bluuebunny/crossref_metadata_2025_split huggingface dataset:
JS1.2 Increased frequency of paraneoplastic encephalitis with anti-Ma2 antibodies in the cancer immunotherapy era
Authors: Vogrig A , Fouret M , Joubert B , Picard G , Rogemond V , Pinto A , Muñiz Castrillo S , Roger M , Raimbourg J , Dayen C , Grignou L , Pallix-Guyot M , Lannoy J , Ducray F , Desestret V , Psimaras D , Honnorat J 
Published: September 2019

Abstract

BACKGROUND
Given the mechanism of action of immune checkpoint inhibitors (ICIs), a possible association with the development of paraneoplastic neurological syndromes (PNS) has been hypothesized. We sought to determine if ICI treatment might trigger anti-Ma2 antibody-associated paraneoplastic neurological syndromes (Ma2-PNS).

MATERIAL AND METHODS
We performed a retrospective nationwide study of all patients with Ma2-PNS developed during ICI treatment between 2017–2018. The frequency of neuronal-antibody detection before and after ICI implementation was also analyzed.

RESULTS
Our series of patients included 5 men and 1 woman (median age, 63 years). The patients were receiving either nivolumab (n = 3), pembrolizumab (n = 2) or a combination of nivolumab and ipilimumab (n=1), for treatment of neoplasms that included lung (n=4) and kidney (n=1) cancers, and pleural mesothelioma (n=1). Median delay between ICI introduction and onset of the neurological syndrome was 4 months. Clinical syndromes included a combination of limbic encephalitis and diencephalitis (n=3), isolated limbic encephalitis (n=2) and a syndrome characterized by opthalmoplegia and head-drop (n=1). Patients with diencephalitis manifested hyperphagia, weight gain and somnolence. Post-ICI Ma2-PNS accounted for 35% of the total 17 Ma2-PNS diagnosed in our center over the 2017–2018 biennium. Eight cases had been detected in the preceding biennium 2015–2016, corresponding to a 112% increase of Ma2-PNS frequency since the implementation of ICIs in France. No other neuronal-antibody demonstrated a similar increment.

CONCLUSION
We show a clear association between ICI use and increased frequency of Ma2-PNS. Physicians need to be aware that ICIs can trigger Ma2-PNS since clinical presentation can be challenging.
OS1.3 Tumor cell-free DNA detection in CSF for primary CNS lymphoma diagnosis
Authors: Rimelen V , Ahle G , Pencreach E , Zinniger N , Debliquis A , Zalmaï L , Harzallah I , Hurstel R , Alamome I , Lamy F , Brinet A , Voirin J , Drénou B 
Published: September 2019

Abstract

BACKGROUND
Primary CNS lymphoma (PCNSL) is a rare disease accounting for around 3% of the primary brain tumors. In the vast majority of cases, PCNSL are classified as diffuse large B-cell lymphoma according to the WHO classification. The diagnosis is based on cranial MRI, in combination with a brain biopsy. In case of classical MRI findings, the identification of lymphoma cells in the cerebrospinal (CSF) or vitreous fluid by cytology and flow cytometry might obviate brain biopsy. The presence of the somatic mutation p.Leu265Pro (L265P) in MYD88 is detectable in 50 to 80% of PCNSL, and might also be helpful to confirm the diagnosis. The aim of our study was to evaluate the contribution of a highly sensitive digital droplet PCR, targeting the mutation L265P MYD88, for the detection of tumoral circulating DNA from CSF supernatant.

MATERIAL AND METHODS
We identified 9 PCNSL expressing the L265P mutation at diagnosis or relapse. The mutation was found by an allele specific PCR technique either on biopsy or in CSF cells. Circulating DNA was isolated from CSF supernatant with the « QiaAmp® circulating nucleic acid» kit. The quantity of DNA collected was estimated by quantitative PCR for a reference gene (albumine) with 7900HT (Life technologies™) device. Subsequently, the L265P MYD88 mutation was quantified by digital droplet PCR Biorad™: The droplets generated were amplified by PCR, detected with the QX200 Reader, and analyzed with the QuantaSoft™ software.

