Diagnosis Of Low-grade Glioma Research Articles

IDH-Mutant Low-grade Glioma: Advances in Molecular Diagnosis, Management, and Future Directions.

IDH-mutant low-grade gliomas (LGG) have emerged as a distinct clinical and molecular entity with unique treatment considerations. Here, we review updates in IDH-mutant LGG diagnosis and classification, imaging biomarkers, therapies, and neurocognitive and patient-reported outcomes. CDKN2A/B homozygous deletion in IDH-mutant astrocytoma is associated with shorter survival, similar to WHO grade 4. The T2-FLAIR mismatch, a highly specific but insensitive sign, is diagnostic of IDH-mutant astrocytoma. Maximal safe resection is currently indicated in all LGG cases. Radiotherapy with subsequent PCV (procarbazine, lomustine, vincristine) provides longer overall survival compared to radiotherapy alone. Temozolomide in place of PCV is reasonable, but high-level evidence is still lacking. LGG adjuvant treatment has important quality of life and neurocognitive side effects that should be considered. Although incurable, IDH-mutant LGG have a favorable survival compared to IDH-WT glioma. Recent advances in molecular-based classification, imaging, and targeted therapies will hopefully improve survival and quality of life.

Comparison Of Adjuvant Versus Salvage Therapy Among IDH Mutant Low-Grade Glioma

Timing of postoperative management in low grade glioma (LGG) is controversial. We sought to evaluate the clinical outcomes among molecularly classified LGG patients (pts) treated with adjuvant (adj) versus (v) salvage treatment (salv). We included pts ≥ 18 yrs old at diagnosis of LGG (WHO grade II) from 1980-2018 with an IDH mutation (mut) and 1p19q data allowing for molecular classification. Pts in the adj group received immediate postoperative treatment (temozolomide [TMZ] and/or radiotherapy [RT]) prior to progression. Salv pts were initially observed then received TMZ and/or RT at disease progression. Endpoints were calculated from date of first surgical resection or biopsy, and included overall survival (OS) and next intervention free survival (NIFS), defined as the date of either surgery or treatment subsequent to adj or salv, or death. 296 IDH mut pts were included. Among the 168 pts with 1p19q codel, median follow up was 8.3 yrs (range, .03 – 26), median age was 43 yrs (range, 20-78), 57% were male, and 29% had GTR (gross total resection). 100 pts (60%) received adj (TMZ, 22%; RT, 65%; TMZ+RT, 13%), which was more likely in pts who were older, had larger tumors, or underwent biopsy alone (p<.05 for each). On univariable analysis (UVA), 5 yr NIFS for adj v salv was 70% (95% CI, 61-80%) v 83% (74-93%; p = 0.06), and 5 yr OS was 90% (84-97%) v 97% (93-100%; p<0.01), respectively. However, when adjusting for high risk factors associated with selection bias on multivariable analysis (MVA, Table), adj was not associated with either NIFS or OS as compared to salv. Among the 128 pts with 1p19q intact, median follow up was 6 yrs (range, 0.04 – 19), median age was 35 yrs (range, 19-66), 52% were male, and 41% had GTR. 49 pts (38%) received adj (TMZ, 29%; RT, 26%; TMZ+RT, 45%), which was more likely in pts who were older, had larger tumors, or underwent biopsy alone (p<.05 for each). On UVA, 5-year NIFS for adj v salv was 69% (95% CI, 56-85%) v 41% (31-56%; p<0.01), and 5-year OS was 85% (75-97%) v 91% (84-98%; p = 0.7), respectively. On MVA (Table), adj remained associated with improved NIFS compared to salv, but had no association with OS. Among IDH mut 1p19q codel pts, adj was not associated with improved NIFS or OS, suggesting initial observation followed by salv at progression is appropriate for this population. In contrast, among IDH mut 1p19q intact pts, adj was associated with improved NIFS, but not OS, supporting a more individualized postoperative management approach.Abstract 3689; TableMVAIDH mut 1p19q codelIDH mut 1p19q intactNIFSOSNIFSOSHR (95% CI)pHR (95% CI)pHR (95% CI)pHR (95% CI)pAdj v salv1.2 (0.8-1.9).421.3 (0.7-2.4).380.4 (0.2-0.7)<.010.9 (0.5-1.6).69Age ≥40 v <401.5 (1.0-2.3).072.1 (1.2-3.8).011.1 (0.7-1.9).631.3 (0.7-2.5).37Biopsy.16.02.09.18GTR0.7 (0.4-1.1).130.4 (0.2-0.8).011.0 (0.5-2.3).910.6 (0.2-1.6).34STR0.7 (0.4-1.1).090.6 (0.3-1.0).051.7 (0.8-3.6).131.3 (0.6-2.7).57Female v male0.8 (0.5-1.2).340.7 (0.4-1.2).230.5 (0.3-0.9).010.5 (0.3-0.9).04 Open table in a new tab

