Diagnosis Of Low-grade Glioma Research Articles

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.

Generalized q-sampling imaging fiber tractography reveals displacement and infiltration of fiber tracts in low-grade gliomas.

Low-grade gliomas (LGGs) are slow growing brain tumors that often cause displacement and/or infiltration of the surrounding white matter pathways. Differentiation between infiltration and displacement of fiber tracts remains a challenge. Currently, there is no reliable noninvasive imaging method capable of revealing such white matter alteration patterns. We employed quantitative anisotropy (QA) derived from generalized q-sampling imaging (GQI) to identify patterns of fiber tract alterations by LGGs. Sixteen patients with a neuropathological diagnosis of LGG (WHO grade II) were enrolled. Peritumoral fiber tracts underwent qualitative and quantitative evaluation. Contralateral hemisphere counterparts were used for comparison. Tracts were qualitatively classified as unaffected, displaced, infiltrated or displaced, and infiltrated at once. The average QA of whole tract (W), peritumoral tract segment (S), and their ratio (S/W) were obtained and compared to the healthy side for quantitative evaluation. Qualitative analysis revealed 9 (13.8%) unaffected, 24 (36.9%) displaced, 13 (20%) infiltrated, and 19 (29.2%) tracts with a combination of displacement and infiltration. There were no disrupted tracts. There was a significant increase in S/W ratio among displaced tracts in the pre-operative scans in comparison with the contralateral side. QA values of peritumoral tract segments (S) were significantly lower in infiltrated tracts. WHO grade II LGGs might displace, infiltrate, or cause a combination of displacement and infiltration of WM tracts. QA derived from GQI provides valuable information that helps to differentiate infiltration from displacement. Anisotropy changes correlate with qualitative alterations, which may serve as a potential biomarker of fiber tract integrity.

An Evaluation of Prognostic Factors of Elderly Patients With Low Grade Glioma

Low grade gliomas (LGG) include a heterogeneous group of tumors generally diagnosed in younger individuals. Understanding how the clinical and pathologic features should influence our treatment recommendations may differ in older patients (≥60 years) compared to younger individuals. With limited data available at individual institutions, we utilized the National Cancer Data Base (NCDB) to examine the impact of clinical and treatment factors on outcomes. We identified patients in NCDB diagnosed with low-grade glioma from 2004-2013 with age >60 years and known treatment records with associated outcomes. Univariate and multivariate Cox proportional hazard models were used to assess covariates related to overall survival (OS). Overall, 2,993 patients met the inclusion criteria with the diagnosis of low-grade glioma. Median age was 69 years at diagnosis. Sixty-eight% were astrocytoma, 22% were oligodendroglioma, and 10% were mixed with a median tumor size of 4.0 cm. For those with known surgical status, gross total resection was achieved in 29%, subtotal in 27%, and biopsy in 44%. Forty-six% received radiation therapy (RT), 28% received chemotherapy, and 21% received chemoradiotherapy. On multivariable analysis worse OS was significantly associated with older age (HR=1.05, p<0.001), higher Charlson/DeyoScore (HR=1.50, p<0.001), community reporting facility (HR=1.25, p<0.001), earlier year of diagnosis (HR=1.38-1.44, p<0.001), astrocytoma/mixed histology (HR=1.66-2.36, p<0.001), eloquent location (HR=1.14, p=0.036), and those not undergoing resection (HR=1.51, p<0.001) were significantly associated with worse OS on multivariate analysis. With respect to overall survival, tumor size and chemotherapy were not significant on univariate analysis whereas RT was significant on univariate but not on multivariate analysis. Patients who were treated at an academic center were more likely to undergo surgical resection (49% vs 38%, p<0.001) and more likely to undergo gross total resection (9% vs 6%, p<0.001). The importance of surgery, and where a patient undergoes evaluation/treatment, should not be underestimated in elderly patients. While previous factors to determine treatment strategies such as age, medical comorbidities, surgical resection, histology, and location are significant in older patients, tumor size may not be. Further studies are needed to better define how to optimize treatment outcomes for elderly patients with low-grade gliomas.

