Adult Low-grade Gliomas Research Articles

Association of the FGFR1 mutation with spontaneous hemorrhage in low-grade gliomas in pediatric and young adult patients.

The authors aimed to investigate genetic alterations in low-grade gliomas (LGGs) in pediatric and young adult patients presenting with spontaneous hemorrhage. Patients younger than 30 years of age with a pathological diagnosis of World Health Organization (WHO) grade I or II glioma and who had undergone treatment at the authors' institution were retrospectively examined. BRAF V600E, FGFR1 N546/K656, IDH1 R132, IDH2 R172, and KIAA1549-BRAF (K-B) fusion genetic alterations were identified, and the presence of spontaneous tumoral hemorrhage was recorded. Among 66 patients (39 with WHO grade I and 27 with grade II tumors), genetic analysis revealed K-B fusion in 18 (27.3%), BRAF V600E mutation in 14 (21.2%), IDH1/2 mutation in 8 (12.1%), and FGFR1 mutation in 4 (6.1%). Spontaneous hemorrhage was observed in 5 patients (7.6%); 4 of them had an FGFR1 mutation and 1 had K-B fusion. Univariate analysis revealed a statistically significant association of an FGFR1 mutation and a diencephalic location with spontaneous hemorrhage. Among 19 diencephalic cases including the optic pathway, hypothalamus, and thalamus, an FGFR1 mutation was significantly associated with spontaneous hemorrhage (p < 0.001). Four FGFR1 mutation cases illustrated the following results: 1) a 2-year-old female with pilomyxoid astrocytoma (PMA) harboring the FGFR1 K656E mutation presented with intraventricular hemorrhage (IVH); 2) a 6-year-old male with PMA harboring FGFR1 K656E and D652G mutations presented with intratumoral hemorrhage (ITH); 3) a 4-year-old female with diffuse astrocytoma harboring FGFR1 K656M and D652G mutations presented with IVH; and 4) a young adult patient with pilocytic astrocytoma with the FGFR1 N546K mutation presented with delayed ITH and IVH after 7 years of observation. Although the mechanism remains unclear, the FGFR1 mutation is associated with spontaneous hemorrhage in pediatric and young adult LGG.

Extent of resection and molecular pathologic subtype are potent prognostic factors of adult WHO grade II glioma

We evaluated prognostic factors of adult low-grade glioma (LGG) according to the new 2016 WHO classification. Records of 153 patients diagnosed with WHO grade II LGG between 2003 and 2015 were retrospectively reviewed. Based on the 2016 WHO classification, 80 patients (52.3%) had diffuse astrocytoma, IDH-mutant; 45 (29.4%) had oligodendroglioma, IDH-mutant and 1p/19q-codeleted (ODG); and 28 (18.3%) had diffuse astrocytoma, IDH-wildtype. Gross total resection (GTR) was performed in 71 patients (46.4%), subtotal resection in 31 (20.3%), partial resection in 43 (28.1%), and biopsy in 8 (5.2%). One hundred two patients (66.7%) received postoperative radiotherapy. The 5- and 10-year progression-free survival (PFS) rates were 72.7% and 51.5%, respectively, and the 5- and 10-year overall survival (OS) rates were 82.5% and 63.5%, respectively. GTR and IDH-mutant and/or 1p/19q codeletion were favorable prognostic factors for PFS and OS. Patients with IDH-wildtype had significantly decreased OS. Among patients with ODG who underwent GTR, no recurrence was observed after radiotherapy. Patients who underwent non-GTR frequently experienced recurrence after radiotherapy (IDH-mutant: 47.6%, IDH-wildtype: 57.9%). In conclusion, molecular classification of LGG was of prognostic relevance, with IDH-wildtype patients having a particularly poor outcome, regardless of the treatment. Favorable results were observed in patients who underwent GTR.

Seizure outcomes and survival in adult low-grade glioma over 11 years: living longer and better.

