bluuebunny/crossref_metadata_2025_split huggingface dataset:
P13.08 Novel Thioridazine derivates: Antiproliferative and apoptosis-inducing activity on glioblastoma cells in vitro
Authors: Schwab S G , Sarnow K , Alme E , Goldbrunner R , Bjørsvik H , Bjerkvig R 
Published: September 2021

Abstract

BACKGROUND
Although withdrawn from the market due to cardiotoxicity, we have shown that the antipsychotic drug Thioridazine shows chemosensitizing effects in combination with Temozolomide (TMZ) for the treatment of glioblastoma multiforme (GBM). Based on our prior observations, the aim of the presented project was through medicinal chemistry, to design and synthesize new compounds based on Thioridazines tricyclic structure, and to determine their therapeutic potential.

MATERIAL AND METHODS
Fourteen compounds were synthesized where variations were made within the tricyclic side chains. The newly synthesized compounds were screened for therapeutic efficacy with or without TMZ using a WST-1 cell viability assay as well as a real-time imaging system (IncuCyte). Tests were performed on both monolayer cell cultures, as well as on glioma stem cell spheroids (GSC). The therapeutic effects were also studied on human astrocytes (NHA) as well as on rat brain organoids (BO). Annexin V/propidium iodide (PI) double staining followed by flow cytometric analysis was performed after 48 hours of treatment.

RESULTS
Following an extensive screening, we identified two novel compounds (EA01 and EA02) that at concentrations of 4 and 9.5 µM showed a strong cytotoxicity on GBM cell lines (U-87 MG p&lt;0,0001, U251 p&lt;0,0001, LN18 p=0,0004) as well as on glioma stem cells (GSC) (P3 p&lt;0,0001) compared to NHA and BOs respectively. Also, when BOs were confronted with GSC spheres in an invasion assay, a selective cytotoxicity was observed in the GSCs. Mechanistically, we show that both compounds induce apoptosis in the GBM cells. Moreover, intravenous delivery of increasing concentrations of EA01 and EA02 revealed no toxicity in animals at concentrations up to 21 mg/kg.

CONCLUSION
We have developed two new tricyclic therapeutic compounds that show a strong selective cytotoxicity in GBM cells with limited systemic toxicity in animals. Ongoing studies are investigating the therapeutic potential of EA01 and EA02 in orthotopic xenografts in vivo.
P14.12 Gyriform infiltration as imaging biomarker for adult diffuse astrocytic glioma, IDH wildtype, with molecular features of glioblastoma
Authors: Mesny E , Barritault M , Izquierdo C , Poncet D , d’Hombres A , Guyotat J , Jouanneau E , Ameli R , Honnorat J , Meyronet D , Ducray F 
Published: September 2021

Abstract

BACKGROUND
Diffuse astrocytic gliomas, IDH wildtype, with molecular features of glioblastoma (molecular glioblastomas) are associated with a poor prognosis. We previously found that these tumors frequently display gyriform infiltration, defined as areas of elective cortical hypersignal on MRI FLAIR sequence. The objective of the present study was to assess the diagnostic value of gyriform infiltration as an imaging marker for these tumors.

MATERIAL AND METHODS
MRI scans from 430 patients with newly diagnosed glioma (molecular glioblastoma n = 31, IDH wildtype glioblastoma n = 298, IDH-mutant astrocytoma n = 50, IDH-mutant and 1p19q codeleted oligodendroglioma n= 51) were evaluated for the presence of a gyriform infiltration by 2 independent reviewers. Sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were calculated to assess the performance of the presence of a gyriform infiltration for identifying molecular glioblastoma.

RESULTS
A gyriform infiltration was observed in 16/31 (52%) patients with a molecular glioblastoma, 40/298 (13%) patients with an IDH-wildtype glioblastoma but in none of the patients with an IDH-mutant astrocytomas or an IDH-mutant and 1p19q codeleted oligodendroglioma. Among the 56 patients with a gyriform infiltration, 54 patients had an IDH wildtype pTERT mutant glioma and 2 an IDH wildtype pTERT wildtype glioma. Interrater agreement was good (κ= 0.68, P &lt; 0.001). Specificity, sensitivity, PPV and NPV of the presence of a gyriform infiltration for the diagnosis of molecular glioblastoma were 90%, 29%, 52% and 96% and for the diagnosis of an IDHwt pTERT mutant glioma were 97%, 15%, 96% and 20%. The presence of a gyriform infiltration was associated with a worse prognosis in the entire cohort (13.6 months vs 29.3 months, P = .001).

