bluuebunny/crossref_metadata_2025_split huggingface dataset:
P15.12.A Amine CEST contrast in gliomas to measure metabolic treatment effect at 7T
Authors: Abecassis Schmitz B , Ercan E , de Bresser J , Dirven L , Taphoorn M J B , van Osch M J P , Koekkoek J A F 
Published: September 2022

Abstract

Background
Chemical exchange saturation transfer (CEST) is an imaging technique that generates contrast based on proton exchange between water and a solute pool of interest. CEST is sensitive to molecules containing amine groups such as glutamate and creatine. Since creatine is a crucial metabolite in cellular metabolism and deregulation in cellular bioenergetics is a hallmark of cancer, CEST could be relevant for glioma imaging, specifically when evaluating treatment response. No clear consensus has been established on its use, therefore we wanted to preliminarily investigate the presence of amine CEST contrast in the contrast enhanced (CE) and non-enhanced (NE) lesions of gliomas, and to assess whether treated tumors would display different CEST contrast compared to treatment naïve tumors.

Material and Methods
We prospectively scanned 12 glioma patients on a whole-body 7 Tesla Philips Achieva MRI scanner (7 treated glioblastomas; 4 treatment naïve glioblastomas; 1 treatment naïve low-grade astrocytoma). Treatment included surgical resection, chemotherapy and radiotherapy. All patients gave informed consent. CEST images were post-processed, including corrections for B0 and B1 inhomogeneities. The CEST Z-spectra and magnetization transfer ratio (MTR) asymmetry were calculated per voxel. To retrieve the CEST values within the tumor lesions and contralateral white matter for normalization, segmentations were manually delineated on the clinical T2-FLAIR or post contrast 3D-T1.

Results
Overall we observed a relative increase of amine CEST contrast in the CE (MTRasym: Mean (x̄)=1.32; Standard deviation (σ)= 0.28) compared to a relative decrease (MTRasym: x̄=1.20; σ= 0.35) in the NE lesion. When evaluating the results from the CE and NE lesions for treated and treatment naïve groups individually, we observed a slightly different trend. In the treatment group, the CE lesions showed a higher amine CEST contrast (MTRasym: x̄=1.38; σ= 0.30) than the NE (MTRasym: x̄ = 1.11; σ = 0.302). In contrast, in the treatment naïve group, the CE lesion showed a slightly lower CEST contrast (MTRasym: x̄ = 1.23; σ=0.21) than in the NE group (MTRasym: x̄ = 1.29; σ= 0.38).

Conclusion
Our results show different amine CEST contrast trends between treated and treatment naïve groups when comparing CE and NE lesions. This suggests that treatment may have an effect on tumor tissue bioenergetics affecting the concentration of creatine. Nevertheless, future work is necessary to verify our results in a larger group of patients.
P16.04.B Palliative CSF diversion in symptomatic leptomeningeal metastasis: a feasibility analysis of risks and benefits
Authors: Alhalabi O T , Unterberg A W , Younsi A 
Published: September 2022

Abstract

Background
Leptomeningeal metastasis (LM) represents a terminal condition in a subset of patients with primary extra-cranial malignancies. With improved survival rates under novel systemic therapies for extra-cranial primary tumors, the role of cerebrospinal fluid (CSF) diversion via ventriculo-peritoneal shunts (VP-shunt) for symptom control of hydrocephalic LM is becoming increasingly important. This study hence aimed to describe this patient cohort and weigh out benefits against adverse events of palliative VP-shunt placement.

Material and Methods
A single-center retrospective analysis of all consecutive adult patients with VP-shunt placement over a period of six years was performed and clinical data (primary disease, clinical presentation, CSF diagnostics, previous therapies) in addition to surgical data (shunt devices, surgeries, and complications) and survival data were collected. Results were compared to a ‘non-oncological’ shunt cohort and statistical analyses was performed.

Results
38 patients with a median age of 53 (18-78) years (13 males, 25 females) underwent VP-Shunt placement. The most common underlying oncological conditions were breast cancer (n=21, 55%) and non-small cell lung cancer (NSCLC, n=11, 29%). The median time between primary tumor and LM diagnosis was 23 months (0 to 180 months). 14 patients (37%) presented with end-stage disease at primary tumor diagnosis, 25 (66%) patients had cranial metastases. Most patients presented with classical symptoms of intracranial hypertension and 11 patients (38%) had already received intrathecal treatment or radiotherapy before shunting. After shunting, symptom relief was achieved in 30 patients (79%) and 24 patients (63%) were eventually discharged home after surgery. Subsequently, 63% of the shunted patients underwent systemic or radiotherapy and 55% received intrathecal therapy. Revision surgery was performed for valve malfunctions and infections (n=3, 8% for either) or distal catheter malposition (n=2, 5%) but comparison with a ‘non-oncological’ shunt cohort showed no differences in complication rates. Median survival from shunting was 2.1 months (95% CI 0.5 to 3 months).

