bluuebunny/crossref_metadata_2025_split huggingface dataset:
OS7.2 Measuring change in health-related quality of life: the added value of analysis on the individual patient level in glioma patients in clinical decision making
Authors: Coomans M , Taphoorn M J B , Aaronson N , Baumert B G , van den Bent M , Bottomley A , Brandes A A , Chinot O , Coens C , Gorlia T , Herrlinger U , Keime-Guibert F , Malmström A , Martinelli F , Stupp R , Talacchi A , Weller M , Wick W , Reijneveld J C , Dirven L 
Published: September 2019

Abstract

BACKGROUND
Health-related quality of life (HRQoL) is often used as an outcome in glioma research, reflecting the impact of disease and treatment on a patient’s functioning and wellbeing. Data on changes in HRQoL scores may provide important information for clinical decision-making, but different analytical methods may lead to different interpretations of the impact of treatment on HRQoL. This study aimed to examine three different methods to evaluate change in HRQoL, and to study whether these methods result in different interpretations.

MATERIAL AND METHODS
HRQoL and sociodemographical/clinical data from 15 randomized clinical trials were combined. Change in HRQoL scores was analyzed in three ways: (1) at the group level, comparing mean changes in scale/item scores between treatment arms over time, (2) at the patient level per scale/item by calculating the percentage of patients that deteriorated, improved or remained stable on a scale/item per scale/item, and (3) at the individual patient level combining all scales/items.

RESULTS
Baseline and first follow-up HRQoL data were available for 3727 patients. At the group scale/item level (method 1), only the item ‘hair loss’ showed a significant and clinically relevant change (i.e. ≥10 points) over time, whereas change scores on the other scales/items showed a statistically significant change only (all p<.001, range in change score: 0.1–6.2). Analyses on the patient level per scale (method 2) indicated that, while a large proportion of patients had stable HRQoL over time (range 27–84%), many patients deteriorated (range: 6–43%) or improved (range: 8–32%) on a specific scale/item. At the individual patient level (method 3), the majority of patients (86%) showed both deterioration and improvement, while only 1% of the patients remained stable on all scales. Clustering on clinical characteristics (WHO performance status, sex, tumor type, type of resection, newly diagnosed versus recurrent tumor and age) did not identify subgroups of patients with a specific pattern of change in their HRQoL score.

CONCLUSION
Different analytical methods of changes in HRQoL result in distinct interpretations of treatment effects, all of which may be relevant for clinical decision-making. Additional information about the joint impact of treatment on all outcomes, showing that most patients experience both deterioration and improvement, may help patients and physicians to make the best treatment decision.
OS8.7 Targeting Pi3k-Akt-mTOR and MAPKinase pathways in aggressive meningiomas: in vitro study
Authors: Mondielli G , Darriet F , Roche C , Lisbonis C , Querdray A , Figarella-Branger D , Dufour H , Barlier A , Graillon T 
Published: September 2019

Abstract

BACKGROUND
Recurrent and aggressive meningiomas remain an unmet medical need in neuro-oncology. In our preclinical model on meningioma primary cell culture, the combination of the mTOR inhibitor, everolimus and the somatostatin analog, octreotide decreased cell viability and proliferation without inducing apoptosis. The interest of the combined treatment everolimus plus octreotide were clinically validated by the CEVOREM clinical trial demonstrating a decrease in growth rate of meningiomas in most treated patients.
Nevertheless, everolimus induced an increase in Akt activity in vitro, which probably limited everolimus efficiency. We hypothesized that targeting Pi3K could prevent this positive feedback on Akt phosphorylation, induced by mTOR inhibition. The involvement of MAPKinase pathway in meningioma tumorigenesis was recently demonstrated. Our aim was to decipher the effect of the Pi3k α inhibitor Alpelisib (BYL719) and the specific inhibitor of MEK1,2 Mekinist (Trametinib) alone or in combination, in comparison to the mTor inhibitor everolimus on human meningioma primary cell cultures.

MATERIAL AND METHODS
The impact of the drugs was studied on 40 meningiomas, well characterized at clinical, histological and molecular level. The cell viability, cell proliferation and apoptosis were analyzed under drugs.

RESULTS
BYL719 induced a dose dependent decrease in cell viability (maximal effect -90%, IC50 10-6M) in all tested meningiomas (n=30). This effect was stronger than those of everolimus (maximal effect -50%, n=24, IC50 10-8M). 22 tumors were sensitive to Trametinib (maximal effect <-50%, IC50 10–5 M), 14 were partially sensitive (maximal effect between -20 and -40% IC50 10–5 M) and 3 were resistant. An apoptotic effect was observed under BYL719 in 6/18 tested tumors whereas no apoptosis was observed under Trametinib and Everolimus. Combination of BYL719 and Trametinib induced a significant stronger decrease in cell viability than each drug alone. Correlation analysis between these functional results, the tumor genomic profile and the activation of ERK/MEK kinase pathway is ongoing.