CONCLUSION
Gyriform infiltration is a specific imaging marker of molecular glioblastomas and IDH wildtype pTERT mutant diffuse gliomas.
P14.13 Severe hematological toxicity during chemoradiation for glioblastoma: Identification of clinical and pharmacological risk factors and consequences for the individual patient
Authors: Grun N , den Otter C A , Sintemaartensdijk M , Osinga J , van den Elzen F E L , van der Vegt A N , de Haan J , Bruynzeel A M E , van Linde M E , Postma T J , Schuur M , de Witt Hamer P C , De Vos F Y F L , Verhoeff J J C , Jongen J L M , Lissenberg-witte B I , Kouwenhoven M C M 
Published: September 2021

Abstract

BACKGROUND
Besides early tumour progression, standard first-line radiation with concurrent and adjuvant temozolomide in de novo glioblastoma patients is abrogated frequently by severe haematological toxicity. This leads to treatment delays with unknown effect on efficacy and to more hospital visits with increased disease burden. In the present study, we identified clinical and pharmacological risk factors for temozolomide induced severe hematological toxicity. Furthermore, we describe the burden of toxicity for patients and evaluate the effect of severe toxicity on prognosis.

METHODS
A retrospective cohort study of adult patients with a histological confirmed glioblastoma (n=363), treated with standard treatment regimen at the Brain Tumor Center Amsterdam between 2000 and -2020. Severe haematological toxicity was defined as a CTCAE (version 5.0) grade ≥3. We used Pearson Chi-Square test to analyze differences in patient characteristics between the groups (no vs. severe toxicity) and paired samples T- Test to analyze fluctuations in cell counts. Univariate and multivariate logistic regression were used to identify patient- and treatment characteristics associated with severe hematological toxicity. Cox Proportional Hazards models were used to estimate Hazard Ratio’s for the association between survival and severe hematological toxicity.

RESULTS
Female gender (OR 8.05, 95%CI 2.96–21.89, p&lt;0.001) and older age (age &gt; 70 years; OR 2.44, 95%CI 1.12–5.31, p=0.025) were independent risk factors for severe toxicity. Concurrent and adjuvant temozolomide was discontinued in respectively 56% and 35% of the patients. In general, patients with severe hematological toxicity had a treatment delay of 22 ± 48 days. Of all patients with severe hematological toxicity during chemoradiation, 96% developed toxicity after ≥4 weeks of treatment (p&lt;0.001). Females who received highest temozolomide-doses (4th quartile) had a longer survival than females with low cumulative temozolomide doses (1st quartile). Patients, who developed severe toxicity had much more hospital visits (20; range 12–26), and were admitted more frequently to the hospital. Severe haematological toxicity was not related to survival (HR 1.04; 95%CI 0.74–1.45).

CONCLUSION
Female gender and age &gt;70 years are risk factors for severe hematological toxicity. Severe hematological toxicity relates to temozolomide exposure and results in a significant treatment burden for patients. Low temozolomide exposure results in decreased survival. Patient tailored therapy may result in better treatment outcomes.
P14.40 Trends in distribution of glioblastoma care and patient’s travel distance; results from the Dutch Brain Tumor Registry
Authors: De Swart M E , Ho V K Y , Lagerwaard F J , Brandsma D , Broen M P , French P , Gijtenbeek A , Geurts M , Hanse M C J , Idema B , Klein M , Koekkoek J A F , Polman S K , Samuels C W , Seute T , Sijben A E J , Smits M , Vos M J , Walenkamp A M E , Wesseling P , De Witt Hamer P C , Kouwenhoven M C M 
Published: September 2021

Abstract

BACKGROUND
Over the past years, increasing worldwide attention towards centralization of complex cancer care has been pursued as higher volume centers have shown improved outcomes. Changes in distribution of care and the impact on travel distance in glioblastoma patients have not been determined yet. In this study, we determine trends in distribution of glioblastoma care in the Netherlands over the last three decades and assess whether the observed trends affected travel distance for individual patients.

