.75; P = .006) and the percentage of resection (hazard ratio, 3.22; 95% CI, 1.79-5.82; P < .001) were associated with overall survival. For IDH-mutant 1p/19q-codeleted oligodendrogliomas, the percentage of resection (hazard ratio, 6.69; 95% CI, 1.57-28.46; P = .01) was associated with overall survival. For IDH-mutant 1p/19q-noncodeleted astrocytomas, presurgical glioma volume (hazard ratio, 3.20; 95% CI, 1.22-8.39; P = .018), postsurgical glioma volume (hazard ratio, 2.33; 95% CI, 1.32-4.12; P = .004), and percentage of resection (hazard ratio, 4.34; 95% CI, 1.74-10.81; P = .002) were associated with overall survival. For IDH-wild-type lower-grade gliomas, pre-/postsurgical glioma volume and percentage of resection were not associated with overall survival. CONCLUSIONS: The extent of surgical resection has a differential survival impact in patients with lower-grade gliomas based on their molecular subtype. IDH-mutant lower-grade gliomas benefit from a greater extent of surgical resection, with the strongest impact observed for IDH-mutant 1p/19q-noncodeleted astrocytomas.

Neuroimaging-Based Classification Algorithm for Predicting 1p/19q-Codeletion Status in IDH-Mutant Lower Grade Gliomas.

BACKGROUND AND PURPOSE: Isocitrate dehydrogenase (IDH)-mutant lower grade gliomas are classified as oligodendrogliomas or diffuse astrocytomas based on 1p/19q-codeletion status. We aimed to test and validate neuroradiologists' performances in predicting the codeletion status of IDH-mutant lower grade gliomas based on simple neuroimaging metrics. MATERIALS AND METHODS: One hundred two IDH-mutant lower grade gliomas with preoperative MR imaging and known 1p/19q status from The Cancer Genome Atlas composed a training dataset. Two neuroradiologists in consensus analyzed the training dataset for various imaging features: tumor texture, margins, cortical infiltration, T2-FLAIR mismatch, tumor cyst, T2* susceptibility, hydrocephalus, midline shift, maximum dimension, primary lobe, necrosis, enhancement, edema, and gliomatosis. Statistical analysis of the training data produced a multivariate classification model for codeletion prediction based on a subset of MR imaging features and patient age. To validate the classification model, 2 different independent neuroradiologists analyzed a separate cohort of 106 institutional IDH-mutant lower grade gliomas. RESULTS: Training dataset analysis produced a 2-step classification algorithm with 86.3% codeletion prediction accuracy, based on the following: 1) the presence of the T2-FLAIR mismatch sign, which was 100% predictive of noncodeleted lower grade gliomas, (n = 21); and 2) a logistic regression model based on texture, patient age, T2* susceptibility, primary lobe, and hydrocephalus. Independent validation of the classification algorithm rendered codeletion prediction accuracies of 81.1% and 79.2% in 2 independent readers. The metrics used in the algorithm were associated with moderate-substantial interreader agreement (κ = 0.56-0.79). CONCLUSIONS: We have validated a classification algorithm based on simple, reproducible neuroimaging metrics and patient age that demonstrates a moderate prediction accuracy of 1p/19q-codeletion status among IDH-mutant lower grade gliomas.

Correction to: Multiple receptor tyrosine kinases converge on microRNA-134 to control KRAS, STAT5B, and glioblastoma.

Following publication of the article, the author named as "B Dey", wished to point out that his full name is "Bijan K. Dey". This was not reflected in the typesetting of the article, and as a consequence the article is not visible on Pub Med when a search is conducted on his full name.

Features of diffuse gliomas that are misdiagnosed on initial neuroimaging: a case control study.

