bluuebunny/crossref_metadata_2025_split huggingface dataset:
P13.09 Genomic analysis of paired IDHwt glioblastoma (GB) reveals recurrent alterations of MPDZ at relapse after radiotherapy and temozolomide (RTCT)
Authors: Chanez B , Appay R , Guille A , Lagarde A , Bequet C , Jiguet-Jiglaire C , Graillon T , Dufour H , Figarella-Branger D , Chinot O , Tabouret E 
Published: September 2019

Abstract

BACKGROUND
GB are highly aggressive tumors which systematically relapse. Our objective was to identify disease progression mechanisms and genomic drivers of GB treatment resistance.

MATERIAL AND METHODS
Ten paired frozen tumors from initial and recurrent surgery after RTCT were screened by CGH Array. Next, NGS of the selected genes was performed on 19 paired tumors (38 samples). Molecular alterations were correlated with patient data. TCGA was used to characterize the molecular profile of MPDZ.

RESULTS
Nineteen IDHwt GB patients with a median age of 54.5 years (37.2–72.8) were included. Using CGH array, unsupervised analysis clustered the whole samples by paired of initial and recurrent tumors. However only 44% of CGH Array alterations were shared between initial and recurrent tumors (amplifications: 55%; deletions: 30%). The new alterations detected at relapse were amplifications in 25% and deletions in 23% of tumors. Two regions corresponding to 171 genes were lost at relapse (p=0.03): 19q13.33 and 19q13.41. Using DAVID genome, 3/171 genes (related to neutrophil chemotactic factors) were identified: FPR1, FPR2, FPR3. Moreover, 24 genes were lost (including MPDZ) and 2 genes were gained in 20% of recurrent tumors. Totally, 29 genes were analyzed by NGS and 4 genes showed pathogenic mutations shared by initial and recurrent tumors: FPR2, REL, TYRP1 and MPDZ. Only MPDZ showed, at relapse, an increasing rate of mutated variants and a new mutation affecting the splicing site. These alterations were independent from classical prognostic factors (age, sexe, karnofsky performans status, MMS and MGMT status) and from patient survivals. To explore MPDZ expression, we used TCGA initial dataset and observed that a lower RNA expression of MPDZ was associated with IDHwt (p<0.001) and grade IV (p<0.001) gliomas, reinforcing the potential pejorative impact of MPDZ loss.

CONCLUSION
Our results suggest that MPDZ is frequently altered at initial diagnosis with increased alterations in recurrent IDHwt GB after RTCT, suggesting that MPDZ impairment could contribute to the resistance/relapse mechanisms. Further investigations are needed to validate these results. Our results suggest that MPDZ is frequently altered at initial diagnosis with increased alterations in recurrent IDHwt GB after RTCT, suggesting that MPDZ impairment could contribute to the resistance/relapse mechanisms. Further investigations are needed to validate these results.
P14.17 Differentiation of treatment-related changes from tumor progression: A direct comparison between dynamic FET PET and ADC values obtained from DWI MRI
Authors: Werner J , Stoffels G , Lichtenstein T , Borggrefe J , Lohmann P , Ceccon G , Fink G R , Langen K , Kabbasch C , Galldiks N 
Published: September 2019

Abstract

BACKGROUND
Following brain cancer treatment, the capacity of anatomical MRI to differentiate neoplastic tissue from treatment-related changes (e.g., pseudoprogression) is limited. This study compared apparent diffusion coefficients (ADC) obtained by diffusion-weighted MRI (DWI) with static and dynamic parameters of O-(2-[18F]fluoroethyl)-L-tyrosine (FET) PET for the differentiation of treatment-related changes from tumor progression.

MATERIAL AND METHODS
Forty-eight pretreated high-grade glioma patients with anatomical MRI findings suspicious for progression (median time elapsed since last treatment, 16 weeks) were investigated using DWI and dynamic FET PET. Maximum and mean tumor-to-brain ratios (TBRmax, TBRmean) as well as dynamic parameters (time-to-peak and slope values) of FET uptake were calculated. For mean ADC calculation, regions-of-interest analyses were performed on ADC maps calculated from DWI co-registered with the contrast-enhanced MR image. Diagnoses were confirmed neuropathologically (21%) or clinicoradiologically. Diagnostic performance was evaluated using receiver-operating-characteristic analyses or Fisher’s exact test for a combinational approach.