There has been a trend toward earlier and more aggressive resection for low-grade gliomas (LGGs). This study set out to compare seizure control and survival of adults with LGG seen in the same neuro-oncology clinic over 11 years and to determine whether a change in surgical philosophy has led to a corresponding improvement in outcomes. We conducted a retrospective analysis using case-note review of 153 adults with histologically verified or radiologically suspected LGG, collecting data on patient, tumor, and seizure characteristics between 2006 and 2017. We studied 79 patients in 2006 and 74 patients in 2017. There was no significant difference between the 2 groups in age at presentation, tumor location, or integrated pathological diagnosis. The numbers of complete or partial resections increased from 21.5% in 2006 to 60.8% in 2017 (P < .05). Five- and 10-year overall survival increased from 81.8% and 51.7% in 2006 to 100% and 95.8% in 2017 (P < .001); similarly, 5- and 10-year progression-free survival increased from 47.0% and 30.7% in 2006 to 93.1% and 68.7% in 2017. The proportion of patients with intractable epilepsy declined from 72.2% in 2006 to 43.2% in 2017 (P < .05). The neurosurgical morbidity rate was identical in both groups (11.8% in 2006 vs 11.1% in 2017). Management of LGG over the last 11 years has led to substantial improvements in survival and seizure control. This is most likely thanks to a change in surgical philosophy, with early resection now favored over watchful waiting where possible.

Rapid fully-automated assay for routine molecular diagnosis of BRAF mutations for personalized therapy of low grade gliomas

Background: BRAF mutation analysis is important to personalize the management with low-grade gliomas (LGG) in children and adults, with therapeutic and prognostic impacts. In recurrent tumors, targeted therapies such as BRAF inhibitors had been reported to induce disease stabilization and significant radiographic responses. This highlights the potential interest of BRAF mutation to stratify patients for targeted therapy. Standard operating procedures (SOP) for BRAF V600E mutation detection can be time-consuming and consequently delay treatment choice in patients with acute deterioration. Here, we evaluated IdyllaTM fully automated PCR (FA-PCR) assay for the rapid determination of BRAF mutational status in children and adult LGG.Methods: Formalin-fixed and paraffin-embedded (FFPE) samples from three histological LGG subtypes (ganglioglioma, pleomorphic xantoastrocytoma, and dysembryoplastic neuroepithelial tumor) with previous SOP-characterized BRAF mutational status were re-analyzed using the FA-PCR. Overall concordance with the mutational status determined using SOP, as well as sensitivity and specificity of FA-PCR technique were assessed.Results: All 14 samples gave interpretable results with FA-PCR. Overall concordance of BRAF mutational status between FA-PCR and SOP was 100%. Sensitivity and specificity were 100%.Conclusion: This study confirms the reliability of FA-PCR for BRAF mutations analysis in children and adult LGG. Considering the short time to results enabled by FA-PCR, providing results in less than 90 minutes, this technique represents an interesting option for the molecular diagnosis of LGG and personalization of treatment.

Survival and Seizure Control have improved for Adult Low-Grade Gliomas over the last eleven years

Abstract Background There has been a trend towards earlier and more aggressive resection for adult Low-Grade Gliomas (LGG) in the last decade. This study set out to compare seizure control and survival of unselected adults with LGG seen in the same neuro-oncology clinic over 11 years and to determine if a change in surgical philosophy has led to a corresponding improvement in outcomes. Methods Retrospective analysis using case-note review of 153 adults with histologically verified or radiologically suspected LGG, collecting data on patient, tumour and seizure characteristics in 2006 and 2017. Results We studied 79 patients in 2006 and 74 patients in 2017. There were no significant differences between the two groups in age at presentation, tumour location or histological or molecular subtype. The numbers of complete or partial resections increased from 21.5 % in 2006 to 60.8% in 2017 (p&lt;0.05). There was a highly significant improvement in 5- and 10-year survival from 81.8% and 51.7% in 2006 to 100% and 95.8% in 2017 (p&lt;0.001); and a similar improvement was seen in progression free survival. The proportion of patients with intractable epilepsy reduced from 72.2% in 2006 to 43.2% in 2017 (p&lt;0.05). The neurosurgical morbidity rate was identical in both groups (11.8% in 2006 vs 11.1% in 2017). Conclusion Increasing use of surgery for LGG over the last eleven years has led to substantial improvements in survival and seizure control but not at the cost of long-term morbidity.