PURPOSE: The neuroimaging diagnosis of diffuse gliomas can be challenging owing to their variable clinical and radiologic presentation. The purpose of this study was to identify factors that are associated with imaging errors in the diagnosis of diffuse gliomas. METHODS: A retrospective case-control analysis was undertaken. 18 misdiagnosed diffuse gliomas on initial neuroimaging (cases) and 108 accurately diagnosed diffuse gliomas on initial neuroimaging (controls) were collected. Clinical, pathological, and imaging metrics were tabulated for each patient. The tabulated metrics were compared between cases and controls to determine factors associated with misdiagnosis. RESULTS: Cases of misdiagnosed diffuse glioma (vs controls) were more likely to undergo initial triage as a stroke workup [OR 14.429 (95% CI 4.345, 47.915), p < 0.0001], were less likely to enhance [OR 0.283 (95% CI 0.098, 0.812), p = 0.02], were smaller (mean diameter 4.4 vs 6.0 cm, p = 0.0008), produced less midline shift (median midline shift 0.0 vs 2.0 mm, p = 0.003), were less likely to demonstrate necrosis [OR 0.156 (95% CI 0.034-0.713), p = 0.008], and were less likely to have IV contrast administered on the initial MRI [OR 0.100 (95% CI 0.020, 0.494), p = 0.008]. CONCLUSION: Several clinical and radiologic metrics are associated with diffuse gliomas that are missed or misdiagnosed on the initial neuroimaging study. Knowledge of these associations may aid in avoiding misinterpretation and accurately diagnosing such cases in clinical practice.

Management of neuro-oncologic emergencies.

Patients with brain tumors and systemic malignancies are subject to diverse neurologic complications that require urgent evaluation and treatment. These neurologic conditions are commonly due to the tumor's direct effects on the nervous system, such as cerebral edema, increased intracranial pressure, seizures, spinal cord compression, and leptomeningeal metastases. In addition, neurologic complications can develop as a result of thrombocytopenia, coagulopathy, hyperviscosity syndromes, infection, immune-related disorders, and adverse effects of treatment. Patients may present with typical disease syndromes. However, it is not uncommon for patients to have more subtle, nonlocalizing manifestations, such as alteration of mental status, that could be attributed to other systemic, nonneurologic complications. Furthermore, neurologic complications are at times the initial manifestations of an undiagnosed malignancy. Therefore a high index of suspicion is essential for rapid assessment and management. Timely intervention may prolong survival and improve quality of life. In this chapter, we will discuss the common neuro-oncologic emergencies, including epidemiology, pathophysiology, clinical presentation, diagnosis, and treatment.

Multiple receptor tyrosine kinases converge on microRNA-134 to control KRAS, STAT5B, and glioblastoma.

Receptor tyrosine kinases (RTKs) are co-deregulated in a majority of glioblastoma (GBM), the most common and most deadly brain tumor. We show that the RTKs MET, EGFR, and PDGFR regulate microRNA-134 (miR-134) in GBM. We find that miR-134 is downregulated in human tumors and cancer stem cells and that its expression inversely correlates with the activation of MET, EGFR, and PDGFR. We demonstrate that miR-134 inhibits cancer cell and stem-cell proliferation, survival, and xenograft growth, as well as cancer stem-cell self-renewal and stemness. We identify KRAS and STAT5B as targets of miR-134, and establish molecular and functional links between RTKs, miR-134, KRAS/STAT5B and malignancy in vitro and in vivo. We show that miR-134 induction is required for the anti-tumor effects of RTK inhibitors. We also uncover the molecular pathways through which RTKs regulate miR-134 expression and demonstrate the involvement of MAPK signaling and the KLF4 transcription factor. We therefore identify miR-134 as a novel RTK-regulated tumor-suppressive hub that mediates RTK and RTK-inhibitor effects on GBM malignancy by controlling KRAS and STAT5B.

Primary CNS posttransplant lymphoproliferative disease (PTLD): an international report of 84 cases in the modern era.

We performed a multicenter, International analysis of solid organ transplant (SOT)-related primary central nervous system (PCNS) posttransplant lymphoproliferative disease (PTLD). Among 84 PCNS PTLD patients, median time of SOT-to-PTLD was 54 months, 79% had kidney SOT, histology was monomorphic in 83% and tumor was EBV+ in 94%. Further, 33% had deep brain involvement, 10% had CSF involvement, while none had ocular disease. Immunosuppression was reduced in 93%; additional first-line therapy included high-dose methotrexate (48%), high-dose cytarabine (33%), brain radiation (24%) and/or rituximab (44%). The overall response rate was 60%, while treatment-related mortality was 13%. With 42-month median follow-up, three-year progression-free survival (PFS) and overall survival (OS) were 32% and 43%, respectively. There was a trend on univariable analysis for improved PFS for patients who received rituximab and/or high-dose cytarabine. On multivariable Cox regression, poor performance status predicted inferior PFS (HR 2.61, 95% CI 1.32-5.17, p = 0.006), while increased LDH portended inferior OS (HR 4.16, 95% CI 1.29-13.46, p = 0.02). Moreover, lack of response to first-line therapy was the most dominant prognostic factor on multivariable analysis (HR 8.70, 95% CI 2.56-29.57, p = 0.0005). Altogether, PCNS PTLD appears to represent a distinct clinicopathologic entity within the PTLD spectrum that is associated with renal SOT, occurs late, is monomorphic and retains EBV positivity.