Conclusion
VP-shunt placement could relieve symptoms of intracranial hypertension secondary to LM of primary solid tumors without a higher risk of shunt complications compared to non-oncological patients, with many LM patients persuing further oncologic therapy. However, decision-making regarding VP-shunt placement in LM patients still retains a palliative nature.
P17.02.A IPAX-1: phase 1/2 study of131I-iodo-phenylalanine (131IIPA) combined with external radiation therapy as treatment for patients with relapsed glioblastoma
Authors: Pichler J , Leibetseder A , Höllmüller I , Traub-Weidinger T , Fitz F , Geinitz H , Feichtinger J , Brown T , Hayward C 
Published: September 2022

Abstract

Background
A novel therapeutic approach using molecularly targeted radiation is currently in development for patients with recurrent GBM. Many tumor types, including GBM, overexpress the L-type amino transporter 1 (LAT-1)4, which is able to internalize the small-molecule amino acid derivative, 4-L-[131I] iodo-phenylalanine (131I-IPA). In preclinical research, combining 131I-IPA with external radiation therapy (XRT) yielded additive cytotoxic effects. Tumoral accumulation of 131I-IPA was confirmed in a proof-of-principle study using single doses of 2-7 GBq 131I-IPA as a monotherapy or in combination with XRT in patients with recurrent GBM. The objective of the IPAX-1 study was to evaluate the safety, tolerability, dosing schedule, and preliminary efficacy of 131I-IPA in combination with second-line radiotherapy in patients with recurrent GBM.

Methods
IPAX-1 is a multi-center, open-label, single-arm, dose-finding phase 1/2 study. Key inclusion criteria: 1. Confirmed histological diagnosis of GBM with evidence of first recurrence 2. History of GBM standard therapy 3. ≥ 6 months since end of first-line XRT 4. Pathologically increased amino acid tumor uptake shown by molecular imaging 5. Current indication for repeat radiation 6. Gross tumour volume of up to 4.8 cm diameter. Treatment: In phase 1 of the study patients received intravenous 131I-IPA at a dose level of 2 GBq administered in one of three different dosing regimens: single dose group with 2 GBq before radiation, 3 (f)-fractionated-parallel group: 3 x 0.67 GBq during XRT and 3 (f)-fractionated-sequential group: 0.67 GBq x 1 → XRT → 0.67 GBq x 2. XRT is delivered in 18 fractions of 2 Gy each.

Results
10 patients were randomized; one patient with Covid related death was withdrawn from analysis. Survival from start of TLX101 therapy showed mPFS2 of 4.33 M (95% -CI 4.18 - 4.48), PFS-6: 18 % and mOS2 of 15.97 M (95% -CI 2.9 - 29.1) at data lock 09/2021. Updated results will be presented at the meeting.

Conclusion
There were no clinically relevant laboratory changes over time. Urinalysis, vital signs, and ECG did not show any clinically relevant changes from baseline. There were no notable differences in safety and tolerability between groups. Injections of single or fractionated doses of 131I-IPA containing a total activity of 2 GBq in combination with XRT in patients with recurrent GBM were safe and well tolerated. Survival data look promising; extension cohort will be treated in a phase II study in Linz; phase 1/2 study in first line setting is planned.
P17.04.B Combination of Trofosfamide and Etoposide in Recurrent Glioma
Authors: Schmidt T , Agkatsev S , Feldheim J , Oster C , Blau T , Sure U , Keyvani K , Kleinschnitz C , Stuschke M , Hermann K , Deuschl C , Scheffler B , Kebir S , Glas M , Lazaridis L 
Published: September 2022

Abstract

Background
Disease relapse almost inevitably occurs in patients with adult-type diffuse glioma. Standard of care treatment options at tumor relapse are still not well defined. Frequently used drugs for adult-type diffuse glioma recurrence include lomustine (CCNU) and bevacizumab. Few studies indicate that the combination of trofosfamide/etoposide, given their high lipid solubility with good blood-brain barrier penetrance, may be feasible in pediatric glioblastoma patients. In this retrospective analysis, we determined tolerability and feasibility of combined trofosfamide/etoposide treatment at disease recurrence of patients with adult-type diffuse glioma.

