bluuebunny/crossref_metadata_2025_split huggingface dataset:
P07.12.A DIAGNOSTIC POTENTIAL OF INFRARED SPECTROSCOPY IN MENINGIOMA PATIENTS
Authors: Richter S , Galli R , Kirsch M , Eyüpoglu I , Uckermann O 
Published: September 2023

Abstract

BACKGROUND
Vibrational spectroscopy probes molecular vibrations in the tissue and can provide optical diagnosis of brain tumors. Here, we investigated its potential for the identification of aggressive meningioma.

MATERIAL AND METHODS
Tissue samples were obtained during routine surgery from 113 meningioma patients (WHO 1 n= 33; WHO 2 n=39; WHO 3 n=41). Infrared (IR) spectroscopic imaging was performed at three positions (170 x 170 µm, 16x16 = 256 spectra) on frozen sections in reference to HE histology. Spectra were labeled according to the clinical diagnosis of the patient. Baseline correction, area normalization and fourfold spectral binning was performed. Spectra displaying artifacts were identified by visual inspection and were excluded from further analysis. The data was split into test and training set. 42825 spectra of 57 specimens (training set) were utilized to develop an algorithm using linear discriminant analysis to identify aggressive WHO 3 meningioma.

RESULTS
The developed algorithm assigned 88.6% of the 40626 spectra of the independent test set to the correct class. Based on these

RESULTS
, the class assignment for each measurement position was calculated as mean of class assignment of the respective spectra: All WHO 1 (16/16) samples, 16/19 WHO 2 and 17/21 WHO 3 meningioma were correctly assigned at all three positions. One sample of meningioma WHO 3 was misclassified at all measurement positions. However, in case of six patients inconclusive results were obtained for the samples as the measurement positions were assigned to different classes. Comparison of IR spectral signatures revealed increased bands at 1114, 1242, 1336 and 1450 cm-1 and decreased bands at 1544 and 1651 and 1734 cm-1 in meningioma WHO 3. This suggests increased phospholipids and decreased proteins as main difference to meningioma WHO 1 and 2 and might form the basis for diagnostic exploitation of IR spectral information.

CONCLUSION
IR spectroscopy qualifies as reliable tool for the identification of aggressive meningioma. Based on the classification results of this study, translational strategies may be deduced. The data suggests, that analysis of the tumor needs to be performed at multiple sites to obtain reliable clinical information. In case of conflicting results at different measurement positions, the tissue should be evaluated as unratable. As infrared spectroscopy can be applied in situ using fiber based systems, it might allow intraoperative meningioma grading and tumor delineation in future translational settings.
P07.15.B NEUROMUSCULAR HIGH-RESOLUTION ULTRASOUND IN PERIPHERAL NEUROTOXICITY OF SYSTEMICALLY TREATED CANCER PATIENTS
Authors: Mäurer I , Hammersen J , Heiling B , Lawson McLean A , Risse C , Leistner N A , Schütze S , Schnetzke U , Schwab M , Hilgendorf I , Senft C , Hartinger S 
Published: September 2023

Abstract

BACKGROUND
Up to 40 % of cancer patients treated with neurotoxic cytostatic chemotherapies develop treatment-induced peripheral neuropathy. Furthermore, in patients treated with immune checkpoint inhibitors neuromuscular immune-related adverse events (irAEs) are the most common neurological complication. The differentiation between various types of peripheral neurotoxicity, neurological comorbidities and (para-)neoplastic conditions requires experienced clinical and neurophysiological diagnostics within an interdisciplinary team of experts. High-resolution ultrasound (HRUS) is a widely used diagnostic tool for peripheral neuropathies. As there are no generally approved biomarkers of treatment-related neurotoxicity so far, HRUS might extend the repertoire of diagnostic and neuromonitoring methods in patients with neuropathies induced by cytostatic agents, immunotherapy, and targeted therapy.