Abstract 2259: Evaluation of polymorphisms in myeloid-associated genes and glioma survival

Abstract BACKGROUND: Gliomas are highly infiltrated by immune cells including microglia, macrophages, and myeloid-derived suppressor cells (collectively, glioma-associated myeloid cells). These cells have been shown to be induced by the tumor to be immune-suppressive and tumor-supportive, and are a negative prognosticator for survival in mouse models. Here, we examine whether inherited variants in genes important to the function of glioma-associated myeloid cells are associated with survival following low-grade glioma diagnosis. METHODS: Subjects for this study were 484 patients with WHO grade II or grade III glioma treated at The University of Texas MD Anderson Cancer Center in Houston, Texas between 1992 and 2008 and followed up for survival through August, 2016. We selected 100 genes for analysis including transcription factors, cytokines and chemokines, receptors, enzymes, and other genes central to the function of glioma-associated myeloid cells. Genotyping was originally performed using the Illumina Human 610-Quad Bead Chip platform and 2,040 tagging SNPs as determined by Haploview Tagger software were selected for analysis with minor allele frequency (AF) ≥ 1%. Associations between selected SNPs and survival were evaluated by Cox regression analysis under an additive allelic model adjusting for age, sex, extent of surgery (biopsy only/partial resection/gross total resection), radiotherapy (yes/no), and chemotherapy (yes/no). Models were examined to ensure that proportional hazards assumptions were not violated. RESULTS: Median survival among low-grade glioma patients was 6.7 years. Age at diagnosis, extent of surgery, and having received radiotherapy or chemotherapy were each significantly associated with survival. Five SNPs were associated with survival at a significance level of p&amp;lt;0.001, and two remained significantly associated with low-grade glioma survival after adjustment for multiple comparisons (FDR-adjusted p-value (q)&amp;lt;0.10). These results indicated inferior survival for carriers of the C allele (AF=1.4%) at rs147960238 in CD163 (HR=5.47, 95% CI: 2.49-11.99, p=2.23x10-5, q=0.046) and for carriers of the G allele (AF=3.8%) at rs17138945 in MET (HR=2.27, 95% CI: 1.52-3.38, p=5.61x10-5, q=0.057). These SNPs are located in the 10th and 2nd introns of CD163 and MET, respectively. CONCLUSIONS: Here we provide preliminary evidence of an association between polymorphisms in two genes related to glioma-associated myeloid cell function and low-grade glioma survival. CD163 is a receptor that is highly expressed on macrophages and may play a role in macrophage-mediated anti-inflammatory responses, while MET is a receptor tyrosine kinase and well-studied proto-oncogene that is also involved in the expansion of myeloid-derived suppressor cell populations. Further investigation of these associations is warranted, and validation of these findings is planned in an independent population. Citation Format: Daniel I. Jacobs, Yanhong Liu, Konrad Gabrusiewicz, Spiridon Tsavachidis, E. Susan Amirian, Georgina N. Armstrong, Renke Zhou, Jun Wei, Cristina Ivan, George Calin, Michael Scheurer, Anna Dahlin, Terri Rice, Paige M. Bracci, Helen M. Hansen, John K. Wiencke, Margaret R. Wrensch, Beatrice Melin, Amy B. Heimberger, Melissa L. Bondy. Evaluation of polymorphisms in myeloid-associated genes and glioma survival [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2259. doi:10.1158/1538-7445.AM2017-2259

