bluuebunny/crossref_metadata_2025_split huggingface dataset:
PL3.4 Intrinsic tumor plasticity in Glioblastoma allows for recreation of stem like-states and efficient tumor cell adaptation to new microenvironments
Authors: Golebiewska A , Dirkse A , Buder T , Yabo Y A , Poovathingal S , Muller A , Nazarov P V , Herold-Mende C , Bjerkvig R , Skupin A , Deutsch A , Voss-Bohme A , Niclou S P 
Published: September 2019

Abstract

BACKGROUND
Cellular heterogeneity has been well established within numerous cancer types, including malignant brain tumours. Initially, cancer stem cells (CSC) have been accounted for formation of phenotypic heterogeneity and tumor progression in glioblastoma (GBM). Recent data, however, suggest that CSCs may not represent a stable entity and intrinsic plasticity plays a key role in tumor adaptation to changing microenvironments. The question arises whether CSCs are a defined subpopulation of tumor cells or whether they represent a changing entity that any cancer cell can adopt depending on the environmental conditions.

MATERIAL AND METHODS
Intra-tumoral phenotypic heterogeneity was interrogated at the single cell transcriptomic and proteomic level in GBM patient-derived orthotopic xenografts (PDOXs) and stem-like cultures. Tumor cell subpopulations were further classified based on expression of four stem cell-associated membrane markers (CD133, CD15, A2B5 and CD44). The resulting 16 subpopulations were FACS isolated and functionally analyzed. Mathematical Markov modelling was applied to calculate state transitions between cell states.

RESULTS
GBM patient biopsies, PDOXs and stem-like cell cultures display remarkable stem cell-associated intra-tumoral heterogeneity. Independent of marker expression, all analysed tumor subpopulations carried stem-cell properties and had the capacity to recreate phenotypic heterogeneity. Mathematical modeling revealed a different propensity in reforming the original heterogeneity over time, which was independent of the proliferation index but linked to tumorigenic potential. Although subpopulations varied in their potential to adapt to new environments, all were able to reach a steady state microenvironment-specific equilibrium.

CONCLUSION
Our results suggest that phenotypic heterogeneity in GBM results from intrinsic plasticity allowing tumor cells to effectively adapt to new microenvironments. Cellular states are non-hierarchical, reversible and occur via stochastic state transitions of existing populations, striving towards an equilibrium instructed by the microenvironment. Our data provides evidence that CSCs do not represent a clonal entity defined by distinct functional properties and transcriptomic signatures, but rather a cellular state that is determined by environmental conditions, which has implications for the design of treatment strategies targeting CSC-like states.
OS2.2 Chemotherapy for spinal gliomas in adults
Authors: Gramatzki D , Felsberg J , Bähr O , Hentschel B , Westphal M , Schackert G , Tonn J C , Herrlinger U , Löffler M , Pietsch T , Steinbach J , Reifenberger G , Roth P , Weller M 
Published: September 2019

Abstract

BACKGROUND
Chemotherapy is a treatment option in patients diagnosed with anaplastic gliomas or glioblastomas of the spinal cord, or with recurrent lower graded WHO spinal gliomas that are no longer amenable to local treatment. The low incidence of spinal cord gliomas, particularly in adults, limits the ability to perform clinical trials. The role of chemotherapy in these tumors has remained unclear.

MATERIAL AND METHODS
We performed a retrospective study of 22 patients diagnosed with spinal gliomas who were treated with chemotherapy at any time during the disease course. Benefit from chemotherapy was estimated by applying Response assessment in neuro-oncology criteria. Data on radiotherapy, as well as the number of neurosurgical interventions were taken into consideration.