RESULTS
The circulating DNA concentration was low, varying between 0 and 2.2 ng/mL of CSF. However, the mutation was detected in the circulating DNA from CSF supernatant in 6 out of 9 cases (66%). The fractional abundance varied from 2.6 to 85%. In 3 cases, the mutation was detected even though cytology and flow cytometry did not reveal leptomeningeal disease. For 3 other cases, the mutation was not detected: The genome copy number was below 1 copy/µL, indicating a low analytical sensitivity for theses samples.

CONCLUSION
This study shows that circulating DNA is present in low concentration in CSF and can be amplified by a sensitive digital PCR for the L265P MYD88 mutation. The detection of circulating PCNSL DNA in CSF is possible and might be used to improve the non-invasive diagnosis of PCNSL. It might also help to select patients for targeted therapies.
OS3.3 Development of an EORTC questionnaire measuring instrumental activities of daily living (IADL) in patients with brain tumours: phase I-III
Authors: Oort Q , Dirven L , Boele F , Grant R , Sato H , Talacchi A , Young T , Reijneveld J C , Taphoorn M J B 
Published: September 2019

Abstract

BACKGROUND
In brain tumour patients, impairments in every day functioning can impact quality of life, and are therefore an important outcome in both clinical trials and practice. One way to measure every day functioning is with an activities of daily living (ADL) questionnaire. Instrumental ADL (IADL) are the cognitively more complex activities, that are essential to function autonomously within society. Cognitive decline may therefore negatively impact IADL, making these activities particularly relevant to brain tumour patients. The aim of this study is to develop a reliable and valid questionnaire to measure IADL in primary malignant and metastatic brain tumour patients.

MATERIAL AND METHODS
The questionnaire development study followed the standard European Organisation for Research and Treatment of Cancer (EORTC) four phase methodology: (I) generation of activities list, (II) construction of item list, (III) pre-testing, and (IV) field testing. This report covers phases I-III. To ensure cross-cultural validity, participants were recruited from different countries (The Netherlands, United Kingdom, Italy, Austria and Japan). In phase I, potential activities were identified based on a literature review and in-depth interviews with patients, proxies and healthcare professionals. In phase II, activities were turned into items, and translated into all required languages by the EORTC Translation Unit. In phase III, the item list was pre-tested in patient-proxy dyads. In accordance with predetermined decision rules to reduce items, final items were selected, and preliminary psychometric properties (i.e. factor structure, validity, reliability) were assessed.

RESULTS
Phase I (N=44 dyads) resulted in 59 IADL activities which were converted into 59 items in phase II. In phase III, N=85 dyads completed and reviewed this item list. The item list was subsequently reduced to 32 items. An exploratory factor analysis indicated several items measuring similar underlying constructs (e.g. domestic life and using computer/smartphone) showing acceptable to good (α≥0.7) internal consistency (range α=0.69–0.89). Seven items were less related to these underlying constructs (e.g. work or managing your own medication), and therefore single items. Construct validity, measured with known-group comparisons analyses between cognitively impaired and unimpaired patients, showed significant differences in scores between the two groups on some scales and several single items.

CONCLUSION
The currently developed EORTC IADL-BN32 questionnaire can be a valuable asset in assessing IADL functioning in brain tumour patients, but further validation in phase IV is required and is planned.
OS3.5 Prescription medications in glioma patients and the prevalence of depression, anxiety and subjective cognitive impairment
Authors: van der Meer P B , Taphoorn M J B , van den Bent M J , Dirven L , Koekkoek J 
Published: September 2019

Abstract

BACKGROUND
Several medications prescribed for the management of symptoms in glioma patients, such as antiepileptic drugs and corticosteroids, have been associated with depression, anxiety and cognitive impairment in glioma patients. However, no previous study has incorporated all prescription medications instead of only one class of medications. The aim of this observational study was to assess the prevalence of depression, anxiety and subjective cognitive impairment associated with prescription medications, that have a potential for such adverse drug effects, in glioma patients.

MATERIAL AND METHODS
Use of prescription medications with a >1% risk of potential depressive, anxiety or cognitive adverse effects was defined as a categorical variable (0, 1 or ≥2), separately for each adverse drug effect. 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 medications with a >1% risk of adverse effects (depression, anxiety or cognitive adverse effects, depending on the outcome analysed), other confounding variables such as seizure severity and Karnofsky Performance Status score were included.

