Diffuse Low-grade Gliomas Research Articles

Timing of Adjuvant Radiotherapy and Survival Analysis for Molecularly Defined Low Grade Glioma

<h3>Purpose/Objective(s)</h3> The optimal treatment for patients with diffuse low-grade glioma (LGG) is controversial. Level I evidence support the use of radiotherapy (RT) for histologic LGG, but incorporation of molecular biomarkers in the WHO classification compels additional investigation to define the optimal treatment and timing of RT. We hypothesized molecularly defined LGG (IDH-mutant astrocytoma [astro] and IDH-mutant, 1p/19q-codeleted oligodendrogliomas [oligo]) have different survival outcomes following early vs delayed RT, knowledge that may guide RT in the context of resection and chemotherapy. <h3>Materials/Methods</h3> We performed a retrospective analysis of adult patients who were newly diagnosed with a WHO Grade 2 IDH-mutant astro or IDH-mutant, 1p/19q-codel oligo and had initial resection at a single institution from Jan 1998 to Nov 2017. Wilcoxon rank sum and Chi-squared tests were used to compare continuous and categorical variables between cohorts, respectively. Survival analysis was performed using the Kaplan-Meier method. Patients without clinical progression or death were censored at last follow-up date. Pre-operative and post-operative tumor volumes were quantified using 3D Slicer and defined as the T2 FLAIR hyperintense lesion to calculate extent of resection (EOR). <h3>Results</h3> 392 patients (202 astro, 190 oligo) were analyzed with a median follow up of 9.3 yr (95% CI: 8.19–10.16). Median overall survival (OS) was 13.0 yr for astro (95% CI: 11.4 – 18.6) and not reached for oligo (95% CI: 19.9 – NA). 168 patients (42.8%) received RT during their treatment course, with the majority (84%) treated at time of first disease progression. Chemotherapy was used in 81.7% of patients who received RT (TMZ in 90.3% of cases). The median RT dose was 54 Gy (range: 40 – 60 Gy). RT was more likely for astro (51.0%) than for oligo (34.2%) (p < 0.001), and a lower median EOR was associated with RT (88% vs 95%; p = 0.017). RT was not associated with increased OS for astro (p = 0.12) or oligo (p = 0.31) for all comers. For patients < 40 yr of age who had subtotal resections of astros (< 85% EOR), RT increased median OS with a trend toward significance when compared to no RT (13.1 yr [95% CI: 7.3 – NA] vs 9.1 yr [95% CI: 5.4 – NA], p = 0.1). RT within 1 yr of diagnosis was associated with improved median PFS compared to patients who received RT after 1 yr for astro (7.0 yr [95% CI: 5.5 – NA] vs 3.6 yr [95% CI: 2.9 – 4.8], p < 0.001), but not for oligo (p = 0.4). RT within 1 yr of diagnosis increased subsequent survival following RT for astro (median 12.9 yr [95% CI: 7.9 – NA] vs 4.4 yr [95% CI: 3.4 – 8.5], p < 0.001), with a trend toward improvement for oligo (p = 0.08). Patients with astro < 40 yr of age exhibited the greatest improvement in subsequent survival following RT, when RT was delivered within 1 yr of diagnosis (0 recorded deaths out of n = 12, p = 0.001). <h3>Conclusion</h3> Retrospective data from a single institution support the use of early RT for patients < 40 yr of age with molecularly-defined astrocytomas. RT may also improve OS in this population after subtotal resection.

The Changing Landscape of Diffuse Low Grade Glioma (DLGG) Management in the West of Scotland: A Single Centres 10-Year Experience

Abstract AIMS Management strategies for patients diagnosed with diffuse low grade glioma (DLGG) remain controversial. Current evidence favours resection over biopsy. This has resulted in more aggressive intervention. We examined management trends in the West of Scotland over a 10 year period. METHOD Patients diagnosed with DLGG between 2010 and 2019 were included and grouped according to time of diagnosis: 1) 2010-2012, 2) 2013-2016 and 3) 2017-2019. Clinical characteristics, management and overall survival (OS) were investigated and comparatively analysed. Survival between resection and biopsy groups was also analysed. RESULTS 84 patients were included (n=25 in Group 1, n=35 in Group 2 and n=24 in Group 3). Biopsy was less commonly performed in Group 2 (17%) and Group 3 (21%) compared to Group 1 (56%) p=0.014. The frequency of post-operative seizures: G1: n=3 (12%), G2: n=1 (2.9%), G3: n=2 (8.3%) (p=0.385) and focal neurological deficit: G1: n=4 (16%), G2: n=8 (22.9%), G3: n=6 (25) (p=0.718) and mean length of stay (LoS) in days: G1: 7.7, G2: 8.8, G3: 7.4 (p = 0.548) were similar across the groups. Survival analysis revealed no significant difference between groups: G1 52%, G2 69%, G3 75% (p=0.172). Patients managed by resection (n=58) versus biopsy (n = 26) observed improved survival (resection OS 70% compared to biopsy OS 39% (p= 0.005)). CONCLUSION Resection results in improved survival over biopsy. This has resulted in an institutional change over time. But no significant difference was observed in OS between different time periods.