MATERIAL AND METHODS
We present the integration of HRUS into a standardized algorithm for suspected peripheral neurotoxicity by characterizing a case series from our neuro-oncological center. We show representative HRUS findings of seven cancer patients (diagnosed with breast cancer, cholangiocarcinoma, colorectal carcinoma, or multiple myeloma) treated with platinum derivates, immune checkpoint inhibitors, bortezomib, or lenalidomide.

RESULTS
We describe the potential of HRUS independently of a certain cancer treatment regimen and beyond that in patients with both neurological co-morbidities and concomitant neoplastic infiltration of the nervous system. In our retrospective cohort, HRUS revealed partly continuous and partly discontinuous nerve swelling as well as compression syndromes. Moreover, we detected enlargements of dorsal roots and vagus nerve in cancer patients with treatment-induced neuropathies for the first time. In addition, we identified significant discordance between clinical, electrophysiological and HRUS findings and discuss how peripheral neurotoxicity may be amenable to complementary HRUS assessment and neuromonitoring.

CONCLUSION
At our institution, neuromuscular ultrasound is an integral part of the interdisciplinary algorithm for peripheral neuropathies in systemically treated cancer patients. HRUS expands the neurological tool inventory for cancer patients and accelerates the differentiation of peripheral neurotoxicity, neurological comorbidities, and neoplastic affection of the nervous system in a non-invasive and cost-sparing manner. Our data may help to detect distinct patterns of nerve enlargement as new biomarkers of peripheral neurotoxicity. Thus, we employed our data to conduct a prospective, cross-sectional trial (PARTICIPATE), which has the potential to define the diagnostic relevance of HRUS for patients treated with agents affecting the PNS and its impact on cancer patient care.
P10.06.B APPLYING TUMOR TREATING FIELDS (TTFIELDS) FOR ENHANCEMENT OF TEMOZOLOMIDE AND LOMUSTINE EFFICACY IN GLIOBLASTOMA CELL LINES
Authors: Fishman H , Monin R , Dor-On E , Kinzel A , Haber A , Giladi M , Weinberg U , Palti Y 
Published: September 2023

Abstract

BACKGROUND
Tumor Treating Fields (TTFields) are electric fields that disrupt cellular processes critical for cancer cell viability and tumor progression, ultimately leading to cell death. TTFields therapy concurrent with maintenance temozolomide (TMZ) is approved for treatment of newly-diagnosed glioblastoma (GBM). Recently, benefit was demonstrated in patients with O6-methylguanine DNA methyltransferase (MGMT) promoter methylation for the combination of TMZ with lomustine (CCNU). The addition of adjuvant TTFields to this treatment regimen further improved patient outcomes, leading to a CE mark. The current study aimed to elucidate the mechanism underlying the benefit of this treatment protocol by utilizing GBM cell lines with different MGMT expression status.

MATERIAL AND METHODS
Human GBM cell lines with different MGMT promoter methylation status [LN-18 (unmethylated MGMT promoter), U-118 MG (partially methylated MGMT promoter), and U-87 MG and LN-229 (methylated MGMT promoter)] were examined for MGMT expression levels. Next, the cells were treated with TTFields (intensity of 0.83 V/cm RMS; frequency of 200 kHz) using the inovitro system. Cell count and colony formation were employed to detect the effectiveness of TTFields concomitant with TMZ and/or CCNU. Western blot allowed the detection of expression levels of DNA repair proteins in control versus TTFields-treated cells.

RESULTS
The cell lines displayed comparable responses to TTFields and CCNU, while they differed in sensitivity to TMZ according to MGMT expression status. TTFields concomitant with TMZ displayed an additive effect, irrespective of MGMT expression levels. The effect of concomitant TTFields with CCNU was additive in MGMT-expressing cell lines, whereas it trended toward synergy in MGMT-non-expressing cell lines. Expression of proteins from the Fanconi Anemia (FA)-BRCA pathway for DNA repair was downregulated following TTFields application. TTFields concurrent with both TMZ and CCNU provided higher efficacy relative to TMZ plus CCNU or TTFields apart, with additivity in MGMT-expressing cell lines and a tendency toward synergy in MGMT-non-expressing cell lines.