P10.13 Outcomes in older patients referred with low grade glioma

OBJECTIVES: To investigate the progression-free (PFS) and overall survival (OS) in patients ≥60 years old referred with a presumed diagnosis of low grade glioma (LGG). DESIGN: Neuro-oncology MDT outcomes from a single institution between 1/1/2009 and 31/12/2013 (n=7158) were retrospectively reviewed. Patients ≥ 60 years old referred with a presumed diagnosis of LGG were identified for further analysis (n=59). Where patients were still alive, overall survival was calculated up to 1/11/2016. Low grade lesions were defined as WHO grade I or II. METHODS: Data was collected from notes, electronic and summary care records for analysis to find index operation type, histology, radiological follow-up, MDT discussion, adjuvant treatments, any re- operations and dates of death. PFS and OS were calculated from this information. Results: Of 59 patients referred with presumed low grade lesions, 40 had a LGG confirmed at biopsy; 9 had a high or intermediate grade tumour identified at biopsy; 7 patients did not have a biopsy and 3 patients had an alternative diagnosis made at biopsy. Median PFS for patients with confirmed LGG was 27.2 months (range 0.1-172.8) and median OS was 36.5 months (range 0.1-222.3). 5-year survival rate in this group was 40.0% (95% CI 23.8-56.2%). In patients with intermediate and high grade tumours, median OS was 12.5 months (range 2.8-52.3) and 5-year survival rate was 11.1% (95% CI 0.5-49.3%). Conclusions: This study suggests that survival rates in older patients with LGG are significantly lower than in younger age groups, and supports the possibility of a different and more aggressive pathology.

Prognosis of older patients with low-grade glioma: A retrospective study.

Clinical behavior, treatment parameters, and prognostic factors are less well defined in older adults with low-grade gliomas (LGG). We conducted a two-institution retrospective review of older patients with LGG to better understand disease characteristics and prognosis in this population. Northwestern University (NU) and The University of Washington (UW) clinical research databases were queried for patients ≥ 50 years of age with a diagnosis of WHO grade II glioma between January 1, 2000 and December 2012 (UW). Medical records were reviewed and data relevant to diagnosis, treatment and outcomes were collected. PFS and OS with respect to prognostic factors were calculated. Log-rank test and multivariate proportional hazards models were calculated for multiple tumor characteristics. Thirty-five patients with a diagnosis of LGG (WHO grade II) were identified; 15 women and 20 men had a median age of 55 (range 50-78). Fourteen had astrocytomas, fourteen had oligodendrogliomas and seven had oligoastrocytomas. Eight patients had contrast enhancement on neuroimaging, 9 of 21 tested had 1p19q co-deletion and 5 of 14 tested had an IDH1 mutation. Five year PFS was 21% with median PFS of 17 months; 20 patients had died (5 year OS=43%, median OS=48 months). On univariate analysis There was a statistically significant improvement in OS for patients with mixed histology (p=0.001), no midline shift at diagnosis (p=0.002) and with IDH1 mutation (p=0.003). LGG appear more aggressive in older patients. Treatment following surgical resection should be considered; ongoing studies may clarify the most appropriate treatments for this age group.

A PERMANENT NEUROSURGICAL CHALLENGE: LOW GRADE GLIOMAS

Introduction. The utilization of Magnetic Resonance Spectroscopy (MRS) brings an important piece of information to an overall MR study, thus aiding the physician in making an accurate assumption regarding the histological grade of a tumor. The purpose of this study is to verify the reliability of MRS in correctly diagnosing both the nature of tumors and their grade. Material and methods. This is an observational study that was conducted from January 2011 to June 2016 on 49 patients confirmed to be low-grade gliomas (LGG) by pathological examination, who were admitted in our Neurosurgery Department in this period. Both retrospective and prospective data were collected. Inclusion criteria comprise unique tumoral lesion at the moment of diagnosis, follow-up for at least one year. Exclusion criteria included: other types of tumors with any location, patient refusal to undergo histopathological examination of the resected tissue, uncompliant and non-collaborating patients. Of all patients, 22 were subjected to an MRS study which suggested the presence of a low-grade glioma subsequently confirmed by the pathological examination. Results. MRS has been shown to provide accurate non-invasive diagnosis of LGG’s, by analyzing the concentration of metabolites inside the lesions which tend to be specific for these tumours: relatively elevated levels of N-acetylaspartate and creatine with reduced levels in the concentration of choline and absent lipids and lactate. It has also been observed that pre-operative MRS assists the physician in selecting the optimal place for biopsy, so that the pathological examination provides conclusive results. Conclusions. With the increased availability of MRI technology, MRS comes as a milestone in the advancement of more accurate and patient-friendly methods of diagnostic for pathologies as LGG’s which constitute a permanent challenge for neurosurgeons. The results of this study underlines the importance of MRS as a method for follow up patients with LGG, but cannot replace the need for obtaining bioptic tissue for pathological examination, especially after the new grading system of WHO, which was published in June 2016. This new grading system takes into account the molecular biology in predicting the natural history of cerebral tumours.