Risk factors for early progression of diffuse low-grade glioma in adults

BackgroundTo explore the risk factors for early progression of diffuse low-grade glioma in adults.MethodsA retrospective analysis of pathologic and clinical data of patients diagnosed with diffuse low-grade gliomas at Southwest Hospital between January 2010 and December 2014. The progression-free survival (PFS) less than 60 months was classified as the early progress group, and the PFS greater than 60 months was the control group for comparative analysis.ResultsA total of 138 patients were included in this study, including 94 cases of astrocytoma and 44 cases of oligodendroglioma. There were 63 cases with 100% resection, 56 cases with 90–100% resection degree, and 19 cases with resection degree < 90%. The average follow-up time was 60 months, of which 80 patients progressed and 58 patients did not progress. The average progression-free survival was 61 months. The median progression-free survival was 60 months. There were 68 patients with PFS≤ 60 months and 70 patients with PFS > 60 months. The two groups were compared for statistical analysis. In univariate analysis, there were significant differences in tumor subtype (p = 0.005), range (p = 0.011), volume (p = 0.005), location (p = 0.000), and extent of resection (p = 0.000). Multifactor analysis shows tumor location (HR = 4.549, 95% CI: 1.324–15.634, p = 0.016) and tumor subtype (HR = 3.347, 95% CI = 1.373–8.157, p = 0.008), and imcomplete resection is factors influencing early progression of low-grade glioma.ConclusionsLow-grade gliomas involving deep location such as basal ganglia, inner capsule, and corpus callosum are more likely to progress early, while incomplete resection is a risk factor in early progression of astrocytoma.

A Personalized Longitudinal Strategy in Low-Grade Glioma Patients: Predicting Oncological and Neural Interindividual Variability and Its Changes over Years to Think One Step Ahead.

Diffuse low-grade glioma (LGG) is a rare cerebral cancer, mostly involving young adults with an active life at diagnosis. If left untreated, LGG widely invades the brain and becomes malignant, generating neurological worsening and ultimately death. Early and repeat treatments for this incurable tumor, including maximal connectome-based surgical resection(s) in awake patients, enable postponement of malignant transformation while preserving quality of life owing to constant neural network reconfiguration. Due to considerable interindividual variability in terms of LGG course and consecutive cerebral reorganization, a multistage longitudinal strategy should be tailored accordingly in each patient. It is crucial to predict how the glioma will progress (changes in growth rate and pattern of migration, genetic mutation, etc.) and how the brain will adapt (changes in patterns of spatiotemporal redistribution, possible functional consequences such as epilepsy or cognitive decline, etc.). The goal is to anticipate therapeutic management, remaining one step ahead in order to select the optimal (re-)treatment(s) (some of them possibly kept in reserve), at the appropriate time(s) in the evolution of this chronic disease, before malignization and clinical worsening. Here, predictive tumoral and non-tumoral factors, and their ever-changing interactions, are reviewed to guide individual decisions in advance based on patient-specific markers, for the treatment of LGG.

Recurrent insular low-grade gliomas: factors guiding the decision to reoperate.