Phase I study of panobinostat in combination with bevacizumab for recurrent high-grade glioma.

Bevacizumab is frequently used to treat patients with recurrent high-grade glioma (HGG), but responses are generally not durable. Panobinostat is a histone deacetylase inhibitor with anti-neoplastic and anti-angiogenic effects and may work synergistically with VEGF inhibitors. We performed a phase I study to evaluate the safety and tolerability of the combination of orally administered panobinostat with bevacizumab in patients with recurrent HGG. Patients with recurrent HGG were treated on a 3 + 3 trial design. Patients received bevacizumab 10 mg/kg every other week in combination with oral panobinostat. The starting dose of panobinostat was 20 mg three times per week, weekly (cohort 1). Due to concerns for thrombocytopenia with the weekly dosing regimen, the protocol was amended to examine an every other week regimen. Cohort 2 received panobinostat 20 mg three times per week, every other week, and cohort 3 received 30 mg three times per week, every other week. Dose-limiting toxicity during the first 30 days was used to determine the maximum-tolerated dose. Twelve patients (median age 50, median KPS 90) with recurrent HGG were enrolled. One dose-limiting toxicity (DLT) (Grade 3 thrombocytopenia) was observed in cohort 1. No DLTs were observed in cohorts 2 and 3. The following grade 3 toxicities were seen in one patient each: thrombocytopenia, hypophosphatemia, esophageal hemorrhage, and deep venous thrombosis. There were no grade 4 or 5 toxicities. There were three patients with partial responses and seven with stable disease. The recommended doses for further study are oral panobinostat 30 mg three times per week, every other week, in combination with bevacizumab 10 mg/kg every other week. A phase II clinical trial in recurrent HGG is underway.

Response assessment in neuro-oncology (a report of the RANO group): assessment of outcome in trials of diffuse low-grade gliomas.

Although low-grade gliomas (LGG) have a less aggressive course than do high-grade gliomas, the outcome of these tumours is ultimately fatal in most patients. Both the tumour and its treatment can cause disabling morbidity, particularly of cognitive functions. Because many patients present with seizures only, with no other signs and symptoms, maintenance of quality of life and function constitutes a particular challenge in LGG. The slow growth pattern of most LGG, and the rare radiological true responses despite a favourable clinical response to treatment, interferes with the use of progression-free survival as the primary endpoint in trials. Overall survival as an endpoint brings logistical challenges, and is sensitive to other non-investigational salvage therapies. Clinical trials for LGG need to consider other measures of patient benefit such as cognition, symptom burden, and seizure activity, to establish whether improved survival is reflected in prolonged wellbeing. This Review investigates clinical and imaging endpoints in trials of LGG, and provides response assessment in neuro-oncology (RANO) criteria for non-enhancing tumours. Additionally, other measures for patients with brain tumours that assess outcome are described. Similar considerations are relevant for trials of high-grade gliomas, although for these tumours survival is shorter and survival endpoints generally have more value than they do for LGG.

Venous thromboembolism in malignant gliomas.

Malignant gliomas are associated with a very high risk of venous thromboembolism (VTE). While many clinical risk factors have previously been described in brain tumor patients, the risk of VTE associated with newer anti-angiogenic therapies such as bevacizumab in these patients remains unclear. When VTE occurs in this patient population, concern regarding the potential for intracranial hemorrhage complicates management decisions regarding anticoagulation, and these patients have a worse prognosis than their VTE-free counterparts. Risk stratification models identifying patients at high risk of developing VTE along with predictive plasma biomarkers may guide the selection of eligible patients for primary prevention with pharmacologic thromboprophylaxis. Recent studies exploring disordered coagulation, such as increased expression of tissue factor (TF), and tumorigenic molecular signaling may help to explain the increased risk of VTE in patients with malignant gliomas.

Focal neuronal gigantism: a rare complication of therapeutic radiation.

Radiation therapy, a mainstay in the treatment of many brain tumors, results in a variety of well-documented acute and chronic complications. Isolated cortical damage following irradiation represents an extremely rare delayed therapeutic complication, described only twice in the medical literature. We report this rare delayed complication in a patient following treatment of a right frontal anaplastic oligodendroglioma.