RESULTS
Most patients were diagnosed with astrocytoma WHO grade I-IV (N=14), the remaining patients were diagnosed with ependymoma (N=8). Median follow-up from start of chemotherapy was 92 months (95% CI, 72.6–111.4). The O6-methylguanyl-DNA-methyltransferase(MGMT)promoter methylation status was available in tumors of 12 patients: 9 tumors (75%) had an unmethylated MGMTpromoter. More than 50% of the patients had more than one neurosurgical intervention. After prior surgery 10 patients in the first-line setting had chemotherapy combined with radiotherapy, while 3 patients received chemotherapy only. The remaining 9 patients had initially received radiation therapy and chemotherapy was given at time of recurrence. In patients diagnosed with astrocytoma mainly temozolomide (TMZ) was applied (N=10), while one patient received CCNU and three patients had combination chemotherapy. Patients diagnosed with ependymoma had hydroxyurea (N=1), CCNU (N=1), TMZ (N=3) or combination chemotherapy (N=3). In the group of patients who had chemotherapy combined with radiation, response rates were as follows: anaplastic astrocytoma 3 stable diseases (SD), glioblastoma 1 complete response (CR) and 1 SD, and anaplastic ependymoma 1 SD. After chemotherapy in the group of patients previously irradiated, the following response rates were observed: 1 SD in pilocytic astrocytoma, 1 SD in diffuse astrocytoma, 3 SD in myxopapillary ependymoma, and 2 SD and 1 partial response (PR) in anaplastic ependymoma. All other patients experienced progressive disease. There was no indication for a favorable prognostic role ofMGMTpromoter methylation.

CONCLUSION
Spinal cord gliomas represent a heterogeneous group of tumors. Survival outcomes in response to chemotherapy in adult spinal glioma patients vary substantially, but individual patients appear to derive benefit from chemotherapy.
OS2.4 Using FineSA MRI for early detection of Spinal Metastases
Authors: Niina A , Davies A , Farooq N , Rowley K , Elias K , Collins I 
Published: September 2019

Abstract

BACKGROUND
Early detection of spinal metastases is important to facilitate early management and delay vertebral fracture or metastatic cord compression. The gold standard investigation to detect spinal metastasis is MRI, but it cannot quantify the metastasis and prognosis is poor due to its late presentation. Fine Structural Analysis (FineSA) is a custom software added to MRI using a non-radiating proprietary data acquisition technique. It analyses data at a resolution 10 times higher than MRI to quantify the trabecular microstructure which has the potential to enable early detection and management of vertebral fracture or metastatic cord compression.

MATERIAL AND METHODS
18 patients with known, symptomatic spinal metastases from Swansea Bay University Health Board and 11 age and sex-matched control subjects were recruited to have a FineSA MRI Spine. FineSA analysed and produced a structural spectrum of a defined area from the metastatic lesion. Statistical comparisons were made with the control data by extracting several metrics from the spectra, which were represented as an index score relative to a normal range.

RESULTS
Preliminary results using One Way ANOVA show a highly significant difference in trabecular microstructure between patients with spinal metastases and the age and sex-matched control patients, where p= 3.99e-11.

CONCLUSION
Preliminary results show that there is a highly significant difference between metastatic and control bone structure. Follow-up of the patients after one year will look at if fracture has occurred and whether there is a difference in the FineSA index score between the two groups. FineSA has the potential to be used to identify which metastatic lesions are most likely to be symptomatic and fracture, so that targeted radiotherapy can be done before symptoms are either present or intrusive.
OS5.4 Characteristics of adult diffuse H3K27M-mutant gliomas at recurrence
Authors: Hodroj K , Meyronet D , Barritault M , Bourg V , Cohen-Moyal E , Cartalat S , Ameli R , Berhouma M , Honnorat J , Ducray F 
Published: September 2019

Abstract

BACKGROUND
Adult diffuse H3K27M-mutant gliomas are rare and associated with a poor prognosis but could benefit in the next future from specific therapeutic strategies. In this context, the aim of the present study was to describe the characteristics of these tumors at recurrence.

MATERIAL AND METHODS
We retrospectively analyzed the characteristics of a series of 27 adult diffuse H3K27M-mutant gliomas at recurrence

RESULTS
Median age at diagnosis was 37 years. Initial treatment consisted of temozolomide radiochemotherapy (n=17, 62%), radiotherapy alone (n=1, 4%), chemotherapy alone (n=4, 15%), wait and see (n=1, 4%) and palliative care (n=4, 15%). Median PFS and median OS were 11 and 22 months in the whole series and 15 and 29 months in the patients who were treated with temozolomide radiochemotherapy. The pattern of recurrence could be analyzed in 19 patients. Ten patients (50%) demonstrated a local recurrence, five patients a local and distant recurrence (25%), two patients only a distant recurrence (10%) and two patients a leptomeningeal progression (10%). At recurrence, 15 patients received an oncological treatment that consisted of an alkylating chemotherapy (n=5), a bevacizumab based chemotherapy regimen (n=9) and of radiotherapy (n=1). Median PFS and OS after first recurrence in these patients were 6 and 14 months, respectively. An activating FGFR1 mutation was identified in 4 out of the 9 patients in whom it was assessed.

