bluuebunny/crossref_metadata_2025_split huggingface dataset:
P12.06 Clinicopathological evaluation of PD-L1 expression and cytotoxic T-lymphocyte infiltrates across intracranial molecular subgroups of ependymomas
Authors: Sharma A 
Published: September 2019

Abstract

BACKGROUND
Immune check-point blockade targeting programmed cell death ligand-1 (PD-L1)/programmed death-1 (PD-1) axis has created paradigm shift in the treatment of advanced cancer. The prognosis of the ‘ST-RELA’ and ‘PF-A’ molecular subgroups of ependymomas (EPN) remains poor. This study aims to understand the potential candidature of EPNs for ICB.

MATERIAL AND METHODS
All supratentorial (ST) Grade II/III EPNs were classified into ST-RELA, ST-YAP and ST-not otherwise specified (NOS), based on L1CAM protein expression and/or presence of RELA/YAP1 fusion transcripts by RT-PCR. All posterior fossa (PF) BEPNs were classified into PF-A and PF-B based on H3K27me3 protein expression and chromosome 1q gain. Immunohistochemistry for PD-L1 (SP263, Ventana) and CD8 was performed. RelA protein enrichment at PDL1 promoter site was analysed by chromatin immunoprecipitation-qPCR (ChIP-qPCR) in three ST-RELA samples.

RESULTS
A total of 83 intracranial EPNs were included as follows: ST-RELA (n=32), ST-YAP (n=1), ST-NOS (n=11), ST-subependymoma (n=1), PF-A (n=25) and PF-B (n=13). Median tumor infiltrating CD8+ cytotoxic T-lymphocyte (CTL) density was 6/mm2, and was higher in ST EPNs (median 10/mm2) as compared to PF EPNs (median 3/mm2). PD-L1 protein expression in ≥1% tumor cells was noted in 17/83 (20%) of all EPNs, including 12/32 (37%) of ST-RELA and rare ST-NOS (2/11), PF-A (2/25) and PF-B (1/13) tumors. Twelve intracranial EPNs (14%, 12/83) showed high CTL density and concurrent PD-L1 positivity, of which majority (83%, 10/12) were ST-RELA EPNs. Enrichment of RelA protein was seen at PD-L1 promoter.

CONCLUSION
Increased CTL densities and upregulation of PD-L1 in ST-RELA ependymomas suggests potential candidature for immunotherapy.
P12.10 Treatment of pharmacoresistent epilepsy by combining stereotactic destruction and authologous mesenchymal stem cells
Authors: Slobina E , Dokukina T , Khlebokazov F , Misyuk N , Makhrov M , Korolevich P , Shamruk I , Marchuk S 
Published: September 2019

Abstract

BACKGROUND
Existing anti-epileptic drugs (AED) have limited efficiency in many patients, necessitating the search for alternative approaches such as stereotactic radiosurgery (SRS) and followed by stem cell therapy to improve results of previous treatment.

MATERIAL AND METHODS
From 2016 to 2017, a prospective study included 6 patients with a combined pathology, a median of 56 years of age, in the past TBI - 3 patients, a solitary metastatic focus in the brain (GM) - 2 patients. The indications for stereotactic intervention were both the presence of a metastatic lesion of the GM, and the bitemporal epilepsy with generalized convulsive, complex and simple partial attacks, regardless of the presence of an organic focus on CT or MRI GM. SRS was undertaken in patients undergoing a course of anticonvulsant drug therapy in combination with other types of symptomatic therapy in the absence of therapeutic effect. The frequency of generalized convulsive seizures ranged from 2–3 to 7–10 per month, complex partial from daily to 2–3 per month. SRS was performed on a stereotactic irradiation system with conical “BrainLab” collimators mounted on a linear CLINAC accelerator and allowing the session of SRS arc arches. Total dose was 12–30 Gy in isocenter, 1 fraction. After 2–3 monthes from SRS the patients received AED supplemented with single intravenous administration of undifferentiated autologous MSC (target dose of 1 × 106 cells/kg), followed by a single intrathecal injection of neurally induced autologous MSC (target dose of 0.1 × 106 cells/kg).

