bluuebunny/crossref_metadata_2025_split huggingface dataset:
JS1.3 Autoimmune encephalitis as immune related adverse event (irAE) of check point inhibitors (CPI) not so rare as we thought
Authors: Taliansky A , Gadot M , Urban D , Bar J , Shapira-Frumer R , Kaufman B , Asher N , Leibowitz-Amit R , Itay A 
Published: September 2019

Abstract

INTRODUCTION
CPI has significant efficacy and toxicities. We describe our experience with CPI treated patients diagnosed with irAE encephalitis.

METHODS
Patients treated with CPI during 2017–2018 were identified from institute’s EMR. Patients treated for irAE encephalitis were identified from the database of the Neuro-Oncology Unit of the Institute. Results: Eleven patients were diagnosed with irAE encephalitis out of 1500 treated with CPI at the Institute (0.73%). Four patients had NSCLC, 3 had melanoma, the one patient had each of SCLC, uterine carcinoma, RCC and breast cancer. Median age was 69 years (49–87). Four of 11 were treated with chemo-CPI, 3-with CPI combinations. Median onset of symptoms was at 19 days (5–180) following initial treatment. All events were high grade severity. Eight patients fully recovered after immunotherapy discontinuation and steroid treatment, of these, 2 melanoma patients underwent uncomplicated CPI re-challenge. Three patients, all non-melanoma, had severe neurological sequelae. Two of them were treated with steroids, PLEX and cyclophosphamide: one improved neurologically although died 6 months later from cancer. One patient was oncologically stable but died from neurological deterioration 7 months later. The additional patient was treated with steroids only because his advanced age and decease in hospice 2 months later.

CONCLUSION
Encephalitis, as an irAE of CPI, seems to be more common and severe than previously thought, predominantly in non melanoma patients. Nevertheless, in the majority of cases it is reversible and in some melanoma patients immunotherapy re-challenge is safe. Future studies will have to define risk factors and severity prediction.
OS1.6 Peripheral blood immune profiles at first recurrence of IDH wild type glioblastoma after standard chemoradiotherapy predict overall survival: secondary analyses of the phase II DIRECTOR trial
Authors: Wirsching H , Terksikh E , Manuela S , Carsten K , Patrick R , Becher B , Weller M 
Published: September 2019

Abstract

BACKGROUND
Isocitrate dehydrogenase (IDH) wildtype glioblastoma is associated with distinctive peripheral blood immune cell profiles that evolve under first line chemoirradiation with temozolomide. Whether peripheral blood immune cell profiles at recurrence are associated with survival of IDH wildtype glioblastoma has not been studied in detail.

PATIENTS AND METHODS
Peripheral blood mononuclear cells (PBMC) of 21 healthy donors and of 52 clinically well-annotated patients with IDH wildtype glioblastoma were analyzed by 11-color flow cytometry at 1st recurrence after standard chemoirradiation with temozolomide and at 2nd recurrence after dose-intensified temozolomide re-challenge. Patients were treated within the randomized phase II trial DIRECTOR, which explored the efficacy of dose-intensified temozolomide at first recurrence of glioblastoma. Patients were classified based on unsupervised analyses of PBMC profiles at 1stand 2ndrecurrence. Associations with survival were explored in multivariate Cox models controlling for established prognostic and predictive factors.

