Molecular Landscape for Malignant Transformation in Diffuse Astrocytoma

Abstract Background Malignant transformation (MT) of low-grade gliomas changes dramatically the natural history to poor prognosis. Currently, factors associated with MT of gliomas have been inconclusive, in particular, diffuse astrocytoma (DA). Objective The present study aims to explore the molecular abnormalities related to MT in the same patients with different MT stages. Methods Twelve specimens from five DA patients with MT were genotyped using next-generation sequencing (NGS) to identify somatic variants in different stages of MT. We used cross-tabulated categorical biological variables and compared the mean of continuous variables to assess for association with MT. Results Ten samples succussed to perform NGS from one male and four females, with ages ranging from 28 to 58 years. The extent of resection was commonly a partial resection following postoperative temozolomide with radiotherapy in 25% of cases. For molecular findings, poly-T-nucleotide insertion in isocitrate dehydrogenase 1 (IDH1) was significantly related to MT as a dose–response relationship (Mann–Whitney's U test, p = 0.02). Also, mutations of KMT2C and GGT1 were frequently found in the present cohort, but those did not significantly differ between the two groups using Fisher's exact test. Conclusion In summary, we have identified a novel relationship between poly-T insertion polymorphisms that established the pathogenesis of MT in DA. A further study should be performed to confirm the molecular alteration with more patients.

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Circumferential sulcus-guided resection technique for improved outcomes of low-grade gliomas

Journal of Neurosurgery ◽

10.3171/2021.9.jns21718 ◽

2022 ◽

pp. 1-11

Keyword(s):

Extent Of Resection ◽

Neurological Complications ◽

Low Grade ◽

Newly Diagnosed ◽

Imaging Data ◽

Volumetric Imaging ◽

Exact Test ◽

Low Grade Gliomas ◽

Presenting Symptoms ◽

Piecemeal Resection

OBJECTIVE Many neurosurgeons resect nonenhancing low-grade gliomas (LGGs) by using an inside-out piecemeal resection (PMR) technique. At the authors’ institution they have increasingly used a circumferential, perilesional, sulcus-guided resection (SGR) technique. This technique has not been well described and there are limited data on its effectiveness. The authors describe the SGR technique and assess the extent to which SGR correlates with extent of resection and neurological outcome. METHODS The authors identified all patients with newly diagnosed LGGs who underwent resection at their institution over a 22-year period. Demographics, presenting symptoms, intraoperative data, method of resection (SGR or PMR), volumetric imaging data, and postoperative outcomes were obtained. Univariate analyses used ANOVA and Fisher’s exact test. Multivariate analyses were performed using multivariate logistic regression. RESULTS Newly diagnosed LGGs were resected in 519 patients, 208 (40%) using an SGR technique and 311 (60%) using a PMR technique. The median extent of resection in the SGR group was 84%, compared with 77% in the PMR group (p = 0.019). In multivariate analysis, SGR was independently associated with a higher rate of complete (100%) resection (27% vs 18%) (OR 1.7, 95% CI 1.1–2.6; p = 0.03). SGR was also associated with a statistical trend toward lower rates of postoperative neurological complications (11% vs 16%, p = 0.09). A subset analysis of tumors located specifically in eloquent brain demonstrated SGR to be as safe as PMR. CONCLUSIONS The authors describe the SGR technique used to resect LGGs and show that SGR is independently associated with statistically significantly higher rates of complete resection, without an increase in neurological complications, than with PMR. SGR technique should be considered when resecting LGGs.

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Proposed therapeutic strategy for adult low-grade glioma based on aggressive tumor resection

Neurosurgical FOCUS ◽

10.3171/2014.10.focus14651 ◽

2015 ◽

Vol 38 (1) ◽

pp. E7 ◽

Cited By ~ 45

Author(s):

Masayuki Nitta ◽

Yoshihiro Muragaki ◽

Takashi Maruyama ◽

Soko Ikuta ◽

Takashi Komori ◽

...

