P14.17 Conventional MRI criteria differentiate true tumour progression from treatment-induced effects in irradiated WHO grade 3 and 4 gliomas

2021 ◽  
Vol 23 (Supplement_2) ◽  
pp. ii41-ii41
Author(s):  
C M Flies ◽  
K H van Leuken ◽  
J J C Verhoeff ◽  
F Y F de Vos ◽  
T Seute ◽  
...  
Keyword(s):  
Model Reduction ◽  
Interrater Reliability ◽  
Tumour Progression ◽  
Diagnostic Model ◽  
Soap Bubble ◽  
High Grade ◽  
Who Grade ◽  
Conventional Mri ◽  
Grade 3 ◽  
Mri Characteristics

Abstract BACKGROUND Post-treatment radiological deterioration of patients with an irradiated high-grade (WHO grade 3 and 4) glioma (HGG) may be the result of true progressive disease (PD) or treatment-induced effects (TIE). Differentiation between these two entities is of great importance, but remains a diagnostic challenge. This study assesses the diagnostic value of conventional MRI characteristics to differentiate PD from TIE in treated HGGs. MATERIAL AND METHODS In this single-centre, retrospective cohort study, we included adult patients with a HGG, who were treated with radiotherapy and subsequently developed a new or increasing contrast-enhancing lesion on conventional follow-up MRI. TIE and PD were defined radiologically as stable/decreased for a minimum of six weeks or progressive according to the RANO criteria, and histologically as predominantly TIE without viable tumour or PD. Demographic and clinical data were retrieved. Twenty-one preselected MRI characteristics of the progressive lesions were assessed by two neuroradiologists. The statistical analysis included logistic regression to develop a) a full multivariable model b) a diagnostic model with model reduction, and a Cohen’s Kappa interrater reliability coefficient. RESULTS 210 patients (median age 61, IQR=54–68, 189 males) with 284 lesions were included, of which 141 (50%) had PD. Median time to PD was 2 (0.7–6.1) and to TIE 0.9 (0.7–3.5) months after RT. In multivariable modelling and after model reduction, the following determinants were significant diagnostic factors: Radiation dose (Odds ratio (OR)=0.68, p=0.017), longer time since radiotherapy (OR=3.56, p<0.0005), certain enhancement patterns (soap bubble enhancement: OR=2.63, p=0.003), isointense apparent diffusion coefficient-signal (OR=2.11, p=0.036), development of multiple new lesions (OR=1.68, p=0.088) and increased marginal enhancement (OR=2.04, p=0.027). ORs of >1 indicate higher odds of PD. The Hosmer & Lemeshow test showed a good calibration (p=0.947) and the area under the ROC-curve was 0.722 (95%-CI=0.66–0.78). Interrater reliability analysis between neuroradiologists revealed moderate to near-perfect agreement for the significantly predictive items, but poor agreement for others. CONCLUSION In patients with irradiated high-grade gliomas, several characteristics from conventional MRI are significant predictors for the discrimination between true progression and treatment-induced effects. Interrater reliability for these characteristics was variable. Conventional MRI characteristics from this study should be incorporated into a multimodal diagnostic model that includes advanced imaging techniques. FUNDING INFORMATION Foundation Vrienden UMC Utrecht and The StophersenkankerNU Foundation.

scholarly journals CTIM-06. DENDRITIC CELL VACCINE STUDY FOR RECURRENT, HIGH-GRADE GLIOMA: TISSUE-BASED RNA SEQUENCING AND SERUM CYTOKINE LEVELS AS POTENTIAL BIOMARKERS

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii33-ii34
Author(s):  
Macarena De La Fuente ◽  
Tulay Koru-Sengul ◽  
Deborah Heros ◽  
Feng Miao ◽  
Alain Fernandez Marrero ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Rna Sequencing ◽  
Tumor Antigens ◽  
High Grade Glioma ◽  
Treatment Discontinuation ◽  
Sequencing Analysis ◽  
High Grade ◽  
Who Grade ◽  
Cytokine Levels ◽  
Grade 3