RESULTS
duration of epilepsy at the time of surgery ranged from 3 to 42 years. Cessation of attacks after 2–3 months after SRS with followed MSC therapy in 2 out of 6 patients was achieved remission (no seizures for one year and more), and 3 patients became responders to AEDs additionally, reduction of the pathological EEG pattern (disappearance of beta focusing, reduction of theta2-index to 23.6). Persistent clinical onco- and neurological remission 18 months. Reduction of the dose of enkorata-chrono - 3 patients, complete abolition of anticonvulsant therapy - 2 patients. MSC injections were well tolerated and did not cause any severe adverse effects.

CONCLUSION
MSC possess unique immunomodulatory properties and are a safe and promising candidate for cell therapy in AED resistant epilepsy patients in the frame of combined treatment.
P13.15 DNA methylation abnormalities in non-promoter regulatory regions are associated with invasive behavior in pituitary tumors
Authors: Mosella M Q S , Sabedot T S , Malta T M , Rock J , Felicella M , Aho T , Noushmehr H , Castro A V 
Published: September 2019

Abstract

BACKGROUND
Despite histologically benign, pituitary tumors (PT) may invade important adjacent neurovascular structures which can incur in significant comorbidities preventing a complete surgical resection and contributing to resistance to medical treatment. DNA methylation clearly stratified PT based on their functional status i.e. nonfunctioning PTs (NFPTs) from functioning PT (FPTs). However associations of methylation aberrations with invasive behavior is less clear.

MATERIAL AND METHODS
In order to evaluate whether DNA methylation alterations in regulatory regions other than promoter and coding regions are associated with invasive behavior we performed a meta-analysis of the genome-wide methylome of three public available PT cohorts plus our own (Illumina HumanMethylation platforms- 450K/EPIC). Pituitary specimens comprised of 43 invasive pituitary tumors (InvPT) and 37 noninvasive (NInvPT); 12 FPT and 68 NFPTs, in addition to 20 non-tumor pituitaries. RNA-seq data were available for one cohort (n=23, 12 InvPT,11NInvPT) and integrated with DNA methylation. Invasiveness criteria was based on Knosp grade >= 2 and/or sphenoid or dural invasion.

RESULTS
Wilcoxon Rank-sum test; Δβ=0.15; p-value <0.001 identified 58 differentially methylated CpG sites in InvPT that were mainly hypomethylated (95%) in relation to NInvPT. NInvPT methylation profile was similar to non-tumor specimens, despite its heterogeneity. Thirty-four percent (n=20) of the differentially methylated CpG sites were located within predicted enhancer regions distributed in intronic (40%), intergenic (40%) and promoter (20%) regions. Predicted enhancer-target genes were enriched for actin filament cell movement, response to starvation, growth factor stimulus and protein autophosporilation pathways. Among them, ZNF625 and INO80E were found mostly negative correlated among methylation and expression data (-0.50 and -0.48, respectively), besides DOC2A found to be one potentially differentially expressed gene under enhancer control (log2FC > 0.2, pvalue <0.05).

CONCLUSION
Our results suggest that methylation alterations in predicted regulatory regions, such as enhancers, annotated in non-promoter regions (introns and intergenic) may contribute to the invasive behavior of PT.
P14.01 Differential diagnosis of IDH mutant/IDH wildtype of glioma by using 11C-methionine, 11C-choline, and18F-fluorodeoxyglucose positron emission tomography
Authors: Takei H , Shinoda J , Ikuta S , Maruyama T , Muragaki Y , Kawasaki T , Ikegame Y , Okada M , Ito T , Asano Y , Yokoyama K , Nakayama N , Yano H , Iwama T 
Published: September 2019

Abstract

BACKGROUND
Positron emission tomography (PET) is important in noninvasive diagnostic imaging of gliomas. There are many PET studies on glioma diagnosis based on the 2007 World Health Organization (WHO) classification; however, there are no studies on glioma diagnosis using the new classification (the 2016 WHO classification).Here we investigated the relationship between PET imaging using 11C-methionine (MET), 11C-choline (CHO), and 18F-fluorodeoxyglucose (FDG) and wildtype isocitrate dehydrogenase (IDH) (IDH-wt)/mutant IDH (IDH-mut) in astrocytic and oligodendroglial tumors according to the 2016 WHO classification.