A Dual Tracer 18F-FCH/18F-FDG PET Imaging of an Orthotopic Brain Tumor Xenograft Model.

Early diagnosis of low grade glioma has been a challenge to clinicians. Positron Emission Tomography (PET) using 18F-FDG as a radio-tracer has limited utility in this area because of the high background in normal brain tissue. Other radiotracers such as 18F-Fluorocholine (18F-FCH) could provide better contrast between tumor and normal brain tissue but with high incidence of false positives. In this study, the potential application of a dual tracer 18F-FCH/18F-FDG-PET is investigated in order to improve the sensitivity of PET imaging for low grade glioma diagnosis based on a mouse orthotopic xenograft model. BALB/c nude mice with and without orthotopic glioma xenografts from U87 MG-luc2 glioma cell line are used for the study. The animals are subjected to 18F-FCH and 18F-FDG PET imaging, and images acquired from two separate scans are superimposed for analysis. The 18F-FCH counts are subtracted from the merged images to identify the tumor. Micro-CT, bioluminescence imaging (BLI), histology and measurement of the tumor diameter are also conducted for comparison. Results show that there is a significant contrast in 18F-FCH uptake between tumor and normal brain tissue (2.65 ± 0.98), but with a high false positive rate of 28.6%. The difficulty of identifying the tumor by 18F-FDG only is also proved in this study. All the tumors can be detected based on the dual tracer technique of 18F-FCH/ 18F-FDG-PET imaging in this study, while the false-positive caused by 18F-FCH can be eliminated. Dual tracer 18F-FCH/18F-FDG PET imaging has the potential to improve the visualization of low grade glioma. 18F-FCH delineates tumor areas and the tumor can be identified by subtracting the 18F-FCH counts. The sensitivity was over 95%. Further studies are required to evaluate the possibility of applying this technique in clinical trials.

The effect of pregnancy on survival in a low-grade glioma cohort.

OBJECTIVE The impact of pregnancy on survival in female patients with low-grade glioma (LGG) is unknown and controversial. The authors designed a retrospective cohort study on prospectively collected registry data to assess the influence of pregnancy and child delivery on the survival of female patients with LGG. METHODS In Norway, the reporting of all births and cancer diagnoses to the Medical Birth Registry of Norway (MBRN) and the Cancer Registry of Norway (CRN), respectively, is compulsory by law. Furthermore, every individual has a unique 11-digit identification number. The CRN was searched to identify all female patients with a histologically confirmed diagnosis of World Health Organization (WHO) Grade II astrocytoma, oligoastrocytoma, oligodendroglioma, or pilocytic astrocytoma who were 16-40 years of age at the time of diagnosis during the period from January 1, 1970, to December 31, 2008. Obstetrical information was obtained from the MBRN for each patient. The effect of pregnancy on survival was evaluated using a Cox model with parity as a time-dependent variable. RESULTS The authors identified 65 patients who gave birth to 95 children after an LGG diagnosis. They also identified 281 patients who did not give birth after an LGG diagnosis. The median survival was 14.3 years (95% CI 11.7-20.6 years) for the entire study population. The effect of pregnancy was insignificant in the multivariate model (HR 0.71, 95% CI 0.35-1.42). CONCLUSIONS Pregnancy does not seem to have an impact on the survival of female patients with LGG.

The role of imaging in the management of adults with diffuse low grade glioma: A systematic review and evidence-based clinical practice guideline.