Keyword(s):

Prognostic Factor ◽

Adjuvant Therapy ◽

Treatment Strategy ◽

Therapeutic Strategy ◽

Tumor Resection ◽

Extent Of Resection ◽

Partial Resection ◽

Low Grade ◽

Diffuse Astrocytoma ◽

Mib 1

OBJECT There is no standard therapeutic strategy for low-grade glioma (LGG). The authors hypothesized that adjuvant therapy might not be necessary for LGG cases in which total radiological resection was achieved. Accordingly, they established a treatment strategy based on the extent of resection (EOR) and the MIB-1 index: patients with a high EOR and low MIB-1 index were observed without postoperative treatment, whereas those with a low EOR and/or high MIB-1 index received radiotherapy (RT) and/or chemotherapy. In the present retrospective study, the authors reviewed clinical data on patients with primarily diagnosed LGGs who had been treated according to the above-mentioned strategy, and they validated the treatment policy. Given their results, they will establish a new treatment strategy for LGGs stratified by EOR, histological subtype, and molecular status. METHODS One hundred fifty-three patients with diagnosed LGG who had undergone resection or biopsy at Tokyo Women's Medical University between January 2000 and August 2010 were analyzed. The patients consisted of 84 men and 69 women, all with ages ≥ 15 years. A total of 146 patients underwent surgical removal of the tumor, and 7 patients underwent biopsy. RESULTS Postoperative RT and nitrosourea-based chemotherapy were administered in 48 and 35 patients, respectively. Extent of resection was significantly associated with both overall survival (OS; p = 0.0096) and progression-free survival (PFS; p = 0.0007) in patients with diffuse astrocytoma but not in those with oligodendroglial subtypes. Chemotherapy significantly prolonged PFS, especially in patients with oligodendroglial subtypes (p = 0.0009). Patients with a mutant IDH1 gene had significantly longer OS (p = 0.034). Multivariate analysis did not identify MIB-1 index or RT as prognostic factors, but it did identify chemotherapy as a prognostic factor for PFS and EOR as a prognostic factor for OS and PFS. CONCLUSIONS The findings demonstrated that EOR was significantly correlated with patient survival; thus, one should aim for maximum tumor resection. In addition, patients with a higher EOR can be safely observed without adjuvant therapy. For patients with partial resection, postoperative chemotherapy should be administered for those with oligodendroglial subtypes, and repeat resection should be considered for those with astrocytic tumors. More aggressive treatment with RT and chemotherapy may be required for patients with a poor prognosis, such as those with diffuse astrocytoma, 1p/19q nondeleted tumors, or IDH1 wild-type oligodendroglial tumors with partial resection.

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A Simple Panel of IDH1 and P53 in Differential Diagnosis Between Low-Grade Astrocytoma and Reactive Gliosis

Clinical Pathology ◽

10.1177/2632010x20986168 ◽

2021 ◽

Vol 14 ◽

pp. 2632010X2098616

Author(s):

Bita Geramizadeh ◽

Mahsa Kohandel-Shirazi ◽

Ahmad Soltani

Keyword(s):