CONCLUSION
The results support the clinical benefit demonstrated for concomitant TTFields with TMZ plus CCNU, showing that the efficacy of TMZ and CCNU may be enhanced by TTFields, with synergism seen for the latter case in cells not expressing MGMT. The BRCAness state induced by TTFields rationalizes this, as in the absence of MGMT DNA damage induced by CCNU requires the FA-BRCA pathway for repair.
P10.14.B PROGRESSION OF IDH-MUTANT ASTROCYTOMAS TO GRADE 4 UNDER TREATMENT-RELATED SELECTION PRESSURE
Authors: Rautajoki K J , Jaatinen S , Hartewig A , Tiihonen A M , Annala M , Salonen I , Valkonen M , Simola V , Vuorinen E M , Kivinen A , Rauhala M J , Nurminen R , Maass K K , Lahtela S , Jukkola A , Yli-Harja O , Helén P , Pajtler K W , Ruusuvuori P , Haapasalo J , Zhang W , Haapasalo H , Nykter M 
Published: September 2023

Abstract

BACKGROUND
The progression of low-grade diffuse astrocytomas into grade 4 tumors significantly impacts patient prognosis, therefore a better understanding of this process is of paramount importance for improved patient care.

MATERIAL AND METHODS
We analyzed next-generation sequencing data from matched IDH-mutant astrocytomas before and after progression to grade 4 from up to 27 patients as well as publicly available The Cancer Genome Atlas (TCGA) data from up to 595 cases. All patients in our discovery cohort with genome-wide sequencing data received radiation, all but one underwent chemotherapy, and no patient received temozolomide before progression to grade 4.

RESULTS
One case in the discovery cohort exhibited a hypermutation signature associated with inactivation of the MSH2 and DNMT3A genes. In other patients, the number of novel chromosomal rearrangements and deletions increased in grade 4 tumors. Tumor progression was associated with upregulated cell cycle progression, migration, and DNA damage repair-related genes. Upon progression, the cell cycle checkpoint genes CDKN2A or RB1 were most commonly inactivated, especially after postoperative radiation and chemotherapy, followed by activating growth factor receptor gene alterations in cases with homozygous CDKN2A deletion. We also detected alterations in DNA repair pathway genes associated with therapy resistance and the promotion of error-prone DNA repair, thus facilitating tumor progression. The homologous recombination repair gene RAD51B was hemizygously deleted in all but one progressed tumor in our discovery cohort. In our retrospective nonrandomized survival analysis, treatment including both radio- and chemotherapy improved relapse-free and overall survival compared to other treatments in cases with primary grade 3 diagnosis. Similar benefit was not observed for cases with primary grade 2 diagnosis, and radiation as sole postoperative treatment was not significantly improving the prognosis in any of the analyses.

CONCLUSION
Our results support the previous notions that treatment-induced DNA damage can contribute to tumor progression to grade 4 and suggest that altered DNA repair has a role in treatment resistance and tumor progression.
P10.26.B EXPLORING POTENTIAL ANTITUMOR EFFECTS OF CANNABIDIOL AND TETRAHYDROCANNABINOL IN A PATIENT-DERIVED GLIOBLASTOMA MODEL
Authors: Zekanovic S , van den Bent M J , Dirven C M F , Lamfers M L M , Leenstra S 
Published: September 2023

Abstract

BACKGROUND
Glioblastoma (GBM) is a CNS malignancy which is in dire need of novel treatment options. Drug repurposing has become a means to circumvent major obstacles that accompany drug development for GBM. The cannabinoids cannabidiol (CBD) and tetrahydrocannabinol (THC) have garnered the interest of the scientific community for the treatment of GBM as they possess pleiotropic effects in other pathologies. In the present study we are investigating potential antitumor effects of these cannabinoids by using our patient derived GBM model which recapitulates GBM in its genetic make-up and heterogeneity.