Reoperation has been established as an effective therapeutic strategy in recurrent diffuse low-grade gliomas (LGGs). Insular gliomas represent a specific surgical challenge because of the surrounding vascular and functional structures. The aim of this study was to investigate the main clinicoradiological factors guiding the decision to reoperate on recurrent insular LGGs (ILGGs). In this retrospective consecutive series, the authors screened all patients operated on for an ILGG in their institution who further presented with a tumor regrowth without the development of contrast enhancement. They compared patients who were subsequently offered a reoperation under awake mapping at recurrence or who underwent reoperation after adjuvant treatment had reduced the volume of the initial tumor recurrence (with a proven pathological diagnosis of LGG after the second surgery) to patients who were not selected for a reoperation. The first group (reoperated group; n = 20) included all recurrent ILGG patients who underwent second resection, and the second group (nonreoperated group; n = 60) included patients who did not undergo reoperation but underwent adjuvant oncological treatment. Factors significantly associated with reoperation were extent of resection (EOR) at first surgery (91.9% vs 89.7%, p = 0.014), residual tumor volume (9.5 ± 7.1 mL [range 0-30 mL] vs 6.3 ± 7.3 mL [range 0-30 mL], p = 0.02) at first surgery and left temporopolar infiltration at the time of tumor recurrence (Liebermeister statistical analysis, 4293 voxels survived false discovery rate correction with p < 0.05; maximal z-statistic = 6.50). Infiltration of the anterior perforated substance at tumor recurrence was significantly anticorrelated to reoperation (179 voxels survived false discovery rate correction with p < 0.05; minimal z-statistic = -4.33). The mean EOR was 83.7% at reoperation with a 90% survival rate at last follow-up (9.3 ± 3.8 years), low postsurgical morbidity (Karnofsky Performance Status score ≥ 80 in 95% of patients), a high rate of postoperative professional resumption (95%), and seizure control in 57.1% of patients. In selected patients with recurrent ILGG without radiographic evidence of malignant transformation, reoperation with intraoperative awake mapping is associated with favorable oncological outcomes and a low postsurgical morbidity. A greater EOR and a lower residual tumor volume at first surgery were significantly associated with reoperation. Patients who benefited from a second surgery typically had a recurrent pattern within cortical areas (such as the temporopolar region), while other patients typically presented with a deeper infiltrative pattern within the anterior perforated substance and the surrounding white matter pathways. Such original findings may be helpful to select the optimal indications of reoperation in recurrent ILGG.

An analysis of prognostic factors in a cohort of low-grade gliomas and degree of consistency between RTOG and EORTC scores

Due to their rarity and heterogeneity and despite the introduction of molecular features in the current WHO classification, clinical criteria such as those from the European Organization for Research and Treatment of Cancer (EORTC) and the Radiation Therapy Oncology Group (RTOG) are still being used to make treatment decisions in low-grade gliomas (LGG). Patients with diffuse low-grade glioma treated at our institution between 2002 and 2018 were analyzed, retrieving and assessing the degree of consistency between the EORTC and RTOG criteria, as well as the isocitrate dehydrogenase 1 and 2 (IDH) gene mutational status. Likewise, multivariate analyses were performed to ascertain the superiority of any of the factors over the others. One hundred and two patients were included. The degree of consistency between the RTOG and EORTC criteria was 71.6% (K = 0.426; p = 0.0001). Notably, 51.7% of those assigned to low risk by the EORTC were classified as high risk according to the RTOG classification. In multivariate analysis, only complete resection, age > 40 years, size and IDH mutation status were independently correlated with OS. When the RTOG and EORTC scores were entered into the model, only the EORTC model was independently associated with mortality. The degree of consistency between the EORT and RTOG criteria is low. Therefore, there is a need to integrate clinical-molecular scores to improve treatment decisions in LGG.

Incidental diffuse low-grade gliomas: A systematic review and meta-analysis of treatment results with correction of lead-time and length-time biases.

Better overall survival (OS) reported in patients with incidental diffuse low-grade glioma (iLGG) in comparison to symptomatic LGG (sLGG) may be overestimated by lead-time and length-time. We performed a systematic review and meta-analysis of studies on adult hemispheric iLGGs according to the PRISMA statement to adjust for biases in their outcomes. Survival data were extracted from Kaplan-Meier curves. Lead-time was estimated by 2 methods: Pooled data of time to become symptomatic (LTs) and time calculated from the tumor growth model (LTg). We selected articles from PubMed, Ovid Medline, and Scopus since 2000. Five compared OS between patients with iLGG (n = 287) and sLGG (n = 3117). The pooled hazard ratio (pHR) for OS of iLGG to sLGG was 0.40 (95% confidence interval [CI] {0.27-0.61}). The estimated mean LTs and LTg were 3.76 years (n = 50) and 4.16-6.12 years, respectively. The corrected pHRs were 0.64 (95% CI [0.51-0.81]) by LTs and 0.70 (95% CI [0.56-0.88]) by LTg. In patients with total removal, the advantage of OS in iLGG was lost after the correction of lead-time. Patients with iLGG were more likely to be female pooled odds ratio (pOR) 1.60 (95% CI [1.25-2.04]) and have oligodendrogliomas (pOR 1.59 [95% CI {1.05-2.39}]). Correction of the length-time bias, which increased the pHR by 0.01 to 0.03, preserved the statistically significant difference in OS. The reported outcome in iLGG was biased by lead-time and length-time. Although iLGG had a longer OS after correction of biases, the difference was less than previously reported.

