bluuebunny/crossref_metadata_2025_split huggingface dataset:
P14.19 The inverse paradigm of IDH-wildtype glioblastoma is fundamental to overcome the two causes of resistance and develop novel effective therapies
Authors: Brognaro E 
Published: September 2019

Abstract

BACKGROUND
IDH-wildtype glioblastoma behaves differently from all other solid tumors. This is the reason why after decades of praiseworthy therapeutic efforts, the prognosis remains very poor. Many clues (radiological, clinical, surgical) and recent indirect experimental evidence converge to indicate that the entire brain parenchyma is micro-infiltrated from the very beginning by the founding clone before the primary bulk has started its growth. Therefore, only in IDH-wildtype glioblastoma the malignant (i.e. distantly infiltrating the organ of origin) and deadly (leading cause to patient’s death) phases coincide and overlap in one single phase.

MATERIALS AND METHODS
Appropriate sampling procedures must absolutely take into consideration both the tumor bulk and the micro-infiltrated brain parenchyma. They can be performed (with full respect for ethical issues) analyzing neoplastic and “healthy” material obtained from living patients (a), using animal models (b), studying post-mortem samples from rapid autopsies (c), comparing local and distant recurrences with the primary bulk (d). The study and analysis of the bulk tumor must be carried out by collecting multiple multiregional spatially separated samples throughout the whole tumor mass. The analysis of the micro-infiltrated brain parenchyma in living patients can be performed appropriately and ethically also from surgical patient tissue.

RESULTS
The phylogenetic tree of the tumor bulk must be inferred and reconstructed by the collection and analysis of multiple regionally separated samples. Additionally, driver and passenger events will be identified as well as the CSCs of samples. The procedures to ethically sample the micro-infiltrated brain parenchyma enable us to collect and identify the founder CSCs which lie quiescent in the perivascular parenchymal niches across the whole brain. Indeed, distant recurrences are due to their activation.

CONCLUSION
IDH-wildtype glioblastoma is the only brain tumor which arises from astrocyte-like cells of the SVZ ribbon layer and it is able to micro-infiltrate the whole supratentorial brain parenchyma before starting its growth. Its unique inverse paradigm explains the emergence of distant recurrences (sharing only truncal mutations with the primary bulk) and adds, in addition to the heterogeneity of the primary bulk and its residues, a second crucial cause of resistance to take into account (i.e. the founder CSCs which reside quiescent, in G0 state, in the perivascular parenchymal niches). Therefore, innovative therapies must identify and selectively target either CSCs unique properties related to their impaired asymmetrical division or stable driver lesions of the founder CSC (without alternative mutations and pathways) or exclusive markers used by the founder CSCs to settle dormant (involving mechanisms of adhesion, anchorage and cell cycle arrest) in their niches.
P14.29 Prediction of overall survival in patients with malignant glioma using dynamic O-(2-[18F]-fluoroethyl)-L-tyrosine PET
Authors: Bauer E K , Stoffels G , Blau T , Reifenberger G , Werner J M , Lohmann P , Rapp M , Fink G R , Langen K , Galldiks N 
Published: September 2019

Abstract

BACKGROUND
Characterization of gliomas according to the revised World Health Organization (WHO) classification of 2016 has gained major importance regarding prognostication. The present study aimed at exploring the prognostic value of dynamic O-(2-[18F]-fluoroethyl)-L-tyrosine (FET) PET in newly diagnosed and molecularly defined astrocytic high-grade glioma (HGG) of the WHO grades III or IV.

MATERIAL AND METHODS
Before initiation of treatment, dynamic FET PET imaging was performed in patients with newly diagnosed glioblastoma (GBM) and anaplastic astrocytoma (AA). Static FET PET parameters such as maximum and mean tumor/brain ratios (TBRmax/mean), as well as the dynamic FET PET parameters time-to-peak (TTP) and slope, were obtained. The predictive ability of FET PET parameters was evaluated with regard to the overall survival (OS). Using ROC analyses, threshold values for FET PET parameters were obtained. Subsequently, univariate Kaplan-Meier and multivariate Cox regression survival analyses were performed to assess their predictive power for OS.