Abstract BACKGROUND Glioblastoma is the most common primary malignant brain tumor. Despite multimodality treatment approach, median progression-free survival (PFS) is only 8 months, median overall-survival (OS) 14 months and 5-year survival rate of under 10%. Dendritic cells (DCs) are the professional antigen presenting cells of the immune system. The rationale for sensitizing dendritic cells to a pool of non-selected tumor antigens is based on the marked heterogeneity present within glioblastoma tumor cells. METHODS Phase 1/feasibility study of DC vaccine for recurrent high-grade glioma was conducted. Pooled, non-selected tumor antigens collected via tumor cell lysate were used for DC sensitization. RNA sequencing analysis was performed on all tumor samples. Cytokine levels in serum were detected using a Luminex cytokine panel. RESULTS A total of 20 patients were enrolled onto this study (median age 58yrs, range: 39–74, 65% male). Pathology showed WHO grade IV glioblastoma in 14 (70%) and grade III anaplastic astrocytoma in 6 (30%) patients. IDH wild type in 19 (95%) patients. Treatment emergent adverse events (all grades, regardless of attribution) occurred in more than 15% of the patients (20% fatigue, 15% dizziness, 15% headache, none leading to treatment discontinuation). There were five grade 3–4 and none grade 5 events. One grade 4 event (seizure) probable related to investigational treatment leading to treatment discontinuation. Four grade 3 events (dysphasia, possible related; intracranial hemorrhage unrelated; muscle weakness, unlikely related and hematoma, unrelated). Median PFS was 3.8 months. Median OS was 11 months. RNA sequencing in tumor samples and correlation with cytokine levels in serum is currently been analyzed. CONCLUSION Tumor lysate pulsed DC vaccination demonstrates acceptable safety and tolerability in high-grade glioma patients. Evaluations of integrating molecular profiling RNA sequencing information and cytokine levels to identify potential subset of patients with significant clinical benefit will be provided.

scholarly journals TERT Alterations Predict Tumor Progression in De Novo High-Grade Meningiomas Following Adjuvant Radiotherapy

2021 ◽  
Vol 11 ◽  
Author(s):  
Jiaojiao Deng ◽  
Shuchen Sun ◽  
Jiawei Chen ◽  
Daijun Wang ◽  
Haixia Cheng ◽  
...  
Keyword(s):  
Tumor Progression ◽  
Adjuvant Radiotherapy ◽  
De Novo ◽  
Predictive Biomarkers ◽  
Progression Free Survival ◽  
Rank Test ◽  
High Grade ◽  
Who Grade ◽  
Kaplan Meier ◽  
Grade 3

BackgroundAdjuvant radiotherapy (RT) is one of the most commonly used treatments for de novo high-grade meningiomas (HGMs) after surgery, but genetic determinants of clinical benefit are poorly characterized.ObjectiveWe describe efforts to integrate clinical genomics to discover predictive biomarkers that would inform adjuvant treatment decisions in de novo HGMs.MethodsWe undertook a retrospective analysis of 37 patients with de novo HGMs following RT. Clinical hybrid capture-based sequencing assay covering 184 genes was performed in all cases. Associations between tumor clinical/genomic characteristics and RT response were assessed. Overall survival (OS) and progression-free survival (PFS) curves were plotted using the Kaplan–Meier method.ResultsAmong the 172 HGMs from a single institution, 42 cases (37 WHO grade 2 meningiomas and five WHO grade 3 meningiomas) were identified as de novo HGMs following RT. Only TERT mutations [62.5% C228T; 25% C250T; 12.5% copy number amplification (CN amp.)] were significantly associated with tumor progression after postoperative RT (adjusted p = 0.003). Potential different somatic interactions between TERT and other tested genes were not identified. Furthermore, TERT alterations (TERT-alt) were the predictor of tumor progression (Fisher’s exact tests, p = 0.003) and were associated with decreased PFS (log-rank test, p = 0.0114) in de novo HGMs after RT.ConclusionOur findings suggest that TERT-alt is associated with tumor progression and poor outcome of newly diagnosed HGM patients after postoperative RT.

scholarly journals The Biological Behavior of High-Grade Glioma in H3K27M Mutant Circumscribed Midline Gliomas

2021 ◽  
Author(s):  
Hainan Li ◽  
Jieyun Tan ◽  
Mingyao Lai ◽  
Wendan Chen ◽  
Minting Liu ◽  
...  
Keyword(s):  
High Grade Glioma ◽  
Clinicopathological Characteristics ◽  
Biological Behavior ◽  
High Grade ◽  
Who Grade ◽  
Significant Difference ◽  
Prognostic Stratification ◽  
Grade 3 ◽  
Elder Adults ◽  
H3k27m Mutation