CONCLUSION
At recurrence, adult diffuse H3K27M-mutant gliomas are associated with a high rate of distant locations. A subset of patients harbor targetable FGFR1 activating mutations.
OS7.7 Educational program for caregivers of patients with brain tumors: AGAPE
Authors: Bourien H , Larible-Lefort C , Pelotte E , Le Brun F , Vauleon E 
Published: September 2019

Abstract

BACKGROUND
Patients with brain tumors suffer from physical, neurocognitive, and psychological decline. Among the potential evolutions of the disease, patients become dependent on caregivers. Nearly half suffer from anxiety or depression, which can significatively impact their quality of life. Better medical information and more effective integration of the caregivers are positively received. Patients and caregivers need more information on supportive care and the specificities of brain tumors. Educational programs may help them better support this new caregiving role and give them more information on the disease.

MATERIALS AND METHODS
At the Comprehensive Cancer Centre in Rennes, we have created an educational program for caregivers of patients with brain tumor, called AGAPE. The aim of AGAPE is to explain more precisely the medical aspects of brain tumors, describe resources that are available to caregivers, and allow a moment of exchange between caregivers. A medical oncologist and a nurse specialized in neuro-oncology organize the program divided into three workshops. During the first workshop, neurocognitive symptoms that may be presented by the patients as well as therapeutics are discussed. The second workshop aims to provide information on instrumental and human resources available, as well as on psychometrics, nutrition, and palliative care units. The last workshop gives each caregiver the opportunity to share their difficulties. In order to objectively evaluate the impact of AGAPE, caregivers are asked to complete a quality of life questionnaire after each workshop: CargoQoL (Caregiver Oncology Quality of Life). We retrospectively analyzed CargoQoL scores for each caregiver during their participation in AGAPE in order to evaluate the impact of AGAPE on the caregiver’s quality of life.

RESULTS
From February 2015 to February 2018, 9 three-month sessions were organized, allowing 45 caregivers to participate. Data for the years 2018 and 2019 are currently being updated. Each group of 3 to 4 caregivers met once a month for a period of 3 months. Final analysis of CargoQoL was based on 21 caregivers (responses with excessive missing data and the experience of caregivers who assisted to only one of the workshops organized every 3 months were not taken into account). For the 9 items of CargoQoL, there was no decrease in quality of life between the first and the last workshop. Even though these findings are not significant, caregivers seem to have a better relationship with healthcare providers and better self-esteem after attending the AGAPE workshops.

CONCLUSION
Diagnosis of brain tumors impacts the quality of life of both patients and caregivers. The assessment of the caregivers’ needs is essential in order to support them in caring for their loved ones and to include them in the healthcare process. AGAPE educational programs help caregivers maintain their quality of life.
OS9.2 Radiomics analysis of lower-grade gliomas, a POLA Network study
Authors: Younan N , Douzane H , Duran-Pena A , Nichelli L , Garcilazo Y , Dehais C , Ducray F , Carpentier C , Mokhtari K , Figarella-Branger D , Delattre J , Idbaih A , Alentorn A 
Published: September 2019

Abstract

BACKGROUND
Lower-grade gliomas (LGG) are divided into three histo-molecular groups: i) IDH-wildtype, ii) IDH mutant and 1p19q intact and iii) IDH mutant and 1p19q co-deleted. The current classification has improved the clinical stratification and its reproducibility. However, LGGs are still associated with an important degree of clinical heterogeneity. We sought to analyze the cross-talk between the spatial distribution and the quantitative imaging features (radiomics) with the clinical evolution and their molecular background (radiogenomics).

MATERIAL AND METHODS
We performed a retrospective multicentric study from 4 cohorts of high-grades gliomas (POLA Network, TCGA, REMBRANDT and LGG-1p19q), totaling 900 gliomas. We performed N4 and WhiteStripe imaging corrections to standardize MRI intensities. We used ITK-SNAP to obtain a mask of the different habitats of the tumor. Then we used PyRadiomics to obtain 2616 radiomic features per sample. We used plsRcox for fitting several Cox model in high-dimensional settings. We assessed the performance of the difference Cox model with the Harrel’s concordance index. We used a Sparse Canonical Correlation analysis to analyze the spatial distribution of the tumors.