RESULTS
Sixty patients (45 GBM, 15 AA) of two university centers were retrospectively identified. Patients with a methylated MGMT promoter as well as with an IDH mutation had a significantly longer OS (both P<0.001). Furthermore, ROC analysis revealed in IDH-wildtype HGG (n=45) that a TTP>25 minutes (AUC, 0.90; sensitivity, 90%; specificity, 87%; P<0.001) was highly prognostic for a longer OS (29 vs. 12 months; P<0.001). Besides a complete resection and a methylated MGMT promoter, TTP remained significant in the multivariate survival analysis (P=0.002, P=0.016, and P=0.003, respectively), indicating an independent predictor for OS. In contrast, both TBRmax and TBRmean were not prognostic (AUC, 0.37 and 0.32, respectively).

CONCLUSION
Data suggest that within the subgroup of patients with newly diagnosed and untreated IDH-wildtype GBM and AA, dynamic FET PET additionally allows the identification of patients with an improved OS.
P14.31 CMV reactivation in a cohort of newly-diagnosed glioblastoma patients treated with temozolomide chemoradiotherapy. A single center analysis
Authors: URSU R , Doridam J , Chaugne E , Zannou H , Belin C , Cuzzubbo S , Sirven-Villaros L , Brichler S , Levy-Piedbois C , Carpentier A 
Published: September 2019

Abstract

BACKGROUND
The Cytomegalovirus (CMV) is a ubiquitous herpes virus which infects 60–80 % of the population in Europe. Although the CMV usually remains latent, reactivation can occur in the context of an immunodepression, such as low CD4-lymphocyte levels in HIV patients. Glioblastoma (GBM) patients frequently show lymphopenia, which is related to both the immunosuppressive nature of the tumor and to the treatment with concomitant temozolomide (TMZ) and radiotherapy (RT). Surprisingly, the incidence of CMV reactivation in GBM patients has not been clearly studied so far. We report here our experience on CMV reactivation in a cohort of newly-diagnosed GBM patients, treated with RT and TMZ. We assessed the incidence of CMV reactivation in these patients and tried to identify risk factors for such reactivation.

MATERIAL AND METHODS
All consecutive patients with histologically confirmed malignant GBM recommended for temozolomide chemoradiotherapy in our institution from October 2013 to December 2015 were reviewed. In all patients, sex, age, Karnofsky performance status (KPS), lymphocyte level, serological CMV status and steroid dosages were recorded at the onset, and one month after completion of the concomitant radio-chemotherapy regimen. A CMV reactivation was defined by a detection of CMV DNA > 1000 copies/ml in the patient’s serum.

RESULTS
103 patients meeting the analysis criteria were reviewed. Within these 103 patients, 34 patients (33%) had initial negative serology for CMV, and none of them developed a seroconversion after treatment with concomitant RT + TMZ. Among patients with positive IgG (n=69), 16 patients (23%) developed a positive viremia at one point during treatment with concomitant RT + TMZ. Age (>60 years), lymphocyte count before RT (<1500/mm3) and use of steroids were correlated with CMV reactivation (p<0.05 in univariate analysis). A positive CMV viremia during RT+TMZ did not impact the progression free survival (PFS) but was associated with a shorter overall survival (OS) when compared to the others patients (median: 12 months vs 15 months; p=0.04). No clinical symptoms suggestive of CMV infection were reported.

CONCLUSION
In this single center series, we showed that CMV reactivation occurs in 23% of the GBM patients having a positive serology for CMV. Reactivation was more frequent in older patients, with low lymphocyte counts and treated with steroids. A positive viremia was not associated with poor PFS, a fact that does not support a promoting role of CMV in glioma oncogenesis, which has been sometimes suggested. Yet, the group of patients with CMV reactivation showed a shorter OS, which might be related to an older age and /or poorer clinical conditions in this group.
P14.35 The modern management of brain metastases
Authors: Wallace N D , Kelly P J 
Published: September 2019

Abstract

BACKGROUND
Technological and clinical advances have improved outcomes for patients with brain metastases. They have also added significantly to the complexity of decision-making in such cases. We set out to review the roles of different treatment options to guide management for patients with newly-diagnosed brain metastases.

MATERIAL AND METHODS
We undertook a comprehensive literature review to examine all treatment options for brain metastases. We particularly focused on recent advances and where these can be applied to clinical practice.We examined the impact of the improvement of SRS technology from older frame-based setups to modern linear accelerator based treatment with the capacity for fractionated stereotactic radiotherapy (SRT). We identified clinical situations where either SRS or WBRT, or a combination of the two, should be most strongly considered. Several novel targeted systemic therapies cross the blood-brain-barrier so we have explored their outcomes for patients with brain metastases from BRAF-mutated melanoma and EGFR or ALK/ROS1 mutated NSCLC. By examining these techniques in detail, we have formulated an algorithm-based approach which can inform management.