Abstract Purpose Due to the prognosis of circumscribed middle gliomas（CMGs）with H3K27M mutation is still unclear. This study explored the prognostic stratification of （CMGs） with H3K27M mutation.Methods: One hundred and sixty middle gliomas（MGs）were identified over 10 years. Immunohistochemistry was done for H3K27M, ATRX, IDH1, and P53, and Sanger sequencing performed for IDH and H3 genes. The clinicopathological characteristics were reviewed and survival analysis performed.Results: 1. H3K27M mutation was associated with a poor prognosis (p = 0.00017) for brainstem gliomas, but not for thalamic gliomas (p = 0.3). In the elder adults (≥40 years), there was no correlation between H3K27M mutation and the prognosis for MGs (p = 0.49).2. For H3K27M mutant MGs, there was no difference in prognosis between diffuse midline gliomas (DMGs) and CMGs (p = 0.211), also between the CNS WHO grades.3. The prognosis of H3K27M mutant CMGs of CNS WHO grade 1 was worse than that of H3K27M wild-type CMGs (p = 0.0024), even worse than of DMGs without H3K27M mutation of CNS WHO grade 2(p = 0.0066). There was no significant difference in prognosis from DMGs with histological grades CNS WHO grade 3 and 4 (p = 0.46).Conclusions: The weight value of H3K27M affecting prognosis is affected by location and age. CMGs with H3K27M mutation have biological behavior similar to high-grade gliomas. It is recommended that Treatment management was referenced to high-grade glioma for CMGs with H3K27 mutation.

scholarly journals Safety and Efficacy of Hypofractionated Stereotactic Radiosurgery for High-Grade Gliomas at First Recurrence: A Single-Center Experience

2020 ◽  
Author(s):  
Yun Guan ◽  
Ji Xiong ◽  
Mingyuan Pan ◽  
Wenyin Shi ◽  
Jing Li ◽  
...  
Keyword(s):  
Planning Target Volume ◽  
Performance Status ◽  
Target Volume ◽  
Salvage Treatment ◽  
High Grade ◽  
Who Grade ◽  
Cyberknife Radiosurgery ◽  
High Grade Gliomas ◽  
First Recurrence ◽  
Grade 3

Abstract Background: The optimal treatment for recurrent high-grade gliomas (rHGG) remains uncertain. This research aimed to investigate the efficacy and safety of CyberKnife radiosurgery as a salvage treatment for high-grade gliomas at first recurrence that within the radiation field.Methods: Between January 2016 and October 2019, rHGG patients treated with CyberKnife radiosurgery were retrospectively analyzed. The primary endpoint was OS, and secondary endpoints included progression-free survival (PFS) and toxicity. Toxicity was assessed using CTCAE 5.0. The prognostic value of key clinical features (age, performance status, planning target volume, dose, use of bevacizumab) were evaluated.Results: A total of 70 patients were included in the study. Forty patients were male and 30 were female. Forty-nine had an initial diagnosis Glioblastoma (GBM), and rest (21) were WHO Grade 3 Gliomas. The median planning target volume (PTV) was 16.68 cm3 (0.81–121.96 cm3). The median prescribed dose was 24 Gy (12-30 Gy) in 4 fractions (2-6 fractions). Median baseline Karnofsky Performance Status (KPS) is 70 (40-90). With a median follow-up of 12.1 months, the median overall survival after salvage treatment was 17.6 months (19.5 and 14.6 months for grade 3 and 4 gliomas; p = 0.039). No grade 3 or higher toxicities was recorded. Multivariate analysis showed concurrent bevacizumab with radiosurgery and KPS>70 were favorable prognostic factors for grade 4 patients.Conclusions: Salvage CyberKnife radiosurgery showed a favorable outcome and acceptable toxicity for rHGG. A prospective phase II study (NCT04197492) is ongoing to further investigate the value of HSRS in rHGG.