RESULTS
A total of 272 grade II-IV glioma patients were included in the study. Prevalence of depression increased significantly from 9% for patients taking 0 medications with >1% risk of depressive adverse effects, to 18% taking 1 medication and 29% (adjusted Odds Ratio [aOR]=3.3 [95% Confidence Interval {CI}=1.3–8.4]) taking ≥2 medications. Prevalence of subjective cognitive impairment also increased significantly, from 14% for patients using 0 medications with a >1% risk of cognitive adverse effects to 25% using 1 and 29% using ≥2 medications, but association was not independent (aOR=2.1 [95%CI=0.8–5.6]). While prevalence of anxiety increased from 18% for patients using 0 medications with >1% risk of anxiety adverse effects to 25% using 1 and 33% (aOR=1.7 [95%CI=0.7–4.1]) using ≥2 medications, this was not significant.

CONCLUSION
Higher number of medications with depressive or cognitive adverse effects used by a glioma patient corresponds with a higher prevalence of depression and subjective cognitive impairment. However, after adjustment of potential confounders the association is only independent for depression.
OS3.6 Prediagnostic symptoms and signs of adult glioma: the patients’ view
Authors: Peeters M C M , Dirven L , Koekkoek J A F , Gortmaker E G , Fritz L , Vos M J , Taphoorn M J B 
Published: September 2019

Abstract

BACKGROUND
Little is known about the symptoms and signs glioma patients experience in the year before diagnosis, either or not resulting in health care usage. The objective of this study was to determine the incidence of several symptoms and signs glioma patients experienced in the year prior to diagnosis, as well as visits to a general practitioner (GP) related to these issues.

MATERIAL AND METHODS
This was a cross-sectional study, including adults diagnosed with a glioma <12 months ago. Patients were asked to complete a 30-item study-specific questionnaire, if possible with input of a proxy, focusing on symptoms and signs they experienced in the 12 months before diagnosis. For each indicated symptom/sign, patients were asked whether they consulted the GP for this issue. In addition, the presence of comorbidity and other chronic complaints were assessed, as well as consulted health care professionals (HCPs) in the year prior to diagnosis. The statistical analyses were corrected for multiple testing.

RESULTS
Between July 2016 and March 2019, 58 patients completed the questionnaires, 54 (93%) with input of a proxy. Forty-one (72%) patients were men, with a median age of 60 years (range 43–78), and the median time since diagnosis was 4 months (range 1–12). Forty (69%) patients had a comorbidity or chronic complaint, and the median number of consulted HCPs was 2 (range 0–8). The median number of symptoms/signs experienced in the year before diagnosis was 8 (range 2–19) in low-grade and 5 (range 0–24) in high-grade glioma (p=0.258). The five most frequently mentioned problems were fatigue (34/58, 59%), mental tiredness (28/58, 48%), sleeping disorder (23/58, 40%), headache (22/58, 38%) and stress (20/58, 34%), with no differences between low- and high grade glioma. Twenty-five (43%) patients had visited the GP with at least one issue. We found that patients who did consult their GP reported significantly more often muscle weakness (11 vs 3, p=0.002), paralysis in for example a hand or leg (10 vs 3, p=0.006), or a change in consciousness (9 vs 3, p=0.013) compared to those that did not consult the GP. However, they did not differ with respect to the number of symptoms (median 7 vs 5), comorbidities and chronic complaints (median 1 vs 1), or overall health care usage (median 3 vs 2).

CONCLUSION
Glioma patients experience a range of problems in the year prior to diagnosis, but patients who consult the GP report significantly more often neurological problems.
OS6.2 Loss of CYP46A1 directs altered cholesterol homeostasis and opens therapeutic opportunities for glioblastoma
Authors: Han M , Wang S , Li X , Wang J , Bjerkvig R 
Published: September 2019

Abstract

BACKGROUND
Dysregulated cholesterol metabolism is a hallmark of many cancers, including glioblastoma (GBM), but its role in disease progression is not well understood. Here, we identified cholesterol 24-hydroxylase (CYP46A1), a brain-specific enzyme responsible for elimination of cholesterol through conversion of cholesterol to 24(S)-hydroxycholesterol (24OHC), as one of the most dramatically dysregulated cholesterol metabolism genes in GBM.