P12.01.B Systemic metabolic features associated with significant insulin resistance in diabetes mellitus type 2 patients are related to the presence of gemistocytes in glioblastoma

Abstract Background Gemistocytes (GCs) are unique phenotype of reactive astrocytes. In diffuse low-grade gliomas, they are associated with grim prognosis. Less is known regarding their pathogenesis and prognostic significance in glioblastoma (GBM). Previous data on-neoplastic central nervous system (CNS) lesions has linked the presence of GCs with states of uncontrolled hyperglycaemia in diabetes mellitus type 2 patients. study purpose is to find a correlation between systemic metabolic features and the presence of GCs in patients with GBM.Also, to try and correlate between the presence of GCs, molecular changes, and use of anti-diabetic drugs on overall survival of GBM patients. Methods Electronic medical records from newly diagnosed GBM patients were retrospectively reviewed and extracted for demographic, clinical, metabolic, radiological and pathological variables with emphasis on different metabolic - related features. A statistic-based comparison was made between GBM patients with and without GCs for the same variables. We compared DM2 GC-GBM patients to DM2 non-GC GBM patients in a cohort of poorly controlled DM2 (i.e., HBA1C ≥ 8.0). A possible influence of metformin administration on OS of DM2 GBM patients, with and without GCs, and with and without TP53 mutations was investigated. Results A total of 220 patients with newly diagnosed GBM were included in the study. 14.5% were defined as GC-GBM (group 1, n=32) and 85.5% were defined as non-GC GBM (group 2, n=188). The incidence of DM2 was 25% in both groups. The rate of poorly-controlled DM2 was nearly as twice in group 1 than in group 2 (18.75% vs. 9.5%; p=0.130). In the DM2 GBM group, significant differences were found between DM2 GC-GBM (group 1a, n=9) and DM2 non-GC GBM (group 2a, n=49) patients with male gender predominance (89% vs. 50%, p=0.073) and obesity. Patients in group 1a were more likely to have weight ≥85kg (OR 6.16; 95% CI 1.3336 to 28.5147, p=0.0019) and had higher BMI values (mean BMI of 34.1±11.42 vs. 28.7±5.44 for group 1a and 2a respectively; OR= 1.095, 95%CI 1.053-1.207;p=0.034). Similar significant findings were in the poorly-controlled DM2 subgroup. None of the poorly-controlled DM2 GC-GBM patients were using insulin prior to diagnosis (0% vs. 61.10%, p=0.016). Survival analyses have shown trends for differences in overall survival between subgroups in correlation with presence of GCs, p53 mutations and use of metformin. Conclusion GBM patients with systemic metabolic factors that are associated with marked insulin resistance and are not using insulin at time of diagnosis are significantly more likely to have GCs in their initial pathology. This is a novel finding that may add to data on glucose metabolism in astrocytes and in astrocytes-associated tumors. The presence of GCs, molecular changes in the tumor, and under the influence of anti-diabetic drugs such as metformin, may affect the prognosis of different GBM subgroups.

P01.15.A Longitudinal assessment of neurocognition and quality of life in low-grade glioma patients receiving first-line Temozolomide

Abstract Background While maximal safe resection is the first therapeutic option in patients with newly-diagnosed diffuse low-grade glioma (DLGG), the timing and choice of further treatments (chemotherapy, radiation therapy or combinations of both) remain controversial. Because the expected survival is long in these young patients, the oncological impact of treatments must be balanced with the possible side effects, in particular regarding neurocognitive functioning and quality of life (QoL). Temozolomide (TMZ), an alkylating agent, is widely used in this setting. Here we aimed at evaluating the feasibility of a longitudinal neurocognitive and QoL assessment in DLGG patients receiving TMZ. Material and Methods We conducted a prospective study including adult DLGG patients receiving TMZ as first-line treatment after surgical resection(s) or biopsy. Neurocognition and QoL were evaluated longitudinally until progression. The feasibility was evaluated in terms of participation and compliance of a complete neurocognitive and QoL assessment (defined as the completion of these assessments at baseline, 6 months and 12 months). Secondary objectives were the description of the proportion of patients with changes in neurocognitive or QoL scores on TMZ. Results Of 29 eligible patients, 26 accepted to enter the study (participation rate 86.7%): 57.7% men, median age 45y. Tumor type was distributed as follows: astrocytoma, IDH-mutant 13/26, astrocytoma, IDH wild-type 1/26 and oligodendroglioma, IDH mutant and 1p19q codeleted 12/26. The compliance rate was 95.6% (evaluable in 23 patients as 3 patients had tumor progression within the first 12 months of TMZ). After TMZ, 13.6% of patients experienced a decline of the MoCA score as compared to baseline (from normal to abnormal). Cognitive complaints according to the FACT-COG assessment were stable for 90.9%. The complete cognitive and QoL evaluations (baseline and after 12 months of TMZ) will be presented. Conclusion Our data shows that a longitudinal evaluation of cognition and QoL is feasible in low-grade glioma patients. It suggests that first-line TMZ does not negatively affect neurocognition and QoL. These results must be evaluated in the long-term setting (evaluations ongoing) and confirmed in a larger, multicenter cohort.