Predictors of early, recurrent, and intractable seizures in low-grade glioma.

Seizures are common among patients with low-grade glioma (LGG) and can significantly affect morbidity. We sought to determine the association between the clinical and molecular factors with seizure incidence and refractoriness in LGG patients. We conducted a retrospective review at the University of Virginia in patients with LGG (World Health Organization, WHO Grade II) evaluated between 2002 and 2015. Descriptive statistics were calculated for variables of interest, and the Kaplan-Meier method was used to estimate survival curves, which were compared with the log-rank test. A total of 291 patients were included; 254 had molecular testing performed for presence of an isocitrate dehydrogenase (IDH) mutation and/or 1p/19q codeletion. Sixty-eight percent of patients developed seizures prior to LGG diagnosis; 41% of all patients had intractable seizures. Using WHO 2016 integrated classification, there was no significant difference in seizure frequency during preoperative and postoperative periods or in developing intractable seizures, though a trend toward increased preoperative seizure incidence among patients with the IDH mutation was identified (P = .09). Male sex was significantly associated with higher seizure incidence during preoperative (P < .001) and postoperative periods (P < .001); men were also more likely to develop intractable seizures (P = .01). Seizures are common among patients with LGG. Differences in preoperative or postoperative and intractable seizure rates by WHO 2016 classification were not detected. Our data showed a trend toward higher seizure incidence preoperatively in patients with IDH-mutant LGG. We describe a unique association between male sex and seizure incidence and intractability that warrants further study.

Return to work following diagnosis of low-grade glioma: A nationwide matched cohort study.

ObjectiveReturn-to-work (RTW) following diagnosis of infiltrative low-grade gliomas is unknown.MethodsSwedish patients with histopathologic verified WHO grade II diffuse glioma diagnosed between 2005 and 2015 were included. Data were acquired from several Swedish registries. A total of 381 patients aged 18–60 were eligible. A matched control population (n = 1,900) was acquired. Individual data on sick leave, compensations, comorbidity, and treatments assigned were assessed. Predictors were explored using multivariable logistic regression.ResultsOne year before surgery/index date, 88% of cases were working, compared to 91% of controls. The proportion of controls working remained constant, while patients had a rapid increase in sick leave approximately 6 months prior to surgery. After 1 and 2 years, respectively, 52% and 63% of the patients were working. Predictors for no RTW after 1 year were previous sick leave (odds ratio [OR] 0.92, 95% confidence interval [CI] 0.88–0.96, p < 0.001), older age (OR 0.96, 95% CI 0.94–0.99, p = 0.005), and lower functional level (OR 0.64 95% CI, 0.45–0.91 p = 0.01). Patients receiving adjuvant treatment were less likely to RTW within the first year. At 2 years, biopsy (as opposed to resection), female sex, and comorbidity were also unfavorable, while age and adjuvant treatment were no longer significant.ConclusionsApproximately half of patients RTW within the first year. Lower functional status, previous sick leave, older age, and adjuvant treatment were risk factors for no RTW at 1 year after surgery. Female sex, comorbidity, and biopsy only were also unfavorable for RTW at 2 years.

Handedness switching as a presenting sign for pediatric low-grade gliomas: An insight into brain plasticity from a short case series.