Material and Methods
We collected clinicopathological data from adult patients with adult-type diffuse glioma treated with the combination of trofosfamide/etoposide at the Division of Clinical Neurooncology at the University Hospital Essen. Only those patients were considered eligible who received trofosfamide/etoposide treatment for more than four weeks (one course). Trofosfamide (100mg/m2/day) and Etoposide (25mg/m2/day) was administered orally in a “one week on, one week off” scheme. A cohort of patients receiving empiric treatment at the investigators’ discretion balanced for tumor entity and canonical prognostic factors (number of previous treatments, MGMT promoter methylation, IDH mutation status, KPS, age, extent of resection) served as control. We collected toxicity data as it pertained to CTCAE (Common Terminology Criteria for Adverse Events, version 5.0) and survival data to explore putative efficacy.

Results
A total of 33 patients were eligible for this analysis. In the IDH wild-type glioblastoma (n=18) subgroup, median progression-free survival (3.8 months versus 2.9 months, HR: 2.09, 95% CI: 1.010-4.312, p=0.0227; PFS-6: 39% versus 6%) and median overall survival (10.4 months versus 5.7 months, HR: 3.05, 95% CI: 1.393-6.655, p=0.0008) were significantly prolonged as compared to the control cohort. In a multivariable Cox regression analysis, treatment with trofosfamide/etoposide emerged as statistically significant prognostic marker regarding progression-free survival and overall survival. We observed high-grade adverse events (CTCAE grade≥III ) in 21 (64%) of all recurrent glioma patients with hematotoxicity comprising most adverse events (n=18, 86%). Lymphopenia was by far the most observed hematotoxic adverse event (n=13, 62%). Among non-hematologic high-grade adverse events was transaminase elevation (n=3, 14%).

Conclusion
This study provides first indication that the combination of trofosfamide/etoposide is safe in patients with adult-type diffuse gliomas and may be associated with prolonged survival in adult patients with recurrent IDH wildtype glioblastoma. Our data provide a reasonable rationale for follow-up of a larger cohort in a prospective controlled trial.
P17.12.B HOXD13 gene plays a role as a putative master epigenetic regulator in glioma recurrence and progression
Authors: Morosini N S , Sabedot T S , Cazacu S L , deCarvalho A , Noushmehr H 
Published: September 2022

Abstract

Background
Adult diffuse glioma is a heterogenous brain tumor group that has malignant potential and recurring properties. Glioma CpG island methylator phenotype (G-CIMP) associated with chromatin remodeling encompasses two different methylation degrees: G-CIMP-high and G-CIMP-low that have high levels of DNA methylation and loss of DNA methylation, respectively. G-CIMP-high confers a more favorable prognosis and better predictive values by altering transcriptional dynamics and inhibiting the gene expression. However, some IDH-mutant G-CIMP-high undergo a demethylation process progressing to G-CIMP-low leading to tumor recurrence and aggressiveness.

Material and Methods
We have performed Chromatin Immunoprecipitation Sequencing (ChIP-Seq) on DNA extracted from nine (9) fresh frozen primary tumor tissues belonging to G-CIMP-high group and four (4) belonging to G-CIMP-low group. We have processed the sequencing data by using FastQC (v.:0.11.5), bwa-mem (v.:0.7.15) and picard tool (v.:2.7.1). The ChIP-seq peaks and the differentially bound peaks were obtained using MACS2 (v.:2.1.1) and DiffBind (v.:3.4.11), respectively. We have integrated transcriptomic, epigenomic and genomic data to investigate the impact of H3K4me3 and H3K27ac in the epigenome of G-CIMP-low and high tumors.

Results
Initial results showed that the differentially bound H3K27ac and H3K4me3 peak gains and losses are located mainly in intronic and intergenic regions. The integration between epigenetic and transcriptomic data revealed that the promoter of the HOXD13 gene upregulated in GCIMP-low presents an active regulatory region and is enriched by H3K27ac and H3K4me3 sites. We were able to identify that GCIMP-low, in addition to presenting more downregulated genes than GCIMP-high, also has greater affinity to the H3K27ac peaks. In GCIMP-low, we identified 312 promoter regions significantly enriched by the epigenetic biomarker H3K27ac and 67 promoters with loss of affinity for H3K27ac, with the regions enriched by H3K27ac highly associated with the presence H3K4me3 marks. Functional genomic analysis targeting HOXD13 by using CRISPR in a representative glioma cell line shows that HOXD13 is critical for impairing the proliferative state that drives glioma progression.Conclusion: We mapped the enrichment of histone modifications in the TSS of differentially expressed genes in G-CIMP-high and G-CIMP-low identifying both the susceptibility of GIMP-low to interact with H3K27ac and the fact that the progression of GCIMP-high to G-CIMP-low can be explained by the association between H3K27ac gain and the inhibition of gene expression. Also, we predicted the HOXD13 gene as a putative master epigenetic regulator of the G-CIMP demethylation process and, consequently, of tumor recurrence and progression, over time.
P17.14.B Strategy of the recurrent Glioblastoma treatment. Three neuro-oncology centers study
Authors: Kalita O , Kazda T , Reguli S , Jancalek R , Fadrus P , Krska L , Slachta M , Valosek J , Vrbkova J , Hrabalek L , Smrcka M , Lipina R 
Published: September 2022