CONCLUSION
PI3K-Akt-mTOR and ERK/MEK kinase pathways constitute relevant targets in aggressive meningioma therapy. In our preclinical model, previously validated by CEVOREM clinical trial, co-targeting Pi3k-Akt-mTOR and MAPkinase pathways improved cell proliferation inhibition in comparison to the target of each pathway alone. BYL719 induced apoptosis which was not achieved by everolimus. These results support the ongoing clinical trial ALTREM combining Alpelisib and Trametinib on patients harboring aggressive recurrent meningiomas.
OS9.7 Telomere length, TERTp mutation and ALT status in adult diffuse gliomas
Authors: Birzu C , Hillairet A , Giry M , Grandin N , Verrelle P , Mokhtari K , Marie Y , Hoang-Xuan K , Delattre J , Idbaih A , Charbonneau M , Sanson M , Alentorn A 
Published: September 2019

Abstract

BACKGROUND
The current classification of adult diffuse gliomas integrates two alternative telomere maintenance mechanisms: reactivation of telomerase activity by TERT promoter (TERTp) mutations or ATRX mutations associated with alternative length telomere (ALT). We investigated here the relation between these two mechanisms, telomere length, and outcome in a large series of diffuse gliomas.

MATERIAL AND METHODS
We performed C-circle assay (CCA) to determine ALT status, determined telomere length in tumor (RTLt) and leukocyte (RTLl) in a cohort of 354 adult diffuse gliomas, and sequenced ATRX gene. We calculated an age-adjusted telomere score considering tumor and leukocyte (blood) telomere length and corrected by age. This score was used in univariate and multivariate survival analyses to evaluate the potential impact of telomere length on the prognosis of gliomas. We used the TCGA LGG-GBM dataset to validate our findings in an independent cohort.

RESULTS
RTLl and RTLt were associated with ATRX mutation and ALT phenotype, and negatively associated with age and TERTp mutations. ATRX mutations (found in 52% (64/123) of samples) were mostly transitions (C>T or T>C), and were associated with ALT phenotype. None of 1p/19q co-deleted oligodendrogliomas harbored an ALT phenotype. No patients with TERTp mutations had ALT phenotype except for a very small subgroup of patients (3/87, 3.4%) suggesting that multiple ways of telomere maintenance, may co-exist in a single tumor, probably expressed in different clones. Telomere age-adjusted score was independently associated with better outcome (HR= 0.73 [95% CI 0.56–0.97], p-value 0.03 adjusted for age, TERTp mutation, IDH mutation, 1p/19q co-deletion and WHO grade). These results were validated using the LGG-GBM TCGA dataset.

CONCLUSION
We unravel the relation between RTLl and RTLt, TERTp mutation and ALT phenotype and describe a novel telomere age-adjusted score independently associated with better prognosis in adult diffuse gliomas.
OS10.6 Infigratinib (BGJ398) in patients with recurrent gliomas with fibroblast growth factor receptor (FGFR) alterations: a multicenter phase II study
Authors: Lassman A B , Sepúlveda-Sánchez J M , Cloughesy T , Gil-Gil J M , Puduvalli V K , Raizer J , De Vos F Y , Wen P Y , Butowski N , Clement P , Groves M D , Belda-Iniesta C , Steward K , Moran S , Ye Y , Roth P 
Published: September 2019

Abstract

BACKGROUND
FGFR mutations and translocations occur in approximately 10% of glioblastomas (GBMs). FGFR3-TACC3 fusion has been reported as predictive of response to FGFR tyrosine kinase inhibitor therapy both pre-clinically and clinically. Infigratinib (BGJ398) is a selective small-molecule pan-FGFR kinase inhibitor that has demonstrated anti-tumor activity in several solid tumors with FGFR genetic alterations. Therefore, we conducted a phase II trial to test the efficacy of infigratinib in FGFR-altered recurrent GBM (NCT01975701).

METHODS
This open-label trial accrued adults with recurrent high-grade gliomas following failure of initial therapy that harbored FGFR1-TACC1 or FGFR3-TACC3 fusions; activating mutations in FGFR1, 2 or 3; or FGFR1, 2, 3, or 4 amplification. Oral infigratinib was administered 125 mg on days 1–21 every 28 days. Prophylaxis for hyperphosphatemia, a common toxicity, was recommended. The primary endpoint was the 6-month progression-free survival (6mPFS) rate by RANO (locally assessed, estimated by K-M method), with a goal of >40%.