RESULTS
Ten of 48 patients had treatment-related changes (21%). The diagnostic performance of FET PET was significantly higher (threshold for both TBRmax and TBRmean, 1.95; accuracy, 83%; AUC, 0.89±0.05; P<0.001) than that of ADC values (threshold ADC, 1.09x10-3 mm2/s; accuracy, 69%; AUC, 0.73±0.09; P=0.13). The addition of static FET PET parameters to ADC values increased the latter’s accuracy to 89%. The highest accuracy was achieved by combining static and dynamic FET PET parameters (93%).

CONCLUSION
Data suggest that static and dynamic FET PET provide valuable information concerning the differentiation of early treatment-related changes from tumor progression and outperform ADC measurement for this highly relevant clinical question.
P14.21 Tehila Kaisman-Elbaz MD/PhD
Authors: Kaisman-Elbaz T , Elbaz Y , Merkin V , Dym L , Noy A , Atar-Vardi M , Bari R , Turiel S , Lavrenkov K , Melamed I 
Published: September 2019

Abstract

BACKGROUND
Glioblastoma is known for its dismal prognosis though its dependency on patients’ readily available RBCs parameters defining the patient’s anemic status such as hemoglobin level and Red blood cells distribution Width (RDW) is not fully established. Several works demonstrated a connection between low hemoglobin level or high RDW values to overall glioblastoma patient’s survival, but in other works, a clear connection was not found. This study addresses this unclarity.

MATERIAL AND METHODS
In this work, 170 glioblastoma patients, diagnosed and treated in Soroka University Medical Center (SUMC) in the last 12 years were retrospectively inspected for their survival dependency on pre-operative RBCs parameters using multivariate analysis followed by false discovery rate procedure due to the multiple hypothesis testing. A survival stratification tree and Kaplan-Meier survival curves that indicate the patient’s prognosis according to these parameters were prepared.

RESULTS
Beside KPS>70 and tumor resection supplemented by oncological treatment, age<70 (HR=0.4, 95% CI 0.24–0.65), low hemoglobin level (HR=1.79, 95% CI 1.06–2.99) and RDW<14% (HR=0.57, 95% CI 0.37–0.88) were found to be prognostic to patients’ overall survival in multivariate analysis, accounting for false discovery rate of less than 5%.

CONCLUSION
A survival stratification highlighted a non-anemic subgroup of nearly 30% of the cohort’s patients whose median overall survival was 21.1 months (95% CI 16.2–27.2) - higher than the average Stupp protocol overall median survival of about 15 months. A discussion on the beneficial or detrimental effect of RBCs parameters on glioblastoma prognosis and its possible causes is given.
P14.25 Venous thromboembolic events in patients with brain metastases: the PICOS score
Authors: Wolpert F , Grossenbacher B , Lareida A , Roth P , Neidert M C , Andratschke N , Le Rhun E , Weller M 
Published: September 2019

Abstract

BACKGROUND
Venous thromboembolic events are significant complications in patients and possibly associated with an unfavorable outcome. Thrombosis risk is poorly defined for patients with brain metastasis, and available risk calculation scores are not validated for these patients.

MATERIAL AND METHODS
We identified 811 patients with brain metastasis followed at our institution and screened electronic charts retrospectively for the occurrence of venous thromboembolic events, along with candidate risk factors. Risk factors were tested in uni- and multivariate analyses and finally integrated in a score model for risk prediction.

RESULTS
Venous thromboembolic events were documented in 97 of 811 patients (12.0%). Primary tumors with high thrombogenicity (p=0.02, odds ratio 1.7, 95% CI 1.1–2.8), dexamethasone (p=0.011, odds ratio 2.27, 95% CI 1.5–4.5), chemotherapy (p=0.005, odds ratio 3.4, 95% CI 1.6–7.5), BMI > 35 kg/m2 (p=0.002, odds ratio 3.4, 95% CI 1.6–7.5) and immobilization (p=0.003, odds ratio 2.4, 95% CI 1.3–4.3) were confirmed as independent predictors of VTE. We derived a score model for venous thromboembolic event prediction, the PICOS (thrombogenic Primary, Immobilization, Chemotherapy, Obesity, Steroids) score (0–7 points). Receiver Operating Characteristic Curve Analysis demonstrated its prognostic accuracy (AUC=0.71, 95% CI 0.64–0.77), and its predictive capability was superior to that of other scores proposed for the evaluation of venous thromboembolic event risk such as the Khorana (AUC=0.51) or CONKO (AUC=0.52) scores.