MATERIAL AND METHODS
In total, 105 patients with newly diagnosed cerebral gliomas (six diffuse astrocytomas [DAs] with IDH-wt, six DAs with IDH-mut, seven anaplastic astrocytomas [AAs] with IDH-wt, 24 AAs with IDH-mut, 26 glioblastomas [GBMs] with IDH-wt, five GBMs with IDH-mut, 19 oligodendrogliomas [ODs], and 12 anaplastic oligodendrogliomas [AOs]) were included. All OD and AO patients had both IDH-mut and 1p/19q codeletion. The maximum standardized uptake values (SUVs) of the tumor/normal cortex mean SUV ratios (T/N ratios) for MET, CHO, and FDG were calculated; the mean T/N ratios of DA, AA, and GBM with IDH-wt/IDH-mut were compared. The diagnostic accuracy for distinguishing gliomas with IDH-wt from those with IDH-mut was assessed using receiver operating characteristic (ROC) curve analysis of the mean T/N ratios for the three PET tracers.

RESULTS
There were significant differences in the mean T/N ratios for all three PET tracers between the IDH-wt and IDH-mut groups including all histological classifications (p<0.001). Among the 27 gliomas with mean T/N ratios higher than the cutoff values for all three PET tracers, 23 (85.2%) were classified into the IDH-wt group using ROC analysis. In DA, there were no significant differences in the T/N ratios for MET, CHO, and FDG between the IDH-wt and IDH-mut groups. In AA, the mean T/N ratios of all three PET tracers in the IDH-wt group were significantly higher than those in the IDH-mut group (p<0.001). In GBM, the mean T/N ratio in the IDH-wt group was significantly higher than that of the IDH-mut group for both MET (p=0.034) and CHO (p=0.01). However, there was no significant difference in the ratio for FDG.

CONCLUSIONS
PET imaging using MET, CHO, and FDG was confirmed to be informative for preoperatively differentiating gliomas according to the 2016 WHO classification, particularly for differentiating IDH-wt and IDH-mut tumors.
P14.05 Treatment of relapsing patients with intracranial germ cell tumors: the French experience
Authors: Callec L , Patte C , Lardy-Cleaud A , Vignon L , Alapetite C , Chastagner P , Faure Conter C , Frappaz D 
Published: September 2019

Abstract

BACKGROUND
Optimal strategy for treatment of relapsing intracranial malignant germ cell tumors remains ill-defined. Authors describe the French experience over a 25-year period.

MATERIAL AND METHODS
Relapsing patients were retrieved by their participation in the SFOP-TGM 90-92 or GCT 96 protocols or from National Childhood Solid Tumour Registry.

RESULTS
The cohort included Group A: documented germinomas (n=14), Group B: patients treated as germinomas without histopathological proof (n=5) and Group C: secreting germ cell tumours (n=25).
Patients all received standard dose chemotherapy, and some high dose chemotherapy (VP16 Thiotepa with stem cell rescue) and/or various type of radiation.
The 5 year EFS and OS post relapse are: 79%[47 to 93%] and 86% [54 to 96%] respectively in group A, 20% [1 to 58%] and 80% [20 to 97%] respectively in group B, 56% [35 to 73%] and 60% [38 to 76%] respectively in group C.
Among 14 Group A patients, 7/12 receiving high dose versus 3/3 receiving standard dose chemotherapy, and 9/11 re-irradiated versus 1/3 not re-irradiated are CR2.
Among 21 Group C patients. who had received radiation in first line, 10/15 receiving high dose versus 1/6 receiving standard dose chemotherapy, and 7/11 re-irradiated versus 4/10 not re-irradiated are CR2.