Differential Diagnosis ◽

Isocitrate Dehydrogenase ◽

P53 Mutation ◽

Reactive Gliosis ◽

World Health ◽

Low Grade ◽

Diffuse Astrocytoma ◽

Glial Tumor ◽

Isocitrate Dehydrogenase 1 ◽

Who Grade

Background: Reactive gliosis is a response of glial tissue to different types of injury such as brain abscess, trauma, hemorrhage, or even neoplastic process. In some circumstances, especially when the tissue biopsy is small, there may be difficulty to discriminate this reactive condition with low-grade diffuse astrocytoma (World Health Organization [WHO] grade II) by conventional hematoxylin and eosin (H&E) slides, so some immunohistochemical and molecular markers have been introduced for this differential diagnosis. One of the important aspects of updated WHO classification in 2016 has been dividing some of the glial tumor according to IDH1 (isocitrate dehydrogenase 1) mutation. Objectives: In this study, we tried to evaluate IDH1 and P53 mutation by immunohistochemistry as a simple and highly specific and sensitive method to differentiate low-grade astrocytoma and reactive gliosis. Material and methods: For 5 years (2013-2018), 50 cases of clinically documented reactive gliosis and 50 cases of low-grade astrocytoma were evaluated for the presence or absence of IDH1 and P53 mutation by immunohistochemistry. Results: Isocitrate dehydrogenase 1 was positive in 92% and 4% of the astrocytoma and reactive gliosis cases and P53 was positive in 90% and 4% of the cases with the final diagnosis of astrocytoma and reactive gliosis, respectively. Discussion and conclusion: Combination of P53 and IDH1 as an immunohistochemical panel showed specificity of 96% and sensitivity of 91% for differential diagnosis of reactive gliosis and low-grade astrocytoma. These 2 markers can be extremely helpful for this differential diagnosis.

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A Case of Diffuse Multicentric Metachronous Astrocytoma of Temporoinsular and Intramedullary Location

Surgery Case Reports ◽

10.31487/j.jscr.2021.01.02 ◽

2021 ◽

pp. 1-4

Author(s):

Jorge Linares Torres ◽

Guillermo Ibanez Botella ◽

Antonio Selfa Rodriguez ◽

Laura Cerro Larrazabal ◽

...

Keyword(s):

Histopathological Study ◽

Low Grade ◽

Diffuse Astrocytoma ◽

High Grade ◽

Musical Ability ◽

Wild Type ◽

Isocitrate Dehydrogenase 1 ◽

Intramedullary Lesion ◽

Multicentric Gliomas ◽

Chronological Time

Multiple gliomas are rare glial tumors with a histology that is typically consistent with high-grade gliomas. A distinction is made between multifocal and multicentric gliomas according to criteria of anatomical continuity, as well as between synchronous and metachronous gliomas according to chronological time of onset. We present the case of a professional saxophonist with a left temporoinsular lesion who underwent awake craniotomy with monitoring of verbal and musical ability as well as primary sensory and motor cortices. Histopathological study revealed an isocitrate dehydrogenase 1 (IDH)-mutant diffuse astrocytoma. After 4 years of complete oncological remission, the patient developed impaired proprioception in all four extremities. An intramedullary lesion was detected at the level of C4 consistent with an IDH wild-type diffuse astrocytoma. We highlight the singularity of this case as it involved two low-grade glial lesions, separated in time (metachronous) and location (multicentric), as well as genetic differences between both lesions (IDH mutant and wild type).

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Radial expansion rates and tumor growth kinetics predict malignant transformation in contrast-enhancing low-grade diffuse astrocytoma

CNS Oncology ◽

10.2217/cns.15.16 ◽

2015 ◽

Vol 4 (4) ◽

pp. 247-256 ◽

Cited By ~ 10

Author(s):

Leith Hathout ◽

Whitney B Pope ◽

Albert Lai ◽

Phioanh L Nghiemphu ◽

Timothy F Cloughesy ◽

...

Keyword(s):

Tumor Growth ◽

Malignant Transformation ◽

Growth Kinetics ◽

Low Grade ◽

Diffuse Astrocytoma ◽

Radial Expansion ◽

Tumor Growth Kinetics

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Impact of 1p/19q Codeletion Status in The Outcome of Patients Affected By Oligodendroglioma and Diffuse Astrocytoma: A Retrospective Single Surgeon Series With 1.5 Io-MRI Guided Surgery

10.21203/rs.3.rs-159206/v1 ◽

2021 ◽

Author(s):

G. D'Andrea ◽

Placido Bruzzaniti ◽

Alessandro Pesce ◽

Veronica Picotti ◽

Giulia Carosi ◽

...