RESULTS
Surgery is most beneficial in patients with a reasonable prognosis and where other treatment options are unlikely to provide equivalent control. SRS to the surgical cavity can frequently be used alone for post-operative consolidation. SRS and fractionated SRT are valuable treatment options for increasingly large lesions and for increasing numbers of lesions. The choice between SRS and WBRT is, in many cases, a trade-off between the improved intracranial control of WBRT and the more favourable side effect profile of SRS. Upfront therapy with some systemic agents with CNS penetration is an acceptable approach in carefully-selected patients whose outcome is felt to be more related to their extracranial disease. Best supportive care is preferable for many patients with poor performance status and/or short prognosis, although more aggressive measures have a role in the case of symptomatic lesions.

CONCLUSION
A multidisciplinary approach involving Neurosurgeons, and both Radiation and Medical Oncologists is needed to fully evaluate the options for individual patients. As many of the treatment decisions are a trade-off between quality of life and outcome metrics, shared decision-making with patients is also critical to ensure that patients receive the best treatment for them.
P14.45 Primary diffuse large B-cell CNS lymphoma over 80 years: an analysis of 110 patients from the french Oculo-Cerebral Lymphoma (LOC) network
Authors: MAAREK A , Maucort-Boulch D , Houillier C , Hoang-Xuan K , Soussain C , Ghesquières H 
Published: September 2019

Abstract

BACKGROUND
in large unselected series, the median age of Primary CNS Lymphoma (PCNSL) patients (pts) is about 70 years. In one USA cancer registry study for PCNSL patients older than 65 years, 14% of them are older than 80 years. Data on clinical characteristics, therapeutical management, toxicity of treatment and outcome of these very elderly pts are limited.

MATERIAL AND METHODS
we reviewed PCNSL pts aged of 80 years or older included in the database of the French Oculo-Cerebral lymphoma (LOC) network. From January 2011, this network prospectively recorded all newly diagnosed PCNSL from 22 regional expert centers in France.

RESULTS
110 pts with a DLBCL PCNSL aged of 80 years or older were diagnosed between January 2011 and January 2018 representing 8% of pts available in the LOC database. The clinical characteristics were as follows: 63% of females; median age: 83y (80–92); performance status (PS) ≥3, 55% of pts. Median creatinine clearance (CKD.EPI) was 70ml/min. Treatment was initiated either by a neuro-oncology or a hematology team in 35% and 65% of cases, respectively. First line treatment was high-dose (HD) methotrexate (MTX) based chemotherapy (CT) in 85 pts (77%), other chemotherapy regimen in 13 pts (12%) and palliative care in 12 pts (11%). Interestingly, no difference of distribution for the main clinical and biological characteristics was observed between these three groups. After first-line induction chemotherapy, response rate for evaluable patients (n=85) were as follows: 37% of complete response, 9% of partial response, 54% of stable or progressive disease. Rituximab was used in combination with CT in 53/98 treated pts (54%). For toxicity, among the 351 infusions performed for the 85 pts who received MTX-based CT, grade 3–4 toxicities were: 46% of any events, 15% of infection, 13% of cytopenia, 11% of acute renal failure and 8% of elevated liver enzymes. 13% of pts presented toxic death. Median progression free survival (PFS) and overall survival (OS) were 5 months and 8 months, respectively. Pts treated with MTX-based CT had a significantly prolonged PFS and OS. In the univariate analysis performed for the 85 pts treated with MTX-based CT, no initial clinical and biological influenced PFS or OS. Intravenous rituximab used in first line therapy significantly improved PFS and OS.