To describe clinical data, rehabilitation services, and outcomes of children with handedness switching as their presenting symptom before low-grade glioma (LGG) diagnosis. A retrospective chart review was performed for five patients (four female and four white) with LGG and confirmed handedness switching before LGG diagnosis. All children were less than 8 years at diagnosis, and two patients were less than 3 years. All children were initially right-handed and experienced loss of motor function, ranging from weakness to paresis, in their dominant hand. The median time from switching handedness to diagnosis was 1 month (range: 0.75-60months). Rehabilitation was offered for three patients, and motor function deficits in the initial dominant hand were resolved in two of the total cohort. At long-term follow-up, hand dominance returned to the initial hand in three patients. Handedness switching should be acknowledged as a potential sign of LGG in children, and early long-term rehabilitation services should be offered for these children.

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.

P04.01 Return to work i patients with low grade glioma

Abstract BACKGROUND We now treat patients with low-grade gliomas (LGG) more aggressively as this prolong survival. Patients are typically in working age, but their ability to return to work (RTW) following treatment has not been studied. We aimed to study patterns of sick leave and return to work among LGG patients in Sweden. In addition, we explored predictors for RTW following LGG diagnosis. MATERIAL AND METHODS We performed a nationwide register-based study of patients with grade II diffuse LGG. Data on adult patients aged 18–60 years with a histopathological diagnosis of LGG between 2005–2015 were obtained from the Swedish Brain Tumor Registry (n=381). A matched control sample (n=1900) was acquired from Statistics Sweden. Patients and controls were linked to the social insurance agency data for individual information on sick leave and disability compensation. Multivariable logistic regression was used in order to find predictors for RTW. RESULTS One year prior to surgery there was no apparent difference between cases and controls with 90 % working. Among LGG patients there was a rapid increase in sick leave starting approximately six months prior to surgery, while the proportion of controls on sick leave remained constant. One year after surgery, 53 % had returned to work with 29 % working full time. Independent predictors for patients working one year after surgery were higher age (OR 0.96, 95 % CI 0.93–0.99, p &lt;0.01) and more days absent from work prior to procedure (OR 0.91, 95 % CI 0.97-0.95, p &lt;0.001), both negatively associated with RTW. CONCLUSIONS In this cohort, more than half of the patients being diagnosed with LGG RTW within one year. Higher prior absence from work and higher age are risk factors for no-RTW. This study provides new information on rates of and factors influencing RTW in patients with LGG. FUNDING This project was funded by research grant from the Swedish Research Council (2017-00944).

Risk of Subsequent Primary Cancers After External Beam Radiotherapy Treatment of Pediatric Low Grade Gliomas: A Surveillance, Epidemiology, and End Results Analysis 1973 to 2015

Abstract INTRODUCTION Past studies have associated external beam radiotherapy (EBRT) with higher incidences of subsequent primary malignancies (SPMs). This link has been documented for leukemias, and prostate, thyroid, and bone cancers. However, the effects of EBRT on SPM development from low grade gliomas (LGGs) are not well understood. The aim of the present study was to characterize the risk of SPM development after EBRT treatment of LGGs. METHODS A total of 1439 pediatric (age 0-17) records between 1973 and 2015 were assembled from the Surveillance, Epidemiology, and End Results (SEER) database. Univariable and multivariable Cox regressions were used to evaluate the prognostic impact of demographic, tumor, and treatment-related covariates. Propensity score matching was used to balance baseline characteristics. Survival and cumulative hazard analyses measured the time to, and risk of, SPM development, stratified by receipt of EBRT. RESULTS Of the 1439 pediatric patients we analyzed, 450 received EBRT and 989 did not. A total of 65 pediatric patients were identified who developed SPMs after LGG diagnosis, and 35 of these patients received EBRT (OR: 2.70). Unadjusted Cox regressions revealed a significantly elevated SPM risk in EBRT-treated pediatric patients with LGGs (HR: 2.22, CI: 1.34-3.67). After adjusting for covariates such as race, gender, income, chemotherapy, and grade (World Health Organization I vs II), there was still a clear association between EBRT and the development of SPMs (HR: 2.52, CI: 1.50-4.23). Propensity score matching across covariates did not significantly impact the hazard ratio. Time-to-event Kaplan Meier curves demonstrated earlier SPM development in the EBRT-treated LGG pediatric population, and Nelson–Aalen cumulative hazard estimates showed higher incidences of SPM development at all time points. CONCLUSION EBRT treatment for LGGs is associated with an elevated incidence of SPMs, even after controlling for available covariates. This suggests less aggressive EBRT use in the pediatric LGG population may be warranted.