MATERIAL AND METHODS
Data were obtained from the Dutch Brain Tumor Registry from 1989 to 2018. All glioblastoma patients (≥18 years) were included for analysis. Patients, neurosurgical centers and radiotherapy centers were geocoded. Data were analyzed in six time intervals of 5 years. High volume hospitals were defined as &gt;50 cases per year. Travel distance was examined in two categories, ≤60km and &gt;60km respectively. Trend analyses for proportions were used to analyze hospital volume changes and travel distances.

RESULTS
A total of 16.477 glioblastoma patients were registered, with an annual increase from 203 patients in 1989 to 917 patients in 2018. Neurosurgical centers increased from 16 to 17 and for radiotherapy from 19 to 22 centers between 1989–1993 and 2014–2018. Mean neurosurgical- and radiotherapy center volumes increased from 12 to 39 (P=0.025) and 7 to 27 (P=0.025) patients per hospital per year from 1989–1993 to 2014–2018. High volume neurosurgical centers were observed since 2004, and an increased number of patients were treated in these centers, 27.8%, 52.6% and 64.1% in the time periods 2004–2008, 2009–2013, and 2014–2018 (P&lt;0.001). High volume radiology centers were observed since 2009, and 15.0% and 27.3% of patients were treated in these centers in the time periods 2009–2013 and 2014–2018 (P&lt;0.001). Patients with a travel distance &gt;60km to the neurosurgical center reduced from 15.8% to 13.2% (P=0.033). Travel distance &gt;60km to the radiotherapy center did not reduce significantly (10.4% to 8.8%, P=0.601).

CONCLUSION
An increasing number of glioblastoma patients were differentially treated in high volume neurosurgery and radiotherapy centers. The observation that this did not translate into increased travel distances, indicates accessible specialized Neuro-Oncology care for glioblastoma patients in The Netherlands.
P14.57 WHO grade II and III meningioma: a large mono-institutional retrospective series
Authors: Simonetti G , Gaviani P , Farinotti M , Legnani F , Pollo B , Pinzi V , Botturi A , Redaelli V , Silvani A 
Published: September 2021

Abstract

BACKGROUND
Meningiomas are usually considered benign lesions, however a part of them can show very aggressive behavior with tendency to metastasize. This subgroup is known as high-grade meningiomas (HGM). Due to the rarity of the disease, effective medical treatments are lacking, especially at the time of recurrence. We aim to describe the clinical, radiological and molecular features of a large population of HGM diagnosed between 2010 and 2018. The secondary aim was to evaluate survival (PFS) and overall survival (OS).

MATERIAL AND METHODS
We collected clinical and survival data from primitive WHO grade II and III meningioma patients treated at Fondazione IRCCS Istituto Neurologico Carlo Besta from January 2010 to December 2018. Records were collected on a web-based platform (Microsoft Excel) that was customized for this study. The database, contained epidemiological, diagnostic (radiological and histological/molecular), surgical, therapeutic and recurrence information, as well as survival data.

RESULTS
183 patients (105 females and 78 males), with median age of 58 years (25–88), were included; 168 were atypical, 12 anaplastic, 3 rhabdoid. Overall, m-PFS was 4.2 years, and m-OS was 10.3 years. Gross-total resection had a 5-year survival rate of 95% compared with subtotal/partial resection (86% and 67%) (p=0.002). Higher expression of Ki-67/MIB-1 seems associated with higher risk of death (HR:1.06 with 95% CI, 1.00–1.12, p=0.03). No statistically significant differences were seen in survival between the group managed with a wait-and-see strategy vs the group treated with RT/SRS while a difference on PFS was seen (4.1 years vs 5.2 years p=0.03). After second recurrence, the most employed treatments were systemic therapies with a very limited effect on disease control.