Malignant Transformation of Adult Low Grade Glioma: Risk Factors and Outcomes in the Molecular Era

To update a previous report on risk factors (RFs) for malignant transformation (MT) and associated outcomes among adult low grade glioma (LGG), now incorporating WHO 2016 molecular classification. We queried an IRB approved LGG (grade 2) database to include patients (pts) ≥ 18 yrs old at diagnosis from 1980-2018 with data sufficient for molecular classification from diagnosis or pathology review via IHC for IDH1-R132H mutation. MT was defined as pathologic confirmation of grade 3-4 glioma or new/increased contrast enhancement diagnostic of MT determined by tumor board. Endpoints included freedom from MT (FFMT) and overall survival (OS), calculated from diagnosis. The χ2 test was used to test associations between variables and treatment groups. The Kaplan Meier method and Cox proportional hazards model were used. Of the 486 pts, median follow up was 5.3 yrs (range, .02-28.4). Median age was 39 yrs (range, 18-78) and 262 (54%) were male. Molecular classification was IDHmut-1p19q-codel, IDHmut-1p19q-noncodel, and IDH1-R132H-negative in 169 (35%), 125 (26%), and 192 (40%) pts, respectively. Surgeon assessed gross- (GTR) and sub-total resection or biopsy alone (STR) occurred in 204 (42%) and 264 (54%) pts, respectively. By RTOG 9802 criteria, 137 (28%) pts were low- and 349 (72%) were high-risk. Immediate adjuvant management was radiation (RT) alone, temozolomide (TMZ) alone, RT with TMZ (RT+TMZ), and observation, in 63 (13%), 82 (17%), 81 (17%), and 246 (51%) pts, respectively. TMZ alone was more likely to be used in the IDHmut-1p19q-codel group (p<.001), and observation in the low risk group (p<.001). After TMZ alone, 64 pts progressed (78%) and 47 (57%) received salvage RT. Of those observed, 74 (30%) progressed and salvage was RT in 10 (4%), TMZ in 36 (15%), and RT+TMZ in 28 (11%) pts. Median OS for the whole group was 15.7 yrs (95% CI 12.3-17.4). MT (67% by pathologic confirmation) occurred in 84 pts (17%), with an estimated 5 yr FFMT of 86% (95% CI 82-90). Median OS after MT was 2.4 yrs (95% CI 1.5-3.2), which was not significantly different whether MT was diagnosed by imaging or pathology (p=0.35). Details of the multivariable analysis (MVA) are provided in the table. Although GTR v STR was significant in univariate analysis (HR .7, 95% CI .6-.9, p=.004), it was not significant on MVA.Abstract 1060; Table 1Factors, MVA for MTPHR95% CIMale v female.0092.11.2-3.6Tumor size ≥5 v <5 cm<.0013.52.0-6.2Group, IDH1-R132H-negativeRefIDHmut-1p19q-noncodel.036.5.3-.95IDHmut-1p19q-codel<.001.2.1-.4Treatment, TMZ aloneRefObservation.012.4.2-.8RT alone.022.3.1-.8RT+TMZ.008.3.1-.7 Open table in a new tab OS after MT is poor. Although low risk pts were more likely to be observed, adjuvant TMZ alone was the only modifiable RF associated with MT despite more IDHmut-1p19q-codel pts treated with this strategy. Non-modifiable RFs included male sex, tumor ≥5 cm, and IDH1-R132H-negative classification. Further study is required for validation and to assess whether MT may serve as a surrogate for OS.