The Role of 5-ALA in Low-Grade Gliomas and the Influence of Antiepileptic Drugs on Intraoperative Fluorescence.

Objectives: Intraoperative tumor visualization with 5-aminolevulinic acid (5-ALA) induced protoporphyrin IX (PpIX) fluorescence is widely applied for improved resection of high-grade gliomas. However, visible fluorescence is present only in a minority of low-grade gliomas (LGGs) according to current literature. Nowadays, antiepileptic drugs (AEDs) are frequently administered to LGG patients prior to surgery. A recent in-vitro study demonstrated that AEDs result in significant reduction of PpIX synthesis in glioma cells. The aim of this study was thus to investigate the role of 5-ALA fluorescence in LGG surgery and the influence of AEDs on visible fluorescence.Patients and Methods: Patients with resection of a newly diagnosed suspected LGG after 5-ALA (25 mg/kg) administration were initially included. During surgery, the presence of visible fluorescence (none, mild, moderate, or bright) within the tumor and intratumoral fluorescence homogeneity (diffuse or focal) were analyzed. Tissue samples from fluorescing and/or non-fluorescing areas within the tumor and/or the assumed tumor border were collected for histopathological analysis (WHO tumor diagnosis, cell density, and proliferation rate). Only patients with diagnosis of LGG after surgery remained in the final study cohort. In each patient, the potential preoperative intake of AEDs was investigated.Results: Altogether, 27 patients with a histopathologically confirmed LGG (14 diffuse astrocytomas, 6 oligodendrogliomas, 4 pilocytic astrocytomas, 2 gemistocytic astrocytomas, and one desmoplastic infantile ganglioglioma) were finally included. Visible fluorescence was detected in 14 (52%) of 27. In terms of fluorescence homogeneity (n = 14), 7 tumors showed diffuse fluorescence, while in 7 gliomas focal fluorescence was noted. Cell density (p = 0.03) and proliferation rate (p = 0.04) was significantly higher in fluorescence-positive than in fluorescence-negative samples. Furthermore, 15 (56%) of 27 patients were taking AEDs before surgery. Of these, 11 patients (73%) showed no visible fluorescence. In contrast, 10 (83%) of 12 patients without prior AEDs intake showed visible fluorescence. Thus, visible fluorescence was significantly more common in patients without AEDs compared to patients with preoperative AED intake (OR = 0,15 (CI 95% 0.012–1.07), p = 0.046).Conclusions: Our study shows a markedly higher rate of visible fluorescence in a series of LGGs compared to current literature. According to our preliminary data, preoperative intake of AEDs seems to reduce the presence of visible fluorescence in such tumors and should thus be taken into account in the clinical setting.

Male gender is associated with seizure risk in low-grade glioma (LGG) patients.

e13520 Background: Up to 90% of LGG patients present with seizures, but the risk of developing seizure is not known. Our goal was to determine the association between clinical and molecular factors with seizure incidence in LGG patients. Methods: Retrospective study from 2/2002-1/2015 involving 291 patients ≥18 years old, with diagnosis of WHO grade II glioma. Intractable seizure was defined as patients needing ≥2 anti-epileptic drugs. Chi-square tests of association were used to test for associations between factors and outcome measures. Results: Study population was 54% men, median age of 51, with oligodendroglioma (47%), oligoastrocytoma (25%), astrocytoma (21%), NOS (7%). Among patients with molecular testing (87%), 32% had IDH mutation (IDHmt) and 1p/19q co-deletion, 37% IDHmt and 1p/19q intact and 18% IDH wildtype LGG. Sixty-eight percent of patients had seizures prior to LGG diagnosis; 41% intractable seizures. A trend toward higher incidence of pre-operative seizure was observed in IDHmt LGG patients (p = 0.09). On univariate analysis (Table), oligodendroglioma was significantly associated with a higher risk of intractable seizures. Male gender was strongly associated with the risk of seizure at presentation, seizure development after surgery, and intractable seizures. Conclusions: Consistent with historical data, the majority of our patients presented with seizure; oligodendroglioma with higher risk of intractable seizures. Unexpectedly, gross resection did not favorably predict seizure outcome, possibly due to our small study population. Our study only showed a trend towards higher seizure occurrence in IDHmt LGG patients. Our finding of association between male gender and seizure risk in LGG patients mirrors that of Pallud et al (Brain 2014) and warrants further investigation into the possible molecular basis of sex differences in epileptogenesis in LGG.[Table: see text]

Is supratotal resection achievable in low-grade gliomas? Feasibility, putative factors, safety, and functional outcome.