MATERIAL AND METHODS
Molecular and clinical data was obtained from publicly genomic databases. Immunohistochemistry was applied to assess protein levels of CYP46A1 in primary GBM samples. Lentiviral constructs expressing CYP46A1 were transduced into LN229, LN18 and primary GBM GSCs for functional assays carried out in vitro and in vivo in an orthotopic xenograft model. RNA-seq was performed to identify downstream targets of 24OHC.

RESULTS
CYP46A1 was significantly decreased in GBM samples compared to normal brain tissue. Reduced CYP46A1 expression was associated with increasing tumour grade and poor prognosis in GBM patients. Ectopic expression of CYP46A1 suppressed cell proliferation and in vivo tumour growth by increasing 24OHC levels. Treatment of GBM cells with 24OHC suppressed tumour growth through regulation of LXR and SREBP signalling. Efavirenz (EFV), an activator of CYP46A1 with BBB penetration, inhibited GBM growth in vivo.

CONCLUSION
Our findings demonstrate that CYP46A1 is a critical regulator of cellular cholesterol in GBM and that the CYP46A1/24OHC axis is a potential therapeutic target.
OS8.3 Gamma knife radiosurgery for large meningiomas: 10 years of experience
Authors: Abdel Karim K , El-Shehaby A , Reda W , Emad Eldin R , Nabeel A , Tawadros S 
Published: September 2019

Abstract

BACKGROUND
The use of gamma knife radiosurgery for the treatment of intracranial meningiomas has been established as an effective and safe treatment modality. Larger meningiomas are typically managed by surgery followed by radiosurgery. For situations where patients are not amenable to surgery fractionated stereotactic radiotherapy is the traditionally suggested treatment. Treatment of large meningiomas (usually defined as >10 cc) by stereotactic radiosurgery has been investigated in some recent reports, either by single-session, volume-staged or hypofractionation technique. However, there are no long-term results. The purpose of this study is to assess the long-term efficacy and safety of gamma knife radiosurgery for large (15 cc or more) intracranial meningiomas.

MATERIAL AND METHODS
In this study we included 80 patients with large meningiomas (³ 15 cc) who were followed up for more than 5 years. Non-benign meningiomas were excluded. Also, meningiomatosis and NF2 patients were not included. There were 18 males (22.5%) and 62 females (77.5%). The mean age was 46 years (20–83 years). Twenty-six patients (32.5%) had previous surgery. Tumor were supratentorial in 14 (17.5%) patients and skull base in 66 (82.5%) patients. The mean tumor volume was 22.3 cc (15–57.3 cc). The mean prescription dose was 11 Gy (9–12 Gy).

RESULTS
The mean follow up period was 8.4 years (5–17 years). The tumor shrank in 43 patients (54%), was stable in 30 patients (37%) and progressed in 7 patients (8%). The tumor control rate was 91%. Adverse radiation effects were observed in 11 patients (14%) but only 5 (6.5%) were symptomatic. These were temporary in all cases.

CONCLUSION
Gamma knife radiosurgery provides an effective and safe treatment option for large meningiomas. Low margin dose appears to be sufficient for tumor control. Surgery remains the first option in these cases.
OS8.4 Impact of brain invasion assessment on outcome in intracranial grade II meningiomas
Authors: Picart T , Dumot C , Ducray F , Durand A , Guyotat J , Berhouma M , Meyronet D 
Published: September 2019

Abstract

BACKGROUND
Brain invasion has already been identified as an independent criterion of meningioma recurrence by Jääskaläinen’s in 1986. While it was only suggested that meningiomas harbouring brain invasion could be staged as grade II in the 2007 WHO Classification of Tumours of the Central Nervous System, brain invasion was clearly listed as a grade II atypical meningioma criterion for the first time in the 2016 version. Since 2007, brain invasion has been carefully screened during the histopathological characterisation of meningiomas in our centre thanks to specific training of the neuropathology department staff. Furthermore, neurosurgeons are asked to provide well-preserved and grossly orientable tumours borders whenever possible. The aim of the present study was to compare the characteristics of patients diagnosed with grade II meningiomas before and after this change of practices.

MATERIAL AND METHODS
We retrospectively reviewed the characteristics of 125 patients with grade II meningiomas diagnosed between 2011 and 2014 (group A) and compared them to those of 166 patients with grade II meningiomas diagnosed between 1998 and 2005 (group B).