RESULTS
At 1strecurrence, two patient clusters were identified which differed in CD4+ T-cell fractions, but not with respect to CD8+ T-cells, CD4+;CD25+;FoxP3+ regulatory T-cells, B-cells or monocytes. The composition of CD4+, CD8+ or regulatory T-cell fractions was similar in both clusters. All control samples clustered with the CD4high cluster. Patients in both clusters did not differ by established prognostic factors, including age, O6-methylguanine-DNA-methyl-transferase (MGMT) gene promoter methylation, tumor volume, Karfnosky performance score or steroid use. Progression-free survival was similar (CD4high vsCD4low 2.1 vs 2.4 months, p=0.19), whereas post-recurrence overall survival was longer among the CD4highcluster (12.7 vs 8.7 months, p= 0.004). At 2nd recurrence, monocyte fractions increased, whereas memory CD4+ T-cell fractions decreased. Unsupervised segregation of patients by CD4+ subpopulations yielded two clusters characterized by the abundance of memory T-cell fractions and higher memory CD4+ fractions were associated with longer overall survival at 2nd recurrence (p=0.004). The reported prognostic associations were retained in multivariate Cox models controlling for established prognostic factors.

CONCLUSION
We conclude that temozolomide-associated memory CD4+ T-cell depletion may have deteriorating effects on the survival of glioblastoma patients.
OS3.1 Antiepileptic drugs and their association with depression, anxiety and subjective cognitive impairment in glioma patients
Authors: van der Meer P B , Taphoorn M J B , van den Bent M J , Dirven L , Koekkoek J A F 
Published: September 2019

Abstract

BACKGROUND
Epileptic seizures are a common symptom in glioma patients and generally treated with antiepileptic drugs (AEDs), which are considered to have the potential of mood-modulating and neurocognitive adverse effects. This observational study aimed to assess the independent association between AEDs and depression, anxiety and subjective cognitive impairment in glioma patients.

MATERIAL AND METHODS
Use of AEDs was defined as a categorical variable (none or at least one). Depression and anxiety were measured with the Hospital Anxiety and Depression Scale, while subjective cognitive impairment was measured with the Medical Outcomes Study-Cognitive Functioning Scale. Hierarchical multivariable logistic regression analyses were performed for each outcome separately. Besides use of AEDs, other confounding variables such as seizure severity and Karnofsky Performance Status score were included. Analyses were repeated for the two most commonly prescribed AEDs separately, levetiracetam or valproic acid, with the same confounding variables.

RESULTS
A total of 272 grade II-IV glioma patients were included in the study, of which 68% used at least one AED. Prevalence of depression was 10% for patients taking 0 AEDs and increased significantly to 21% (adjusted Odds Ratio [aOR]=2.4 [95%Confidence Interval {CI}=1.0–5.8]) for those taking ≥1. Prevalence was not significantly different between patients using 0 and using ≥1 AEDs for both anxiety (19% versus 26%, aOR=1.1 [95%CI=0.6–2.2]) and subjective cognitive impairment (16% versus 21%, aOR=1.2 [95%CI=0.6–2.5]). Although prevalences of depression (13% versus 23%, aOR=1.6 [95%CI=0.8–3.2]) and anxiety (17% versus 31%, aOR=1.8 [95%CI=0.9–3.3]), but not subjective cognitive impairment (20% versus 18%, aOR=1.7 [95%=0.4–1.4]), differed significantly between patients not using and using levetiracetam, these associations were not independent. No significant differences were found between patients not using and using valproic acid on the three outcome measures.

CONCLUSION
After adjustment of confounders, only depression was associated with the use of AED’s. No such relation was found for anxiety or subjective cognitive impairment. Use of levetiracetam or valproic acid were not independently related to depression, anxiety or subjective cognitive impairment.
OS6.1 Targeting Purine Metabolism to Overcome Therapeutic Resistance in Glioblastoma
Authors: Ahmed A U , Shireman J , Atashi F , Saathoff M , Ali E , Lee G , Park C , Savchuk S , Rayyan J , James C , Ben-Sahra I 
Published: September 2019

Abstract

BACKGROUND
A distinguishing characteristic of all cancers is uncontrolled cell division, and they require additional nucleotide bases such as purines, the building blocks of DNA and RNA, to sustain their uncontrolled growth. Purines can be synthesized from scratch by de novo pathway or salvaged by recycling surrounding nucleotides that are released by hydrolytic degradation. Even though the central nervous system (CNS), as well as CNS associated malignancies like glioblastoma (GBM), rely more heavily on the salvage pathway due to its energy efficiency, its precious role in promoting chemoresistance and GBM recurrence is yet to be elucidated.