Surgery for low-grade gliomas (LGGs) aims to achieve maximal tumor removal and maintenance of patients' functional integrity. Because extent of resection is one of the factors affecting the natural history of LGGs, surgery could be extended further than total resection toward a supratotal resection, beyond tumor borders detectable on FLAIR imaging. Supratotal resection is highly debated, mainly due to a lack of evidence of its feasibility and safety. The authors explored the intraoperative feasibility of supratotal resection and its short- and long-term impact on functional integrity in a large cohort of patients. The role of some putative factors in the achievement of supratotal resection was also studied. Four hundred forty-nine patients with a presumptive radiological diagnosis of LGG consecutively admitted to the neurosurgical oncology service at the University of Milan over a 5-year period were enrolled. In all patients, a policy was adopted to perform surgery according to functional boundaries, aimed at achieving a supratotal resection whenever possible, without any patient or tumor a priori selection. Feasibility, general safety, and tumor or patient putative factors possibly affecting the achievement of a supratotal resection were analyzed. Postsurgical patient functional performance was evaluated in five cognitive domains (memory, language, praxis, executive functions, and fluid intelligence) using a detailed neuropsychological evaluation and quality of life (QOL) examination. Total resection was feasible in 40.8% of patients, and supratotal resection in 32.3%. The achievement of a supratotal versus total resection was independent of age, sex, education, tumor volume, deep extension, location, handedness, appearance of tumor border, vicinity to eloquent sites, surgical mapping time, or surgical tools applied. Supratotal resection was associated with a long clinical history and histological grade II, suggesting that reshaping of brain networks occurred. Although a consistent amount of apparently MRI-normal brain was removed with this approach, the procedure was safe and did not carry additional risk to the patient, as demonstrated by detailed neuropsychological evaluation and QOL examination. This approach also improved seizure control. Supratotal resection is feasible and safe in routine clinical practice. These results show that a long clinical history may be the main factor associated with its achievement.

SIOP-E-BTG and GPOH Guidelines for Diagnosis and Treatment of Children and Adolescents with Low Grade Glioma.

Low grade gliomas (LGGs) constitute the largest, yet clinically and (molecular-) histologically heterogeneous group of pediatric brain tumors of WHO grades I and II occurring throughout all pediatric age groups and at all central nervous system (CNS) sites. The tumors are characterized by a slow growth rate and may show periods of growth arrest. Around 40% of all LGG patients can be cured by complete neurosurgical resection and are followed by close observation. In case of relapse, second resection often is possible. Following incomplete resection observation is recommended, as long as there is no radiologic tumor growth and the patient does not suffer from significant, tumor-related symptoms. This also applies to patients with a diagnosis of LGG on the basis of radiological criteria. By contrast, clinical worsening and / or radiologic progression are an indication to treatment with either chemo- or radiotherapy. Overall survival is around 90%, and many patients survive with residual tumor, i. e. they suffer from chronic disease. All patients need comprehensive neuro-oncological care, the principles and details of which are summarized in the current guidelines. These represent standard of care for diagnostic work-up (including neuroimaging and neuropathology), and for therapeutic decisions (including the indications to non-surgical treatment) as well as concepts for neurosurgical intervention, chemotherapy and radiotherapy as well as surveillance and rehabilitation. The current treatment algorithm was compiled by members of the LGG working group of the SIOP-E brain tumor group (SIOP-E-BTG) and is based upon the results of previous European LGG studies and international reports.