P11.62.A The link between gliomas infiltrationandwhite matter architecture investigated with electron microscopy and diffusion tensor imaging

Abstract Background Diffuse low-grade gliomas (DLGG) display different preferential locations in eloquent and secondary associative brain areas. The reason for this tendency is still unknown. We hypothesized that the intrinsic architecture and water diffusion properties of the white matter bundles in these regions may facilitate gliomas infiltration. Material and Methods Magnetic resonance imaging of sixty-seven diffuse low-grade gliomas patients were normalized to/and segmented in MNI space to create three probabilistic infiltration weighted gradient maps according to the molecular status of each tumor group (IDH mutated, IDH wild-type and IDH mutated/1p19q co-deleted). Diffusion tensor imaging (DTI)- based parameters were derived for five major white matter bundles, displaying regional differences in the grade of infiltration, averaged over 20 healthy individuals acquired from the Human connectome project (HCP) database. Transmission electron microscopy (TEM) was used to analyze fiber density, fiber diameter and g-ratio in 100 human white matter regions, sampled from cadaver specimens, reflecting areas with different gliomas infiltration in each white matter bundle. Histological results and DTI-based parameters were compared in anatomical regions of high- and low grade of infiltration (HIF and LIF) respectively. Results We detected differences in the white matter infiltration of five major white matter bundles in three groups. IDHm infiltrated left fronto-temporal subcortical areas. IDHwt were detected in the posterior-temporal and temporo-parietal regions bilaterally. IDHm/1p19q infiltrated anterior subcortical regions of the frontal lobes bilaterally. Regional differences within the same white matter bundles were detected by both TEM- and DTI analysis linked to different topographical variables. Our multimodal analysis showed that HIF regions, common to all the groups, displayed a smaller fiber diameter, lower FA and higher RD compared with LIF regions. Conclusion Our results suggest that the both morphological features and diffusion parameters of the white matter may be different in regions linked to the preferential location of DLGG.

The need to consider return to work as a main outcome in patients undergoing surgery for diffuse low-grade glioma: a systematic review.

For a long time, return to work (RTW) has been neglected in patients harboring a diffuse low-grade glioma (LGG). However, a majority of LGG patients worked at time of diagnosis. Moreover, these patients now live longer given current treatment paradigms, especially thanks to early maximal surgery. We systematically searched available medical databases for studies that reported data on RTW in patients who underwent resection for LGG. A total of 30 studies were selected: 19 considered RTW (especially rate and timing) as an outcome and 11 used scales of health-related quality of life (HRQoL) which included work-related aspects. Series that considered RTW as a main endpoint were composed of 1014 patients, with postoperative RTW rates ranging from 31 to 97.1% (mean 73.1%). Timing to RTW ranged from 15days to 22months (mean 6.3months). Factors related to an increased proportion of RTW were: younger age, better neurologic status, having a white-collar occupation, working pre-operatively, being the sole breadwinner, the use of awake surgery, and greater extent of resection. Female sex, older age, poor neurologic status, pre-operative history of work absences, slow lexical access speed, and postoperative seizures were negatively related to RTW. No studies that used HRQoL scales directly investigated RTW rate or timing. RTW was scarcely analyzed in LGG patients who underwent resection. However, because they are usually young, with no or only mild functional deficits and have a longer life expectancy, postoperative RTW should be assessed more systematically and accurately as a main outcome. As majority (61.5-100%) of LGG patients were working at time of surgery, the responsibility of neurosurgeons is to bring these patients back to their previous activities according to his/her wishes. RTW might also be included as a critical endpoint for future prospective studies and randomized control trials on LGGs.

Long-term wellbeing and neurocognitive functioning of diffuse low-grade glioma patients and their caregivers: A longitudinal study spanning two decades.

