Wenya Linda Bi

Oncogenic PI3K mutations are as common as AKT1 and SMO mutations in meningioma

BACKGROUND Meningiomas are the most common primary intracranial tumor in adults. Identification of SMO and AKT1 mutations in meningiomas has raised the possibility of targeted therapies for some patients. The frequency of such mutations in clinical cohorts and the presence of other actionable mutations in meningiomas are important to define. METHODS We used high-resolution array-comparative genomic hybridization to prospectively characterize copy-number changes in 150 meningiomas and then characterized these samples for mutations in AKT1, KLF4, NF2, PIK3CA, SMO, and TRAF7. RESULTS Similar to prior reports, we identified AKT1 and SMO mutations in a subset of non-NF2-mutant meningiomas (ie, ∼9% and ∼6%, respectively). Notably, we detected oncogenic mutations in PIK3CA in ∼7% of non-NF2-mutant meningiomas. AKT1, SMO, and PIK3CA mutations were mutually exclusive. AKT1, KLF4, and PIK3CA mutations often co-occurred with mutations in TRAF7. PIK3CA-mutant meningiomas showed limited chromosomal instability and were enriched in the skull base. CONCLUSION This work identifies PI3K signaling as an important target for precision medicine trials in meningioma patients.

Novel Tumor-Specific Isoforms of BEHAB/Brevican Identified in Human Malignant Gliomas

Malignant gliomas are deadly brain tumors characterized by diffuse invasion into the surrounding brain tissue. Understanding the mechanisms involved in glioma invasion could lead to new therapeutic strategies. We have previously shown that BEHAB/brevican, an extracellular matrix protein in the central nervous system, plays a role in the invasive ability of gliomas. The mechanisms that underlie BEHAB/brevican function are not yet understood, due in part to the existence of several isoforms that may have different functions. Here we describe for the first time the expression of BEHAB/brevican in human brain and characterize two novel glioma-specific isoforms, B/b(sia) and B/b(Deltag), which are generated by differential glycosylation and are absent from normal adult brain and other neuropathologies. B/b(sia) is an oversialylated isoform expressed by about half the high- and low-grade gliomas analyzed. B/b(Deltag) lacks most of the carbohydrates typically present on BEHAB/brevican and is the major up-regulated isoform of this protein in high-grade gliomas but is absent in a specific subset of low-grade, indolent oligodendrogliomas. B/b(Deltag) is detected on the extracellular surface, where it binds to the membrane by a mechanism distinct from the other BEHAB/brevican isoforms. The glioma-specific expression of B/b(Deltag), its restricted membrane localization, and its expression in all high-grade gliomas tested to date suggest that it may play a significant role in glioma progression and make it an important new potential therapeutic target. In addition, its absence from benign gliomas prompts its use as a diagnostic marker to distinguish primary brain tumors of similar histology but different pathologic course.

Diffusion MRI in the early diagnosis of malignant glioma.

ObjectiveA subset of patients with malignant glioma comes to medical attention before their masses show rim enhancement and central necrosis. Tumors in those cases are frequently located in eloquent areas of the brain. Tissue diagnosis is limited to stereotactic biopsy providing limited material for accurate grading. We conducted this study to determine whether imaging characteristics of early stages of malignant gliomas could aid in timely definitive diagnosis.MethodsWe retrospectively analyzed patients with newly diagnosed malignant glioma seen at the Yale Brain Tumor Center between 2002 and 2005. Patients with typical radiographic presentation were excluded.ResultsOf 89 patients, eight meeting the inclusion criteria were identified. In five patients, patchy or small nodular enhancing lesions without central necrosis were present within the tumor mass. Diffusion-weighted imaging (DWI) showed areas of increased signal intensity in all cases. Apparent diffusion coefficient maps (ADC) revealed low-signal intensity in corresponding areas. At the time of imaging, biopsy was performed in seven patients but diagnosis of malignant glioma could only be established prior to further tumor growth in four cases.ConclusionsThe diagnosis in the early stages of malignant glioma can be challenging in a subset of cases. Information obtained through DWI should be incorporated in the clinical decision-making process. Mass lesions displaying decreased water diffusion indicating high cellularity, are suggestive of a high-grade glioma. Biopsies are recommended. However, even when biopsies are inconclusive, a strong suspicion of malignant glioma should be considered.