Oncolytic polio/rhinovirus recombinant (PVSRIPO) against WHO grade IV malignant glioma (MG): Experience with retreatment of survivors from the phase I trial.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 2060-2060
Author(s):  
Annick Desjardins ◽  
Matthias Gromeier ◽  
James Emmett Herndon ◽  
Dina Randazzo ◽  
Stevie Threatt ◽  
...  
Keyword(s):  
Study Drug ◽  
Disease Recurrence ◽  
Dose Finding ◽  
Additional Patient ◽  
Soap Bubble ◽  
Eligibility Criteria ◽  
Who Grade ◽  
Finding Study ◽  
Grade 3 ◽  
The Impact

2060 Background: We completed a study evaluating a single intratumoral delivery of PVSRIPO in recurrent WHO grade IV MG patients (N Engl J Med. 2018 Jul 12;379(2):150-161). Some patients who originally benefitted from the infusion of PVSRIPO demonstrated tumor recurrence, and we hypothesized that retreatment could trigger an immune recall effect, further extending their survival. We now report the impact of second and third intratumoral reinfusion of PVSRIPO in patients treated in the original dose finding study. Methods: Eligible patients were adults with recurrent supratentorial WHO grade IV MG who were experiencing disease recurrence after having benefitted from the first infusion of PVSRIPO. Additional eligibility criteria included: solitary tumor 1-5.5cm in diameter; ≥4 weeks after chemotherapy, bevacizumab or study drug; adequate organ function; KPS≥70%; and positive anti-polio titer. One patient each was retreated at 1 x 107 TCID50 and 1 x 1010 TCID50, and three patients were retreated on the identified phase 2 dose of 5 x 107 TCID50. Results: As of 2/09/2019, five patients have received a second intratumoral dose of PVSRIPO on study, one of which received a total of 3 doses. The patients who received two infusions of PVSRIPO were retreated 72 months, 43 months, 34 months, and 6 months after the first infusion. One additional patient received a second infusion of PVSRIPO 60 months after the first infusion and a third infusion of PVSRIPO 78 months after the first infusion. All patients demonstrated soap bubble degeneration on imaging, and two patients demonstrated tumor contraction. No grade 3 or higher adverse events related to PVSRIPO were observed after retreatment. Three of these patients remain alive more than 81, 80 and 52 months following the first PVSRIPO infusion and more than 9, 20 and 18 months after the second infusion, respectively. Two patients died 63 months and 20 months after the first infusion of PVSRIPO and 19.6 and 14 months after the second, respectively. The patient treated 3 times received the third infusion more than 2 months ago. Conclusions: Intratumoral reinfusion of PVSRIPO via CED is safe, and encouraging efficacy results have been observed. Clinical trial information: NCT01491893.

scholarly journals Distinct genomic subclasses of high-grade/progressive meningiomas: NF2-associated, NF2-exclusive, and NF2-agnostic

2020 ◽  
Vol 8 (1) ◽  
Author(s):  
Erik A. Williams ◽  
Sandro Santagata ◽  
Hiroaki Wakimoto ◽  
Ganesh M. Shankar ◽  
Fred G. Barker ◽  
...  
Keyword(s):  
Low Frequency ◽  
High Grade ◽  
Who Grade ◽  
Hybridization Capture ◽  
Chromatin Regulators ◽  
Genomic Analyses ◽  
Genomic Studies ◽  
Male Sex ◽  
Grade 3 ◽  
Pathology Reports