CONCLUSION
in this large series of consecutive PCNSL pts aged of 80y or over prospectively recorded in a national database, we showed that the prognosis remains poor with major toxicity under conventional treatment. No clinical predictor of survival was highlighted in our series. Patients initially treated with MTX-based CT in combination with rituximab had an improved outcome. The development of target and innovative therapies is needed for this category of patients representing 8% of all PCNSL in the database of the LOC network.​
P14.52 Differential methylation of a single CpG site in the CD95 ligand promoter affects gene activity and correlates with invasiveness of glioma cells
Authors: Merz C , Sykora J , Krendyukov A , Wiestler B , Gieffers C , Wick W 
Published: September 2019

Abstract

BACKGROUND
CD95 ligand (TNFSF6/APO-1L/FASLG) is a member of the Tumour Necrosis Factor Super Family (TNF-SF). Binding of the CD95 ligand (CD95L) to CD95 expressed on intrinsically apoptosis-resistant cancer cells like glioblastoma, triggers intracellular signal transduction resulting in increased tumour growth and invasiveness. A phase II clinical trial in patients with recurrent glioblastoma (NCT01071837) treated by Asunercept (a recombinant glycosylated fusion protein, which selectively binds and inhibits CD95L activity) was followed by a genome-wide assessment of DNA methylation. Here, a CpG-site (designated CpG2) within the CD95L-promotor was identified, exhibiting differential methylation between Asunercept responders (PFS>5 months) and non-responders (PFS < 2 months) with a significant survival benefit achieved in Asunercept treated patients with low CpG2 methylation (HR 0.34, p = 0.025).

METHODS AND RESULTS
We have performed in vitro studies to establish a link between the CpG2 methylation status and cellular characteristics of glioblastoma cell lines. A 3-dimensional spheroid invasion assay showed that highly methylated glioma cells like T98G did not grow and invade the surrounding matrix as aggressively compared to spheroids formed from low methylated glioma cells, e.g. U87-MG. Invasive growth of U87-MG spheroids in these assays was suppressed in the presence of Asunercept. A 1 kb fragment of the T98G CD95L promoter was subsequently cloned into a CpG-free reporter gene plasmid. Luciferase-based reporter gene assays of in vitro methylated and unmethylated plasmids in transfected HEK cells indicate that the CD95L promoter, despite the observed sparseness of CpG sites, is at least partially regulated by its methylation level. Furthermore, mutational disruption of the CpG2 site completely silenced reporter gene activity in vitro, which insinuates that both methylation level and gene promoter sequence are involved in regulation of the CD95L gene.

CONCLUSION
In essence, the level of CpG2 methylation correlates to aggressiveness of glioma derived cancer spheroids in vitro, and methylation of the CD95L promoter in glioblastoma tissue from patients might warrant use as a potential biomarker predicting response to therapy with Asunercept. We are currently developing a specific and sensitive assay to quantify CpG2 methylation considered as a companion diagnostic for further clinical studies.
P14.56 Recurrent Glioblastomas: Should we operate a second and even a third time
Authors: Yahia-Cherif M , De Witte O , Mélot C , Lefranc F 
Published: September 2019

Abstract

BACKGROUND
The aim of this study was i) to analyse the effect of repeat surgeries on the survival of patients with focally recurrent glioblastoma who have benefited from temozolomide treatment and ii) to identify potential prognostic factors for survival.

MATERIAL AND METHODS
Cases from 2005 to 2014 in the glioblastoma database of our department were retrospectively reviewed. The Kaplan-Meier method was used to estimate overall survival (OS) as a function of time after one, two and three surgical resections. All patients received the standard of care after the first surgery (temozolomide during and after radiotherapy) and adjuvant treatment after repeat surgeries.

RESULTS
One hundred-thirty-two glioblastoma patients (median age: 57 years) were included in the study. Among them, 68, 53 and 11 patients underwent one, two and three surgical resections, respectively. The median OS was 11, 16 and 18 months, respectively, for patients who underwent one, two and three surgical resections. Patients who underwent two (p<0.001) or three (p<0.01) surgeries survived significantly longer than patients who underwent only one. No significant difference was observed between patients who underwent two versus three surgeries (p=0.76). A second resection performed more than 6 months after the initial resection was the only factor associated with prolonged survival (p=0.008).

CONCLUSION
Glioblastoma patients who benefited from temozolomide treatment and underwent surgery for recurrent glioblastoma exhibited a significant increase in survival compared with patients who did not undergo a second surgery. By contrast, a third surgery for a second recurrence did not contribute to any significant survival benefit.
P14.57 Association of tryptophan metabolism and depression in patients with primary brain tumors
Authors: Juhasz C , John F , Michelhaugh S K , Muzik O , Barger G R , Mittal S 
Published: September 2019

Abstract

BACKGROUND
Patients with brain tumor have an increased risk for depressive disorder, whose underlying pathomechanism may involve dysregulated tryptophan/kynurenine metabolism. In this study, we analyzed the relation of depression to cerebral and systemic tryptophan metabolism in patients with primary brain tumors.