RESULTS
As of the Sep 2017 data cut-off, 26 patients (16 men, 10 women; median age 55 years, range 20–76 years; 50% with ≥2 prior regimens) were treated, and 24 (92.3%) discontinued for disease progression (n=21) or other reasons (n=3). All patients had FGFR1 or FGFR3 gene alterations, and 4 had >1 gene alteration. The estimated 6mPFS rate was 16% (95% CI 5.0–32.5%); median PFS was 1.7 months (95% CI 1.1–2.8 months); median OS was 6.7 months (95% CI 4.2–11.7 months); ORR was 7.7% (95% CI 1.0–25.1%). The best overall response was: partial response 7.7% (FGFR1 mutation n=1; FGFR3 amplification n=1); stable disease 26.9%; progressive disease 50.0%; missing/unknown 15.3%. The most common (>15%) all-grade treatment-related adverse events (AEs) were hyperphosphatemia, fatigue, diarrhea, hyperlipasemia, and stomatitis. There were no grade 4 treatment-related AEs. Eleven patients (42.3%) had treatment-related AEs requiring dose interruptions or reductions (most commonly hyperphosphatemia).

CONCLUSIONS
Infigratinib induced partial response or stable disease in approximately one-third of patients with recurrent GBM and/or other glioma subtypes harboring FGFR alterations. Most AEs were reversible and manageable. Further potential combinations are being explored in patients with proven FGFR-TACC fusion genes and analysis of biomarker data is ongoing.
OS12.5 Small GTPase RHOE/RND3, a new critical regulator of NF-êB signaling in glioblastoma multiforme?
Authors: Liu B , Chen Q 
Published: September 2019

Abstract

Background
Abnormal activation of NF-κB signaling is a major mechanism of apoptosis resistance in glioblastoma multiforme (GBM). Therefore, better understanding of the regulation of NF-κB signaling has a significant impact for GBM therapy. Here, we uncovered a critical role of the small GTPase RND3 in regulating the p65 subunit of NF-κB and NF-κB signaling in GBM.

MATERIALS AND METHODS
Human GBM samples, GBM cells and a human orthotopic GBM-xenografted animal model were used. The mechanisms of RND3 in regulation of NF-κB signaling and GBM cell apoptosis were examined by luciferase assay, quantitative PCR, immunostaining, immunoblotting, immunofluorescence, co-immunoprecipitation, TUNEL staining, JC-1 analysis and flow cytometry.

RESULTS
Overexpression of RND3 led to reduced p65 activity in GBM cultured cells and a GBM animal model, indicating that the NF-κB pathway is negatively regulated by RND3 in GBM. Mechanistically, we found that RND3 bound p65 and promoted p65 ubiquitination, leading to decreased p65 protein levels. Furthermore, RND3 enhanced cleaved-caspase 3 levels and promoted apoptosis in GBM cells, and RND3 expression was positively correlated with cleaved-caspase 3 and IL-8 in human GBM samples. The effect of RND3 on promoting apoptosis disappeared when p65 ubiquitination was blocked by protease inhibitor carfilzomib or upon co-expression of ectopic p65.

CONCLUSION
RND3 binds p65 protein and promotes its ubiquitination, resulting in reduced p65 protein expression and inhibition of NF-κB signaling to induce GBM cell apoptosis.
P03.05 Could suspected Glioblastomas be Treated without Hystological Diagnosis?
Authors: Cortés Mateus K , Valduvieco Ruíz I , Verger Fransoy E , Pineda Losada E , Oleaga Zufiria L , Pujol Farre T , González Sánchez J , Pedrosa Eguílaz L , Graus Ribas F , Barreto Zambrano T , Muñoz Guglielmetti D , Castro Cuevas C , Escudero López E , Lloret Puerto A , Sáez Beltrán J , Camacho López C , Conill Llobet C , Oses González G , Garrido Alcantud S , Mollà Armada M 
Published: September 2019

Abstract

BACKGROUND
Probable unresectable Glioblastomas (GB) diagnosed by imaging techniques withouth anatomo-pathological (ap) confirmation could be treated under standard treatment. We reported the outcomes from this strategy in our center after tumor board evaluation.

MATERIAL AND METHODS
From January/10 to September/16, 303 patients (pt) with GB were assessed by tumor board, during the same period 66 patients were consecutive analyzed with suspected GB by radiological criteria without histological diagnosis. We focus in the last group and analyzed the demographic/radiological data, non-biopsy causes, treatment type (concomitant Radio-Chemotherapy (RT/Ch), exclusive RT or Ch or Best supportive care (BSC)), Karnofsky index (KI) and degree of comorbidity (Charlson index (CI)).