Malignant Transformation of Molecularly Classified Adult Low-Grade Glioma

Malignant transformation (MT) of adult grade 2 glioma (low-grade glioma [LGG]) is associated with adverse survival. We sought to describe the incidence, outcomes, and risk factors for MT of molecularly classified LGG. We reviewed a single-institutional database of adults who received a diagnosis of LGG with data allowing for molecular classification from 1980 to 2018 to evaluate time to MT and its associated risk factors. MT was defined as pathologic confirmation of grade 3-4 glioma and/or imaging characteristics consistent with MT by multidisciplinary consensus. Among the included 486 adults with molecularly classified LGG, median agewas 39 years (range, 18-78), median tumor size was 3.9 cm (range, 0.3-13.0), and 262 (54%) were male. Molecular classification was IDHmut1p/19qcodel in 169 (35%), IDHmut1p/19qintact in 125 (26%), and IDHwt in 192 (40%) patients. Adjuvant management was observation in 246 (51%) patients, temozolomide alone in 82 (16%), radiation therapy alone in 63 (13%), and radiation therapy concurrent with temozolomide in 81 (17%). Temozolomide monotherapy was more likely to be given to IDHmut1p/19qcodel patients (P < .001). Median follow-up was 5.3 years. MT occurred in 84 (17%) patients, with a 5-year freedom from MT of 86% (95% confidence interval [CI], 82%-90%). Median overall survival after MT was 2.4 years (95% CI, 1.5-3.3) and was associated with molecular classification (P = .03) and grade at MT (P < .001). Factors associated with MT were male sex (hazard ratio [HR], 2.1; 95% CI, 1.2-3.6; P = .009), tumor size ≥5 cm (HR, 3.5; 95% CI, 2.0-6.2; P < .001), IDHmut1p/19qintact (HR, 2.7; 95% CI, 1.3-5.6; P = .009) or IDHwt classification (HR, 5.5; 95% CI, 2.5-11.8; P < .001), and adjuvant temozolomide monotherapy (HR, 3.8; 95% CI, 1.4-10.3; P = .008). MT of LGG has a poor prognosis associated with unfavorable molecular groups. Analysis of our large cohort identified adjuvant temozolomide monotherapy as the only modifiable risk factor for MT and provides the first clinical evidence of temozolomide-associated MT among molecularly classified adult LGG. This novel finding supplements our understanding of temozolomide-induced hypermutation and informs precision management of LGG.

Rehabilitation and Longitudinal Follow-up of Cognition in Adult Lower Grade Gliomas

Rehabilitation and Longitudinal Follow-up of Cognition in Adult Lower Grade Gliomas

SAT-457 Hypothalamic-Pituitary Disorders after Conformal Radiation Therapy for Childhood and Young Adult Low-Grade Glioma or Ependymoma

Purpose To describe the prevalence, risk factors, latency time and adverse health outcomes of hypothalamic-pituitary (HP) disorders among children and young adults who received focal conformal radiation therapy (RT) for brain tumors. Methods Cohort study of 355 patients, aged ≤ 25 years at diagnosis, treated with high-dose (54-59.4 Gy) RT using photons between 1996 and 2016 for low-grade glioma or ependymoma. Patients (median age, 6.4 years at RT exposure) received systematic endocrine follow-up for a median of 10.1 years (range 0.1-19.6). Associations between HP disorders and risk factors, as well as adverse health outcomes were determined using multivariable regression analysis. Results The prevalence was 37.2% (95% CI 32.1%-42.4%) for growth hormone (GH) deficiency (GHD), 17.7% (95% CI 13.2%-23.0%) for luteinizing hormone/follicle-stimulating hormone deficiency (LH/FSHD), 14.9% (95% CI 11.2%-19.2%) for thyroid-stimulating hormone deficiency (TSHD), 10.3% (95% CI 7.3%-14.1%) for adrenocorticotropic hormone deficiency (ACTHD), and 12.6% (95% CI 8.8%-17.2%) for central precocious puberty (CPP). Tumor involvement in the HP region and shorter follow-up time were significantly associated with GHD, LH/FSHD, TSHD and ACTHD. CPP primarily occurred in patients with HP tumor involvement. GHD, treated in 84 (63.6%) patients, was associated with a higher odds of short stature (OR 2.77; 95% CI 1.34-5.70) and low bone mineral density (BMD) (OR 3.47; 95% CI 1.16-10.40), while TSHD demonstrated an independent association with dyslipidemia (OR 5.54; 95% CI 1.66-18.52). TSHD (P = 0.02), ACTHD (P = 0.0002), LH/FSHD (P = 0.01) and CPP (P = 0.002) were associated with lower intelligence quotient scores; GHD (P = 0.02), ACTHD (P = 0.01), LH/FSHD (P = 0.01) and CPP (P = 0.04) with worse attention scores; GHD (P = 0.0003), ACTHD (P = 0.02) and LH/FSHD (P = 0.02) with lower memory scores. GH treatment was associated with a higher risk for secondary tumors (OR 2.22; 95% CI 1.05-4.67), but did not increase the risk for tumor recurrence or mortality. Conclusion HP disorders occur frequently during follow-up in patients exposed to high-dose RT and may have a significant impact on physical and neurocognitive well-being. Whether further optimization of endocrine management could allow better outcomes, requires additional investigation.