What is the optimal imaging technique to be used in the diagnosis of a suspected low grade glioma, specifically: which anatomic imaging sequences are critical for most accurately identifying or diagnosing a low grade glioma (LGG) and do non-anatomic imaging methods and/or sequences add to the diagnostic specificity of suspected low grade gliomas? These recommendations apply to adults with a newly diagnosed lesion with a suspected or histopathologically proven LGG. In patients with a suspected brain tumor, the minimum magnetic resonance imaging (MRI) exam should be an anatomic exam with both T2 weighted and pre- and post-gadolinium contrast enhanced T1 weighted imaging. CRITICAL IMAGING FOR THE IDENTIFICATION AND DIAGNOSIS OF LOW GRADE GLIOMA: In patients with a suspected brain tumor, anatomic imaging sequences should include T1 and T2 weighted and Fluid Attenuation Inversion Recovery (FLAIR) MR sequences and will include T1 weighted imaging after the administration of gadolinium based contrast. Computed tomography (CT) can provide additional information regarding calcification or hemorrhage, which may narrow the differential diagnosis. At a minimum, these anatomic sequences can help identify a lesion as well as its location, and potential for surgical intervention. IMPROVEMENT OF DIAGNOSTIC SPECIFICITY WITH THE ADDITION OF NON-ANATOMIC (PHYSIOLOGIC AND ADVANCED IMAGING) TO ANATOMIC IMAGING: Class II evidence from multiple studies and a significant number of Class III series support the addition of diffusion and perfusion weighted MR imaging in the assessment of suspected LGGs, for the purposes of discriminating the potential for tumor subtypes and identification of suspicion of higher grade diagnoses. Multiple series offer Class III evidence to support the potential for magnetic resonance spectroscopy (MRS) and nuclear medicine methods including positron emission tomography and single-photon emission computed tomography imaging to offer additional diagnostic specificity although these are less well defined and their roles in clinical practice are still being defined. Which imaging sequences or parameters best predict the biological behavior or prognosis for patients with LGG? These recommendations apply to adults with a newly diagnosed lesion with a suspected or histopathologically proven LGG. Anatomic and advanced imaging methods and prognostic stratification Multiple series suggest a role for anatomic and advanced sequences to suggest prognostic stratification among low grade gliomas. Perfusion weighted imaging, particularly when obtained as a part of diagnostic evaluation (as recommended above) can play a role in consideration of prognosis. Other imaging sequences remain investigational in terms of their role in consideration of tumor prognosis as there is insufficient evidence to support more formal recommendations as to their use at this time. What is the optimal imaging technique to be used in the follow-up of a suspected (or biopsy proven) LGG? This recommendation applies to adults with a newly diagnosed low grade glioma. In patients with a diagnosis of LGG, anatomic imaging sequences should include T2/FLAIR MR sequences and T1 weighted imaging before and after the administration of gadolinium based contrast. Serial imaging should be performed to identify new areas of contrast enhancement or significant change in tumor size, which may signify transformation to a higher grade. Advanced imaging utility may depend on tumor subtype. Multicenter clinical trials with larger cohorts are needed. For astrocytic tumors, baseline and longitudinal elevations in tumor perfusion as assessed by dynamic susceptibility contrast perfusion MRI are associated with shorter time to tumor progression, but can be difficult to standardize in clinical practice. For oligodendrogliomas and mixed gliomas, MRS may be helpful for identification of progression.

Advanced MRI may complement histological diagnosis of lower grade gliomas and help in predicting survival.