RESULTS
Sixty six patients, 17.88% of the total GB cases (with/without ap). Average age: 77 years (33–91). Biopsy: non-diagnostic in 4pt. No biopsy: 62pt; due to non medical indication (71%), localization (22.7%), voluntary (4.5%). Treatment Type: Active: 43.93%, without biopsy due to non-medical indication (44.8%) and localization (41.37%). BSC: 53.03%, without biopsy due to non-medical indication 82.85%, localization 8.5%, voluntary 5.7%. Overall survival: 11.65 months in patients with active treatment and 4.8 months in BSC, greater benefit in <70 years and KI≥ 70 with statistical signification.

CONCLUSION
The diagnosis of GB by radiological criteria with the new imaging techniques has a good diagnostic-therapeutic correlation. In cases where surgical intervention is not possible, standard treatment offers good results. Age and KPS are variables that allow predicting a better evolution course. Although it was not possible to obtain a histological diagnosis, in this type of cases liquid biopsy could contribute to diagnosis this type of lesions inaccessible to biopsy.
P03.09 Real world management and prognosis of glioma patients:SYSUCC report from China
Authors: Li D , Chen Y , Guo C , Yang Q , Wu S , Xia Y , Zeng J , zhang X , Ke C , Sai K , Wang J , Mou Y , Chen Z 
Published: September 2019

Abstract
Background: The conventional way of patient treatment should be following guidelines. While in clinical practice, patients received treatments very often away from suggested guideline. In this report, we reviewed glioma patients received real world treatment at Sun Yat-sen University Cancer Center (SYSUCC) and results of this patient series.
Methods: Total of 1215 glioma patients received surgery at SYSUCC from 2000 to 2017 were enclosed for analysis. The pathologic diagnosis of patients has followed WHO classification (initially 2007 standard, than 2016 standard).
Results: A total of 1001 newly diagnosed brain glioma patients were analyzed, including 90 cases WHO grade I, 307 grade II, 239 grade III and 365 grade IV. The median age of onset was 14 (1–75), 35 (2–69), 41 (8–82) and 50 (2–86) years old, respectively, for grade I, II, III and IV glioma patients. Tumor total resection was achieved in 567 patients (57.5%). Among all patients, 331 high-grade gliomas (54.8%) and 159 low-grade glioma (40.1%) received radiotherapy, whereas 285 high-grade gliomas (47.1%) and 80 low-grade tumors (20.2%) received chemotherapy. Among high-grade gliomas, the median OS of glioblastoma, anaplastic astrocytoma and anaplastic oligodendroglial tumors were 17.7 months (15.7–19.7 months), 33.7 months (24.0–43.4 months) and 110.6 months (43.5–177.7 months), respectively, whereas the median OS of low-grade gliomas was not reach. The 5-year survival rate of grade I, II, III and IV gliomas was 94.7%, 73.7%, 45.1% and 18.6%, respectively. Multivariate analysis identified that onset age, Karnofsky performance status, tumor location, preoperative seizure, pathological subtype, resection extent and post-surgical treatment were independent predictors of OS for patients with high-grade gliomas. Patients received post-surgical radiotherapy and (or) chemotherapy had better survival than those without adjuvant treatment (grade III: 53.3 vs. 20.6 months, p =0.012; grade IV: 22.9 vs. 12.3 months, p < 0.001). For low-grade gliomas, patients’ age, Ki-67 index, tumor subtype and resection extent were associated with clinical outcomes.
Conclusions: Glioma patients received treatments do not always following guidelines in clinical practice. Although standard care for patients may beneficial for prognosis, personalized treatment may more acceptable for patients and even resulting better outcome which should keep in mind in routine clinical practice.
P03.14 New features of modern 3D conformal external radiotherapy (RT) of benign head tumors in children
Authors: Antonenko F , Slobina E , Abbasova E , Smyslov A , Dykina A , Sidibe N , Abdullaeva S , Vasilyev V 
Published: September 2019

Abstract

BACKGROUND
demonstrate the possibilities of radiation therapy (LT) in children with benign head tumors using IMRT, VMAT, IGRT techniques - high-precision modern 3D conformal radiation therapy

MATERIAL AND METHODS
From 1990 to 2007 for the first time in Russia, 88 children with juvenile angiofibromas were treated in Russian Scientific Center of Roentgenoradiology. The studies were carried out on the gamma-therapeutic apparatus “AGAT-P1” and on the linear accelerator “Phillips SL75” Total dose was 35–45 Gy. In 2014–2018 we treated 29 patients aged 3–17 years with benign tumors of the skull base and brain (angiofibromas, craniopharyngiomas, hemangiomas) using high-precision techniques (IMRT, VMAT, IGRT). 15 of 29 patients were repeatedly operated in various domestic and foreign clinics and were admitted to RT with the threat of bleeding, with recurrent growth of tumors, including after multiple selective angioembolization.