MATERIAL AND METHODS
We have examined the role of purine biosynthesis in GBM by using stable isotope tracing analysis as well as utilizing a knockdown (KD) system to investigate its effect on i) DNA damage response during temozolomide (TMZ) therapy, ii) tumor engraftment and iii) therapeutic responses in vivo.

RESULTS
Through gene expression and protein-protein interaction analysis, we have identified ARL13B, member of ADP-ribosylation factor-like protein family, as a novel regulator of the purine biosynthesis pathway in GBM. ARL13B can physically interacting with the inosine monophosphate dehydrogenase 2 (IMPDH2), a key rate-limiting enzyme for purine biogenesis. Isotope tracer analysis under normal physiological conditions revealed that during TMZ treatment, salvage recycling activity was decreased by 50% while de novo pathway activity remains unchanged. In contrast, TMZ treatment of ARL13B knock-out cells results in a ~50% decrease in de novo pathway activity (p-value=0.004), whereas purine salvage pathway activity is upregulated ~6-fold (p-value <0.0001). ARL13B knockdown cells treated with TMZ show a robust increase in DNA double-strand breaks compared to control cells exposed to TMZ, as demonstrated by gH2X staining. Mice orthotopically engrafted with KD cells experience prolonged survival relative to mice engrafted with unmodified cells.

CONCLUSION
We propose that ARL13B-IMPDH2 interaction has two consequences: i) augmentation of de novo purine biosynthesis activity, and ii) inhibition of nucleotide recycling. The increasing de novo purine biosynthesis during TMZ therapy helps GBM cells reduce the recycling of nucleotides via the salvage pathway that have been modified as a result of TMZ alkylation. This, in turn, protects the cells from deleterious effects of incorporating modified nucleotides into newly-synthesized DNA while maintaining a supply of purine building blocks to support uncontrolled proliferation. Our results indicate that the interaction of ARL13B-IMPDH2 functions as a purine biosynthesis regulator that could be targeted for increasing efficacy of TMZ treatment of GBM. ​
OS6.5 ERGO2: A prospective randomized trial of a 9-day schedule of calorically restricted ketogenic diet and fasting or standard diet in addition to re-irradiation for malignant glioma
Authors: Voss M , Wagner M , von Mettenheim N , Harter P N , Wenger K , Franz K , Bojunga J , Gerlach R , Glatzel M , Paulsen F , Hattingen E , Baehr O , Ronellenfitsch M W , Fokas E , Imhoff D , Steinbach J P , Rödel C , Rieger J 
Published: September 2019

Abstract

BACKGROUND
Ketogenic diet (KD) and fasting have anticancer effects in tumor models, possibly due to a differential stress response with sensitization of tumor cells and protection of normal tissue. We therefore set up ERGO2 (NCT01754350), the first randomized clinical trial of calorically-restricted KD and intermittent fasting (KD-IF) in addition to re-irradiation for recurrent malignant gliomas.

MATERIAL AND METHODS
Patients were randomized 1:1 to re-irradiation combined with either calorically unrestricted diet (standard diet, SD) or KD-IF. The KD-IF schedule included 3 days of KD (21–23 kcal/kg/d), followed by 3 days of fasting and again 3 days of KD. The primary endpoint was progression-free survival (PFS) rate at 6 months (PFS6). Secondary endpoints were PFS, local control, overall survival (OS), frequency of epileptic seizures, rate of ketosis and quality of life.