MATERIAL AND METHODS
Thirty-four patients with newly-diagnosed (n=19) or recurrent (n=15) primary brain tumors (25 gliomas, 8 meningiomas, 1 dysembryoplastic neuroepithelial tumor) underwent pre-treatment alpha-[11C]methyl-L-tryptophan (AMT)-PET and completed the Beck Depression Inventory-II (BDI-II) questionnaire. MRI and AMT-PET images were co-registered, and AMT K values (estimate of unidirectional tryptophan uptake, related to tryptophan metabolism) were measured in contralateral non-tumoral cortical and subcortical regions and correlated with BDI-II total and subscale (cognitive, affective, and somatic) scores. In a subset of 28 patients, plasma tryptophan metabolite levels were also measured and correlated with BDI-II scores.

RESULTS
In the whole group (n=34), 35% of the patients (n=12) had BDI-II scores indicating depression, while only a minority of them (n=5) were treated with selective serotonin reuptake inhibitors (SSRI). No difference was observed in AMT K values between gliomas vs. non-gliomas or between newly-diagnosed vs. recurrent tumors. Frontal cortical and thalamic AMT K values positively correlated with BDI-II total and somatic subscale scores (r=0.49, p=0.004 and r=0.53, p=0.001, respectively), and these correlations became stronger when patients with SSRI treatment were excluded. Levels of plasma tryptophan and its metabolites were not different between gliomas vs. non-gliomas, newly-diagnosed vs. recurrent tumor nor depressed vs. non-depressed patients. SSRI treatment showed no effect on plasma tryptophan metabolite levels. No correlation was found between depression and plasma tryptophan and its metabolite levels.

CONCLUSION
While plasma levels of tryptophan metabolites are not associated with depressive symptoms, higher tryptophan metabolism in the frontal cortex and thalamus, measured by PET, may serve as an imaging biomarker of brain tumor-associated depression and supports the role of dysregulated tryptophan/kynurenine metabolism in this condition.
P14.63 The use of TTFields for newly diagnosed GBM patients in Germany in routine clinical care (TIGER: TTFields in Germany in routine clinical care)
Authors: Bähr O , Tabatabai G , Fietkau R , Goldbrunner R , Glas M G 
Published: September 2019

Abstract

BACKGROUND
Despite various clinical phase 3 trials, survival for the most common brain tumour, glioblastoma (GBM), has not improved since 2005. Alternating electric fields with low-intensity and intermediate frequency, known as tumor treating fields (TTFields) were shown to inhibit cancer cell division. In the EF-14 phase 3 trial, the addition of TTFields to adjuvant temozolomide (TMZ) chemotherapy demonstrated significant extension of median overall, progression-free and long-term survival in newly diagnosed GBM (ndGBM) patients. As there is very high interest among prescribing physicians from all disciplines in Germany to further evaluate these effects in routine clinical care, the aim of the TIGER study is to assess safety and efficacy of TTFields in routine clinical care as well as reasons for patients refusing TTFields treatment, changes in quality of life within 4 months after start of therapy, treatment duration and compliance.

METHODS
The TIGER study is a multi-centre, prospective, non-interventional study in Germany (NCT03258021). All ndGBM patients who are eligible for TTFields therapy are asked for consent for study participation and comprehensively introduced to the therapy to allow them to make a conscious positive or negative therapy decision. At baseline and 2–4 months after treatment start, demographic data as well as the QoL and reasons for therapy decision are evaluated applying the EORTC-QLQ-C30/BN-20 and TTFields questionnaire, respectively. A number of about 1000 patient is planned (500 in each arm with positive and negative treatment decision, respectively) with a follow-up period of 18 months.

RESULTS
At the time point of the last data cut-off (March 2019), more than 460 patients in the trial have made a decision for or against treatment with TTFields. Within this population, more than 80% of patients agreed to undergo TTFields therapy. The median age of patients included in the trial is actually 58.4 years (range 19–85). In this population 47 % received complete resection, 32 % partial resection and 22 % biopsy.

CONCLUSION
Systematic and prospective data analysis for the use of TTFields in routine clinical care including patient’s therapy decision can be assessed in the TIGER trial. Additionally, the study supports the evaluation of treatment duration and usage rate, which could drive future analysis of TTFields treatment duration. Most recent data will be presented at the EANO annual meeting.