RESULTS
Radiomics features allow identification in an unsupervised manner IDH-mutant gliomas with a median AUC of 0.96 [0.92–0.98]. Interestingly, in the analysis of survival, radiomics features provided additional information to clinical or genetics covariates and the model with only radiomics features obtained a C-Index of 0.78 [0.72–0.82]. In addition, survival model with the best performance in the prediction of overall survival was the one combining radiomics, clinics and genetics features with a C-Index 0.85 [0.82–0.92] and was validated in the other cohorts. The analysis of spatial distribution showed a very strong distribution of 1p19q co-deleted oligodendrogliomas in the frontal lobes.

CONCLUSION
Radiomics features may provide additional relevant clinical information by improving the prognosis of LGG. Radiomics allow non-invasive prediction of the most relevant molecular alterations of LGG.
OS9.4 The added value of radiomics to a clinical prognostic model in patients with low-grade glioma
Authors: van Riel M , Incekara F , van der Voort S , Wijnenga M , Klein S , van den Bent M , Smits M 
Published: September 2019

Abstract

BACKGROUND
In recent years, radiomics has become of increasing interest in studies of patients with low-grade glioma (LGG). Imaging features extracted from Magnetic Resonance Imaging (MRI) have shown to have the potential to predict genotype and overall survival in patients with LGG. However, until now, the potential of radiomics to add prognostic value to clinical prognostic models has hardly been investigated.The purpose of this study is to investigate the added prognostic value of quantitative magnetic resonance imaging features to a clinical prognostic model for patients with LGG.

MATERIAL AND METHODS
This retrospective cohort study included adult patients with newly diagnosed LGG who underwent tumor resection or biopsy between October 2002 and March 2017 at the Erasmus MC, University Medical Center Rotterdam (EMC). A set of 77 imaging features were extracted from preoperative T1w and T2w magnetic resonance sequences. These included first order histogram, texture, shape and location features of the volume of interest. The primary outcome of our study was overall survival (OS) and the secondary outcomewas progression-free survival (PFS).

RESULTS
A total of 259 patients were included. The median follow-up was 5.3 years (interquartile range, 3.4–8.2). The median OS was 9.08 years (95% CI: 6.70–11.5). Four imaging features increased the fit of our clinical prognostic model for OS significantly: T1 local binary pattern peak (hazard ratio (HR) 1.028, p=0.041), T2 histogram energy (HR 1.000, p<0.001), T2 histogram peak (HR 1.000, p=0.002) and standard deviation of radial distance (SDRD) (HR 1.412, p<0.001). The median PFS was 4.14 years (95% CI: 3.49–4.79). Only one imaging feature increased the fit of our clinical prognostic model for PFS significantly: standard deviation of radial distance (HR 1.278, p=0.006).

CONCLUSION
This study demonstrates that several radiomics features have the potential to help predict OS and PFS in patients with LGG more accurately than models constituted only by clinical features. In our study, four quantitative MRI features were found to be of added prognostic value. However, future studies should validate our results.
OS9.8 Genomic landscape of medulloblastoma in adults
Authors: Goschzik T , zur Mühlen A , Dörner E , Waha A , Friedrich C , Hau P , Pietsch T 
Published: September 2019

Abstract

BACKGROUND
Medulloblastoma (MB) is a rare disease in adults. Therefore, only few cohorts have been studied so far.

METHODS
Histological features were evaluated and annotation of the tumors to WNT-MB, SHH-MB, and non-WNT/non-SHH-MB was performed by immunohistochemistry. Systematic analysis of tumor samples for genome-wide copy alterations was done by molecular inversion probe array. WNT- and SHH-activated MB were screened by NGS panel and Sanger sequencing for known MB-related genes.