CONCLUSION
Data confirmed the aggressive behavior of HGM. The extent of resection seems to correlate with a favorable outcome regardless histological subtypes. The role of RT/SRS remains controversial, with no statistically significant impact on OS but a possible role on PFS. At relapse, no chemotherapies are able to achieve disease control and recurrent HGM remains the real challenge for future research, focusing on biological/molecular predictors in order to achieve a patient-tailored treatment.This retrospective study allowed to analyzed the largest national recent series of aggressive meningiomas with the purpose of identify relevant outcome measures for future prospective studies. Our findings could be important to give a snapshot of the current attitude to treat aggressive meningiomas but also to inspire national and international collaboration in order to provide evidence-based management strategies trying to obtain a standard of care.
P14.77 Efficacy and safety of Tumor-Treating Fields associated with Depatux M and metronomic temozolomide for recurrent glioblastoma: a case-report
Authors: Pellerino A , Bruno F , Muscolino E , Rudà R , Soffietti R 
Published: September 2021

Abstract

BACKGROUND
Patients with glioblastoma (GBM) have a poor prognosis following an extensive resection, radiotherapy (RT) and concomitant/adjuvant temozolomide (TMZ). Once GBM progresses after SOC, lomustine is the standard second-line treatment, while rechallenge with TMZ may be employed in selected patients with methylated promoter of MGMT, and bevacizumab is reserved for patients with extensive edema and need for steroids. New treatment modalities have been investigated at first recurrence, including alternating electric fields (TTFields) or antibody direct against epidermal growth factor receptor (EGFR), such as depatuximab mafodontin (ABT-414, Depatux-M), that have shown some activity in terms of disease control and progression-free survival (PFS).

CLINICAL PRESENTATION
In September 2018, a 38 year-old man developed reduced strength in left upper limb and daily focal seizures. MRI showed an enhancing right fronto-temporal lesion which was subtotally removed with a diagnosis of glioblastoma (IDH 1/2 wild type, MGMT methylated - 40%, EGFR amplified, EGFRvIII positive). As the patient had a poor KPS (50), in October 2018 a hypofractionated RT (DFT 40 Gy/15 fractions) with concomitant TMZ (140 mg/day) was performed, followed by adjuvant standard TMZ (340 mg/day); however, chemotherapy was stopped after 3 cycles due to local progression on MRI coupled with strength worsening, increased seizure frequency, and need for steroids. Pseudoprogression was ruled out due to tumor growth out of the field of RT. Based on the high level of methylation of the MGMT promoter and EGFR amplification, a combined treatment with metronomic TMZ (100 mg/day continuously) plus Depatux-M (1.25 mg/kg every 2 weeks) was started (February 2019), but a brain MRI performed after 3 months of treatment displayed no significant changes on both MRI and neurological status. At this time point (May 2019) TTFields treatment was added. An initial decrease of tumor size was observed on MRI after 5 months, while a reduction of tumor size more than 90% has been progressively achieved after 1 year of treatment (April 2020). Moreover, a seizure-free status was observed without changing the antiepileptic medication. The patient developed a grade 3 ocular side effect (CTCAE version 5.0) with photophobia, blurred vision, foreign body sensation in the eyes after 6 months of treatment, which improved after dose delays and dose reduction of Depatux-M. The patient is still alive, and free of progression after 30 months and 25 months from diagnosis and first recurrence, respectively.

CONCLUSION
To our knowledge, this is the first report of a recurrent GBM with a significant and long-lasting neuroradiological response following a combined treatment with TTFields, Depatux-M, and intensified schedule of TMZ. A synergistic effect of TTFields with compounds interfering with the microtubular system should be further investigated.
P14.81 Brain metastases of lung adenocarcinoma - Clinicopathological profile and outcomes of a single-centre
Authors: Sousa M J , Basto R , Magalhães J C , Costa C , Garcia R , Domingues I , Jesus E , Sousa G 
Published: September 2021

Abstract

BACKGROUND
Brain metastases (BM) in patients with non-small cell lung cancer (NSCLC) are considered a major determinant of overall survival (OS). Historically, surgical resection (SR), stereotactic radiosurgery (SRS), or/and whole-brain radiation therapy (WBRT) followed by chemotherapy has been the treatment modalities for BM from lung adenocarcinoma. Recent insights into the biology of adenocarcinoma have led to a wealth of novel therapies, including tyrosine kinase inhibitors (TKIs). Here, we review the pattern of brain metastasis in lung adenocarcinoma patients and management strategies in our centre.

MATERIAL AND METHODS
We performed a single-centre retrospective analysis of patients with lung adenocarcinoma and BM between 2017–2020. Data were collected from electronic medical records, including clinical and histopathological features and outcomes. Survival curves were estimated with the Kaplan-Meier method and compared using the log-rank test.