Keyword(s):

Tumor Resection ◽

Extent Of Resection ◽

Survival Advantage ◽

Oncologic Outcomes ◽

Low Grade ◽

Diffuse Astrocytoma ◽

Guided Surgery ◽

Significant Survival ◽

Single Operator ◽

Craniotomy For Tumor Resection

Abstract Purpose: The real impact of the Extent of Resection in respect to the 1p/19q codeletion status in determining the outcomes of Low Grade Glioma (LGG) patients is extensively debated. The aim of this paper is to retrospectively analyze the oncologic outcomes of a homogeneous cohort of LGG patients who underwent surgery by a single operator, first author of the present paper (GDA).Methods: A total of 66 patients suffering LGG who underwent craniotomy for tumor resection were operated on and retrospectively evaluated between 2008 and 2016 in a single center in which the operative theater was equipped with an Io-MRI system. We compared a subgroup of 37 patients suffering from Diffuse Astrocytoma to a second subgroup of 29 patients affected by Oligodendroglioma. Volumetric analyses of the Extent of Resection (EOR) were performed, PFS and OS were accurately recorded and used as endpoint variable, as well as the 1p/19q codeletion status of every patient included in the final cohort.Results: GTR produced a statistically significant survival advantage in respect to those associated with STR. This finding is confirmed even in patients suffering from Oligodendrogliomas (in the 1p/19q codeletion group 73.27 versus 101.73 months p=.0001). Similar findings were confimed for patients affected by Diffuse Astrocytomas(81.63 versus 60.44 months p < 0.012), despite the globally shorter survival.Conclusions: We can affirm that the EOR is an independent predictor of survival advantage. The 1p/19q codeletion is an independent prognostic factor significantly associated to a globally longer survival and a longer time to malignant transformation.

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Clinical and Molecular Characteristics of Malignant Transformation of Low-Grade Glioma in Children

Journal of Clinical Oncology ◽

10.1200/jco.2006.06.8213 ◽

2007 ◽

Vol 25 (6) ◽

pp. 682-689 ◽

Cited By ~ 140

Author(s):

Alberto Broniscer ◽

Suzanne J. Baker ◽

Alina N. West ◽

Melissa M. Fraser ◽

Erika Proko ◽

...

Keyword(s):

Malignant Transformation ◽

Cumulative Incidence ◽

Low Grade Glioma ◽

Molecular Characteristics ◽

Low Grade ◽

Molecular Alterations ◽

Molecular Abnormalities ◽

Incidence Estimate ◽

Before And After ◽

Study Interval

Purpose To analyze the clinical and molecular characteristics of malignant transformation (MT) of low-grade glioma (LGG) in children. Patients and Methods The clinical, radiologic, and histologic characteristics of children treated at our institution who experienced MT of LGG were reviewed. Molecular alterations in these tumors were analyzed by fluorescent in situ hybridization, immunohistochemistry, and TP53 sequencing. Cumulative incidence estimate and risk factors for MT were determined for 65 patients with grade 2 astrocytoma treated at our institution during the study interval. Results Eleven patients who experienced MT were identified (median age at diagnosis of LGG, 13.3 years). Initial diagnoses were grade 2 astrocytoma (n = 6) and other grade 1/2 gliomas (n = 5). The median latency of MT was 5.1 years. Histologic diagnoses after MT were glioblastoma (n = 7) and other high-grade gliomas (n = 4). The 15-year cumulative incidence estimate of MT among 65 patients with grade 2 astrocytoma was 6.7% ± 3.9%; no risk factor analyzed, including radiotherapy, was associated with MT. Tissue was available for molecular analysis in all patients, including nine with samples obtained before and after MT. TP53 overexpression was more common after MT. Deletions of RB1 and/or CDKN2A were observed in 71% of LGGs and in 90% of tumors after MT. PTEN pathway abnormalities occurred in 76% of patients. One of five oncogenes analyzed (PDGFRA) was amplified in one patient. Conclusion The molecular abnormalities that occur during MT of LGG in children are similar to those observed in primary and secondary glioblastoma in adults.