RESULTS
50 patients were included. Four patients quit the trial before treatment and three patients stopped KD-IF prematurely. Of the 20 patients who completed KD-IF, 17 patients developed ketosis at day 6, and glucose levels declined significantly. KD-IF was well-tolerated with a modest weight loss of -2.1±1.8 kg. No severe adverse events attributable to the diet occurred. There was no difference in PFS6 between the two groups (KD-IF: 20%, SD: 16%). Similarly, no difference in PFS, local PFS6 and OS were observable. Explorative analysis revealed that among patients of the KD-IF group, those who achieved ketosis of at least 1.5 mmol/l had significantly longer PFS compared to those with lesser or no ketosis.

CONCLUSION
KD-IF is feasible and effective in inducing ketosis in heavily pretreated patients with recurrent glioblastoma. However, the short schedule reported here failed to increase the efficacy of re-irradiation.
OS7.3 Health-related quality of life (HRQoL) evaluation in the REGOMA trial: a randomized, phase II clinical trial analyzing regorafenib activity in relapsed glioblastoma patients
Authors: Lombardi G , Del Bianco P , Brandes A , Eoli M , Rudà R , Ibrahim T , Lolli I , Pace A , Daniele B , Pasqualetti F , Rizzato S , Bergo E , Caccese M , Padovan M , Soffietti R , De Salvo G , Zagonel V 
Published: September 2019

Abstract

BACKGROUND
REGOMA trial showed that regorafenib (REG) significantly improved OS and PFS in patients (pts) with relapsed GBM with respect to lomustine (LOM). REG showed a different toxicity profile compared to LOM. Here, we report final results of the HRQoL assessment, a secondary end point.

MATERIAL AND METHODS
HRQoL was measured using the European Organization for Research and Treatment of Cancer (EORTC) core questionnaire (QLQ-C30) and brain module (QLQ-BN20) administered before any MRI assessments, every 8 weeks (+/- 2 weeks) until disease progression. To evaluate treatment impact on HRQoL, questionnaires at progression were excluded. Mixed-effect linear models were fitted for each of the HRQOL domain to examine the change over progression-free time within and between arms. The models included the time of questionnaire assessment, the treatment group and their interaction, as fixed effects, and a compound symmetry covariance structure for the random effects. Differences of at least 10 points were classified as a clinically meaningful change. To correct for multiple comparisons and to avoid type I error, the level of significance was set at P=0.01 (2-sided).

RESULTS
Of 119 randomized pts, 117 partecipated in the HRQoL evaluation, and 114 had a baseline assessment (n=56 REG; n=58 LOM). No statistically significant differences were observed in any generic or cancer specific domain during treatment in the REG and LOM arms, or between the two arms, except for the appetite loss scale which was significantly worse in PTS treated with REG (Global mean 14.7 (SD=28.6) vs 7.6 (SD=16.0); p=0.0081). The rate of pts with a clinically meaningful worsening for appetite loss was not statistically different between the two arms (9 out of 24 and 0 out of 13 in the REG and LOM arm, respectively;p=0.02).

CONCLUSION
In the REGOMA trial, HRQoL did not change during regorafenib treatment. Pts treated with regorafenib and lomustine reported no significant difference in HRQoL.
OS7.5 Healthcare utilization, medication use, and productivity loss in glioma patients with depressive symptoms and their family caregivers
Authors: Boele F W , Jansen F , Meads D , Verdonck-de Leeuw I M , Heimans J J , Reijneveld J C , Short S C , Klein M 
Published: September 2019

Abstract

BACKGROUND
Gliomas are associated with great societal burden through both direct (health and social care) and indirect (e.g., productivity loss) costs, but socioeconomic reports are scarce. We describe costs in a sample of glioma patients at high risk for depression and their family caregivers, and explore relationships between costs and treatable symptoms (depression; fatigue; cognitive complaints).