Primary CNS lymphoma with intraocular involvement: International PCNSL Collaborative Group Report.

OBJECTIVE: To describe the demographics, diagnostic details, therapeutic management, and outcome in patients with primary CNS lymphoma (PCNSL) with ocular involvement. METHODS: A retrospective study of 221 patients was assembled from 16 centers in seven countries. Only HIV-negative, immunocompetent patients with brain and ocular lymphoma were included; none had systemic lymphoma. RESULTS: Median age at diagnosis was 60. Fifty-seven percent were women. Median Eastern Cooperative Oncology Group performance status was 2. Ocular disturbance and behavioral/cognitive changes were the most common presenting symptoms. Diagnosis of lymphoma was made by brain biopsy (147), vitrectomy (65), or CSF cytology (11). Diagnosis of intraocular lymphoma was made by vitrectomy/choroidal/retinal biopsy (90) or clinical ophthalmic examination (141). CSF cytology was positive in 23%. Treatment information was available for 176 patients. A total of 102 received dedicated ocular therapy (ocular radiotherapy 79, intravitreal methotrexate 22, and both 1) in addition to treatment for their brain lymphoma. Sixty-nine percent progressed at a median of 13 months; sites of progression included brain 52%, eyes 19%, brain and eyes 12%, and systemic 2%. Patients treated with local ocular therapy did not have a statistically significant decreased risk of failing in the eyes (p = 0.7). Median progression free survival and overall survival for the entire cohort were 18 and 31 months. CONCLUSION: This is the largest reported series of primary CNS lymphoma (PCNSL) with intraocular involvement. Progression free and overall survival was similar to that reported with PCNSL. Dedicated ocular therapy improved disease control but did not affect overall survival.

Primary intraocular lymphoma: an International Primary Central Nervous System Lymphoma Collaborative Group Report.

BACKGROUND: Primary intraocular lymphoma (PIOL) is an uncommon subset of primary central nervous system lymphoma. Because it is rare and difficult to diagnose, the natural history and optimal management are unknown. PATIENTS AND METHODS: A retrospective study of 83 HIV negative, immunocompetent PIOL patients was assembled from 16 centers in seven countries. RESULTS: Median age at diagnosis was 65. Median ECOG performance status was 0. Presenting symptoms included blurred vision, decreased visual acuity, and floaters. Median time to diagnosis was 6 months. Diagnosis was made by vitrectomy (74), choroidal/retinal biopsy (6) and ophthalmic exam (3). Eleven percent had positive CSF cytology. Initial treatment was categorized as focal in 23 (intra-ocular methotrexate, ocular radiotherapy) or extensive in 53 (systemic chemotherapy, whole brain radiotherapy). Six received none; details are unknown in one. Forty-seven relapsed: brain 47%, eyes 30%, brain and eyes 15%, and systemic 8%. Median time to relapse was 19 months. Focal therapy alone did not increase risk of brain relapse. Median progression free (PFS) and overall survival (OS) were 29.6 and 58 months, respectively, and unaffected by treatment type. CONCLUSION: Treatment type did not affect relapse pattern, median PFS or OS. Focal therapy may minimize treatment toxicity without compromising disease control.

Cognitive functions in primary central nervous system lymphoma: literature review and assessment guidelines.

BACKGROUND: Treatment-related neurotoxicity has been recognized as a significant problem in patients with primary central nervous system lymphoma (PCNSL) as effective treatment has increased survival rates. There is, however, a paucity of research on cognitive functions in this population. DESIGN: In a review of the literature, a total of 17 articles that described cognitive outcome in adult PCNSL patients were identified. RESULTS: The studies that assessed cognitive functions after whole-brain radiotherapy combined with chemotherapy reported cognitive impairment in most patients. Patients treated with chemotherapy alone had either stable or improved cognitive performance in most studies. Methodological problems, however, limited the ability to ascertain the specific contribution of disease and various treatment interventions to cognitive outcome. On the basis of the literature review, a battery of cognitive and quality-of-life (QoL) measures to be used in prospective clinical trials was proposed. The battery is composed of five standardized neuropsychological tests, covering four domains sensitive to disease and treatment effects (attention, executive functions, memory, psychomotor speed), and QoL questionnaires, and meets criteria for use in collaborative trials. CONCLUSION: The incorporation of formal and systematic cognitive evaluations in PCNSL studies will improve our understanding of treatment-related neurotoxicity in this population.