Recent work has demonstrated that nearly all diffuse gliomas display nuclear immunoreactivity for the bHLH transcription factor OLIG2, and the R132H mutant isocitrate dehydrogenase 1 (IDH1) protein ...is expressed in the majority of diffuse gliomas other than primary glioblastoma. However, these antibodies have not been widely applied to rarer glioblastoma variants, which can be diagnostically challenging when the astrocytic features are subtle. We therefore surveyed the expression patterns of OLIG2 and IDH1 in 167 non-conventional glioblastomas, including 45 small cell glioblastomas, 45 gliosarcomas, 34 glioblastomas with primitive neuroectodermal tumor-like foci (PNET-like foci), 23 with an oligodendroglial component, 11 granular cell glioblastomas, and 9 giant cell glioblastomas. OLIG2 was strongly expressed in all glioblastomas with oligodendroglial component, 98% of small cell glioblastomas, and all granular cell glioblastomas, the latter being particularly helpful in ruling out macrophage-rich lesions. In 74% of glioblastomas with PNET-like foci, OLIG2 expression was retained in the PNET-like foci, providing a useful distinction from central nervous system PNETs. The glial component of gliosarcomas was OLIG2 positive in 93% of cases, but only 14% retained focal expression in the sarcomatous component; as such this marker would not reliably distinguish these from pure sarcoma in most cases. OLIG2 was expressed in 67% of giant cell glioblastomas. IDH1 was expressed in 55% of glioblastomas with oligodendroglial component, 15% of glioblastomas with PNET-like foci, 7% of gliosarcomas, and none of the small cell, granular cell, or giant cell glioblastomas. This provides further support for the notion that most glioblastomas with oligodendroglial component are secondary, while small cell glioblastomas, granular cell glioblastomas, and giant cell glioblastomas are primary variants. Therefore, in one of the most challenging differential diagnoses, IDH1 positivity could provide strong support for glioblastoma with oligodendroglial component, while essentially excluding small cell glioblastoma.
Central neurocytomas are uncommon intraventricular neoplasms whose optimal management remains controversial due to their rarity. We assessed outcomes for a historical cohort of neurocytoma patients ...and evaluated effects of tumor atypia, size, resection extent, and adjuvant radiotherapy. Progression-free survival (PFS) was measured by Kaplan–Meier and Cox proportional hazards methods. A total of 28 patients (15 males, 13 females) were treated between 1995 and 2014, with a median age at diagnosis of 26 years (range 5–61). Median follow-up was 62.2 months and 3 patients were lost to follow-up postoperatively. Thirteen patients experienced recurrent/progressive disease and 2-year PFS was 75 % (95 % CI 53–88 %). Two-year PFS was 48 % for MIB-1 labeling >4 % versus 90 % for ≤4 % (HR 5.4, CI 2.2–27.8,
p
= 0.0026). Nine patients (32 %) had gross total resections (GTR) and 19 (68 %) had subtotal resections (STR). PFS for >80 % resection was 83 versus 67 % for ≤80 % resection (HR 0.67, CI 0.23–2.0,
p
= 0.47). Three STR patients (16 %) received adjuvant radiation which significantly improved overall PFS (
p
= 0.049). Estimated 5-year PFS was 67 % for STR with radiotherapy versus 53 % for STR without radiotherapy. Salvage therapy regimens were diverse and resulted in stable disease for 54 % of patients and additional progression for 38 %. Two patients with neuropathology-confirmed atypical neurocytomas died at 4.3 and 113.4 months after initial surgery. For central neurocytomas, MIB-1 labeling index >4 % is predictive of poorer outcome and our data suggest that adjuvant radiotherapy after STR may improve PFS. Most patients requiring salvage therapy will be stabilized and multiple modalities can be effectively utilized.
Malignant peripheral nerve sheath tumors (MPNST) are highly aggressive sarcomas with variable patient survival and few known prognostically relevant genomic biomarkers. To identify ...survival-associated genomic biomarkers, we performed high-resolution array-based comparative genomic hybridization (aCGH) on a large set of MPNSTs.