The management of low-grade gliomas in adults.

Low grade gliomas (LGGs) are WHO grade II tumors that affect mostly adult patients and include diffuse astrocytomas and oligodendrogliomas. New diagnostic criteria based on histology and molecular characterization with IDH mutation status and 1p/19q codeletion status have provided further categorization of these tumors and additional insights into prognosis and treatment response. In general, the current management of LGG favors maximum upfront resection with consideration of combined chemoradiation for patients deemed "high risk." In this review, we summarize the defining molecular features, important prognostic factors, recommended pre-operative imaging work-up, as well as therapeutic management of WHO Grade II low grade gliomas in adults.

Recent developments and future directions in adult lower-grade gliomas: Society for Neuro-Oncology (SNO) and European Association of Neuro-Oncology (EANO) consensus.

The finding that most grades II and III gliomas harbor isocitrate dehydrogenase (IDH) mutations conveying a relatively favorable and fairly similar prognosis in both tumor grades highlights that these tumors represent a fundamentally different entity from IDH wild-type gliomas exemplified in most glioblastoma. Herein we review the most recent developments in molecular neuropathology leading to reclassification of these tumors based upon IDH and 1p/19q status, as well as the potential roles of methylation profiling and deletional analysis of cyclin-dependent kinase inhibitor 2A and 2B. We discuss the epidemiology, clinical manifestations, benefit of surgical resection, and neuroimaging features of lower-grade gliomas as they relate to molecular subtype, including advanced imaging techniques such as 2-hydroxyglutarate magnetic resonance spectroscopy and amino acid PET scanning. Recent, ongoing, and planned studies of radiation therapy and both cytotoxic and targeted chemotherapies are summarized, including both small molecule and immunotherapy approaches specifically targeting the mutant IDH protein.