Extent of resection and overall survival for patients with atypical and malignant meningioma

The prognosis for patients with atypical and malignant meningioma is guarded; whether the extent of resection is associated with survival‐based outcomes in this population remains poorly defined. This study investigated the association between gross total resection (GTR) and all‐cause mortality in patients with atypical and malignant meningioma.

Multimodal MRI features predict isocitrate dehydrogenase genotype in high-grade gliomas

Background. High-grade gliomas with mutations in the isocitrate dehydrogenase (IDH) gene family confer longer overall survival relative to their IDH-wild-type counterparts. Accurate determination of the IDH genotype preoperatively may have both prognostic and diagnostic value. The current study used a machine-learning algorithm to generate a model predictive of IDH genotype in high-grade gliomas based on clinical variables and multimodal features extracted from conventional MRI. Methods. Preoperative MRIs were obtained for 120 patients with primary grades III (n = 35) and IV (n = 85) glioma in this retrospective study. IDH genotype was confirmed for grade III (32/35, 91%) and IV (22/85, 26%) tumors by immunohistochemistry, spectrometry-based mutation genotyping (OncoMap), or multiplex exome sequencing (OncoPanel). IDH1 and IDH2 mutations were mutually exclusive, and all mutated tumors were collapsed into one IDH-mutated cohort. Cases were randomly assigned to either the training (n = 90) or validation cohort (n = 30). A total of 2970 imaging features were extracted from pre- and postcontrast T1-weighted, T2-weighted, and apparent diffusion coefficient map. Using a random forest algorithm, nonredundant features were integrated with clinical data to generate a model predictive of IDH genotype. Results. Our model achieved accuracies of 86% (area under the curve [AUC] = 0.8830) in the training cohort and 89% (AUC = 0.9231) in the validation cohort. Features with the highest predictive value included patient age as well as parametric intensity, texture, and shape features. Conclusion. Using a machine-learning algorithm, we achieved accurate prediction of IDH genotype in high-grade gliomas with preoperative clinical and MRI features.

ARID1A and TERT promoter mutations in dedifferentiated meningioma

Unlike patients with World Health Organization (WHO) grade I meningiomas, which are considered benign, patients with WHO grade III meningiomas have very high mortality rates. The principles underlying tumor progression in meningioma are largely unknown, yet a detailed understanding of these mechanisms will be required for effective management of patients with these high grade lethal tumors. We present a case of an intraventricular meningioma that at first presentation displayed remarkable morphologic heterogeneity-composed of distinct regions independently fulfilling histopathologic criteria for WHO grade I, II, and III designations. The lowest grade regions had classic meningothelial features, while the highest grade regions were markedly dedifferentiated. Whereas progression in meningiomas is generally observed during recurrence following radiation and systemic medical therapies, the current case offers us a snapshot of histologic progression and intratumoral heterogeneity in a native pretreatment context. Using whole exome sequencing and high resolution array-based comparative genomic hybridization, we observed marked genetic heterogeneity between the various areas. Notably, in the higher grade regions we found increased aneuploidy with progressive loss of heterozygosity, the emergence of mutations in the TERT promoter, and compromise of ARID1A. These findings provide new insights into intratumoral heterogeneity in the evolution of malignant phenotypes in anaplastic meningiomas and potential pathways of malignant progression.

Pediatric low-grade gliomas: How modern biology reshapes the clinical field

Low-grade gliomas represent the most frequent brain tumors arising during childhood. They are characterized by a broad and heterogeneous group of tumors that are currently classified by the WHO according to their morphological appearance. Here we review the clinical features of these tumors, current therapeutic strategies and the recent discovery of genomic alterations characteristic to these tumors. We further explore how these recent biological findings stand to transform the treatment for these tumors and impact the diagnostic criteria for pediatric low-grade gliomas.

Clinical implementation of integrated whole-genome copy number and mutation profiling for glioblastoma