MATERIAL AND METHODS
Data from a nationwide randomised trial comparing internet-based therapy for depressive symptoms with waitlist controls were used.
Healthcare utilization, medication use, and productivity loss based on the
Trimbos/iMTA questionnaire for Costs associated with Psychiatric Illness (TIC-P) were described and costs in the past 4 weeks were calculated. Caregivers reported on their own costs and wellbeing
We used generalized linear regression models to predict costs using multiple observations per participant and robust standard errors. We included depressive symptoms (CES-D), fatigue (CIS), cognitive complaints (MOS), tumour grade (low-/high-grade), and disease status (stable/progression/active treatment).

RESULTS
Data from 91 glioma patients and 46 caregivers were used with multiple assessments from baseline through 12 months follow-up. Baseline data showed that over a 4 week period, 64.8% of patients (M=€394.99, sd=856.83) and 41.3% of caregivers (M=€131.11, sd=392.89) had used healthcare services. Medication was used by 90.1% of patients (M=€100.83, sd=191.07) and 43.5% of caregivers (M=€13.19, sd=21.03). Productivity loss resulted in M=€1231.19, sd=2185.35 for patients and M=€310.92, sd=841.36 for caregivers. In total, mean direct and indirect costs were €1632.22 (sd=2314.25) for patients and €447.85 (sd=1002.94) for caregivers. In patients, more depressive symptoms and cognitive complaints were associated with increased healthcare use costs; higher tumour grade and active disease were linked with higher medication costs (all p<.05). Active treatment was related to higher overall costs (p<.05). In caregivers, increased caregiver fatigue was associated with higher productivity loss and overall costs; more caregiver cognitive complaints were associated with higher total costs; higher tumour grade was associated with higher healthcare use and total costs; and patient active treatment was linked with higher healthcare use costs (all p<.05).

CONCLUSION
Direct and indirect costs are substantial in glioma patients and caregivers. This indicates that the true cost of brain tumours is a burden shared between patients, caregivers, the healthcare system, and society more widely. Tentative links between costs and symptoms of depression, fatigue, and cognitive complaints indicate that adequate support may lead to cost reductions. Multivariable regression models are currently being prepared.
OS7.6 Socioeconomic burden and associations with quality of life in meningioma patients
Authors: Wirsching H , Morel C , Roth P , Weller M 
Published: September 2019

Abstract

BACKGROUND
Socioeconomics affect the outcome of neurological patients, but the socioeconomic burden of brain tumors has not been studied in detail.

PATIENTS AND METHODS
This survey study in a clinically well-annotated cohort of meningioma patients was designed to explore socioeconomic status parameters at diagnosis and one year thereafter. The survey comprised level of education, profession, employment status, subjective work ability, monthly income and the EPICES social deprivation score. Quality of life (QoL) and symptom burden were queried utilizing the EORTC-QLQ-C30/BN20 and MDASI-BT. A multivariate binary regression model was applied to explore associations of socioeconomics with QoL.

RESULTS
Completed surveys were obtained from 249 of 410 patients (61%) who were invited to participate. The level of education was an apprenticeship or higher in 214 patients (86%). One year after diagnosis, there was a 20% decline in the fraction of employed patients and a more than twofold increase in unemployment and disability (p<0.001). There was a decrease in monthly income among patients with a baseline income below national average (p=0.008). On multivariate analyses, there was an association of inferior QoL with pre-operative unemployment or retirement (OR 2.43, 95% CI 1.02–5.88), whereas a subjective work ability of >70% was associated with better QoL (OR 0.37, 95% CI 0.15–0.92).

CONCLUSION
Socioeconomics assessments should be incorporated in prospective neuro-oncology clinical trials. A more detailed knowledge of the effects of socioeconomics on patient outcome will aid in identifying patients at risk for deterioration and allow to implement improved preventive and supportive strategies.
OS8.6 Sensitivity of human meningioma cells to the cyclin-dependent kinase inhibitor, TG02
Authors: Le Rhun E , von Achenbach C , Sahm F , Wang S S , Neidert M C , Rushing E , Lawhon T , Schneider H , von Deimling A , Weller M 
Published: September 2019

Abstract

BACKGROUND
Standards of care for meningioma include surgical resection, which may be curative, and radiotherapy as required. Pharmacotherapy plays only a minor role in this disease; however, novel systemic approaches are urgently needed for patients who are no longer candidates for local therapy.