CONCLUSION
The outcome of relapsing germinoma is favourable and intensity of second line remains matter of debate. High dose chemotherapy with radiotherapy, when feasible, should remain the reference for treatment of a relapsed non germinoma, though more active treatments are warranted.
P14.18 Prognostic value of serial dynamic O-(2-[18F]-fluoroethyl)-L-tyrosine PET in patients with non-resectable malignant glioma undergoing chemoradiation
Authors: Rosen J , Stoffels G , Lohmann P , Bauer E K , Werner J , Rapp M , Felsberg J , Fink G R , Langen K , Galldiks N 
Published: September 2019

Abstract

BACKGROUND
A complete resection of high-grade gliomas (HGG) is associated with improved survival, which, however, cannot be achieved in a considerable number of patients. We here evaluated the prognostic value of serial O-(2-[18F]-fluoroethyl)-L-tyrosine (FET) PET in patients with newly diagnosed, non-resectable astrocytic HGG undergoing chemoradiation with temozolomide.

MATERIAL AND METHODS
Serial dynamic FET PET scans were performed in 18 newly diagnosed patients with molecularly defined, non-resectable HGG at baseline and after chemoradiation (8±3 weeks). Both static (tumor/brain ratios, FET tumor volumes) and dynamic FET PET parameters (time-to-peak, slope), as well as MRI changes according to RANO criteria at first follow-up after chemoradiation (8±3 weeks), were obtained. The predictive ability of FET PET parameters and RANO criteria was evaluated with regard to the progression-free survival (PFS). Using ROC analyses, threshold values for FET PET parameters were obtained. Subsequently, univariate and multivariate survival analyses were performed to assess their predictive power for PFS.

RESULTS
ROC analysis revealed that the mean tumor/brain ratio (AUC, 0.84), FET tumor volume (AUC, 0.89), and slope (AUC, 0.72) at baseline were predictive for a prolonged PFS (9.3 vs. 5.7 months, P=0.05; 10.3 vs. 5.9 months; P=0.03; 13.5 vs. 6.2 months, P=0.02, respectively). Furthermore, FET tumor volume and slope remained significant in the multivariate survival analysis (both P<0.05). In contrast, relative changes of static or dynamic FET PET parameters at follow-up and MRI changes according to RANO criteria were not significant in this albeit small series of patients.

CONCLUSION
Results suggest that before initiation of chemoradiation FET PET parameters at baseline can be used to predict PFS in patients with non-resectable HGG.
P14.30 Treatment outcomes of newly-diagnosed glioblastoma multiforme (GBM) by O6-methylguanine DNA methyltransferase promoter (MGMT) status: a multi-country study
Authors: Fu A Z , Hall J P , Bailey A , Kemp J , Thompson G J , Lee C 
Published: September 2019

Abstract

INTRODUCTION
This study evaluated the relationship of MGMT status with first-line (1L) treatment outcomes of patients with newly-diagnosed GBM in France, Germany, Italy, Spain, the UK (EU5), and Canada.

MATERIALS AND METHODS
Medical oncologists and neuro-oncologists across EU5 and Canada completed a point in time, cross-sectional survey for the next 8 GBM patients seen between May and July 2016 within EU5 and Canada. All results apart from time to progression (TTP) were presented for patients receiving 1L active drug treatment. TTP was calculated from initiation of 1L treatment to initiation of second-line treatment. Results presented are statistically significant (p<0.05) unless otherwise specified. Bases vary depending on data availability.