Abstract Background Genomic studies of high-grade/progressive meningiomas have reported a heterogeneous mutation spectrum, identifying few recurrently mutated genes. Most studies have been underpowered to detect genomic subclasses of aggressive meningiomas due to relatively small number of available samples. Here, we present a genomic survey of one of the largest multi-institutional cohorts of high-grade/progressive meningiomas to date. Methods 850 high-grade/progressive meningiomas, including 441 WHO grade 2 and 176 WHO grade 3 meningiomas and 220 progressive WHO grade 1 meningiomas, were tested as part of a clinical testing program by hybridization capture of 406 cancer-related genes to detect base substitutions, indels, amplifications, deletions, and rearrangements. Information from pathology reports, histopathology review, and patient clinical data was assessed. Results Genomic analyses converged to identify at least three distinct patterns of biologically-aggressive meningiomas. The first and most common contained NF2-mutant tumors (n = 426, 50%), was associated with male sex (64.4% %, p = 0.0001) and often harbored additional mutations in CDKN2A/B (24%), and the chromatin regulators ARID1A (9%), and KDM6A (6%). A second group (NF2-agnostic) featured TERT promoter (TERTp; n = 56) or TP53 mutations (n = 25) and were either NF2-mutant or wild-type, and displayed no association with either sex (p = 0.39). The remaining group generally lacked NF2 mutations, and accounted for 40% of the cases—with three subgroups. One consistent primarily of grade 3 lesions harboring alterations in chromatin regulators BAP1 (n = 22) or PBRM1 (n = 16). A second subgroup contained AKT1 (n = 26), PIK3CA (n = 14) and SMO (n = 7) mutant skull-based meningiomas, and a third mixed subgroup included 237 meningiomas with a heterogeneous spectrum of low frequency and non-recurrent alterations. Conclusions Our findings indicate that the patterns of genomic alterations in high-grade/progressive meningiomas commonly group into three different categories. The most common NF2-associated canonical group frequently harbored CDKN2A/B alterations, which is potentially amenable to targeted therapies. An NF2-agnostic group harbored frequent TERTp and TP53 mutations. The final subclass, distinct from the canonical NF2 mutant associated pathway, was partly characterized by BAP1/PBRM1 alterations (rhabdoid/papillary histology) or skull-base disease. Overall, these data increase our understanding of the pathobiology of high-grade/progressive meningiomas and can guide the design of clinical trials. IRB approval status Reviewed and approved by Western IRB; Protocol No. 20152817.

PATH-37. DISTINCT GENOMIC SUBCLASSES OF HIGH-GRADE/PROGRESSIVE MENINGIOMAS: NF2-ASSOCIATED, NF2-EXCLUSIVE, AND NF2-AGNOSTIC

2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi123-vi123
Author(s):  
Erik Williams ◽  
Sandro Santagata ◽  
Hiroaki Wakimoto ◽  
Fred Barker ◽  
Priscilla Brastianos ◽  
...  
Keyword(s):  
Low Frequency ◽  
High Grade ◽  
Who Grade ◽  
Tp53 Mutations ◽  
Hybridization Capture ◽  
Chromatin Regulators ◽  
Genomic Analyses ◽  
Genomic Studies ◽  
Male Sex ◽  
Grade 3

Abstract BACKGROUND Genomic studies of high-grade/progressive meningiomas have reported a heterogeneous mutation spectrum. Here, we present a genomic survey of one of the largest multi-institutional cohorts of high-grade/progressive meningiomas to date. METHODS 850 high-grade/progressive meningiomas, including 441 WHO grade 2 and 176 WHO grade 3 meningiomas and 220 progressive WHO grade 1 meningiomas, were tested as part of a clinical testing program by hybridization capture of 406 cancer-related genes. Information from histopathology review and patient clinical data was assessed. RESULTS Genomic analyses converged to identify at least three distinct patterns of biologically-aggressive meningiomas. The first and most common contained NF2-mutant tumors (n = 426, 50%), was associated with male sex (64.4%, p = 0.0001) and often harbored additional mutations in CDKN2A/B (24%), and the chromatin regulators ARID1A (9%), and KDM6A (6%). A second group (NF2-agnostic) featured TERTp (n = 56) or TP53 mutations (n = 25) and were either NF2-mutant or wild-type, and displayed no association with either sex. The remaining group generally lacked NF2 mutations, and accounted for 40% of the cases-with three subgroups. One consistent primarily of grade 3 lesions harboring alterations in chromatin regulators BAP1 (n = 22) or PBRM1 (n = 16). A second subgroup contained AKT1 (n = 26), PIK3CA (n = 14) and SMO (n = 7) mutant skull-based meningiomas, and a third mixed subgroup included 237 meningiomas with a heterogeneous spectrum of low frequency and non-recurrent alterations. CONCLUSIONS Our findings indicate that the patterns of genomic alterations in high-grade/progressive meningiomas commonly group into three different categories. The most common NF2-associated canonical group frequently harbored CDKN2A/B alterations, which is potentially amenable to targeted therapies. An NF2-agnostic group harbored frequent TERTp and TP53 mutations. The final subclass, distinct from the canonical NF2 mutant associated pathway, was partly characterized by BAP1/PBRM1 alterations (rhabdoid/papillary histology) or skull-base disease.

scholarly journals ACT-5 Prognosis of IDH-mut lower-grade gliomas in Hokkaido University Hospital