MATERIAL AND METHODS
We generated primary cultures from surgically removed meningiomas to explore the activity of a novel cyclin-dependent kinase inhibitor, TG02, in meningioma cell cultures. Tumor and cell cultures were characterized by mutation profiling and DNA methylation profiling. DNA methylation data were used to allot each sample to one out of six previously established meningioma methylation classes: benign (ben)-1, 2, 3, intermediate (int)-A, B, and malignant (mal). The activity of TG02 was assessed by standard cell culture assays.

RESULTS
Cell cultures were derived from nine meningiomas. Four tumors assigned to the methylation class ben-2 showed the same class in the cell culture whereas cell cultures from five non-ben-2 tumors showed a different class, a more malignant class in four of five patients. Cell cultures were uniformly sensitive to the growth inhibitory effects of TG02 in the nanomolar range. Assignment of the cell cultures to a more malignant methylation classifier appeared to be more closely associated with TG02 sensitivity than assignment to a higher WHO grade of the primary tumors.

CONCLUSION
Primary cell cultures from meningioma facilitate the investigation of the anti-meningioma activity of novel agents. TG02, an orally available cyclin-dependent kinase inhibitor, warrants further exploration in this disease.
OS9.3 Clinical, molecular and radiomic profile of gliomas with FGFR3-TACC3 fusion
Authors: Picca A , Alentorn A , Saragoussi E , Bielle F , Ducray F , Villa C , Schmitt Y , Lerond J , Leclerc J , Lasorella A , Iavarone A , Mokhtari K , Savatovsky J , Sanson M , Di Stefano A 
Published: September 2019

Abstract

PURPOSE
Actionable oncogenic fusion FGFR3-TACC3 (F3T3) is found in 3% of gliomas. Our goal was to characterize the clinical, radiological and molecular features of patients with F3T3-positive glioma.

PATIENTS AND METHODS
Overall, we screened 1112 gliomas by RT-PCR (861 WHO grade IV, 140 grade III and 111 grade II) and identified 50 F3T3-positive cases. We performed a radiological and radiomic case control study.

RESULTS
F3T3 fusion was exclusively found in IDH wild-type gliomas. F3T3 was mutually exclusive with the EGFR amplification (0/38 versus 143/336 of F3T3-negative cases, P=0.01), whereas it was associated with CDK4 amplification (7/33 versus 22/321 of F3T3-negative cases, P=0.04) and MDM2 amplification (6/33 versus 15/354 of F3T3-negative cases, P=0.03). F3T3-positive gliomas showed a longer overall survival than F3T3-negative gliomas (median OS 40.1 and 20.0 months, P=0.02), particularly in the grade IV subgroup (40.1 versus 19.0 months, P=0.006). Multivariate analysis showed that F3T3 fusion is an independent predictor of favorable outcome for glioblastoma patients. F3T-positive gliomas were associated with involvement in non-eloquent areas (r=0.31 P=0.007), cortico-subcortical regions and insula involvement (adjusted p<0.001), poorly defined enhancing margins (r=0.48 P<0.001), poorly defined non-enhancing margins (r=0.61 P<0.001), and higher proportion of edema (r=0.43 P<0.001). Radiomics analysis correctly classified F3T3-positive glioma with an AUC of 0.82. We compared different Cox proportional hazards models using Harrel’s C-Index. Although radiomics alone obtained a high C-Index (0.75, SD 0.04), the model combining clinical, genetic and radiomic data showed the highest C-index (0.81, SD 0.04).

CONCLUSION
Gliomas harboring F3T3 gene fusions show specific molecular features, distinct radiological and radiomic features and a less aggressive clinical evolution.