MRI grading of grade II and III gliomas may have an important impact on treatment decisions. Occasionally,both conventional MRI (cMRI) and histology fail to clearly establish the tumour grade. Three cMRI features(no necrosis; no relevant oedema; absent or faint contrast enhancement) previously validated in 196 patients with supratentorial gliomas directed our selection of 68 suspected low-grade gliomas (LGG) that were also investigated by advanced MRI (aMRI), including perfusion weighted imaging (PWI), diffusion weighted imaging(DWI) and spectroscopy. All the gliomas had histopathological diagnoses. Sensitivity and specificity of cMRI preoperative diagnosis were 78.5 and 38.5 %, respectively, and 85.7 and 53.8 % when a MRI was included, respectively. ROC analysis showed that cut-off values of 1.29 for maximum rCBV, 1.69 for minimum rADC, 2.1 for rCho/Cr ratio could differentiate between LGG and HGG with a sensitivity of 61.5, 53.8, and 53.8 % and a specificity of 54.7, 43 and 64.3 %, respectively. A significantly longer OS was observed in patients with a maximum rCBV<1.46 and minimum rADC>1.69 (80 vs 55 months, p = 0.01; 80 vs 51 months, p = 0.002, respectively). This result was also confirmed when cases were stratified according to pathology (LGG vs HGG). The ability of a MRI to differentiate between LGG and HGG and to predict survival improved as the number of a MRI techniques considered increased. In a selected population of suspected LGG,classification by cMRI underestimated the actual fraction of HGG. aMRI slightly increased the diagnostic accuracy compared to histopathology. However, DWI and PWI were prognostic markers independent of histological grade.

Use of Magnetic Resonance Spectroscopy of the Brain to Differentiate Low Grade Glioma and its Clinical Relevance

Background and purpose: Nuclear magnetic resonance (NMR) spectroscopic examination plays an important role in diagnosis of low grade gliomas. We compared the spectroscopic examination with the histopathological results of low grade gliomas concerning its reliability and their clinical relevance. Materials and methods: The charts of 29 patients with low grade gliomas were collected. Only in 19 cases of them an NMR-spectroscopic examination was performed. Due to choline, N-acetylaspartate (NAA) and lipid content the gliomas were classified into astrocytoma WHO II or III or in low or high grade gliomas. After stereotactic biopsy or neurosurgical removal histopathological examination was performed. Results: We found 18 astrocytomas WHO II and 1 oligodendroglioma WHO II at the histopathological examination. In the spectroscopic examination we found 13 low grade gliomas II and 6 high grade gliomas. 68.4% of the 19 low grade gliomas WHO II correspond to the spectroscopic examination. 6 cases showed high choline contents suitable for high grade glioma and one of them with very high choline content which correspond to a glioblastoma. These tumours were classified as low grade gliomas WHO II in the histopathological examination. Conclusion: We compared the NMR-spectroscopic findings with the histopathological results of the tumours. The actual spectroscopical method does not seem to be reliable enough in the diagnosis of low grade gliomas but can play an important role in assessing the clinical condition and follow-up. Whether the NMR-spectroscopic findings correlate with the clinical course better than with the histopathological findings remains to be clarified.

Health related quality of life (HRQOL) in long-term survivors of pediatric low grade gliomas (LGGs).

The purpose of this study was to assess the health-related quality of life (HRQOL) and the impact of treatment on HRQOL in long-term survivors of pediatric low-grade gliomas (LGGs) using an adult instrument. QOL of 121 patients with a diagnosis of LGG from the Mayo Clinic were assessed using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC-QLQ-C30 for cancer in general) and (EORTC QLQ-BN20 specific for brain tumors). Median follow-up was 21.9 years for the participants. Median age at diagnosis was 11.8 years and at assessment was 33 years. Mean (standard deviation) global QOL score for the study was 78 (18) and 76.4 (22.8) in a reference population of healthy adults. Using QLQ-C30, radiation treated patients compared to non-radiation patients reported lower physical functioning (p = 0.002), role functioning (p = 0.004), and more constipation problems (p < 0.001). Patients with tumor recurrence reported lower role functioning (p = 0.016), social functioning (p = 0.040), and more financial problems (p = 0.029) compared to their counterparts. Using QLQ-BN20, patients with deep tumors compared to cortical tumors reported more bladder control problems (p = 0.016). Radiation treated patients also reported more bladder control problems (p < 0.001) compared to their counterparts. In the multivariable analysis, radiation therapy remained an independent predictor of physical and role functioning as well as symptoms related to brain tumors like visual disorders and motor dysfunction. Global QOL of long-term survivors of pediatric LGGs is similar to that of a reference population of healthy adults. The following tumor and treatment related factors were most consistently associated with poorer QOL: CNS tumor location, post-operative radiation, and tumor recurrence. Future studies are necessary to identify strategies to improve QOL in this subgroup of patients.