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NCOG-38. CLINICAL CHARACTERISTICS OF LOW GRADE GLIOMA PATIENTS WITH NON-CANONICAL IDH1 AND IDH2 MUTATIONS

Neuro-Oncology ◽

10.1093/neuonc/noaa215.576 ◽

2020 ◽

Vol 22 (Supplement_2) ◽

pp. ii137-ii137

Author(s):

Katherine Peters ◽

Eric Lipp ◽

Gloria Broadwater ◽

James Herndon ◽

Margaret Johnson ◽

...

Keyword(s):

Clinical Characteristics ◽

Point Mutations ◽

Progression Free Survival ◽

Idh1 Mutation ◽

Low Grade ◽

Isocitrate Dehydrogenase 1 ◽

Who Grade ◽

Targeted Mutation ◽

Kaplan Meier ◽

Idh1 And Idh2 Mutations

Abstract BACKGROUND Low grade gliomas (LGGs) develop in young adults and represent 10-15% of all glial tumors. While LGG patients can have longer survival than higher grade tumors, progression, transformation, and ultimately mortality occurs. Mutations in Isocitrate dehydrogenase 1/2 (IDH1/IDH2) are prevalent in LGG and are responsible for gliomagenesis. The classic IDH1 mutation is located at 132 codon and represented as p.Arg132His, but there are non-canonical IDH1 and IDH2 mutations. We sought to compare clinical characteristics of LGG patients with classic IDH1 p.Arg132His mutation to LGG patients with non-canonical IDH1 and IDH2 mutations. METHODS We queried an IRB-approved registry retrospectively from 12/2004- 9/2019. We included IDH1/IDH2 mutant LGG (WHO grade II) and known IDH1 and IDH2 targeted mutation analysis using standard PCR followed by DNA sequencing to detect point mutations in IDH1/IDH2 genes. We obtained available clinical and histopathological data. We estimated progression-free survival (PFS), time to transformation (TT), and overall survival (OS) using Kaplan-Meier methods. RESULTS We identified 267 LGG patients with median follow-up of 9.1 yrs (95%CI 8.4-9.9 yrs). Classic IDH1 p.Arg132His mutation occurred in 223 (83.9%) patients. IDH2 mutations occurred in 14 (5.2%) patients. Non-canonical IDH1 mutations were in 30 (11.2%) patients and included the following mutations: p.Arg132Cys (13), p.Arg132Gly (10), p.Arg132Ser (4), p.Arg132Leu (1), p.Arg119Gln (1), and p.Arg172Met (1). Initial presentation, OS, and TT did not differ between IDH1/IDH2 groups. PFS differed significantly between groups with improved median PFS in IDH2 mutant LGG (5.4 yrs; 95%CI 3.5-25.2) versus classic IDH1 mutant LGG (4.1 yrs; 95%CI 3.7-4.9 yrs) and non-canonical IDH1 mutant LGG (2.6 yrs; 95%CI 2.1-4.8) (log-rank p=0.019). Notably, non-canonical mutations were more common in astrocytoma (22/30; 73.3%) than other LGG histologies (p=0.018). CONCLUSIONS In this cohort, LGG patients with non-canonical mutations have a shorter time to progression than patients with classic p.Arg132His mutation and IDH2 mutations.

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HGG-02. ADOLESCENT AND YOUNG ADULT (AYA) GLIOMA WITH BRAF V600E-MUTANTATION

Neuro-Oncology ◽

10.1093/neuonc/noaa222.294 ◽

2020 ◽

Vol 22 (Supplement_3) ◽

pp. iii344-iii344

Author(s):

Yui Kimura ◽

Yukitomo Ishi ◽

Yuko Watanabe ◽

Yoshiko Nakano ◽

Shigeru Yamaguchi ◽

...