Candidate gene alterations identified by aCGH in 38 MPNSTs were validated at the DNA, RNA, and protein levels on these same tumors and an independent set of 87 MPNST specimens.
aCGH revealed highly complex copy number alterations, including both previously reported and completely novel loci. Four regions of copy number gain were associated with poor patient survival. Candidate genes in these regions include SOX5 (12p12.1), NOL1 and MLF2 (12p13.31), FOXM1 and FKBP1 (12p13.33), and CDK4 and TSPAN31 (12q14.1). Alterations of these candidate genes and several others of interest (ERBB2, MYC and TP53) were confirmed by at least 1 complementary methodology, including DNA and mRNA quantitative real-time PCR, mRNA expression profiling, and tissue microarray-based fluorescence in situ hybridization and immunohistochemistry. Multivariate analysis showed that CDK4 gain/amplification and increased FOXM1 protein expression were the most significant independent predictors for poor survival in MPNST patients (P < 0.05).
Our study provides new and independently confirmed candidate genes that could serve as genomic biomarkers for overall survival in MPNST patients.
Abstract Introduction Pleomorphic xanthoastrocytoma (PXA) is a unique meningocerebral glioma with relatively favorable prognosis. PXA also possess a variant with anaplastic features (aPXA) that is ...associated with poor outcomes. To date, few studies have examined the clinico-pathologic importance of these anaplastic features. Methods From 1999 to 2012, 8 patients with aPXA were treated at the University of California, San Francisco. Cases were re-confirmed by neuropathology, and clinical information regarding patient demographics, tumor characteristics, and treatment outcomes were assembled. Tumors were classified as aPXA according to the WHO diagnostic criteria established in 2007. Results There were 5 female and 3 male patients in our cohort, ranging in age from 4 to 74 years at initial diagnosis. Seizure was the most common presenting symptom (44%), and the majority of tumors arose in the frontal or temporal lobes (89%). Six patients received subtotal resection (STR), and all suffered from progression despite adjuvant radiotherapy and chemotherapy. Median time to progression was 20 months, with a 1 year progression-free survival rate of 57%. Three aPXA patients expired with a median survival of 87 months. Four patients developed disseminated disease. Three of 8 (38%) showed BRAFv600 mutation. Conclusion aPXA is associated with poorer clinical outcomes compared to PXA. Gross total resection should be the goal of initial treatment. It remains unclear whether adjuvant radiation and chemotherapy are able to prevent progression or dissemination. Long-term monitoring of all patients is a critical step in management due to the potential for tumors to transform into higher grade lesions.
Objective:
Malformations of cortical development (MCDs) are a major cause of medically refractory epilepsy. Our aim was to examine a surgical series of patients with cortical malformations to ...determine the prognostic factors associated with long‐term seizure control.
Methods:
We conducted a retrospective review of 143 patients with MCD who underwent resective surgery for medically refractory epilepsy. Demographic, imaging, histopathologic, and surgical variables were analyzed for potential association with seizure freedom. Preoperative magnetic resonance imaging (MRI) was evaluated in a blind fashion and classified according to a new imaging/embryologic MCD classification system.
Results:
Gray‐white blurring on MRI, smaller lesions, complete resection of structural lesions, complete resection of abnormal electrocorticographic areas, and locally confined electrocorticographic abnormalities are favorable prognosticators of seizure freedom on univariate analysis. Imaging features consistent with abnormal proliferation (Barkovich class I) were associated with better outcome compared to those related to abnormal neuronal migration (class II) or abnormal cortical organization (class III). Multivariate logistic regression revealed complete resection of tissue manifesting electrocorticographic and/or MRI anatomic abnormalities as the main independent predictor of seizure freedom. Other histopathologic or demographic factors were not associated with seizure control. Long‐term follow‐up of patients demonstrated sustained overall rates of seizure control (72% at 2 years, 65% at 5 years, and 67% at 10 years).