BACKGROUND Multidimensional genotyping of formalin-fixed paraffin-embedded (FFPE) samples has the potential to improve diagnostics and clinical trials for brain tumors, but prospective use in the clinical setting is not yet routine. We report our experience with implementing a multiplexed copy number and mutation-testing program in a diagnostic laboratory certified by the Clinical Laboratory Improvement Amendments. METHODS We collected and analyzed clinical testing results from whole-genome array comparative genomic hybridization (OncoCopy) of 420 brain tumors, including 148 glioblastomas. Mass spectrometry-based mutation genotyping (OncoMap, 471 mutations) was performed on 86 glioblastomas. RESULTS OncoCopy was successful in 99% of samples for which sufficient DNA was obtained (n = 415). All clinically relevant loci for glioblastomas were detected, including amplifications (EGFR, PDGFRA, MET) and deletions (EGFRvIII, PTEN, 1p/19q). Glioblastoma patients ≤40 years old had distinct profiles compared with patients >40 years. OncoMap testing reliably identified mutations in IDH1, TP53, and PTEN. Seventy-seven glioblastoma patients enrolled on trials, of whom 51% participated in targeted therapeutic trials where multiplex data informed eligibility or outcomes. Data integration identified patients with complete tumor suppressor inactivation, albeit rarely (5% of patients) due to lack of whole-gene coverage in OncoMap. CONCLUSIONS Combined use of multiplexed copy number and mutation detection from FFPE samples in the clinical setting can efficiently replace singleton tests for clinical diagnosis and prognosis in most settings. Our results support incorporation of these assays into clinical trials as integral biomarkers and their potential to impact interpretation of results. Limited tumor suppressor variant capture by targeted genotyping highlights the need for whole-gene sequencing in glioblastoma.

Utility of dynamic computed tomography angiography in the preoperative evaluation of skull base tumors.

OBJECT The anatomical complexity of skull base tumors mandates detailed preoperative planning for safe resection. In particular, the location of critical vascular and bony structures can influence the surgical approach. Traditional methods, such as MRI, MR angiography and/or venography (MRA/MRV), CT angiography and/or venography (CTA/CTV), and digital subtraction angiography, each have their limitations. One alternative that combines the benefits of both detailed anatomy compatible with intraoperative image guidance and visualization of the vascular flow is the 320-detector row dynamic volume CTA/CTV. The authors investigated this techniques impact on the surgical approach used in a series of complex intracranial tumors. METHODS All patients with complex intracranial tumors who had undergone preoperative dynamic CTA/CTV as well as MRI in the period from July 2010 to June 2012 were retrospectively reviewed. Those in whom only routine CTA/CTV sequences had been obtained were excluded. Clinical records, including imaging studies, operative reports, and hospital course, were reviewed. Ease in detecting specific major arterial and venous tributaries using dynamic CTA/CTV was graded for each case. Furthermore, 2 skull base neurosurgeons projected a desired surgical approach for each tumor based on MRI studies, independent of the CTA/CTV sequences. The projected approach was then compared with the ultimately chosen surgical approach to determine whether preoperative awareness of vasculature patterns altered the actual operative approach. RESULTS Sixty-four patients were eligible for analysis. Dynamic CTA/CTV successfully demonstrated circle of Willis arteries, major draining sinuses, and deep internal venous drainage in all cases examined. The superior petrosal sinus, vein of Labbé, tentorial veins, and middle fossa veins were also identified in a majority of cases, which played an important role in preoperative planning. Visualization of critical vascular-especially venous-anatomy influenced the surgical approach in 39% (25 of 64) of the cases. CONCLUSIONS Dynamic CTA/CTV has been applied to few neurosurgical disease pathologies to date. This noninvasive technology offers insight into vascular flow patterns as well as 3D anatomical relationships and provides thin-cut sequences for intraoperative navigation. The authors propose dynamic CTA as an addition to the preoperative planning for complex skull base tumors.

The growing teratoma syndrome after subtotal resection of an intracranial nongerminomatous germ cell tumor in an adult: case report.

OBJECTIVE AND IMPORTANCE:We report a rare complication after resection of a recurrent intracranial nongerminomatous germ cell tumor in an adult. The growing teratoma syndrome, as originally described with pediatric germ cell neoplasms, represents tumor recurrence, often cystic, that sometimes is observed after partial response to multimodality therapy and despite decreasing tumor serum markers. The enlarging tumor consists of elements of a mature teratoma that presumably are refractory to chemotherapy or radiation. To our knowledge, this is only the third case of the growing teratoma syndrome in an adult patient with nongerminomatous germ cell tumor. CLINICAL PRESENTATION:A 26-year-old man had signs of recurrent obstructive hydrocephalus 6 months after multimodality treatment of a diencephalic yolk sac tumor and endoscopic third ventriculostomy. Imaging studies revealed large multilocular cystic masses originating from the tumor bed and partially obstructing the ventriculostomy. INTERVENTION:Near total tumor resection and fenestration was performed. Histopathological analysis demonstrated a mature teratoma. CONCLUSION:Surgical resection, if feasible, is the treatment of choice for the growing teratoma syndrome to establish the correct diagnosis and prevent complications.