Abstract

Background
The prognosis for patients with Glioblastoma (GBM) remains dismal. The most aggressive multimodal therapy (maximally radical and safe tumor resection, followed by the Stupp protocol oncotherapy) has yielded the best treatment outcomes. Notwithstanding the slowly prolonged patient′s overall survival, this tumor inevitable recurs. An optimal therapy of the recurrent GBM is still a controversial theme.The aim of our study is to evaluate our treatment strategy of recurrent GBM.

Material and Methods
For this study, we retrospectively selected a group of resected recurrent GBM patients in a period from June 1, 2009 to December 31, 2019, which were treated in tree Czech neuro-oncologic centers. All patients underwent early post-surgical MRI (within 72 h) to determine resection radicality. Following resection, patients received periodic checkups with MRI every 3 months until death. Patients with psedoprogession were excluded. Information about all surgeries, oncotherapies, patient clinical condition, MRI, PET/CT, and results of histological, immunohistochemical, molecular genetic, and cytogenetic investigations was gathered.We consider surgery for recurrent GBM in case, if:
1.The tumor volume increasing &gt; 20-30% or tumor rediscovery after radiologic disappearing.
2.Clinic condition - Karnofsky score (KS) ≥ 70% and Performance status (PS) WHO ≤ gr. 2.
3.Localized tumor, without multilfocality.
4.Assumed the least tumor volume reduction &gt; 80%.

Results
We gathered 122 patients with recurrent GBM, 98,9% of tumors was determined as wild-type, age median was 53,36 years. All patients underwent Stupp protocol oncotherapy after prime surgery. Median of OS from prime surgery was 21 months (15.8, 29.6). The best results proved a surgery of GBM recurrency proceeding more than 6 months after diagnosis. OS2 (from redo up to the death) was 7.4 months (6.41, 11.3). 43.3% of patients recalled temozolomide chemotherapy. We confirmed positive link between OS and resection radicality, negative relations between OS and a postoperative neurologic deficits. Only limited relation was presented between OS and repeated oncotherapy. Relation to the further histologic, imunohistochemic, cytogenetic and molecular markers will be discussed.

Conclusion
Due to the common unfavorable outcomes of GBM therapy, out of despair, we often decided for repeated surgery. The aim of our study was avoid ineffective surgical overtreatment. The best results of surgery yield right selected recurrent GBMs. Surgery of GBM regrown during initial oncotherapy (6 months after prime surgery) presented unsatisfactory effects. Positive effect of the surgical radicality and clinic status were confirmed. Again, necessity of second-line oncotherapy has been emerged. Supported by Ministry of Health of the Czech Republic, grant nr. NV19- 04-00281 and grant nr. NU21-03-00195
P17.16.B Additional antitumoral activity of TTFields stimulation and Chloride Intracellular Channel 1 inhibition in human glioblastoma primary culture
Authors: Mazzanti M , Castiglione S , Mercurio C A , Cannavale G , Verduci I , Cianci F 
Published: September 2022

Abstract

Background
Glioblastoma relapse inevitably occurs in the majority of patients after surgery. Chemo- and radiotherapy are in most cases ineffective, while Tumor Treating Fields (TTFields) therapy delays average tumor recurrence by a few months. It is widely accepted that tumor reappearance is a result of the proliferation of residual glioblastoma stem cell (GSC) subpopulation, which escaped surgery. Previous experiments demonstrated that inhibition of the membrane form of Chloride Intracellular Channel 1 (tmCLIC1) is particularly efficient to hit GSCs in glioblastoma human primary cultures. tmCLIC1 is an ideal target as it is express only in the tumor cell membranes. tmCLIC1 blockage slowdown GSC cell cycle at G1/S transition. On the contrary, TTFields act mainly during G2/M progression. The objective of our study is to test the therapeutic potential of combining TTFields exposure with the inhibition of the protein transmembrane Chloride Intracellular Channel 1 (tmCLIC1), which is crucial for GSCs proliferation.