Interpretation:
Surgery for MCDs can result in high rates of seizure freedom. Complete resection of electrocorticographic and anatomic abnormalities appears to be most predictive of long‐term seizure control. ANN NEUROL 2011
The Hippo signaling pathway is functionally conserved in Drosophila melanogaster and mammals, and its proposed function is to control tissue homeostasis by regulating cell proliferation and ...apoptosis. The core components are composed of a kinase cascade that culminates with the phosphorylation and inhibition of Yes-associated protein 1 (YAP1). Phospho-YAP1 is retained in the cytoplasm. In the absence of Hippo signaling, YAP1 translocates to the nucleus, associates with co-activators TEAD1-4, and functions as a transcriptional factor promoting the expression of key target genes. Components of the Hippo pathway are mutated in human cancers, and deregulation of this pathway plays a role in tumorigenesis. Loss of the NF2 tumor suppressor gene is the most common genetic alteration in meningiomas, and the NF2 gene product, Merlin, acts upstream of the Hippo pathway. Here, we show that primary meningioma tumors have high nuclear expression of YAP1. In meningioma cells, Merlin expression is associated with phosphorylation of YAP1. Using an siRNA transient knockdown of YAP1 in NF2-mutant meningioma cells, we show that suppression of YAP1 impaired cell proliferation and migration. Conversely, YAP1 overexpression led to a strong augment of cell proliferation and anchorage-independent growth and restriction of cisplatin-induced apoptosis. In addition, expression of YAP1 in nontransformed arachnoidal cells led to the development of tumors in nude mice. Together, these findings suggest that in meningiomas, deregulation of the Hippo pathway is largely observed in primary tumors and that YAP1 functions as an oncogene promoting meningioma tumorigenesis.
We investigated whether brain arteriovenous malformation silent intralesional microhemorrhage, that is, asymptomatic bleeding in the nidal compartment, might serve as a marker for increased risk of ...symptomatic intracranial hemorrhage (ICH). We evaluated 2 markers to assess the occurrence of silent intralesional microhemorrhage: neuroradiological assessment of evidence of old hemorrhage-imaging evidence of bleeding before the outcome events-and hemosiderin positivity in hematoxylin and eosin-stained paraffin block sections.
We identified cases from our brain arteriovenous malformation database with recorded neuroradiological data or available surgical paraffin blocks. Using 2 end points, index ICH or new ICH after diagnosis (censored at treatment, loss to follow-up, or death), we performed logistic or Cox regression to assess evidence of old hemorrhage and hemosiderin positivity adjusting for age, sex, deep-only venous drainage, maximal brain arteriovenous malformation size, deep location, and associated arterial aneurysms.
Evidence of old hemorrhage was present in 6.5% (n=975) of patients and highly predictive of index ICH (P<0.001; OR, 3.97; 95% CI, 2.1-7.5) adjusting for other risk factors. In a multivariable model (n=643), evidence of old hemorrhage was an independent predictor of new ICH (hazard ratio, 3.53; 95% CI, 1.35-9.23; P=0.010). Hemosiderin positivity was found in 36.2% (29.6% in unruptured; 47.8% in ruptured; P=0.04) and associated with index ICH in univariate (OR, 2.18; 95% CI, 1.03-4.61; P=0.042; n=127) and multivariable models (OR, 3.64; 95% CI, 1.11-12.00; P=0.034; n=79).
The prevalence of silent intralesional microhemorrhage is high and there is evidence for an association with both index and subsequent ICH. Further development of means to detect silent intralesional microhemorrhage during brain arteriovenous malformation evaluation may present an opportunity to improve risk stratification, especially for unruptured brain arteriovenous malformations.
Summary Inflammatory myofibroblastic tumor (IMT) is a distinctive spindle cell lesion and occurs primarily in soft tissue. Recent evidence suggests a neoplastic nature, although historically, both ...neoplastic and nonneoplastic processes were combined in this category. Originally described as a nonneoplastic process, the term inflammatory pseudotumor (IP) has been used synonymously with IMT. IMTs have been linked to ALK gene (2p23) rearrangements, and some have suggested an association with the human herpesvirus 8 (HHV-8). IMT in the central nervous system (CNS) is rare, its characteristics are poorly defined, and its relation to similar tumors at other sites is unclear. To better characterize IMT within the CNS, we studied clinicopathologic features of 6 IMTs and compared them with 18 nonneoplastic lesions originally classified as IP. The IMT group consisted of 2 male and 4 female patients with a median age of 29 years. Of the six IMTs, 5 occurred within the cerebral hemispheres, and one was in the posterior fossa. All tumors were composed of neoplastic spindle cells and a variable amount of inflammatory infiltrate. Eighteen IPs included in this study consisted of predominantly inflammatory masses occasionally seen in the setting of systemic diseases. Only 1 IMT and none of the IPs recurred during the follow-up period. Four IMTs had either ALK protein overexpression or 2p23 rearrangement, and 1 case demonstrated both. None of the IPs were positive for ALK. Neither IMT nor IP cases demonstrated HHV-8 expression. We suggest that IMT in the CNS is distinct from the nonneoplastic IP, and distinguishing IMT from nonneoplastic lesions should enable better decisions for patient management.