CONCLUSION
We report a rate of venous thrombotic events of 12.0% in our cohort of 811 patients with brain metastasis. We define a risk model for prediction in of venous thrombotic events in patients with BM, the PICOS score. It may become a valuable tool for the identification of brain metastasis patients at high risk for venous thromboembolic events and be helpful for guidance of clinicians towards decision whether to start thrombosis prophylaxis. Further, the PICOS score might be used for stratification in controlled studies.
P14.32 Spatial discrepancies between FET PET and conventional MRI in patients with newly diagnosed glioblastoma
Authors: Lohmann P , Stavrinou P , Lipke K , Bauer E K , Ceccon G , Werner J , Fink G R , Shah N J , Langen K , Galldiks N 
Published: September 2019

Abstract

BACKGROUND
In patients with glioblastoma, the tissue showing contrast enhancement (CE) in MRI is usually the target for resection or radiotherapy. However, the solid tumor mass typically extends beyond the area of CE. Amino acid PET can detect tumor parts that show no CE. We systematically investigated tumor volumes delineated by amino acid PET and MRI in newly diagnosed, untreated glioblastoma patients.

MATERIAL AND METHODS
Preoperatively, 50 patients with subsequently neuropathologically confirmed glioblastoma underwent O-(2-[18F]-fluoroethyl)-L-tyrosine (FET) PET, fluid-attenuated inversion recovery (FLAIR), and CE MRI. Areas of CE were manually delineated. FET PET tumor volumes were segmented using a tumor-to-brain ratio ≥ 1.6. The percentage of overlapping volumes (OV), as well as Dice and Jaccard spatial similarity coefficients (DSC; JSC), were calculated. FLAIR images were evaluated visually.

RESULTS
In 86% of patients (n = 43), the FET PET tumor volume was significantly larger than the volume of CE (21.5 ± 14.3 mL vs. 9.4 ± 11.3 mL; P < 0.001). Forty patients (80%) showed both an increased uptake of FET and CE. In these 40 patients, the spatial similarity between FET and CE was low (mean DSC, 0.39 ± 0.21; mean JSC, 0.26 ± 0.16). Ten patients (20%) showed no CE, and one of these patients showed no FET uptake. In 10% of patients (n = 5), increased FET uptake was present outside of areas of FLAIR hyperintensity.

CONCLUSION
Our results show that the metabolically active tumor volume delineated by FET PET is significantly larger than tumor volume delineated by CE. The data strongly suggest that the information derived from FET PET should be integrated into the management of newly diagnosed glioblastoma patients.

FUNDING
This work was supported by the Wilhelm-Sander Stiftung, Germany
P14.38 Clinical experience with tumor treating fields (TTFields) treatment for posterior fossa tumors
Authors: Taliansky A , Vagner T , Jan E , Zach L 
Published: September 2019

Abstract
Introduction: TTFields brought a new concept in the treatment of brain tumors. It was tested and recommended for use in supra-tentorial lesions. There is a paucity of data available about TTFields safety and efficacy for infra-tentorial lesion.
Method: Patients with posterior fossa tumors were treated with the Optune® system. Initial transducer array positioning and all technical characteristic were performed with technical support from Novocure.
Results: Two patients with posterior fossa glial tumors were treated. The first is a 27 years old male with DIPG (without pathological confirmation of the tumor grade) who was treated with Stupp protocol. Treatment with TTFields commenced with TMZ adjuvant phase. The second patient is a 33 years old female with cerebello-pontine astrocytoma WHO grade III, IDH I mutated. This patient was treated with partial resection and Stupp protocol. TTFields treatment was started after completing 12 TMZ adjuvant cycles with measurable stable disease. Duration and compliance of TTFields treatment for first patient is 286 days and 86% and for second patient is 168 days and 93.6%. The skin toxicity is minimal and did not require treatment interruption. There is no other TTFields related toxicity. The MRI evaluation had showed improvement in the first patient and stable disease in the second.
Conclusion: According to our knowledge, this is the first report of clinical experience with TTFields treatment for posterior fossa tumors. In our experience, the treatment is feasible and with equal toxicity to previously reported supra-tentorial lesions. Small patient population and short follow up do not allow efficacy evaluation.
P14.41 Temporal muscle thickness is an independent prognostic marker in patients with progressive glioblastoma: translational imaging analysis of the EORTC-26101 trial
Authors: Furtner J , Genbrugge E , Gorlia T , Bendszus M , Nowosielski M , Golfinopoulos V , Weller M , van den Bent M J , Wick W , Preusser M 
Published: September 2019

Abstract

BACKGROUND
Temporal muscle thickness (TMT) was described as surrogate marker of skeletal muscle mass and prognostic parameter in brain metastasis patients. This study aimed to evaluate the prognostic relevance of TMT in patients with progressive glioblastoma.