Effect of preoperative peripheral blood neutrophil-to-lymphocyte ratio and platelet-to-lymphocyte ratio on clinical prognosis of patients with lower-grade glioma

Objective To investigate the prognostic values of neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) in patients with lower-grade gliomas. Methods 242 patients with pathological diagnosis of lower-grade gliomas (WHO Ⅱ and WHOⅢ) were enrolled in the study, and relevant data were collected. Kaplan-Meier method was used to calculate the survival rates. Cox regression model was used to conduct multivariate analysis. Results The best cut-off values for NLR and PLR were 1.95 and 197.22. The 3-year and 5-year survival rate for NLR≤1.95 and NLR>1.95 subgroups were 0.809 vs. 0.649 and 0.675 vs. 0.462, respectively (P 197.22 subgroups were 0.809 vs. 0.649 and 0.675 vs. 0.462, respectively (P<0.01). High NLR (P<0.01) and PLR (P<0.05) were independent prognostic factors influencing the survival of lower-grade gliomas. Conclusion NLR and PLR were potential factors for predicting the survival of lower-grade gliomas. Key words: Neutrophil-to-lymphocyte ratio; Platelet-to-lymphocyte ratio; Lower-grade gliomas; Prognosis

I6P7 peptide modified superparamagnetic iron oxide nanoparticles for magnetic resonance imaging detection of low-grade brain gliomas.

Glioma, the most severe primary brain malignancy, has very low survival rates and a high level of recurrence. Nowadays, conventional treatments for these patients are suffering a similar plight owing to the distinctive features of the malignant gliomas, for example chemotherapy is limited by the blood-brain barrier while surgery and radiation therapy are affected by the unclear boundaries of tumor from normal tissue. In the present study, a novel superparamagnetic iron oxide (SPIO) nanoprobe for enhanced T2-weighted magnetic resonance imaging (MRI) was developed. A frequently used MRI probe, SPIO nanoparticles, was coated with a silica outer layer and for the first time was covalently modified with interleukin-6 receptor targeting peptides (I6P7) to promote transportation through the blood-brain barrier and recognition of low-grade gliomas. The efficiency of transcytosis across the blood-brain barrier was examined in vitro using a transwell invasion model and in vivo in nude mice with orthotopic low-grade gliomas. The targeting nanoprobe showed significant MRI enhancement and has potential for use in the diagnosis of low-grade gliomas.

Prognostic values of isocitrate dehydrogenase and telomerase reverse transcriptase promoter mutations for predicting clinical outcomes in patients with lower-grade gliomas

Objective To investigate the prognostic values of isocitrate dehydrogenase (IDH) and telomerase reverse transcriptase (TERT) promoter mutations in patients with lower-grade gliomas. Methods 260 patients with pathological diagnosis of lower-grade gliomas (WHO Ⅱ and WHOⅢ) were enrolled in the study, and their data were collected. Kaplan-Meier method was used to calculate the survival rates. Cox regression model was used to conduct multivariate analysis. Results The median survival time for IDH mut and IDH wt subgroups were 42.00 and 27.55 months with statistical significane (P=0.001). The median survival time for TERT mut and TERT wt subgroups were 42.00 and 33.50 months, respectively (P=0.660). The survival analysis for IDH/TERT combination demonstrated that the suvival of IDH wt/TERT mut subgroup was the worst (P=0.001), the survival of IDH mut subgroups were favourable (P=0.001). Conclusion IDH mutation has strong prognostic values for the survival of lower-grade gliomas. And TERT promoter mutation could contribute to IDH mutation in predicting the survival of lower-grade gliomas. IDH/TERT mutations could be significant prognostic factors influencing the survival of lower-grade gliomas. Key words: Isocitrate dehydrogenase; Telomerase reverse transcriptase; Lower-grade gliomas; Prognosis

Neurosurgical patterns of care for diffuse low-grade gliomas in Sweden between 2005 and 2015.

