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Abstracts
ii95
NEURO-ONCOLOGY • September 2022
ation, we further investigated nuclear localisation of beta-catenin levels. The
results showed the both beta-catenin and c-myc expression in the nucleus
was suppressed after combination therapy. CONCLUSION: In meningioma
cells, radiotherapy in combination with HDAC6 inhibitor reduces the nu-
clear localisation of beta-catenin and synergistically decreases cell survival.
Our ndings demonstrate a potential therapeutic strategy of Cay10603 to
improve the radiosensitisation for meningioma cells.
P18.05.A. BEVACIZUMAB IN ATYPICAL AND ANAPLASTIC
MENINGIOMAS: THE BEMEN STUDY
G.Cerretti1,2, A.Bosio3,2, M.Maccari3,2, M.Padovan1, M.Caccese1,
V. Zagonel1, G.Lombardi1; 1Veneto Institute of Oncology IOV – IRCCS,
Oncology 1, Padua, Italy, 2University of Padova, Medical Oncology School
of Specialization, Padua, Italy, 3Veneto Institute of Oncology IOV – IRCCS,
Padua, Italy.
BACKGROUND: meningiomas are the most frequent primary brain tu-
mours. The current standard treatment for atypical and anaplastic meningioma
can include surgical resection and radiotherapy. Despite the high rate of relapse
no systemic treatment is indicated. Few data are available regarding the effect-
iveness of bevacizumab (BEV) in this setting. We performed a retrospective
analysis investigating the efcacy and safety of BEV in meningioma patients
relapsed after receiving surgery and radiotherapy. Gene mutations were also
collected MATERIAL AND METHODS: we retrospectively analyzed pa-
tients treated with off-label BEV at the Veneto Institute of Oncology from July
2019 to February 2022. Major inclusion criteria were histologically-conrmed
diagnosis of grade 2-3 meningioma (according to WHO 2016 classication),
previous treatment with surgery and radiotherapy, no indication to further sur-
gical reintervention or reirradiation, absence of major contraindications to the
use of BEV. Data were estrapolated from local clinical records. Bevacizumab
was administered at 10 or 5mg/Kg every 2 weeks (at physician’s discretion)
until progressive disease/death or unacceptable toxicity. Kaplan-Meier curves
were used to estimate the survival rate; CTCAE v 5.0 was used to estimate
treatment-related toxicities; RANO criteria were used for radiological assess-
ment; NGS Foundation One panel was used to examine molecular data RE-
SULTS: the median follow up was 13 months (3-30 range). 26 patients were
enrolled. Median age was 68 ys (29-84); male pts were 16 (61%); 61% (16pts)
with atypical meningioma, 38.5% (10pts) with anaplastic meningioma; 27%
(7pts) had underwent 2 or more surgeries; 58% had had 2 or more RT treat-
ments; 96.1% (25pts) received <2 previous lines of systemic treatment. 77%
(20pts) and 23% (6) received BEV 10 and 5mg/Kg every 2 weeks, respectively.
For 61% of patients (16pts), NGS analyses were available; 62% (10pts) har-
boured NF2 mutations (1 patient had a conrmed diagnosis of neurobroma-
tosis type 2), 23% (6pts) CDKN2A/2B deletion, 11% (3pts) PTEN mutation,
8% (2pts) FGFR mutation, 8% (2pts) JAK alteration. Overall survival (OS)
rate was 82% and 62% at 6 and 12months respectively; 6 months PFS rate
was 83%. 4 patients showed PR, 11 SD, 6 PD, no patient had CR; 5 patients
were not evaluable for response. Among evaluable patients the disease control
rate (stability+response) was 71% and the objective response rate was 19%.
Median PFS and OS were not reached19% (5pts) experienced CTCAE grade 1
or 2 toxicity, mainly hypertension (4pts); 1 patient experienced grade 3 hyper-
tension. CONCLUSION: BEV showed very promising activity in recurrent
grade 2-3 meningioma. The treatment was well tolerated. BEV should be con-
sidered an optimal therapeutic option in this setting of meningioma patients.