MATERIAL AND METHODS
TMT was analyzed on the baseline cranial magnetic resonance (MR) images of 596 patients with progression of glioblastoma after radio-chemotherapy enrolled in the EORTC 26101 trial. An optimal TMT cutoff for overall survival (OS) and progression free survival (PFS) was defined in the training cohort (n=260 patients enrolled in phase 2 part of EORTC 26101). Patients were grouped as “below” or “above” the TMT cutoff and associations with OS and PFS were tested using the Cox model. The findings were validated in a test cohort (n=308 patients enrolled in phase 3 part of EORTC 26101).

RESULTS
An optimal baseline TMT cutoff of 7.2 mm was obtained in the training cohort for both OS and PFS (AUC=0.64). Univariate analyses estimated a hazard ratio (HR) of 0.54 (95% CI:0.42, 0.70, p<0.0001) for OS and a HR of 0.49 (95% CI: 0.38, 0.64, p<0.0001) for PFS for the comparison of training cohort patients above versus below the TMT cutoff. This was confirmed in multivariate testing for OS (HR of 0.54, 95% CI: 0.41, 0.70, p<0.0001) and PFS (HR of 0.47, 95% CI: 0.36, 0.61, p<0.0001) adjusted for the important risk factors with relevance in the trial for OS (Steroid use at baseline, HR of 1.58, 95% CI: 1.19, 2.11, p = 0.002; MGMT Status, HR of 0.51, 95% CI: 0.36, 0.72, p<0.001; maximum diameter ≥ 40mm, HR of 2.49, 95% CI: 1.41, 4.41, p = 0.002; central hemisphere involvement, HR of 1.97, 95% CI: 1.37, 2.84, p<0.001) and PFS (Neurological deficit, HR of 1.44, 95% CI:1.09, 1,92, p = 0.011; Steroid use at baseline, HR of 1.42, 95% CI: 1.08, 1.86, p = 0.011; MGMT status, HR of 0.61, 95% CI: 0.43, 0.87, p = 0.007; Number of target lesion >1, HR of 2.47, 95% CI: 1.38, 4,41, p = 0.002). Similar results were obtained in the validation cohort.

CONCLUSION
TMT is an independent prognostic parameter in patients with progressive glioblastoma. This parameter is easily assessable on routine MR images and may help to better define frail patient populations and thus facilitate patient management by supporting patient stratification for therapeutic interventions or clinical trials.
P14.43 Histone H3F3A and HIST1H3B K27M mutations in pediatric high-grade gliomas: the Florentine experience
Authors: Guidi M 
Published: September 2019

Abstract

Background
Pediatric high- grade gliomas (HGGs) represent a malignancy with a poor survival. The genetic analysis of these entities has identified useful mutations for an improved prognostic framing. The research of mutations in all H3 histone variants (HIST1H3B and H3F3A) could be usefull to define tumors with different prognosis and phenotypes inasmuch they seems to drive two distinct oncogenic programmes.

MATERIALS E METHODS
We performed a retrospective analysis of pediatric HGGs. We evaluated the type of histone H3 mutated and we performed a meta-analysis comparing our results with literature data.

RESULTS
We evaluated 41 cases of pediatric HGGs (median age of patients: 7 years old, range: 0–32):): 32 anaplastic astrocytoma (78,5%), 9 glioblastoma multiforme (25,9%), We have researched the K27M mutations in the distinct histone H3 variants (i.e. HIST1H3B and H3F3A). The mutation H3F3A K27M was found in 6 patients instead HIST1H3B K27 mutations was found in a single patient with GBM. All the patients with H3F3A K27M mutation had a progression disease but without statistical correlation (p:0,07). They had a worse prognosis with a median overall survival of 15,5 months (p: 0.0014) versus wild type patients (not reached). H3.3K27M mutation status is a signiﬁcant predictor of OS with a hazard ratio of 4.499 (p = 0.0001). The patient with HIST1H3B K27 mutation died after first line of therapy.

Conclusions
Due to the low incidence of the mutation HIST1H3B in our series we can’t define the difference with two variants. However, the research of K27M mutation in HGGs has diagnostic and prognostic role. The role of histone H3 mutated could predict the outcome in HGGs patients and it could give us more informations compared to the clinic and radiological characteristic of the tumors.
P14.54 Association of EGFR Expression and Copy Number with Outcome in Depatux-m (ABT-414) Randomized Phase II Study of the EORTC Brain Tumor Group
Authors: van den Bent M J , Gorlia T , Sun Y , Kular R , Looman J , Bain E E , Robberts-Rapp L , Ansell P J , Golfinopoulos V , French P 
Published: September 2019