RESULTS
We identified 29 patients, 65% male, median age 65 years (range 38–84); 55% ECOG PS 0–1; 59% smokers; 55% had extracranial metastases (ECM) and 66% were symptomatic, 24% were EGFR mutated, the frequency of ALK rearrangement was 14%, in 14% the molecular testing was not performed. We treated 59% with WBRT, 12% with SRS, 11% with SR+WBRT and 4% with SR+SRS; 14% were referred for palliative care. Clinical deterioration during local therapy was observed in 32% of the patients and, consequently, they haven’t undergone systemic treatment. After local treatment, 26% received chemotherapy (CT) and 28% received TKIs therapy. Median OS (mOS) was 11.3 months (95% CI 2.4–20.3) for the CT subgroup; mOS for the TKIs subgroup was not reached, but the 1-year survival rate was 67%.

CONCLUSION
BM confers a worse prognosis in lung adenocarcinoma patients. Currently, targeted systemic treatments in patients with driver mutations improve survival and have demonstrated efficacy in lung adenocarcinoma metastatic to the brain. Further research is needed to find better treatments for BM in NSCLC patients with no driver mutations.
P16.11 Vitamin C levels and the hypoxic pathway in human glioma tissues
Authors: Burgess E R , Crake R L I , Phillips E , Morrin H R , Royds J A , Vissers M C M , Robinson B A , Dachs G U 
Published: September 2021

Abstract

BACKGROUND
Gliomas are the most common brain cancer and survival is poor, with 11–15 months for high-grade glioblastoma patients, despite treatment. Gliomas are hypoxic tumours, which increases with tumour grade. Under hypoxia, the transcription factor hypoxia inducible factor-1 (HIF) accumulates and upregulates expression of genes involved in tumour development and progression. HIF-1 levels and activity are controlled by HIF hydroxylases which target HIF-1α for degradation and prevent co-activation. HIF hydroxylases are part of the 2-oxoglutarate (2-OG)-dependent dioxygenase enzyme family, that require 2-OG and oxygen as substrates and ascorbate and iron as co-factors. The role of ascorbate in regulating the hypoxic pathway in cancer is of interest, with previous research showing reduced HIF pathway activity with increasing tumour ascorbate levels. Brain tissue has one of the highest ascorbate levels in the body, and is one of the last to become depleted under deficiency, indicating an important role for ascorbate in this tissue. One previous study has analysed ascorbate levels in 11 human glioblastoma patients, and showed lower ascorbate in tumour tissue compared to normal brain tissue. There have been no studies investigating the relationship between ascorbate levels and the hypoxic pathway in human glioma tissues.

MATERIAL AND METHODS
Human glioma tissues (n = 39), obtained from the Cancer Society Tissue Bank Christchurch (ethics approval H19/163), were processed for ascorbate and hypoxic pathway proteins (HIF-1α, CA-IX, BNIP3, HKII, GLUT1 and VEGF). Ascorbate levels were quantified by HPLC-ED, and proteins were measured by Western blotting and ELISA. Spearman’s correlations were used to identify relationships between ascorbate and HIF pathway proteins.

RESULTS
Of the samples, 64% were GBM. Ascorbate was significantly lower in GBM compared to low-grade gliomas (p = 0.04). VEGF was significantly higher in GBM compared to astrocytomas (p = 0.01). Increased tumour ascorbate was associated with lower VEGF and CA-IX proteins. HIF-1α and BNIP3 protein were positively associated, and VEGF was positively associated with HKII and CA-IX. VEGF inversely associated with BNIP3, and CA-IX inversely associated with HKII. The hypoxic pathway score (calculated from protein levels of members of the hypoxic pathway) was reduced in tumours with higher ascorbate but this did not reach significance (p = 0.2).

CONCLUSION
This is the first study to show that ascorbate levels were reduced in high-grade gliomas compared to low-grade. Some members of the hypoxic pathway were associated with ascorbate levels. The overall hypoxic pathway score did not significantly correlate with ascorbate and increased numbers of samples are required to confirm any associations. Other variables, such as IDH-1 mutation status of the tumours may affect the correlation and will be analysed next.