AT-44 * RELEARNING NEURO-ONCOLOGY: BAYES' THEOREM PROVIDES A NEW WORLD ORDER

INTRODUCTION: All clinicians are Bayesian theoreticians, and implicitly use this calculus to make all treatment decisions . We explicitly applied Bayes' theorem to the most compelling randomized controlled trials (RCTs) in the field of neuro-oncology and discovered that our most widely accepted paradigms are incorrect. METHODS: We analyzed all high quality RCTs addressing: 1.) extent of resection for high-grade glioma; 2). Stupp regimen for newly diagnosed GBM; 3.) upfront bevacizumab for GBM; 4.) anticonvulsant prophylaxis for brain tumors; 5.) PCI in non-small cell lung cancer; and 6.) radiation at the time of diagnosis of low grade glioma. We applied Bayesian logic to trials sequentially in the order that they were published assuming various initial convictions ranging from true believer to confirmed with respect to belief in the current paradigm. We also calculated the characteristics of a RCT that would be required to change a clinician's mind. RESULTS: Bayesian analysis of the literature shows that clinicians should reasonably have a very strong conviction in favor of aggressive resection (despite flawed trials); Stupp regimen (despite only one RCT); and bevacizumab treatment at diagnosis (despite two conflicting RCTs). The study size, significance and power required to change a clinician's mind about these questions are nearly unattainable. Despite five RCTs, no clinicians' minds should be changed regarding anticonvulsant prophylaxis. Changing a skeptic to an advocate of prophylaxis with a new RCT should be easy. CONCLUSION: Explicit and unbiased application of Bayes' theorem to the most compelling studies in the field of neuro-oncology reveals profound flaws in our understanding of the most cherished tenants of neuro-oncology patient care.

P17.24 * OUTCOME OF GLIOBLASTOMA IN YOUNG PATIENTS: A SINGLE INSTITUTION EXPERIENCE

GBM is the most frequent brain tumor affecting adults. More than 80% of the patients are older than 50. Unfortunately the prognosis remains poor with a median overall survival of 14.6% and a 5 years survival of 9.8%. Between January 2002 and November 2013, 16 patients (7 men and 9 women; median age 40; range 26-50) affected by GBM were followed at our Institution. All patients had a diagnosis of GBM. Thirteen patients (81%) had a primary GBM, 3 patients (19%) had a secondary GBM arising from a low grade glioma diagnosed 3.6 years before (1-6 years). Eleven patients were radically operated (69%), 5 patients were submitted to partial exeresis (31%). After surgery, 13 patients (81%) received concomitant chemo- and radiotherapy (RT) (Stupp regimen); 3 patients were not submitted to RT (19%) as they received it years before, after the diagnosis of low grade glioma. Among the patients receiving chemoRT, 12 patients (92%) were submitted to adjuvant chemotherapy following Stupp regimen (number of cycles: 3-12), 1 patient (8%) died before starting adjuvant chemotherapy due to disease progression. Among the patients with a secondary GBM, 2 (67%) received Temozolomide as adjuvant treatment post-surgery, 1 patients (33%) received BCNU chemotherapy. Median time to progression (TTP) among the patients having completed adjuvant chemotherapy is 20 months (range 3-108). Among all the 16 patients described, 7 patients (44%) are alive at a median time of 32.7 months (range 6-90), 9 patients (56%) died and had a median overall survival (OS) of 27.4 months (range 4-108). Globally, patients under 50 affected by GBM have a longer median TTP and OS than patients over 50. Such a situation can be determined by the best Perfomance Status, the absence of comorbidities and the best physical reserve of the patients under 50 compared to the ones of older patients. Further studies are needed to evaluate the outcome of GBM in patients under 50.

Is the volume of low-grade glioma measurable and is it clinically relevant?

Is the volume of low-grade glioma measurable and is it clinically relevant?

The Cancer Genome Atlas expression profiles of low-grade gliomas.