RESULTS
The cohort of tumors from 117 patients contained 14.5% WNT-MB, 63.2% SHH-MB, and 22.2% non-WNT/non-SHH MB. Classic histology was found in WNT-MB, non-WNT/non-SHH-MB and 22% of SHH-MB; 78% of SHH-MB showed desmoplastic/nodular histology. In WNT-MB, CTNNB1 mutations were found in 88.2% and monosomy 6 in 52.9% of cases. In SHH-MB, PTCH1 mutations were present in 40% of cases and chromosome 9q loss including the PTCH1 locus was the most frequent copy number event in SHH-MB (50%), while SMO and SUFU mutations were found only in 15.4% resp. 7.7%. Mutations in the TERT promoter region were found in 92.3% of SHH-MBs. Only 2 (3%) of the SHH-MB were TP53-mutated (1.7% of the whole cohort). In non-WNT/non-SHH-MB, isochromosome 17q was the most frequent chromosomal alteration (84.6%). A previously published whole chromosomal aberration (WCA) signature with ≥1 WCA was found in 69.2% of cases. For 85 cases, survival data were available. WNT-MB presented no relapses (5-year OS: 100%), while SHH-MB with wildtype TP53 and non-WNT/non-SHH-MB showed similar outcomes (5-year OS: 78.1% and 69.1%, respectively). Both SHH-MB patients with mutant TP53 died of disease. Patients with non-WNT/non-SHH-MB characterized by the cytogenetic WCA phenotype showed - as described in pediatric standard-risk MB - significant better overall survival compared to patients with tumors lacking any WCA (p=0.01).

CONCLUSIONS
Adult MB represent four defined biological/genomic entities. In contrast to previously published data adult patients with WNT-MBs showed excellent survival. However, the number of patients with WNT-MB was limited so that this result has to be interpreted with caution. While in our cohort SHH-MB-TP53wt were standard risk independent of their mutational or chromosomal status, non-WNT/non-SHH-MB patients could be divided into two risk-groups according to the presence or absence of WCA in the tumors as previously published for childhood standard-risk MB by our group.
OS10.5 Outcome of unresectable de novo IDH wild-type GBM: A decade analysis of factors influencing survival
Authors: Hamdan A , Homyer K , Swan G , Bankov G , Alfadhel S , Sinan L , Aw A , Grivas A 
Published: September 2019

Abstract

BACKGROUND
Patients with unresectable GBM represent an understudied and underpowered disease subgroup for which limited outcome data exist to support treatment recommendations. In this study, we present a ten-year analysis on outcome of unresectable GBM patients at our unit.

MATERIAL AND METHODS
We collected data for all consecutive adult de novo IDH wild-type (IDHwt) GBM patients who had undergone biopsy at our unit (2009–18, N= 177) and analysed those that had complete data on performance status, radiology, MGMT status, and adjuvant treatment (N= 156). We used step-wise cox proportional hazards regression to analyse factors associated with survival and outcomes.

RESULTS
Of 156 patients, mean age was 60.8 years old (range 19–89, 34/21.8% >69 years old), 63 (40.4%) were females, and 50 (32.1%), 26 (16.7%) and 12 (7.7%) had multifocal, butterfly or both lesion types respectively. 101 (64.7%) patients had good performance status (ECOG 0–1), and 49 (31.4%) had methylated MGMT lesions. Adjuvant treatment modalities were best supportive care (41, 26.3%), RT only (33, 21.2%), TMZ only (20, 12.8%), RT and TMZ (10, 6.4%), concurrent TMZ/RT only (29, 18.6%) and concurrent TMZ/RT plus adjuvant TMZ [TMZ/RT+TMZ] (23, 14.7%).
Median OS was 6.1 months (range 0–50.7), with 22% and 2% 1- and 2-year OS respectively. Patients who were MGMT methylated, had good performance status, and received TMZ/RT+TMZ had the highest survival (median OS 18.7 vs 5.5 months, P<0.0001).
Multivariate analysis revealed factors associated with worse OS; these include male sex (HR 1.6, 95%CI 1.1–2.2), unmethylated MGMT (1.8, 1.3–2.8), poor performance status ie ECOG>1 (2.4, 1.6–3.3), not receiving TMZ/RT+TMZ (3.1, 1.8–5.1). In addition, univariate analysis initially revealed that older age (>69yrs) was significantly associated with poorer outcome, however in multivariate analysis, this effect was obliterated (HR 1.3, 95%CI 0.9–2.1).

CONCLUSION
In this study, we provide one of the largest series of unresectable IDHwt GBM outcome in the literature. Survival of patients harbouring unresectable IDHwt GBM can be unexpectedly long, and may even reach nearly twice that of the unselected, biopsy-only GBM patients receiving TMZ/RT+TMZ studied in the original Stupp trial (median OS of 9.4 months). For this subgroup of IDHwt GBM patients, advanced age may not necessarily predict poor outcome, once adjusted for other outcome predictors. Future randomised trials looking into unresectable IDHwt GBM should stratify patients according to the factors revealed above.