2021 ◽  
Vol 3 (Supplement_6) ◽  
pp. vi10-vi10
Author(s):  
Shigeru Yamaguchi ◽  
Yukitomo Ishi ◽  
Michinari Okamoto ◽  
Ryousuke Sawaya ◽  
Hiroaki Motegi ◽  
...  
Keyword(s):  
Primary Treatment ◽  
University Hospital ◽  
Treatment Intensity ◽  
Low Grade ◽  
Lower Grade ◽  
High Grade ◽  
Who Grade ◽  
Idh Mutations ◽  
Histological Malignancy ◽  
Grade 3

Abstract Background: WHO grade 2 and 3 adult gliomas are nowadays getting together as lower-grade gliomas (LrGGs), but we had been recognized grade 3 (G3) tumors as high-grade and grade 2 (G2) tumors as low-grade. In this report, we investigate the treatment and prognosis of the patients with LrGG harboring IDH mutations in our institutions. Methods:We retrospectively review primary treatments and their prognosis for LrGG patients with IDH mutation since 2003. They categorized as astrocytomas and oligodendrogliomas according to 1p/19q loss-of-heterozygosity status. Prognosis were evaluated by overall survival. Postoperative primary treatments applied chemo-radiotherapy (CRT), radiotherapy only (RT), chemotherapy only (CT), and observation (Ob). Results: 36 astrocytomas and 60 oligodendrogliomas were identified. In astrocytomas, the patients with G3 (N=16) were treated by CRT (N=14) or CT (N=2), and the patients with G2 (N=20) were treated by CRT (N=2), RT (N=3), CT (N=3), or Ob (N=12). In oligodendrogliomas, the patients with G3 (N=34) were treated by CRT (N=32) or CT (N=2), and the patients with G2 (N=26) were treated by CRT (N=3), RT (N=1), CT (N=5), or Ob (N=17). 10-year survival rate (10yOS) of astrocytomas and oligodendrogliomas are 54% and 90%, respectively (p=0.002). According to histological malignancy, 10yOS of G3 and G2 astrocytomas were 54% and 54%, respectively (p=0.97) and that of G3 and G2 oligodendrogliomas were 86% and 100%, respectively (p=0.64). In both group, there are no different of prognosis according to histological malignancy. Discussion: There was no prognostic different between G2 and G3 astrocytomas in our institution. Since the treatment intensity for G2 and G3 astrocytomas were clearly different, the primary treatment for G2 astrocytomas might be insufficient. On the other hand, there were no prognostic different between G2 and G3 oligodendrogliomas in our institution, as with recent reports, so the primary treatment intensity for oligodendrogliomas should be appropriate.

scholarly journals CAPTEM in Metastatic Well-Differentiated Intermediate to High Grade Neuroendocrine Tumors: A Single Centre Experience

2019 ◽  
Vol 2019 ◽  
pp. 1-7 ◽  
Author(s):  
Arvind Sahu ◽  
Michael Jefford ◽  
Julia Lai-Kwon ◽  
Alesha Thai ◽  
Rodney J. Hicks ◽  
...  
Keyword(s):  
Overall Survival ◽  
Neuroendocrine Tumors ◽  
Functional Imaging ◽  
Low Grade ◽  
Significant Activity ◽  
High Grade ◽  
Who Grade ◽  
Well Differentiated ◽  
Grade 3 ◽  
Imaging Response