Abstract A078: Dissecting the myeloid lineage in human gliomas

Abstract The immune cell composition of the tumor microenvironment can be a decisive factor for tumor pathogenesis. Gliomas are tumors that develop from the glial cells of the brain and spinal cord and make up to 30% of all brain tumors. In gliomas, microglia and infiltrating macrophages can comprise up to 30 to 50% of total tumor-associated cells. Increased CD68 staining, a marker of microglia/macrophages, in adult gliomas is positively associated with histologic tumor grade. Despite the accumulated evidence substantiating a critical role for microglia and infiltrating macrophages in gliomagenesis, little is known is about the molecular mechanisms driving microglial contribution to tumor growth and whether microglia/macrophages are therapeutic targets in both low- and high-grade gliomas. Despite microglia sharing common properties with other tissue-resident macrophages, they express hundreds of genes at higher levels compared to other tissue-resident macrophages, many of which are influenced by the brain micro-environment. Additionally, engraftment of bone-marrow derived cells into the central nervous system fails to produce microglia identical to yolk sac-derived microglia at the transcriptional level. Hence, in any inflammatory context, including cancer, an interesting question arises: how does each population contribute to the pathogenesis and/or resolution of inflammation? To elucidate the role(s) of microglia/macrophages in gliomas, we isolated the myeloid fraction from primary pediatric and adult low-grade and high-grade gliomas using flow cytometry. By integrating bulk and single-cell transcriptome analysis, we find significant inter- and intratumoral heterogeneity within the myeloid population. Additionally, we find evidence for tumor environment-dependent gene change. In combination with ongoing comparative analysis of the corresponding epigenetic landscapes of the myeloid populations, we seek to decipher how the tumor microenvironment reprograms the transcription factor network in microglia/macrophages to generate tumor-promoting cells. Citation Format: Claudia Z. Han, Sascha H. Duttke, Zhengyu Ouyang, Sebastian Preissl, Johannes C.M. Schlachetzki, Alexander Nott, Conor Fitzpatrick, Carolyn O'Connor, Nicole G. Coufal, Mihir Gupta, David D. Gonda, Michael L. Levy, Ben-Haim Sharona, Barba David, Joseph D. Ciacci, Alexander A. Khalessi, Clark C. Chen, Bing Ren, Christopher K. Glass. Dissecting the myeloid lineage in human gliomas [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr A078.

Is awake brain surgery in high-grade glioma patients and a severe aphasia feasible? A case study.

Is awake brain surgery in high-grade glioma patients and a severe aphasia feasible? A case study.

IDH mutations but not TERTp mutations are associated with seizures in lower-grade gliomas.

Glioma is the most common malignant tumor in the central nervous system (CNS). Lower-grade gliomas (LGG) refer to Grade II and III gliomas. In LGG patients, seizure often appears as an initial symptom and play an important role in clinical performance and quality of life of the patients. To date, the relationship between the onset of seizures and the molecular pathology in gliomas is still poorly investigated. In this study, we investigate the potential relationship between isocitrate dehydrogenase (IDH)/telomerase reverse transcriptase promoter (TERTp) mutations and preoperative seizures in patients with LGG. 289 adult LGG patients were enrolled in this study. Data of clinical characteristics and molecular pathology were acquired. Sanger sequencing was used to detect IDH/TERTp mutations. Chi-square test was performed to determine if the IDH/TERTp mutations were associated with seizures and seizure types. In 289 LGG patients, preoperative seizures accounted for 25.3% (73/289), IDH mutations accounted for 34.3%(99/289), and TERTp mutations accounted for 44.3% (128/289). The correlation analysis demonstrated that IDH mutation is a significant factor influencing the occurrence of tumor-related epilepsy (P <.001, chi-square test). On the other hand, the statistical analysis revealed no significant correlation between TERTp mutations and seizure in LGG patients (P = .102, chi-square test). The tumor-related epilepsy rates vary among different subgroups according to IDH/TERTp mutations. However, there is no definite correlation between the IDH (P = 1.000, chi-square test)/TERTp (P = .613, chi-square test) mutations and the types of epileptic seizure. IDH mutations are more common in preoperative LGG patients with epileptic symptoms, suggesting that this mutation is positively correlated with seizures. However, there was no significant correlation between TERTp mutations and seizures. Different molecular pathologic types based on IDH/TERTp have different incidences of tumor-associated epilepsy in LGGs.

Therapeutic Interventions in Adult Low-Grade Gliomas.

Treating adult low-grade gliomas (LGGs) is particularly challenging due to the highly infiltrative nature of this type of brain cancer. Although surgery, radiotherapy, and chemotherapy are the mainstay treatment modalities for LGGs, the optimal combination management plan for a particular patient based on individual symptoms and the risk of treatment-induced toxicity remains unclear. This review highlights the competency and limitations of standard treatment options while providing an essential therapeutic update regarding current clinical trials aimed at implementing targeted therapies with morbidity rates lower than those for current LGG treatments and also augmenting the killing of cancerous cells while maintaining an improved quality of life.

Impact of adjuvant treatments on survival in Korean patients with WHO grade II gliomas: KNOG 15-02 and KROG 16-04 intergroup study.