Keyword(s):

Braf Inhibitor ◽

Clinical Information ◽

Early Recurrence ◽

Pleomorphic Xanthoastrocytoma ◽

Adolescent And Young Adult ◽

Braf V600e ◽

Low Grade ◽

Diffuse Astrocytoma ◽

Genetic Features ◽

Epithelioid Glioblastoma

Abstract BACKGROUND Biological features of pediatric glioma differ significantly from those of adult glioma, and limited data are available on those of AYA patients. Here, we focused on AYA patients with glioma, especially those harboring BRAF V600E mutation, and investigated their clinical and genetic features. METHOD: We retrospectively analyzed AYA patients with brain tumors harboring BRAF V600E, who were treated in two hospitals in Japan. RESULTS Clinical information was available for 14 patients. The median age at diagnosis was 25 years (range: 15–38). Five patients were diagnosed with glioblastoma (GBM), including one epithelioid type. These patients were over 25. Although one patient with GBM died of the disease 6.9 years after initial diagnosis, the remaining patients were alive. Two patients were alive without recurrence at 38 and 51 months after the treatment. The patient with epithelioid glioblastoma experienced early recurrence. The remaining nine patients (64%) were diagnosed with low-grade glioma, including ganglioglioma, pilocytic astrocytoma, diffuse astrocytoma, oligodendroglioma, pleomorphic xanthoastrocytoma, and polymorphous low-grade neuroepithelial tumor of the young. No patients died of the disease, and four patients are alive without recurrence after initial operation without adjuvant treatment. Two patients are (epithelioid glioblastoma and ganglioglioma) currently undergoing treatment with a BRAF inhibitor for recurrent tumors. DISCUSSION Although the number of this study is limited, our study suggested that the prognosis of AYA patients with BRAF-V600E positive GBM may not be as dismal as that of children or adults.

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Comorbid chronic tic disorder and tourette syndrome in children requiring inpatient mental health treatment

Clinical Child Psychology and Psychiatry ◽

10.1177/13591045211007918 ◽

2021 ◽

pp. 135910452110079

Author(s):

Shaheen Zinna ◽

Rebecca Luxton ◽

Efstathios Papachristou ◽

Danai Dima ◽

Marinos Kyriakopoulos

Keyword(s):

Mental Health ◽

Tourette Syndrome ◽

Mental Health Treatment ◽

Autism Spectrum ◽

Continuous Variables ◽

Tic Disorder ◽

Exact Test ◽

Compulsive Disorder ◽

Inpatient Mental Health ◽

Chronic Tic Disorder

Objective: Children needing admission to an inpatient mental health unit often present with severe neuropsychiatric disorders characterised by complex psychopathology. We aimed to examine all admitted children with comorbid chronic tic disorder (CTD) and Tourette syndrome (TS) over a 10-year period and determine the clinical significance of these diagnoses. Method: A retrospective, naturalistic study was conducted, comparing children with and without CTD/TS in terms of co-morbid diagnoses, medication use, access to education, aggression contributing to the admission, duration of admission, functional outcomes and satisfaction with treatment. Data were analysed using Chi-square/Fisher’s exact test and t-test for categorical and continuous variables, respectively, and subsequently with unadjusted and adjusted linear and logistic regression analyses. Results: A relatively high proportion of children had co-morbid CTD/TS (19.7%). There was a significant association with co-morbid obsessive-compulsive disorder, intellectual disability and autism spectrum disorder but not attention deficit hyperactivity disorder. CTD/TS were associated with longer admissions even after adjustments for confounding but did not seem to be independently associated with other examined clinical characteristics. Conclusions: The prevalence of CTD/TS in children needing inpatient treatment is significant. In our sample, comorbid CTD/TS seem to represent a marker of overall symptom severity as evidenced by longer admissions.

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