The NGS results might be useful in identifying targetable mutations in case of
further recurrence
P18.06.B. ETS-TRANSCRIPTION FACTOR INHIBITORS ARE
EFFECTIVE IN TERT PROMOTER MUTATED MENINGIOMA CELLS
IN VITRO
K.Neumayer1, L.Kastler2, M.Laaber1, C.Roschger3, S.Lenz4,
D.Lötsch-Gojo5, W. Berger6, A.Gruber2, S.Spiegl-Kreinecker2;
1Department of Neurosurgery, Kepler University Hospital GmbH, Linz,
Austria, 2Department of Neurosurgery, Kepler University Hospital, Faculty
of Medicine, Johannes Kepler University, Linz, Austria, 3Department of
Cardiovascular and Thoracic Surgery, Kepler University Hospital, Faculty
of Medicine, Johannes Kepler University, Linz, Austria, 4Clinical Institute
of Pathology and Molecular Pathology, Kepler University Hospital GmbH,
Linz, Austria, 5Department of Neurosurgery, Medical University of Vienna,
Vienna, Austria, 6Institute of Cancer Research and Comprehensive Cancer
Center, Medical University of Vienna, Vienna, Austria.
BACKGROUND: TERT promoter mutations in meningiomas were re-
cently found to be strongly prognostic and associated with malignant
progression and risk of recurrence. As result, the mutation in the TERT pro-
moter generates a binding site for E twenty-six (ETS) transcription factors.
Consequently, ETS-transcription factor inhibition might represent a novel
strategy to impede meningioma growth. In a prior study we could demon-
strate effectiveness of the ETS-transcription factor inhibitor YK-4-279 in
TERT promoter mutant meningiomas. Recently, TK216 the clinical deriva-
tive of YK-4-279 was developed. Therefore, we aimed to clarify whether
TK216 might have an increased effect as compared to YK-4-279 in TERT
promoter mutated meningioma cells in vitro. METHODS: A meningioma-
derived cell line (BTL695) generated from a TERT promoter mutated
(C228T) anaplastic meningioma served as cell model for the experiments.
BTL695 was characterized by high telomerase activity and TERT mRNA ex-
pression as analysed by the TRAP assay and RT-PCR, respectively. Genomic
aberrations were veried using Ion Torrent Oncomine Comprehensive Assay
v3-based next-generation sequencing (NGS). The sensitivity of BTL695 to
YK-4-279 and TK216 was determined using an MTT-based viability assay
(EZ4U). To elucidate the effectiveness of TK216 on cell cycle and apop-
tosis, cells were stained with PI and annexin V, respectively, and measured
by ow cytometry. The effect of TK216 on the protein expression of the
cleaved poly(ADP-ribose) polymerase-1 (PARP-1), indicative for apoptosis,
was investigated by western blot. Additionally, a TK216-resistant cell model
(BTL695res) was generated and analysed by NGS. RESULTS: BTL695 was
signicantly more sensitive to TK216 as compared to YK-4-279 (p<0.0001)
characterized by the distinctly lower IC50 value of TK216 exposed cells
(0.7 µM TK216; 1.6 µM YK-4-279). Flow cytometry analysis revealed a
TK216 induced G2M cell cycle arrest and increased apoptosis rate, which
was additionally veried by the expression of cleaved PARP-1 expression
using western blot. Genomic aberrations were found in 18 genes including
NF2, CDKN2A/B, ARID1A and PTEN. Interestingly, although the majority
of genomic alterations was persistent in the TK216 resistant cell model, a
p53 mutation was newly acquired as compared to the parental cell line.
CONCLUSION: In summary, our results indicate that ETS transcription
factor inhibition by TK216 exerts antitumour activity in our TERT pro-
moter mutant meningioma cell model. Additionally, the sensitivity against
TK216 is superior to YK-4-279 and therefore TK216 may represent a prom-
ising new therapeutic option for patients with aggressive, TERT promoter
mutated meningioma.
P18.07.A. HIPPO SIGNALING PATHWAY IS STRONGLY INVOLVED
IN MENINGIOMA TUMORIGENESIS
G.Mougel1,2, G.Mondielli1, R.Appay3, A.Querdray1, C.Roche2,
A.Jijon1, I.Konstantinova4, A.Soude4, T.Graillon1,5, A.Barlier1,2;
1Marseille Medical Genetics, Aix-Marseille University, Marseille, France,
2Molecular Department, La Conception Hospital, Marseille, France,
3Pathology Department, La Timone Hospital, Marseille, France, 4Inventiva
Pharma, Daix, France, 5Neurosurgery Department, La Timone Hospital,
Marseille, France.