BackgroundIn the last decade, increasing evidence has evolved for early and maximal safe resection of diffuse low-grade gliomas (LGGs) regarding survival. However, changes in clinical practice are known to occur slowly and we do not know if the scientific evidence has yet resulted in changes in neurosurgical patterns of care.MethodsThe Swedish Brain Tumor Registry was used to identify all patients with a first-time histopathological diagnosis of LGG between 2005 and 2015. For analysis of surgical treatment patterns, we subdivided assessed time periods into 2005-2008, 2009-2012, and 2013-2015. Population-based data on patient and disease characteristics, surgical management, and outcomes were extracted.ResultsA total of 548 patients with diffuse World Health Organization grade II gliomas were identified: 142 diagnosed during 2005-2008, 244 during 2009-2012, and 162 during 2013-2015. Resection as opposed to biopsy was performed in 64.3% during 2005-2008, 74.2% during 2009-2012, and 74.1% during 2013-2015 (P = .08). There was no difference among the 3 periods regarding overall survival (P = .11). However, post hoc analysis of data from the 4 (out of 6) centers that covered all 3 time periods demonstrated a resection rate of 64.3% during 2005-2008, 77.4% during 2009-2012, and 75.4% during 2013-2015 (P = .02) and longer survival of patients diagnosed 2009 and onward (P = .04).ConclusionIn this nationwide, population-based study we observed a shift over time in favor of LGG resection. Further, a positive correlation between the more active surgical strategy and longer survival is shown, although no causality can be claimed because of possible confounding factors.

T57. Prediction of early tumor progression based on pre- and post-operative seizure frequency in low grade gliomas

Low-grade gliomas (LGG) are slow-growing tumors characterized by an infiltrative growth pattern and cortical predilection in the central nervous system (CNS). Up to 90% of LGG patients may have seizures as the initial presentation leading to tumor diagnosis, and up to 15% of them develop refractory epilepsy. Predicting which patient will evolve into refractory epilepsy versus have more benign disease course remains a challenge. Moreover, seizure recurrence following surgical resection may predict early tumor recurrence, especially in patients who have achieved long seizure-freedom period. This study analyzed 148 patients meeting inclusion criteria (age > 18 years, LGG diagnosis, at least one seizures event at some point of the disease process). All patients were treated by the Department of Neuro-Oncology and Neurosurgery at University of Texas MD Anderson Cancer Center (MDACC) from Jan/2000 and Dec/2015. Seizure frequency was divided in 4 categories: none, one, few (2–3 seizures) and several (>4 seizures). Perioperative seizures (up to 48 h from surgery) were excluded from this analysis. One hundred sixteen (78.4%) patients had seizures as the initial presentation. On average, the first seizure occurred 4.75 months prior to surgical resection (range 0.1–24.2). Pre-operatively, 54 (36.5%) patients had a single seizure, 23 (15.5%) patients had few seizures and 39 (26.4%) patients had several seizures. After initial event, most patients (74%) were started on antiepileptic drugs (AED). Ninety-two (63%) patients accomplished partial resection, whereas 54 (37%) patients accomplished gross total resection of the tumor. Univariate analysis of seizure frequency between the 6-month pre-op and post-op periods was significant in predicting recurrence-free survival in the following 2 (2-RFS) and 5 (5-RFS) years (p = 0.0379). Patients with no/one seizure pre-op who continued to have no/one seizure in the 6-month post-op period had the highest 2-RFS and 5-RFS (0.984 and 0.667 [CI 95%, 0.889–0.998 and 0.528–0.773], respectively); patients who had no/one seizure pre-op and developed few/several seizures in the 6-month post-op period had the lowest probability of being progression-free in the following 2 and 5 years (0.750 and 0.545 [CI95%, 0.463–0.898 and 0.274–0.753], respectively). Multicovariate cox-regression analysis on RFS based on the seizure frequency change between pre-op and post-op periods revealed that patients with no/one seizure pre-op who had increase in seizure frequency to few/several seizures on the 6-month post-op period had significantly more risk of progression compared to patients who initially had no/one seizure pre-op and continued to have no/one seizure in the 6-month post-op period (HR 2.431 [CI95% 1.318, 4.482], p = 0.0044). Seizure frequency following surgical resection of LGG and the seizure frequency change between the 6-month pre-op and post-op periods predict early tumor recurrence in LGG.

Sequential Apparent Diffusion Coefficient for Assessment of Tumor Progression in Patients with Low-Grade Glioma.