RESULTS
A total of 241 physicians reported on 1747 patients with GBM. 875 were receiving 1L active drug treatment at time of survey. Mean age was 59.7 years (median=61) and 34.6% were women. Mean life expectancy was 14.9 months (median=12) at diagnosis and mean TTP was 8.5 months (median=7.3). Surgery was performed in 62% of patients (n=546) prior to 1L drug treatment; 38% of patients (n=329) had no surgery. Patients with surgery had a higher life expectancy at diagnosis vs patients with no surgery prior to 1L (mean=16.4 vs 12.2 months; median=15.0 vs 12.0). Patients who received corticosteroids (n=524) vs no corticosteroids during radiotherapy (n=64) had a shorter life expectancy at diagnosis (mean=15.0 vs 16.8 months, p=0.07; median=12.5 vs 13.9) and were more likely to have 8 or more inpatient days due to GBM (21% vs 8%, p=0.07) in the last 3 months prior to the survey. 62% of patients (n=541) had an MGMT-status recorded (tested: methylated or unmethylated), and 38% (n=334) were untested/ awaiting results (untested) at 1L. MGMT-tested patients had better life expectancy at diagnosis (mean=16.1 vs 12.9 months; median=15.0 vs 12.0) and longer TTP (mean=8.9 vs 7.8 months; median=7.8 vs 6.4) than untested patients. Among MGMT-tested patients, 58% were methylated and 42% were unmethylated. Methylated patients had similar life expectancy at diagnosis (mean=15.9 vs 16.3 months, p=0.85; median=15.0 vs 15.0) and TTP (mean=9.0 vs 8.8 months, p=0.42; median=8.0 vs 7.5) as unmethylated patients.

CONCLUSIONS
This analysis provides valuable insights into the 1L treatment outcomes of GBM patients in EU5 and Canada. Patients who did not undergo surgery had worse treatment outcomes. Steroid use appears to be associated with worse outcomes and higher healthcare resource utilization. Patient treatment outcomes varied depending on whether they are MGMT tested.
P14.39 How far should it be removal beyond the Gd-enhanced edge in Glioblastoma cases? -Preoperative removal range identification using Methionine-PET and Thallium-SPECT fusion image
Authors: Nakayama N , Yano H , Takei H , Miwa K , Shinoda J , Iwama T 
Published: September 2019

Abstract

BACKGROUND
Mostly, the removal rate of glioblastoma has been discussed in the Gd enhanced area, but tumor cells are surely infiltrated beyond the Gd enhanced edge. Although Methionine-PET (MET) and Thallium-SPECT (Tl) are useful for preoperative tumor invasion range identification, they are off-label use in most countries, and their respective accumulation ranges do not match completely. In this study, Gd-MRI, MET, and Tl were performed, and the accumulation range was compared from the fusion images, and the prediction method of the tumor cell infiltration range was examined.

MATERIAL AND METHODS
The mean interval period between MET and Tl administration was 16.3 days in 21 cases of glioblastoma (12 male and 9 female, average age 59.1 ± 17.8 years). Fusion images were generated using iPlan Cranial 3.0.The MET-area, Tl-area, Overlap-area where MET and Tl overlap, and Accumulation-area where MET and Tl are maximally accumulated were measured in the same cross section as the Gd-enhanced maximum area (Gd-area, X cm2) in axial view. Each volume was also measured similarly.

RESULTS
Gd-area was correlated with all of MET-area, Tl-area, Overlap-area, and Accumulation-area (p ≦0.0001).Gd-volume (X’cm3) showed correlation with all of MET-volume, Tl-volume, Overlap-volume, and Accumulation-volume (p ≦0.0001). The linear approximation was calculated as follows. Overlap-area = 1.942X + 1.0208 (R = 0.937), Accumulation-area = 1.3299X + 6.098 (R = 0.889), Overlap-volume = 1.1539X ‘+ 7.0573 (R = 0.927), Accumulation-volume = 1.8668X ‘+30.06 (R = 0.893).

CONCLUSION
These linear approximations can be used to predict the tumor invasion range from the Gd-enhanced maximum area or Gd-enhanced volume without using off-label use drugs.
P14.42 Diagnostic challenges of infratentorial hemangioblastomas: improvement of current radiological classification scheme
Authors: Jung I , Kim E , Moon J , Kang S , Chang J 
Published: September 2019

Abstract

BACKGROUND
Hemangioblastomas (HBMs) are known to exhibit very typical radiological features and thus classified by well-established radiological classification scheme. However, after we have experienced unusual cases in which current radiological classification system was not enough to categorize them, we reviewed our series of infratentorial HBMs in order not only to evaluate the relevance of current classification scheme, but also to possibly improve it. Also, we added descriptions on several cases with unusual radiological magnetic resonance imaging (MRI) findings in which differential diagnosis was challenging.