BACKGROUND: Recurrent and aggressive meningiomas remain an unmet
medical need in neuro-oncology. In mammals, Hippo signaling pathway is re-
sponsible for the growth of organs by regulating cell proliferation and apoptosis.
The tumor suppressor NF2 protein belongs to the core of the Hippo pathway
and a defect of its gene is present in 50% of meningiomas. Absence of NF2
keeps Hippo pathway inactive allowing the translocation of YAP/TAZ to the
nucleus and the formation of a complex with TEADs. This complex then pro-
motes the transcription of anti-apoptotic and proliferative genes such as CTGF,
CYR61 and AXL. Here we present experimental results on human meningioma
fragments and primary cell cultures supporting that Hippo pathway plays a
critical role in meningioma tumorigenesis. MATERIAL AND METHODS: The
role of the Hippo pathway was studied on 57 meningiomas, well characterized
at clinical, histological and molecular level. The genomic prole, target tran-
scripts of the complex YAP/TAZ-TEADs, cell viability, and cell proliferation
were analyzed after siRNA transfection targeting YAP, TAZ, YAP+TAZ and
TEADs. RESULTS: Fifty-seven meningiomas were randomly selected including
27 WHO grade II and III tumors. Thirty (53%) presented a defect on the NF2
gene (NF2def) including 19(65%) grade II/III. NF2def meningiomas presented
a signicant increase of expression levels of Hippo pathway target transcripts
CTGF, CYR61 and AXL in comparison with NF2 wild-type tumors (p<0.0001,
p=0.0072 and p=0.0191, respectively). This increase was not correlated with
the grade, the sex or with the cerebral localization of the meningiomas. On
the other side, IHC analysis suggested this increase was correlated with the
nuclear localization of YAP. Disturbing the YAP/TAZ-TEADs complex using
siRNA on 10 meningiomas (5 NF2 wild-type and 5 NF2 def) induced a signi-
cant decrease on cell proliferation but not on cell viability. This decrease was
more important when TAZ was turned off in comparison to turning off of YAP.
CONCLUSION: Our experimental results strongly support the importance of
the Hippo pathway in meningioma tumorigenesis, supporting its relevance as a
new target in meningioma therapy. A.Barlier reports receiving research grants
from Inventiva Pharma. No potential conicts of interest were disclosed by the
other authors.
P18.08.B. FULLY AUTOMATIC MENINGIOMA SEGMENTATION
USING T1-WEIGHTED CONTRAST-ENHANCED MR IMAGES ONLY
S.M.Boelders1,2, W. DeBaene2, G.J.M.Rutten1, K.Gehring1,2,
L.L.Ong2; 1Elisabeth-Tweesteden Hospital, Tilburg, Netherlands, 2Tilburg
University, Tilburg, Netherlands.
BACKGROUND: Manual segmentation of brain tumors requires ex-
pertise, is time-consuming, and is subject to inter-rater variability. Fully auto-
matic brain tumor segmentation is possible for glioma and meningioma when
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Abstracts
ii96 NEURO-ONCOLOGY • September 2022
volumetric T1, T1 contrast-enhanced (T1c), T2, and Fluid-attenuated inver-
sion recovery (FLAIR) MRIs are available. In clinical care of meningiomas,
however, often only volumetric T1c scans are available. In this work, we
trained a deep learning network to segment meningiomas using only T1c
scans for use in clinical research. MATERIAL AND METHODS: NnU-Net,
a deep learning model that is optimized for medical image segmentation,
was trained to segment meningiomas from T1c images. This was performed
on a large clinically collected meningioma dataset (n=374) of T1c scans with
semi-automatically generated enhancing tumor masks and additional data
from the BraTS2020 glioma dataset. Model performance was compared
against inter-rater reliability, between different models, between anatom-
ical tumor locations, and against models using multiple MRI modalities.
RESULTS: The best performing model obtained a Dice score of 0.90. This
performance was 0.03 points lower when compared to inter-rater reliability
(Dice=0.93) and almost equal to models using multiple MRI modalities.
Model performance split over anatomical tumor locations was between 0.90
and 0.97 (Dice). CONCLUSION: Fully automatic meningioma segmenta-
tion using only T1c images is possible with an accuracy that is similar to
inter-rater reliability and models using multiple imaging modalities.