While patients with diffuse low-grade glioma (LGG) often survive for years, there is a risk of tumor progression which may impact patients' long-term health-related quality of life (HRQOL) and neurocognitive functioning (NCF). We present a follow-up of LGG patients and their informal caregivers (T3) who took part in our previous HRQOL investigations (T1, M = 7 and T2 M = 13 years after diagnosis). Participants completed HRQOL (short form-36 health survey [SF-36]; EORTC-BN20), fatigue (Checklist Individual Strength [CIS]), and depression (Center for Epidemiological Studies-Depression [CES-D]) questionnaires and underwent NCF assessments. T3 scores were compared with matched controls. Changes over time (T1-T2-T3) on group and participant level were assessed. Where available, histology of the initial tumor was revised and immunohistochemical staining for IDH1 R132H mutant protein was performed. Thirty patients and nineteen caregivers participated. Of N = 11 with tissue available, 3 patients had confirmed diffuse LGG. At T3, patients (M = 26 years after diagnosis) had HRQOL and NCF similar to, or better than controls, yet 23.3% and 53.3% scored above the cut-off for depression (≥16 CES-D) and fatigue (≥35 CIS), respectively. Caregivers' HRQOL was similar to controls but reported high rates of fatigue (63.2%). Over time, patients' mental health improved (P < .05). Minimal detectable change in HRQOL over time was observed in individual patients (30% improvement; 23.3% decline; 20% both improvement and decline) with 23.3% remaining stable. NCF remained stable or improved in 82.8% of patients. While HRQOL and NCF do not appear greatly impacted during long-term survivorship in LGG, depressive symptoms and fatigue are persistent.

Editors' Note: Effect of Levetiracetam Use Duration on Overall Survival of Isocitrate Dehydrogenase Wild-Type Glioblastoma in Adults: An Observational Study

Dr. Pallud et al. investigated whether the duration of levetiracetam use during the standard chemoradiation protocol affected the overall survival of patients with IDH wild-type glioblastoma in an observational single-center cohort study of 460 patients. Levetiracetam use during the whole duration of the standard chemoradiation protocol independently predicted longer overall survival, and the authors concluded that levetiracetam should be considered in the antitumor strategy of future multicenter trials. In response, Dr. Mazzucchi et al. comment that because levetiracetam was likely initiated in these patients for new epilepsy or epilepsy resistant to other drugs, the study findings reinforce the hypothesis that uncontrolled epilepsy may be a risk factor for glioma progression. They also note that other antiseizure medications have been reported to display experimental antitumoral properties. Nevertheless, they caution against starting levetiracetam in patients without a prior history of seizures. Responding to these comments, the authors note that epilepsy was actually associated with improved survival in patients with glioblastomas and diffuse low-grade gliomas in their previous study. They emphasize that the discrepant findings among studies may relate to their focus on seizure control at the time of diagnosis rather than postoperatively. They also note that there were only a few patients without seizures who were on levetiracetam in their study. They agree that randomized controlled trials are needed to clarify the role of antiepileptic drugs in the treatment of diffuse gliomas. This exchange highlights both the promise and uncertainty presented by certain antiepileptic drugs such as levetiracetam in the treatment of patients with gliomas. Dr. Pallud et al. investigated whether the duration of levetiracetam use during the standard chemoradiation protocol affected the overall survival of patients with IDH wild-type glioblastoma in an observational single-center cohort study of 460 patients. Levetiracetam use during the whole duration of the standard chemoradiation protocol independently predicted longer overall survival, and the authors concluded that levetiracetam should be considered in the antitumor strategy of future multicenter trials. In response, Dr. Mazzucchi et al. comment that because levetiracetam was likely initiated in these patients for new epilepsy or epilepsy resistant to other drugs, the study findings reinforce the hypothesis that uncontrolled epilepsy may be a risk factor for glioma progression. They also note that other antiseizure medications have been reported to display experimental antitumoral properties. Nevertheless, they caution against starting levetiracetam in patients without a prior history of seizures. Responding to these comments, the authors note that epilepsy was actually associated with improved survival in patients with glioblastomas and diffuse low-grade gliomas in their previous study. They emphasize that the discrepant findings among studies may relate to their focus on seizure control at the time of diagnosis rather than postoperatively. They also note that there were only a few patients without seizures who were on levetiracetam in their study. They agree that randomized controlled trials are needed to clarify the role of antiepileptic drugs in the treatment of diffuse gliomas. This exchange highlights both the promise and uncertainty presented by certain antiepileptic drugs such as levetiracetam in the treatment of patients with gliomas.

Repeated Awake Surgical Resection(s) for Recurrent Diffuse Low-Grade Gliomas: Why, When, and How to Reoperate?