RESULTS
Tumour location and socio-demographic parameters were comparable in group A and B with a median age of 62 years in both groups (p=0.18). There were more de novo meningiomas in group A (84% vs 68.7%, p=0.004). Brain invasion was found in 59% in group A and 9% in group B (p=0.00001) while median Ki67 labelling was of 8.4% in group A and 10.5% in group B (p=0.04). Consistently, tumour borders were irregular in 52% in group A and 29% in group B (p=0.0002). Progression free survival was similar in the two groups (65 vs 66 months, p=0.92) but grade progression was more frequently observed in group B (18.9% vs 0%, p=0.006). In group A, meningiomas that were classified as grade II exclusively based on brain infiltration (n=33, group A-bi) had a similar progression rate compared to meningiomas with other criteria of atypia (27% vs 25%, p=0.98) and a similar time to progression (32 vs 32 months, p=0.74). The median time to progression of group A-bi meningiomas was also comparable to that of the other 258 pooled meningiomas (32 vs 40 months, p=0.40).

CONCLUSION
In accordance with the 2016 WHO Classification of Tumours of the Central Nervous System, the outcome of meningiomas defined as atypical solely based on brain infiltration seems to be comparable to that of meningiomas with other criteria of atypia. Appropriate coordination between neurosurgeons and neuropathologists is mandatory to optimally assess this criterion.
OS10.1 Survival analysis of IDH wildtype astrocytomas with molecular features of glioblastoma, WHO grade IV
Authors: Tesileanu C M S , Koekkoek J A F , Dirven L , Dubbink H J , Kros J M , van Duinen S G , Smits M , French P J , Taphoorn M J B , van den Bent M J 
Published: September 2019

Abstract

BACKGROUND
Recently, isocitrate dehydrogenase wildtype (IDHwt) lower grade gliomas (LGGs) that have a telomerase reverse transcriptase (TERT) promoter mutation and/or gain of chromosome 7 combined with loss of chromosome 10 and/or epidermal growth factor receptor amplification have been reclassified as IDHwt astrocytomas with molecular features of glioblastoma, WHO grade IV (‘astrocytomas IDHwt, WHO IV’). Survival of these tumors meeting the criteria of these tumors is less well studied. The objective of this study is to compare the overall survival (OS) between the IDHwt astrocytomas, WHO IV and histological glioblastomas (GBMs).

MATERIAL AND METHODS
In this retrospective multicenter cohort study, all adult patients with a newly diagnosed IDHwt LGG (histologically WHO grade II or III) and with molecular data available were selected from the Erasmus MC and the LUMC from October 2002 to April 2019. LGG patients showing contrast enhancement with necrosis on the MRI at the time of histological diagnosis were excluded. Molecular data were determined using a diagnostic NGS panel. A historical cohort of 195 patients with IDHwt GBMs with molecular data available was used to compare OS. OS was measured from the date of the first diagnostic MR scan.

RESULTS
79 IDHwt LGG patients were identified of which 62 patients had molecular features of glioblastoma (‘astrocytomas IDHwt, WHO IV’), 11 patients did not have these molecular features (‘astrocytomas IDHwt, WHO II & III’). In the remaining 6 patients the molecular data were not conclusive (astrocytomas IDHwt, WHO NOS). Patients with astrocytomas IDHwt, WHO IV were slightly older at diagnosis (median age = 57 years) than patients with GBMs IDHwt in the reference cohort or astrocytomas IDHwt, WHO II & III (respectively: median age 55 years, p=0.032 and 47 years, p=0.035). The relatively young age of our GBM IDHwt cohort reflects more extensive molecular testing in younger patients and histologically lower grade tumors. The median OS of astrocytomas IDHwt, WHO IV (23.8 months) was similar to the median OS of GBMs (19.2 months, log-rank test p=0.37). The median OS in 19 patients with only TERT promoter mutations was 16.8 months, similar to GBMs (p=0.94).

CONCLUSION
There is no statistically significant difference between the OS of IDHwt astrocytomas with molecular features of glioblastoma and the OS of true glioblastomas. Grade II and III IDHwt astrocytoma with molecular features of glioblastoma should be designated WHO grade IV. The presence of TERT promoter mutations alone in this histological context also qualifies for this designation.