P18.09.A. SINGLE-SESSION STEREOTACTIC RADIOSURGERY FOR
LARGE PARASELLAR MENINGIOMAS
R.M.EmadEldin1, K.M.AbdelKarim2, W.A.Reda3, S.R.Tawadros4,
A.M.Nabil5, A.M.N.ElShehaby4; 1Radiation Oncology dep. National
Cancer Institute Cairo University and Gamma Knife Center Nasser
Institute, Cairo, Egypt, 2Clinical oncology dep. Ain Shams University and
Gamma Knife Center Nasser Institute, Cairo, Egypt, 3Neurosurgery dep.
Ain Shams University and Gamma Knife Center Nasser Institute, Cairo,
Egypt, 4Neurosurgery dep Ain Shams University and Gamma Knife Center
Nasser Institute, Cairo, Egypt, 5Neurosurgery dep. Benha University and
Gamma Knife Center Nasser Institute, Cairo, Egypt.
BACKGROUND: The purpose of this study is to assess the long-term
efcacy and safety of single-session stereotactic radiosurgery for large (10
cc or more) perioptic intracranial benign meningiomas. MATERIAL AND
METHODS: In this retrospective study we included 175 patients with large
perioptic benign meningiomas (≥ 10 cc) who were treated by single-session
SRS. Perioptic meningiomas were dened as meningiomas touching, com-
pressing or within 3mm of the optic pathway. The median tumor volume
was 15 (10-57.3 cc (IQR 8.4 cc)). The median prescription dose was 12
Gy (9-14 Gy (IQR 1 Gy)). RESULTS: The median follow up period was
72months (13-217months (IQR 65months)). The tumor control rate was
92%. The PFS at 5- and 10- years was 97% and 80%. Favorable (better/
stable) visual outcome was reported in 169 patients (97%) and unfavorable
(worse) outcome in 6 patients (3%). Temporary adverse radiation effects
were observed in 21 patients (12%) but only 7 (4%) were symptomatic.
Sixty-three patients had a blind/non-useful eye according the pre-treatment
visual eld examination. Visual improvement was observed in blind/non-
useful eye in 17 patients (27%) while vision remained unchanged in 46 pa-
tients (73%). Ocular nerve palsy improved in 36 patients (61%). Tumor
shrinkage was not a prerequisite for cranial nerve improvement. CONCLU-
SION: Stereotactic radiosurgery provides an effective and safe treatment
option for large perioptic meningiomas.
P18.10.B. NATURAL HISTORY OF MENINGIOMAS - A SERIAL
VOLUMETRIC ANALYSIS OF 240 TUMORS
P. Thomann1, L.Häni1, S.Vulcu1, A.Schütz1, M.Frosch2, C.M.Jesse1,
M.El-Koussy3, N.Söll1, A.Hakim1, A.Raabe1, P. Schucht1; 1University
Hospital Bern, Bern, Switzerland, 2Medical Center - University of Freiburg,
Freiburg, Germany, 3Hospital of Emmental, Burgdorf, Switzerland.
BACKGROUND: The management of asymptomatic intracranial
meningiomas is controversial. Through the assessment of growth predictors,
we aimed to create the basis for practicable clinical pathways for the man-
agement of these tumors. MATERIAL AND METHODS: We volumet-
rically analyzed meningiomas radiologically diagnosed at our institution
between 2003 and 2015. For this purpose, we used exclusively thin-layered
MR images (i.e. ≤ 2mm slice thickness). The primary endpoint was tumor
growth dened as a 14.35% increase in tumor volume. We identied pre-
dictive clinical and radiological characteristics and used the signicant vari-
ables from a multivariable regression model to construct a decision tree
based on the exhaustive Chi-squared Automatic Interaction Detection (ex-
haustive CHAID) algorithm. RESULTS: Of 240 meningiomas, 159 (66.3%)
demonstrated growth during a mean observation period of 46.9 months.