Early maximal surgical resection is the first treatment in diffuse low-grade glioma (DLGG), because the reduction of tumor volume delays malignant transformation and extends survival. Awake surgery with intraoperative mapping and behavioral monitoring enables to preserve quality of life (QoL). However, because of the infiltrative nature of DLGG, relapse is unavoidable, even after (supra)total resection. Therefore, besides chemotherapy and radiotherapy, the question of reoperation(s) is increasingly raised, especially because patients with DLGG usually enjoy a normal life with long-lasting projects. Here, the purpose is to review the literature in the emerging field of iterative surgeries in DLGG. First, long-term follow-up results showed that patients with DLGG who underwent multiple surgeries had an increased survival (above 17 years) with preservation of QoL. Second, the criteria guiding the decision to reoperate and defining the optimal timing are discussed, mainly based on the dynamic intercommunication between the glioma relapse (including its kinetics and pattern of regrowth) and the reactional cerebral reorganization—i.e., mechanisms underpinning reconfiguration within and across neural networks to enable functional compensation. Third, how to adapt medico-surgical strategy to this individual spatiotemporal brain tumor interplay is detailed, by considering the perpetual changes in connectome. These data support early reoperation in recurrent DLGG, before the onset of symptoms and before malignant transformation. Repeat awake resection(s) should be integrated in a global management including (neo)adjuvant medical treatments, to enhance long-lasting functional and oncological outcomes. The prediction of potential and limitation of neuroplasticity at each step of the disease must be improved to anticipate personalized multistage therapeutic attitudes.

Immunohisto Chemical Expression of IDH1, ATRX and P53 in Low Grade Diffuse Gliomas at Armed Forces Institute of Pathology, Rawalpindi

Objective: To determine the immune histochemical expression of IDH1, ATRX and p53 in low-grade diffuse gliomas.&#x0D; Study Design: Cross-sectional study.&#x0D; Place and Duration of Study: Department of Histopathology, Armed Forces Institute of Pathology, Rawalpindi Pakistan, from Jan to Jun 2020.&#x0D; Methodology: Forty-two cases of low-grade diffuse glioma were included in the study. The cases were stratified into diffuse astrocytoma and oligodendroglioma based on results of immunohistochemistry expression for IDH1, ATRX and p53.&#x0D; Results: The frontal lobe was the most commonly affected site 14 (33.3%). Based on the results of immunohistochemistry expression, 26 cases (61.9%) were diagnosed as an oligodendroglioma, while 16 cases (38.1%) were diagnosed as diffuse astrocytoma. All cases were assigned who grade II out of IV. In oligodendrogliomas, all cases (100%) were IDH1 mutants with the retained expression of ATRX and wild type expression of p53. Among the 16 cases of diffuse astrocytoma, IDH1 was mutant in 12 cases (75%), ATRX expression was lost in all cases, and p53 was mutant in 6 cases (37.5%).&#x0D; Conclusion: The study showed that low-grade diffuse gliomas could be stratified and sub-classified in accordance with the World Health Organization (WHO) classification of CNS tumours (2016) successfully by application of immunohistochemistry for IDH1, ATRX and p53.

Clinical implications of the 2021 edition of the WHO classification of central nervous system tumours.

A new edition of the WHO classification of tumours of the CNS was published in 2021. Although the previous edition of this classification was published just 5 years earlier, in 2016, rapid advances in our understanding of the molecular underpinnings of CNS tumours, including the diversity of clinically relevant molecular types and subtypes, necessitated a new classification system. Compared with the 2016 scheme, the new classification incorporates even more molecular alterations into the diagnosis of many tumours and reorganizes gliomas into adult-type diffuse gliomas, paediatric-type diffuse low-grade and high-grade gliomas, circumscribed astrocytic gliomas, and ependymal tumours. A number of new entities are incorporated into the 2021 classification, especially tumours that preferentially or exclusively arise in the paediatric population. Such a substantial revision of the WHO scheme will have major implications for the diagnosis and treatment of patients with CNS tumours. In this Perspective, we summarize the main changes in the classification of diffuse and circumscribed gliomas, ependymomas, embryonal tumours and meningiomas, and discuss how each change will influence post-surgical treatment, clinical trial enrolment and cooperative studies. Although the 2021 WHO classification of CNS tumours is a major conceptual advance, its implementation on a routine clinical basis presents some challenges that will require innovative solutions.

Sexual Dysfunction of Patients with Diffuse Low-Grade Glioma: A Qualitative Review of a Neglected Concern.