Optimal treatment strategies for low-grade glioma (LGG) remain controversial. We analyzed treatment outcomes and evaluated prognostic factors of adult LGG patients in Korea. We reviewed the medical records of 555 patients diagnosed with WHO grade II LGG (astrocytoma 37.8%, oligoastrocytoma 15.3%, and oligodendroglioma 46.8%) at 14 institutions between 2000 and 2010. Primary and secondary endpoints were progression-free survival (PFS) and overall survival (OS). Propensity-score matching (PSM) analyses were performed to correct imbalances in patient/tumor characteristics among adjuvant treatment groups. The median follow-up time was 83.4 months, and the 5-year PFS and OS rates were 52.2% and 83.0%, respectively. Male, older age, poorer performance status, multiple lobe involvement, and astrocytoma histology were associated with poorer survival. Among the treatment factors, gross total resection (GTR) was associated with better PFS and OS, and adjuvant chemotherapy with improved PFS. Interestingly, adjuvant radiotherapy (RT) did not improve PFS; rather, it was related with poorer OS. Regarding patient/tumor characteristics, the RT group had poorer characteristics than the non-RT group. After PSM, we detected a tendency for improved PFS in the matched RT group, and no significant difference in OS compared with the matched non-RT group. The achievement of GTR is important to improve survival in LGG patients. Adjuvant chemotherapy may enhance PFS, but adjuvant RT did not improve survival outcomes. After PSM, we observed potential impacts of adjuvant RT on PFS. Our results may reflect real-world practice and consequently may help to optimize treatment strategies for LGG.

The role of clinical and molecular factors in low-grade gliomas: what is their impact on survival?

To evaluate relevance of clinical and molecular factors in adult low-grade gliomas (LGG) and to correlate with survival. We reviewed records from adult LGG patients from 1991 to 2015 who received surgery and had sufficient tissue to molecular biomarkers characterization. 213 consecutive LGG patients were included: 17.4% were low-risk, according to Radiation Therapy Oncology Group (RTOG) risk assessment. IDH 1/2 mutation, 1p/19q co-deletion, MGMT methylation were found in 93, 50.8 and 65.3% of patients. Median follow-up was 98.3months. In univariate analysis, overall survival was influenced by extent of resection (p=0.011), IDH mutation (p<0.001), 1p/19q co-deletion (p=0.015) and MGMT methylation (p=0.013). In multivariate analysis, RTOG clinical risk (p=0.006), IDH mutation (p<0.001) and 1p/19q co-deletion (p=0.035) correlated with overall survival. RTOG clinical risk (p=0.006), IDH mutation (p<0.001) and 1p/19q co-deletion (p=0.035) correlated with overall survival. Both clinical and molecular factors are essential to determine prognosis and treatment strategies.

Pediatric low-grade gliomas can be molecularly stratified for risk.

Pediatric low-grade gliomas (PLGGs) consist of a number of entities with overlapping histological features. PLGGs have much better prognosis than the adult counterparts, but a significant proportion of PLGGs suffers from tumor progression and recurrence. It has been shown that pediatric and adult low-grade gliomas are molecularly distinct. Yet the clinical significance of some of newer biomarkers discovered by genomic studies has not been fully investigated. In this study, we evaluated in a large cohort of 289 PLGGs a list of biomarkers and examined their clinical relevance. TERT promoter (TERTp), H3F3A and BRAF V600E mutations were detected by direct sequencing. ATRX nuclear loss was examined by immunohistochemistry. CDKN2A deletion, KIAA1549-BRAF fusion, and MYB amplification were determined by fluorescence in situ hybridization (FISH). TERTp, H3F3A, and BRAF V600E mutations were identified in 2.5, 6.4, and 7.4% of PLGGs, respectively. ATRX loss was found in 4.9% of PLGGs. CDKN2A deletion, KIAA1549-BRAF fusion and MYB amplification were detected in 8.8, 32.0 and 10.6% of PLGGs, respectively. Survival analysis revealed that TERTp mutation, H3F3A mutation, and ATRX loss were significantly associated with poor PFS (p < 0.0001, p < 0.0001, and p = 0.0002) and OS (p < 0.0001, p < 0.0001, and p < 0.0001). BRAF V600E was associated with shorter PFS (p = 0.011) and OS (p = 0.032) in a subset of PLGGs. KIAA1549-BRAF fusion was a good prognostic marker for longer PFS (p = 0.0017) and OS (p = 0.0029). MYB amplification was also a favorable marker for a longer PFS (p = 0.040). Importantly, we showed that these molecular biomarkers can be used to stratify PLGGs into low- (KIAA1549-BRAF fusion or MYB amplification), intermediate-I (BRAF V600E and/or CDKN2A deletion), intermediate-II (no biomarker), and high-risk (TERTp or H3F3A mutation or ATRX loss) groups with distinct PFS (p < 0.0001) and OS (p < 0.0001). This scheme should aid in clinical decision-making.