Abstract

BACKGROUND
Patients with glioblastoma (GBM) have a dismal prognosis and are in desperate need of better therapy than the standard of care (SOC). Epidermal growth factor receptor (EGFR) gene amplification is reported in more than 50% of GBMs as an important target for therapeutic intervention and as a potential predictive biomarker. Depatuxizumab mafodotin (depatux-m, ABT-414) is an antibody-drug conjugate that preferentially binds cells with EGFR active conformation, internalized and releases the cytotoxin, leading to cell death. In the primary analysis we reported a trend (in EORTC 1410; HR: 0.71, 95% CI [0.50–1.02], p = 0.06) at topline analysis which continued to improve with ad hoc follow up (HR of 0.66, 95%CI [0.47–0.93]; p = 0.016) was observed towards improved overall survival (OS) in patients with EGFR amplified (amp) recurrent glioblastoma treated with depatux-m in combination with temozolomide. OS was equivalent in the depatux-m monotherapy and chemotherapy control arms. Here, we evaluate the association of EGFR mRNA expression and EGFR copy number with outcome using the updated efficacy data.

METHODS
Eligible were patients with centrally confirmed EGFR amp GBM at first recurrence after temozolomide chemo-irradiation. Patients were randomized to either a) depatux-m 1.0–1.25 mg/kg combined with temozolomide 150–200 mg/m2 day 1–5 every 4 weeks, b) depatux-m 1.0–1.25 mg/kg monotherapy or c) either temozolomide or lomustine (TMZ/LOM) depending on the time of relapse. Primary endpoint was OS. Long-term follow-up data (24 months follow-up; 237 events) were utilized for this EGFR analysis. The expression level of EGFR was determined using RT-PCR. The absolute copy number of EGFR was determined using next generation sequencing. EGFR mRNA and EGFR copy number were treated as continuous variables and compared to OS using a generalized additive cox proportional hazards model.

RESULTS
The outcome of the long-term follow-up was that when used in combination with TMZ, depatux-m addition resulted in improved OS as compared to TMZ/ LOM control regardless of EGFR expression or absolute copy number of EGFR. In contrast, in depatux-m monotherapy, a trend was observed that depatux-m improved the outcome only at highest expression levels and highest absolute EGFR copy number.

CONCLUSIONS
The long-term follow-up trial results demonstrated that addition of depatux-m to SOC showed a trend to increased survival as compared to SOC alone in EGFR amp patients as determined using Fluorescent in situ hybridization (FISH) analysis. Further retrospective analysis supports this efficacy advantage is observed at all expression and amplification levels. When used in combination with SOC and regardless of the absolute copy number of EGFR, the trend for OS improvement was observed at all expression levels.
P14.55 FOXP2 as a prognostic biomarker in glioblastoma
Authors: Plata-Bello J , Fariña H , Betancor I , Quintero Y , Salido E , Garcia-Marin V 
Published: September 2019

Abstract

Background
FOXP2 is an essential transcription factor for the development of language. It has also a high expression in some neosplasm, with a differential role as a prognostic biomarker. However, the role of FOXP2 in glioblastoma (GBM) has not been studied until now.

AIM
To study the role of FOXP2 as a prognostic biomarker in GBM.

METHODS
This is a retrospective observational case series study in which the expression of FOXP2 has been analyzed at the protein level (immunochemistry, in probes from patients treated in our Center) and at the level of mRNA (RNAseq, in a cohort of GBM patients from The Cancer Genome Atlas [TCGA] database). The expression of some target genes of FOXP2 (RNAseq) has also been studied in the TCGA cohort. Survival analysis using Log-Rank test and COX regression (uni- and multivariate) have been used. The analysis included also other molecular and clinical features of interest in GBM.

RESULTS
At protein level, FOXP2 was expressed in more than 90% of patients, with a mean positivity of 28.33% (SD=32.29). At mRNA level, FOXP2 was expressed in 79% of patients, with a mean expression of 29.72 RPKM (SD=63.77). Patients with a high expression of FOXP2 at protein level showed a worse prognosis than those patients with low expression in both, progression free survival (HR=1.711; p=.034) and overall survival (HR=1.809; p=.014). These associations maintained their significance in multivariate analysis. Nevertheless, no prognostic association was found with mRNA FOXP2 expression. Interestingly, FOXP2 target genes did not show the expected regulation described in previous works. Some of these genes has been involved in oncogenesis.

CONCLUSION
FOXP2 is expressed in many GBM patients. Higher expression of FOXP2 protein may be associated with a worse prognosis, but this has not been confirmed at mRNA. Furthermore, a dysregulation of FOXP2 function may be present in tumoral cells.