Simple SummaryPatients suffering from diffuse Low-Grade Glioma (LGG) are usually young adults and present long life expectancy thanks to multimodal therapeutic management. In this context, the preservation of quality of life (QoL) is essential, and sexual health is part of it. We reviewed here the current knowledge about sexual dysfunction in LGG patients. We highlighted how this issue has been largely neglected, despite an incidence from 44 to 62% in the rare series of the literature. Thus, there is a need to assess more systematically the occurrence of SD in clinical routine in order to adapt cancer treatments accordingly, to manage actively these troubles, and finally to improve patients’ QoL in the long run.Diffuse low-grade gliomas (LGG) commonly affect young adults and display a slow evolution, with a life expectancy that can surpass 15 years, thanks to multimodal therapeutic management. Therefore, preservation of quality of life (QoL), including sexual health, is mandatory. We systematically searched available medical databases of Pubmed, Cochrane, and Scopus for studies that reported data on sexual activity or dysfunction (SD) in LGG patients. We analyzed results to determine incidence of SD and its association with QoL in this population. Three studies focused on SD incidence in patients presenting specifically LGG, or brain tumors including LGG. They comprised 124 brain tumor patients, including 62 LGG, with SD incidence ranging from 44 to 63%. SD was reported by more than 50% of interrogated women in the three studies. Regarding QoL, two out of the three studies found significant associations between SD and alterations of QoL parameters, particularly in the field of social and functional wellbeing. Finally, we discussed those results regarding methods of evaluation, inherent biases, and therapeutic implications regarding antiseizure medications and also planning of surgery, chemo-, and radiotherapy. Our review showed that SD is highly prevalent but still poorly studied in LGG patients. As those patients are usually young and enjoy an active life, there is a need to assess more systematically the occurrence of SD in clinical routine, in order to adapt cancer treatments accordingly, to manage actively these troubles, and finally to improve patients’ QoL in the long run.

Molecular Aberrations Stratify Grade 2 Astrocytomas Into Several Rare Entities: Prognostic and Therapeutic Implications.

The identification of specific molecular aberrations guides the prognostic stratification and management of grade 2 astrocytomas. Mutations in isocitrate dehydrogenase (IDH) 1 and 2, found in the majority of adult diffuse low-grade glioma (DLGG), seem to relate to a favorable prognosis compared to IDH wild-type (IDH-wt) counterparts. Moreover, the IDH-wt group can develop additional molecular alterations worsening the prognosis, such as epidermal growth factor receptor amplification (EGFR-amp) and mutation of the promoter of telomerase reverse transcriptase (pTERT-mut). This review analyzes the prognostic impact and therapeutic implications of genetic alterations in adult LGG.

Author Response: Effect of Levetiracetam Use Duration on Overall Survival of Isocitrate Dehydrogenase Wild-Type Glioblastoma in Adults: An Observational Study.

We read with great interest the comment on our article.1 Epilepsy is associated with an improved survival in the context of glioblastomas and diffuse low-grade gliomas, as studied by our team.2 This differs from the research cited by Mazzucchi et al.3 in which persistent seizures after surgery were associated with a shorten survival. This is probably related to the fact that our study considered seizures and seizure control at diagnosis, not after surgery. The extent of resection is itself a clear predictor of both postoperative seizure control and survival, making the argument circular and difficult to analyze.

DIPG-35. Personalized treatment for molecularly heterogeneous Diffuse midline glioma, H3 k27-altered Paediatric case

Abstract Diffuse midline glioma, H3 k27-altered (DMG) is a type of Paediatric- type diffuse high grade gliomas according to the 2021 WHO CNS tumors Classification. Diffuse intrinsic pontine glioma (DIPG) is another acceptable related term when it located in the pons with fatal prognosis. The combination of H3K27M with BRAF V600 mutations rarely reported in DMG although more commonly in Paediatric-type low grade gliomas (Diffuse low-grade glioma, MAPK pathway-altered). We present a twenty-month-old boy, previously healthy, presented with 2 weeks history of unsteady gait, drooling, cranial nerves palsy MRI imaging showed diffuse pontine mass with classic radiological features of DIPG. 2.6 x 1.6 x 3.2 (AP x TV x CC) with no evidence for spinal metastases. Patient underwent right retro sigmoid approach and open biopsy of lesion he received focal Radiation Therapy 54GY/30fx as stander of care of DIPG with mild neurogical improvement Pathological &amp; molecular Diagnosis was Diffuse midline glioma, H3 k27-altered with Co-occurrence BRAF V600E mutation. Two months after end of radiation, he presented with vomiting, and neurological deterioration with new right-side hemiplegia. Imaging studies showed interval increase in the pontine lesion with increased edema causing narrowing of the fourth ventricle, no active hydrocephalus. He was started on combination therapy BRAF inhibitor Dabrafenib and MEK Inhibitor Trametinib as maintenance therapy the patient gradually showed Marked neurological and clinical improvement. A 6-month MRI after start of targeted therapy showed favorable treatment response with complete resolution of the previous diffusion restriction, reduced tumor volume on MR perfusion ,reduced perilesional edema otherwise almost stabilization of nonenhancing pontine lesion. The poor prognosis of recurrent DIPG is well known but our patient is clinically and radiologically stable with excellent quality of life and well tolerating the therapy . Our case show that personalized treatment approach that address molecular heterogeneity of H3K27M glioma are safe and feasible