Medulloblastoma (MB) is the most common pediatric CNS malignancy. We identify EAG2 as an overexpressed potassium channel in MBs across different molecular and histological subgroups. EAG2 knockdown ...not only impairs MB cell growth in vitro, but also reduces tumor burden in vivo and enhances survival in xenograft studies. Mechanistically, we demonstrate that EAG2 protein is confined intracellularly during interphase but is enriched in the plasma membrane during late G2 phase and mitosis. Disruption of EAG2 expression results in G2 arrest and mitotic catastrophe associated with failure of premitotic cytoplasmic condensation. While the tumor suppression function of EAG2 knockdown is independent of p53 activation, DNA damage checkpoint activation, or changes in the AKT pathway, this defective cell volume control is specifically associated with hyperactivation of the p38 MAPK pathway. Inhibition of the p38 pathway significantly rescues the growth defect and G2 arrest. Strikingly, ectopic membrane expression of EAG2 in cells at interphase results in cell volume reduction and mitotic-like morphology. Our study establishes the functional significance of EAG2 in promoting MB tumor progression via regulating cell volume dynamics, the perturbation of which activates the tumor suppressor p38 MAPK pathway, and provides clinical relevance for targeting this ion channel in human MBs.
Based on clinical presentation, glioblastoma (GBM) is stratified into primary and secondary types. The protein 53 (p53) pathway is functionally incapacitated in most GBMs by distinctive type-specific ...mechanisms. To model human gliomagenesis, we used a GFAP-HRas ⱽ¹² mouse model crossed into the p53ER ᵀᴬᴹ background, such that either one or both copies of endogenous p53 is replaced by a conditional p53ER ᵀᴬᴹ allele. The p53ER ᵀᴬᴹ protein can be toggled reversibly in vivo between wild-type and inactive conformations by administration or withdrawal of 4-hydroxytamoxifen (4-OHT), respectively. Surprisingly, gliomas that develop in GFAP-HRas ⱽ¹²;p53 ⁺/ᴷᴵ mice abrogate the p53 pathway by mutating p19 ᴬᴿF/MDM2 while retaining wild-type p53 allele. Consequently, such tumors are unaffected by restoration of their p53ER ᵀᴬᴹ allele. By contrast, gliomas arising in GFAP-HRas ⱽ¹²;p53 ᴷᴵ/ᴷᴵ mice develop in the absence of functional p53. Such tumors retain a functional p19 ᴬᴿF/MDM2-signaling pathway, and restoration of p53ER ᵀᴬᴹ allele triggers p53-tumor–suppressor activity. Congruently, growth inhibition upon normalization of mutant p53 by a small molecule, Prima-1, in human GBM cultures also requires p14 ᴬᴿF/MDM2 functionality. Notably, the antitumoral efficacy of p53 restoration in tumor-bearing GFAP-HRas ⱽ¹²;p53 ᴷᴵ/ᴷᴵ animals depends on the duration and frequency of p53 restoration. Thus, intermittent exposure to p53ER ᵀᴬᴹ activity mitigated the selective pressure to inactivate the p19 ᴬᴿF/MDM2/p53 pathway as a means of resistance, extending progression-free survival. Our results suggest that intermittent dosing regimes of drugs that restore wild-type tumor-suppressor function onto mutant, inactive p53 proteins will prove to be more efficacious than traditional chronic dosing by similarly reducing adaptive resistance.
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