Material and Methods
Cell preparation: human primary culture from patients’ biopsies. Stimulation device: NOVOCURE Inovitro system®. Stimulation procedure: long-term TTFields stimulation in in-vitro experiments mimics glioblastoma cells’ recrudescence. Analysis: cytofluorimetry for stem cell recognition, cell-cycle progression, and cell count.

Results
Cell growth is inhibited after the first three days of TTFields exposure. However, despite the chronic presence of TTFields stimulation in prolonged experiments, glioblastoma cells reestablish the ability to proliferate. At the end of twelve days, exponentially growing cells show an increase in stemness markers, a drop in the membrane resistance with a related increase of membrane current, and an average depolarized membrane potential. Twelve days of TTFields treatment resulted in a progressive increase in GSCs in the tumor cell population from 10% to more than 30%. Thus, experiments have been designed to combine TTFields stimulation with tmCLIC1 inhibition. This would include in the treatment of the vast majority of the glioblastoma cell population. After twelve days, the parallel antiproliferative activities show a complete impairment in cell proliferation.

Conclusion
The additive effect of TTFields stimulation and tmCLIC1 ion channel inhibition could represent an efficacious step forward to optimize an antitumoral therapy against glioblastoma expansion.
P17.19.B Incidence of treatment-associated imaging changes in newly diagnosed MGMT promoter-methylated glioblastoma treated with cilengitide (EORTC 26071 - CENTRIC study): interim analysis
Authors: Flies C M , Friedrich M , Lohmann P , van Garderen K , Smits M , Tonn J C , Weller M , Galldiks N , Snijders T J 
Published: September 2022

Abstract

Background
In patients with glioblastoma, radiological recurrence of enhancing tissue after chemoradiotherapy can originate from progressive disease (PD) or from pseudoprogression/treatment-associated changes. There are no widely approved consensus criteria for treatment-associated changes. In the randomised EORTC-CENTRIC study (NCT00689221), patients with MGMT promoter-methylated glioblastoma were treated with chemoradiotherapy or chemoradiotherapy with cilengitide, an integrin inhibitor. We assessed the rate of treatment-associated changes in these groups according to the modified response assessment in neuro-oncology (RANO) criteria of 2017.

Methods
CENTRIC patients from both study arms with ≥3 follow-up MRIs were included. Preliminary PD (PPD) was defined as a ≥25% increase of the sum of perpendicular diameter (SPD) of a new or increasing lesion compared to baseline or nadir on the T1-MRI with gadolinium. Subsequent PD was defined as a second ≥25% increase of the SPD, at least 4 weeks later, or as a new lesion outside the radiation field. Treatment-associated changes were defined as stabilisation on ≥2 follow-up MRIs after PPD, each one 4 weeks later, or partial/complete regression on ≥1 follow-up MRI 4 weeks later.

Results
In total, 4,051 MRIs from 584 patients were available. This interim analysis included data on 462 patients with similar proportions in the cilengitide and control arm (50.9% and 49.1%). Due to missing MRIs or values, 128 were excluded. Of the remaining 334 patients, 157 (47%) patients showed RANO measurable disease at baseline or nadir (median SPD, 0mm2; interquartile range (IQR) 552.1 (0-552.1). After chemoradiotherapy with or without cilengitide, PPD occurred in 214 patients (64.1%) after a median time of 6.08 months after finishing radiation (IQR 11.4 (2.4-13.8), and 3.65 months after baseline or nadir (IQR 6.4 (2.1-8.5). After follow-up of these 214 patients, treatment-associated changes were diagnosed in 62 (18.6%) and PD was diagnosed in 48 (14.4%). The remaining 104 (31.1%) patients had no further follow-up MRI after PPD, mostly because a clinical decision to call PD was made. In the cilengitide group of 178 patients, 37 (20.8%) patients developed treatment-associated changes, and 23 (12.9%) patients developed PD, whereas in the control group of 156 patients, 25 (16%) patients developed treatment-associated changes, and 25 (16%) patients PD.

Conclusion
With the modified RANO criteria, the rate of treatment-associated changes was low compared to previous studies in newly diagnosed MGMT promoter-methylated glioblastoma. This rate did not change with addition of cilengitide. RANO-recommended radiological follow-up was not always awaited, which reflects clinical practice. Full data will be presented.