MATERIAL AND METHODS
We retrospectively reviewed preoperative MRI of 118 patients with pathologically diagnosed infratentorial HBMs at our institution between 2002 and 2015. Total 128 tumors were included to this study and classified into four categories based on the presence and nature of cystic components: extratumoral cystic (Type Ce, classical cystic with a mural nodule), intratumoral cystic (Type Ci), mixed cystic (Type Cm), and solid (Type S). The association with von Hippel-Lindau (VHL) disease was also investigated.

RESULTS
In 118 patients (65 male and 53 female), 79 (66.9%) had solitary HBMs and 39 (33.1%) were diagnosed with VHL disease. Type Ce with typical radiological findings was the most prevalent type of HBM (63.3%), followed by Type S (21.1%). HBMs with intratumoral cysts were uncommon (Type Ci, 11.7%) and mixed extratumoral and intratumoral cysts (Type Cm) accounted for only 3.9%. No intergroup differences were observed in the proportions of each subtype between the solitary and VHL disease-associated HBMs.

CONCLUSION
Radiological features of HBMs are usually typical thus preoperative presumption is not difficult in majority of cases. Improved radiological classification scheme is more practical because it does not only help surgeons determine whether the cystic wall should be removed or not, but also covers cases with atypical radiological presentations. For solid and extraparenchymal HBMs, differential diagnosis is more difficult as well as very critical as surgical removal is often very challenging.
P14.48 Identification of subsets of IDH-mutant glioblastomas with distinct epigenetic and copynumber alterations and stratified clinical risks
Authors: CHAN A K , Li K K , Shi Z F , Ng H K 
Published: September 2019

Abstract

BACKGROUND
IDH-mutant glioblastoma is classified by the 2016 CNS WHO as a group with good prognosis. However, the actual number of cases examined in the literature is relatively small. We hypothesize that IDH-mutant glioblastoma is not a uniform group and should be further stratified.

MATERIAL AND METHODS
We conducted methylation profiles and estimated copy number variations in 64 IDH-mutant glioblastomas.

RESULTS
Our results showed that 10.9%, 53.1%, and 35.9% of tumors belonged to Codel, G-CIMPhigh, and G-CIMP-low methylation subgroups, respectively. G-CIMP-low subgroup was associated with significantly worse OS as compared to G-CIMP-high (P=0.005) and Codel groups (P=0.009). CDKN2A deletion (37.5%) was the most common gene copy number variation, and was associated with G-CIMP-low subgroup (P=0.001). Other frequent copy number changes included MET (4.7%), CCND2 (17.2%), PDGFRA (14.1%), CDK4 (12.5%), and EGFR (12.5%) amplification. Both CDKN2A deletion (P=0.008) and MET amplification (P<0.001) were associated with poor OS in IDH-mutant glioblastomas. Combined epigenetic signatures and gene copy number variations separated IDH-mutant glioblastomas into Group 1 (Codel), Group 2 (GCIMP- high), Group 3 (G-CIMP-low without CDKN2A and MET alterations), and Group 4 (G-CIMP-low with CDKN2A/MET alteration). Survival analysis revealed Group 1 had a favorable OS (median survival: 41.3 months), while Groups 2 and 3 exhibited an intermediate OS (median survival: 20.6 and 21.8 months, respectively). Group 4 exhibited the worst OS (median survival: 8.4 months). Multivariable analysis confirmed the independent prognostic significance of our Groups.

CONCLUSION
IDH-mutant glioblastomas should be stratified for risk with combined epigenetic signature and CDKN2A/MET status and some cases have poor outcome.