Introduction. Capecitabine-temozolomide (CAPTEM) has significant activity in patients (pts) with metastatic low grade pancreatic neuroendocrine tumors (NETs). However, there is limited data regarding its activity in pts with metastatic well-differentiated intermediate and high grade pancreatic and nonpancreatic NETs. The objective of this study was to assess the functional imaging response, survival, and tolerability of CAPTEM in this population.Methods. A retrospective audit of pts with metastatic well-differentiated intermediate (WHO grade 2) or high grade (WHO grade 3) NETs treated at Peter MacCallum Cancer Centre between March 2013 and March 2017. Pts received capecitabine 750 mg/m2orally twice daily (bd) from days1 to 14 and temozolomide 100 mg/m2bd from days 10 to 14 every 28 days. Data regarding functional imaging response, progression-free and overall survival, and toxicities was collected.Results. Thirty-two pts received a median of 6 cycles (range: 2-16) of CAPTEM for grade 2 (n=21, 66%) or grade 3 (n=11, 34%), Ki67 <55% (n= 7, 21.9%) or Ki67 ≥55% (n= 4, 12.5 %) NET. Primary site included gastroenteropancreatic (n= 17, 53%), lung (n= 12, 37.5%), and unknown origin (n = 3, 9.4%). Twenty-two percent received CAPTEM as first-line therapy. After a median of 31 months of follow-up, the two-year overall survival (OS) was 42%, with a median OS of 24 months. There was a trend towards improved median progression-free survival (PFS) in pts with low grade 3 (Ki67<55%) versus high grade 3 (Ki67 ≥55%) NETs (15 vs 4 months, p= 0.11). Ten (31.3%) experienced grade 3/4 toxicity, with nausea (15.6%), thrombocytopaenia (12.5%), and fatigue (9.4%) the most common toxicities reported.Conclusion. CAPTEM has significant activity in patients with metastatic grades 2 and 3 NETs with manageable toxicity. The PFS benefit observed in the grade 3 subgroup with Ki67<55% warrants further evaluation in a larger randomized trial.

P04.07 The molecular evolution of oligodendrogliomas

2021 ◽  
Vol 23 (Supplement_2) ◽  
pp. ii20-ii20
Author(s):  
M Padovan ◽  
W Vallentgoed ◽  
I de Heer ◽  
G Lombardi ◽  
M van den Bent ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Clinical Data ◽  
De Novo ◽  
Tumour Progression ◽  
Dna Demethylation ◽  
Methylation Analysis ◽  
Who Grade ◽  
Malignancy Grade ◽  
Grade 3 ◽  
Dna Methylation Analysis

Abstract BACKGROUND Oligodendroglioma (OD) is defined by the presence of both IDH1/2 mutation and 1p/19q codeletion. Although prognosis of OD patients is relatively favorable, tumours usually relapse and often evolve to a higher malignancy grade, with some acquiring the treatment induced hypermutated phenotype. To better understand how these tumours evolve in time, we examined the molecular differences between matched primary and recurrent ODs. MATERIAL AND METHODS We identified 21 patients who underwent surgery at least twice [male: 11, female: 10, median age: 44 years (31–66)]. Clinical data were available for 14/21 patients: 5/14 received a treatment between resections [4 radiotherapy, 1 radiotherapy followed by PCV chemotherapy]; median time from the first to the second surgery was 71.5 months (12–158). Whole genome DNA-methylation analysis was performed using Illumina’s MethylationEPIC ‘850K’ BeadChip. Results were evaluated using the Molecularneuropathology.org platform (version 3.1.5) and in R. RESULTS Most samples were WHO grade 2 ODs [14, 10 and 1 tumours in first, second and third resection group, respectively]; WHO grade 3 was found in 6, 10 and 3 tumours in first, second and third resection, respectively; in 4 patients the tumour showed malignant progression from grade 2 to 3. Most ODs exhibited an IDH1 R132H mutation [17/21 patients]; in no cases was IDH1/2 mutation lost during progression. DNA methylation analysis was successfully performed in 41/45 cases [primary OD: 17, recurrent OD: 24] for a total of 18 matched pairs. 37 samples were assigned to the “IDH mutant glioma, subclass 1p/19q codeleted OD”; the remaining 4 were assigned to various other methylation classes but CNV (copy number variation) analysis confirmed the 1p19q codeletion in all samples. Recurrent tumours exhibited de novo loss of chromosome 4 in 3/24 cases (12.5%) and loss of chromosome 13 in 3/24 cases (12.5%). In unsupervised analysis of the 1000 most variable CpG sites, samples from the same patient clustered together. This indicates that the inter-tumour variability is greater than the intra-, temporal- or grading variability between tumours. There were no overt differences in DNA methylation levels between the primary and matched recurrent OD. However, lower genome wide DNA methylation levels were observed in tumours that dedifferentiated to grade 3 ODs compared to those of grade 2, indicating that DNA demethylation is associated to higher malignancy grade. CONCLUSION DNA methylation analysis in a cohort of primary and recurrent oligodendrogliomas highlights the genomic and epi-genetic changes that are acquired at tumour progression. We are currently expanding the cohort and collecting/integrating the clinical data to better explore the evolution of recurrent ODs.

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