On multivariable logistic regression analysis, older age (OR=0.979 (0.958-
1.000), p=0.048) and presence of calcication (OR=0.442 (0.224-0.872),
p=0.019) had a negative predictive value for tumor growth, while T2-signal
iso-/hyperintensity (OR=4.415 (2.056-9.479), p<0.001) had a positive pre-
dictive value. Adecision tree model yielded three growth risk groups based
on T2-signal intensity and presence of calcications with a proportion
of growing tumors of 34.1% in the low risk group, 60.0% in the inter-
mediate risk group and 80.2% in the high risk group. Median tumor volume
doubling time (Td) was 185.7months in the low risk, 100.1months in the
intermediate risk and 51.7months in the high risk group (p<0.001). While
0% of meningiomas in the low and intermediate risk group had a Td of
≤12 months, 8.9% in the high risk group did so (p=0.021). CONCLU-
SION: Most meningiomas demonstrated growth during follow-up. The
presence or absence of calcications and the signal intensity on T2-weighted
imaging allow a practical and simple stratication of meningiomas into low,
intermediate and high risk tumors. Small tumors in the low or intermediate
risk categories can be monitored with longer follow-up intervals, whereas
in the high risk category proactive management decisions can be justied.
P18.11.A. ACTIVE BEAM SCANNING PROTON THERAPY FOR
LARGE SKULL BASE BENIGN MENINGIOMAS: LONG-TERM
RESULTS
D.Amelio1, L.LoFaro2, F. Corsini3, D. Donner4, F.Chiof5, F. Volpin5,
L.Volpin6, F. Chierichetti4, S.Sarubbo3, D.Scartoni1; 1Proton Therapy
Center, Trento, Italy, 2Humanitas Radiation Therapy Department, Milano,
Italy, 3Neurosurgery Department, Trento, Italy, 4Nuclear Medicine
Department, Trento, Italy, 5Neurosurgery Department, Padova, Italy,
6Neurosurgery Department, Vicenza, Italy.
PURPOSE: To report long-term results of active beam scanning proton
therapy (PT) for large skull base benign meningiomas MATERIAL AND
METHODS: Eighty-two patients (pts) with large skull base meningiomas
were treated with PT between April 2015 and December 2021. Median
age was 62years (range, 48-82) while KPS ranged between 60 and 100
(median 90); 60 were female (73%), and 22 were male (27%). Thirty-two
pts (39%) had histologically proven World Health Organization (WHO)
Grade Itumors. In remaining pts diagnosis was based on the typical im-
aging appearance of benign meningioma. All patients received PT for
residual, progressive or non-operable lesions. Newly diagnosed tumors re-
ceived total dose of 50 GyRBE (RBE: relative biologic effectiveness) while
progressing meningiomas 54 GyRBE. All the treatments were delivered
at 2 GyRBE per fraction. All pts were treated with active beam scan-
ning PT using 3 elds with single eld optimization technique. Treatment
planning was based on morphological magnetic resonance imaging (MRI)
with contrast enhancement medium administration. All pts received also
68-Ga-DOTATOC-PET. Gross tumor volume ranged from 21 to 64 cc.
Toxicity was assessed according to Common Terminology Criteria for Ad-
verse Events version 4.0. Median follow-up time was 40months (range,
3-83). RESULTS: All pts completed the treatment without breaks. Regis-
tered acute side effects include grade 1 (19%) and grade 2 (8%) skin ery-
thema, grade 1 (5%) and grade 2 (5%) alopecia, grade 1 (40%) fatigue,
grade 1 (5%) and grade 2 (10%) conjunctivitis, grade 1 (10%) pain, grade
1 (5%) blurred vision, grade 1 (10%) headache, and grade 2 (5%) skin
hyperpigmentation. One pts (1%) experienced grade 3 pain. There were
no further grade 3 or higher acute toxicities. Registered late side effects
include grade 1 (2%) and grade 2 (5%) alopecia, grade 1 (21%) fatigue,
grade 1 (5%) and grade 2 (5%) headache, grade 1 (6%) dizziness, grade
1 (3%) blurred vision, grade 1 (3%) and grade 2 (6%) pain, grade 1 (2%)
dry eye, and grade 1 (5%) skin hyperpigmentation. Two pts (2%) experi-
enced grade 3 pain. Two further pts (2%) experienced grade 3 optic neur-
opathy. There were no further grade 3 or higher late toxicities. During
follow-up one pts (1%) with cavernous sinus meningioma experienced
complete obstruction of intracavernous carotid artery with mild transient
symptoms that resolved in few days and brain tissue ischemia detected
at MRI (grade 2). Before irradiation this pts already had a meningioma-
related near-complete obstruction of the intracavernous carotid artery
and received a vascular surgery evaluation. Currently, absolute tumor
control is 99%. Moreover, relief of symptoms recorded before irradiation
occurred in 40% of pts. CONCLUSION: PT is safe and effective treat-
ment for pts with large skull base benign meningiomas.
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