Differentiating between low-grade gliomas (LGGs) of astrocytic and oligodendroglial origin remains a major challenge in neurooncology. Here the authors analyzed The Cancer Genome Atlas (TCGA) profiles of LGGs with the goal of identifying distinct molecular characteristics that would afford accurate and reliable discrimination of astrocytic and oligodendroglial tumors. They found that 1) oligodendrogliomas are more likely to exhibit the glioma-CpG island methylator phenotype (G-CIMP), relative to low-grade astrocytomas; 2) relative to oligodendrogliomas, low-grade astrocytomas exhibit a higher expression of genes related to mitosis, replication, and inflammation; and 3) low-grade astrocytic tumors harbor microRNA profiles similar to those previously described for glioblastoma tumors. Orthogonal intersection of these molecular characteristics with existing molecular markers, such as IDH1 mutation, TP53 mutation, and 1p19q status, should facilitate accurate and reliable pathological diagnosis of LGGs.

Association of carcinoid tumor and low grade glioma

BackgroundLung carcinoid tumor and low grade glioma are two uncommon malignancies.Patients and methodsWe report the case of 24-year-old man who presented with respiratory disease. Imaging investigations showed a right lung tumor and histological analysis confirmed a typical carcinoid tumor. As part of initial staging, brain MRI revealed an asymptomatic right frontal lesion. First, a right pulmonary lobectomy was performed without adjuvant treatment. In second time, brain tumorectomy was performed. Histological examination confirmed the diagnosis of low grade glioma (LGG). The patient remained in complete remission 2.5 years after the initial diagnosis.ResultsThis is the first case reporting the association between LGG and lung carcinoid tumor, while no association between LGG and a systemic tumor have been published to date. Association of lung carcinoid tumor with other malignant diseases has been reported but remained uncommon. Only minimal data support a potential molecular common origin.ConclusionThis exceptional association may be fortuitous. However, their concomitant diagnoses suggest a potential association between both rare diseases. A genetic susceptibility remains possible.

Levetiracetam-induced interstitial nephritis in a patient with glioma

A 45-year-old man with a new diagnosis of low grade glioma was started on an escalating dose of levetiracetam (Lev) for seizure management. He gradually developed intractable nausea/vomiting and a high creatinine concentration due to acute renal failure which was attributed to Lev-induced interstitial nephritis. The medication was changed and his renal function rapidly improved to his baseline.

Stereotactic brachytherapy of low-grade cerebral glioma after tumor resection

The purpose of this study was to assess the impact of stereotactic brachytherapy (SBT) on survival time and outcome when applied after resection of low-grade glioma (LGG) of World Health Organization grade II. From January 1982 through December 2006 we treated 1024 patients who had glioma with stereotactic implantation of iodine-125 seeds and SBT in accordance with a prospective protocol. For the present analysis, we selected 95 of 277 patients with LGG, in whom SBT was applied to treat progressive (43 patients) or recurrent (52 patients) tumor after resection. At 24 months after seed implantation, the tumor response rate was 35.9%, and the tumor control rate was 97.3%. The median progression-free-survival (PFS) duration after SBT was 52.7 ± 7.1 months. Five-year and 10-year PFS probabilities were 43.4% and 10.7%, respectively. Malignant tumor transformation, the diagnosis "astrocytoma," and tumor volume >20 mL were significantly associated with reduced PFS. Tumor progression or relapse after SBT (53 of 95 patients) was treated with tumor resection, a second SBT, chemotherapy, and/or radiotherapy. The median overall survival duration (from the first diagnosis of LGG until the patient's last contact) was 245.0 ± 4.9 months. Patients still under observation after seed implantation had a median follow-up time of 156.4 ± 55.7 months. Perioperative transient morbidity was 1.1%, and the frequency of permanent morbidity caused by SBT was 3.3%. In conclusion, SBT of recurrent or progressive LGG after resection located in functionally critical brain areas has high local efficacy and comparably low morbidity. Referred to individually adopted glioma treatment concepts SBT provides a reasonably long PFS, thus improving overall survival. In selected patients, SBT can lead to delays in the application of chemotherapy and/or radiotherapy.