RESULTS
Up to 80% of patients had a 5-year stable remission, and the optimal total dose for radiation therapy of benign head tumors in children was scientifically substantiated. It was found that there is a high risk of continued growth after RT in children under 8 years of age, complications in 10% of patients in the coming years after RT and in 100% of those reirradiated. In all 29 cases of RT in children, we observed a positive clinical effect - stopping bleeding from the nasopharynx after 1–3 sessions of 3D conformal RT (Dose per fraction 1.8 Gy, total dose 45–54 Gy), positive clinical symptoms under the supervision of an Head and Neck surgeon. The effect of hardening and stopping the growth of tumors according to MRI data were followed up after 3 months, 6 months, 1 year.

CONCLUSION
The development of navigational, endosurgical and fibro-endoscopic minimally invasive technologies in the last 30 years has allowed to expand the indications for surgical methods of treatment for benign head tumors in children, which has reduced their flow to RT. However, after modern surgical interventions, 6–10% of these patients experience recurrences and bleeding, the number of which can be reduced with timely RT. New technologies in LT provide minimal impact on surrounding healthy tissues and allow wider use of RT in recurrent and difficult-to-reach benign skull base tumors in children
P04.02 Postponing the medical treatment is possible in selected cases of diffuse low-grade glioma with foci of WHO grade III-IV after total or subtotal resection
Authors: Darlix A , Rigau V , Fraisse J , Gozé C , Fabbro M , Duffau H 
Published: September 2019

Abstract

BACKGROUND
Diffuse low-grade gliomas (DLGG) are defined by a continuous growth and an unavoidable malignant transformation. Foci of malignant transformation may be found within DLGG samples obtained from surgical resections. As the medical management is classically based on the higher tumor grade, an immediate adjuvant treatment is usually proposed (radiotherapy [RT] with Temozolomide or PCV), whatever the extent of resection. Yet, early RT has no impact on overall survival compared with late RT, and is associated with cognitive toxicity. An alternative approach consists in postponing the medical treatment in selected patients.

MATERIAL AND METHODS
We conducted a monocentric retrospective analysis of a consecutive series of patients managed with this conservative approach. Inclusion criteria were: DLGG (WHO 2016 grade II) with at least one focus of malignant transformation (grade III-IV); no previous chemotherapy or RT; no less than a subtotal resection of the FLAIR tumor volume; no intention of treating with immediate adjuvant therapy; at least two years of postoperative follow-up. The time interval to the next medical treatment (chemotherapy and/or radiotherapy) was assessed, as well as the functional and survival results.

RESULTS
Forty-five DLGG patients, of median age 36.5 years, were included in the analysis (median time interval from diagnosis: 7.3 months). The histo-molecular diagnosis was diffuse astrocytoma, IDH mutant in 46.7% of cases, astrocytoma, IDH wild-type in 13.3% and oligodendroglioma, IDH mutant and 1p/19q codeleted in 40.0%. Ten tumors presented with grade IV foci. The quality of resection was subtotal (FLAIR tumor residue ≤15 cm3) in 73.3%, total (no FLAIR tumor residue) in 24.4% and supratotal in 2.2%. After surgery, patients were managed with regular clinical and radiological follow-up. With a median postoperative follow-up of 6.3 years, 75.5% of patients received a subsequent medical treatment, after a median time interval of 3.7 years. The first treatment after surgery consisted of repeated surgery in 11 patients, Temozolomide in 28 patients, RT in one patient. At the time of analysis, 19 patients (42.2%) had been treated with RT, after a median time interval of 9.5 years. Nine patients (20.0%) had died (median overall survival not reached, 5-years and 7-years survival rates: 95.2% and 67.0%). Most surviving patients were still active professionally (69.4%), with a median Karnofsky performance status of 90, and no or rare seizures.

CONCLUSION
In this series, total or subtotal resection of DLGG with a least one focus of grade III-IV glioma radically changed the natural history of these tumors and allowed delaying the following medical treatment by several years. This strategy is feasible in selected patients and should be considered on a case-by-case basis in patients with foci of malignant transformation following total or subtotal resection.