Oligodendrogliomas in pediatric and teenage patients only rarely exhibit molecular markers and patients have excellent survivals

Although oligodendrogliomas appear histologically similar in adult and pediatric patients, the latter have only been rarely studied and most of those studies did not have long follow-up. We examined 55 oligodendroglial tumors from pediatric and teenage patients for their biomarkers with formalin-fixed paraffin-embedded tissues and studied their survival status. None of the tumors harbored 1p/19q codeletion or IDH mutation. Mutations in TERTp (4%), BRAF (11%), FGFR1 (3%) and H3F3A (5%), fusions of BRAF (8%) and FGFR1 (8%) were found sparingly and almost all in a mutually exclusive manner. Molecular events were exclusively found in tumors with classic oligodendroglial histology. Survival analysis showed remarkably excellent prognosis compared to the adult counterparts. 5-year overall survival was 95% in our cohort with median follow-up of 8.1years and in nine patients with follow-up more than 10 years, the 10-year overall survival was 100%. The 5-year and 10-year progression-free survivals of our cohort were 89 and 77%, respectively. FGFR1 fusion seemed to confer a poor prognosis in pediatric oligodendrogliomas. Patients receiving adjuvant chemotherapy (p = 0.046) or harboring Grade II histology (p < 0.001) had longer interval to recurrence. Our study demonstrated the distinct indolent clinical course of pediatric and teenage oligodendrogliomas compared to the adult tumors. Molecular markers commonly seen in adult oligodendrogliomas and other pediatric low-grade gliomas were only rarely seen. Since there is no clinical or molecular evidence suggesting that pediatric "oligodendrogliomas" are the same as adult oligodendrogliomas albeit histologic similarity, a case can be made for their separation from adult oligodendrogliomas in the next WHO classification.

Increased expression of von Willebrand factor gene is associated with poorer survival in primary lower grade glioma.

Venous thromboembolism is a common complication in patients with glioma. The clotting factor von Willebrand factor (VWF) is a highly adhesive procoagulant molecule that mediates platelet adhesion to endothelial and subendothelial surfaces. In the current analysis, we examined The Cancer Genome Atlas (TCGA) data to assess the effect of VWF gene expression on prognosis in patients with lower grade gliomas (LGGs). For newly diagnosed gliomas, we evaluated the association between and overall survival in the genomic data commons TCGA LGG dataset in TCGA. Survival data of the glioma subgroup were extracted for analysis and generation of Kaplan-Meier curves for overall survival. Lower grade gliomas with less VWF gene expression had significantly better survival than those with more VWF gene expression (hazard ratio 0.64, 95% confidence interval 0.44-0.92, P 0.015 log rank test). The effect of VWF gene expression on survival was even more evident when the sample was analyzed as three groups (P = 0.00019). IDH1, TP53, and ATRX mutations are present in 40% or more adult LGGs. The deleterious prognostic effect of VWF expression in LGGs is not surprising, given its role in other cancers. Therefore, VWF gene expression may be a clinically important risk marker in LGG.