Early and accurate identification of tumor progression in patients with low-grade gliomas is challenging. We aimed to assess the role of quantitative ADC analysis in the sequential follow-up of patients with low-grade gliomas as a potential imaging marker of tumor stability or progression. In this retrospective study, patients with a diagnosis of low-grade glioma with at least 12 months of imaging follow-up were retrospectively reviewed. Two neuroradiologists independently reviewed sequential MR imaging in each patient to determine tumor progression using the Response Assessment in Neuro-Oncology criteria. Normalized mean ADC (ADCmean) and 10th percentile ADC (ADC10) values from FLAIR hyperintense tumor volume were calculated for each MR image and compared between patients with stable disease versus tumor progression using univariate analysis. The interval change of ADC values between sequential scans was used to differentiate stable disease from progression using the Fisher exact test. Twenty-eight of 69 patients who were evaluated met our inclusion criteria. Fifteen patients were classified as stable versus 13 patients as having progression based on consensus reads of MRIs and the Response Assessment in Neuro-Oncology criteria. The interval change of ADC values showed greater concordance with ultimate lesion disposition than quantitative ADC values at a single time point. The interval change in ADC10 matched the expected pattern in 12/13 patients with tumor progression (overall diagnostic accuracy of 86%, P <.001). On average, the ADC10 interval change predicted progression 8 months before conventional MR imaging. The interval change of ADC10 values can be used to identify progression versus stability of low-grade gliomas with a diagnostic accuracy of 86% and before apparent radiologic progression on conventional MR imaging.

Low-Grade Glioma of the Neurohypophysis: Clinical Characteristics and Surgical Outcomes

Low-grade glioma (LGG) of the neurohypophysis is an extremely rare tumor arising from the pituicytes of the posterior pituitary or the infundibulum. The preoperative imaging findings of these tumors mimic those of pituitary adenomas, and radical resection is often challenging in affected patients due to the hypervascularity of the tumor. Here we describe the clinical and radiologic features of this clinical entity. We identified 8 patients with LGG of the neurohypophysis who underwent surgery at Toranomon Hospital between January 2007 and March 2017. We retrospectively reviewed the clinical and radiologic data for these patients. The patient cohort comprised 5 men and 3 women, with a mean age of 57 years. The presenting symptoms included visual disturbance in 7 patients and anterior pituitary dysfunction in 7 patients. No patient had diabetes insipidus (DI). Preoperative magnetic resonance imaging (MRI) showed a thick anterior pituitary gland located anterior to the tumor in 3 patients and flow voids on T2-weighted images in 6 patients. All patients underwent transsphenoidal surgery, and gross total resection was achieved in 4 patients. Postoperative morbidities included deterioration of anterior pituitary function in 4 patients and permanent DI in 3 patients. Anterior displacement of a thick anterior pituitary by a tumor combined with evidence of flow voids on preoperative MRI is helpful in the preoperative diagnosis of LGG of the neurohypophysis. Radical resection should be attempted in these tumors, especially during primary surgery, even though it is associated with postoperative pituitary dysfunction.

A novel high-sensitivity assay to detect a small fraction of mutant IDH1 using droplet digital PCR.

Detection of mutations in the isocitrate dehydrogenase 1 (IDH1) gene is useful for accurate diagnosis of lower grade gliomas, as described in the 2016 World Health Organization classification of tumors of the central nervous system. Conventional analysis tools, including Sanger DNA sequencing and immunohistochemistry, might fail to detect a small fraction of mutant IDH1 owing to their limited sensitivity. Considering that lower grade gliomas are infiltrative in nature, a highly sensitive detection assay for IDH1 mutation is required for their accurate diagnosis. In this study, we successfully established a droplet digital PCR (ddPCR) system to detect a small fraction of IDH1 mutation. We could detect 0.05% of mutant IDH1 allele in 30ng DNA. Using this assay, we could detect a small fraction of mutant IDH1 in a glioma case, identified as a wildtype tumor according to the conventional assays. Additionally, in a small amount of DNA derived from the cerebrospinal fluid, we could detect an IDH1 mutation. In conclusion, the ddPCR system is useful to identify a small fraction of IDH1 mutation in diffuse infiltrative gliomas. This might be useful for precision medicine of these gliomas in the near future and also for the non-invasive diagnosis of these gliomas.