MATERIAL AND METHODS
To assess potential antitumor effects in vitro, we performed a screen on 20 patient derived GBM cultures to obtain a sensitivity profile for both cannabinoids. These cultures ranged in background regarding primary/recurrence and IDH mutation. To investigate effects of these cannabinoids on GBM radio-and-chemosensitivity, combination studies with either lomustine (CCNU) or irradiation (RTx) were performed on recurrent GBM cultures. The zero-interaction potential method was used to quantify synergy between the cannabinoids. The enhancement factor was used to quantify potential radiosensitization or ratio-effects between the cannabinoids.

RESULTS
Screening of both cannabinoids revealed CBD to possess a higher level of cytotoxicity than THC. IC50 values of CBD ranged from 2.5 - 18.5 µM and the values of THC ranged from 7.20 - 47.60 µM. In a panel of 8 cultures, combinations of CBD with THC, CBD with CCNU and THC with CCNU was tested to gain insight in combination effects. In 1/8 cultures synergy was observed between CBD and THC. In 1/8 cultures synergy between CBD and CCNU was observed and in 4/8 cultures synergy between THC and CCNU. When combined with irradiation, no enhancement was observed in any of the 4 cultures tested. No ratio-dependent enhancement between the cannabinoids was observed when combined in a 1:1, 1:4 or 4:1 ratio of CBD:THC.

CONCLUSION
Screening of the cannabinoids CBD and THC revealed that CBD displays a stronger cytotoxic effect than THC. Combinations of either of the two with each other or CCNU revealed moderate additive effects in the majority of cultures and synergy in a small subset. We did not observe radiosensitizing effects in our patient derived GBM model. Relating in vitro found cytotoxic concentrations to clinically achievable concentrations, we found that CBD requires approximately 3 times higher plasma concentrations and THC &gt;40 times to achieve an antitumor effect. Currently we are investigating long term treatment effects of CBD and its mechanism of action.
P10.29.A FUNCTIONALLY INSTRUCTED COMBINATION-TREATMENTS INVOLVING REGORAFENIB IN EXPERIMENTAL GLIOMA
Authors: Haeusser L A , Kuhlburger L , Walter B , Becker H , Merk D J , Tabatabai G 
Published: September 2023

Abstract

BACKGROUND
Glioblastoma are incurable primary tumors of the central nervous system. The standard of care for newly diagnosed glioblastoma outside clinical trials includes a combination of radiation therapy, alkylating chemotherapy and tumor-treating fields. Yet, for progressive glioblastoma, only lomustine is registered in Europe. The REGOMA trial (Lombardi et al., Lancet Oncol 2019) had investigated regorafenib versus lomustine in a phase 2-trial. Furthermore, the use of regorafenib in a compassionate-use-program was recently reported (Tzaridis et al., Neuro Oncol 2019) Yet, the regorafenib arm in the Glioblastoma Adaptive Global Innovative Learning Environment (GBM Agile) master protocol was stopped after an interim analysis that showed a low probability of improvement of overall survival compared with control (press release 21 September 2022). We investigated here a functional genomics-based approach to discover and validate potential modulators of response to regorafenib treatment in experimental glioma in vitro, in vivo and ex vivo.

MATERIAL AND METHODS
We performed CRISPR/Cas9 activation (Calabrese P65-HSF activation library) and knockout (genome-wide knockout library Brunello) screens during treatment with regorafenib, sequenced and analyzed the genomic DNA of the remaining cells.

RESULTS
We discovered functionally-instructed molecular hits, designed a drug library for further validation by functional assays in vitro and combination treatments in murine glioma models in vivo.

CONCLUSION
Taken together, we discovered and validated functionally-instructed combination treatment options involving regorafenib. Our finalized results will be presented.
P10.32.B SCREENING FOR OPTIMAL MULTI-TARGET DRUG COMBINATIONS TARGETING THREE MAJOR PROLIFERATION PATHWAYS IN GLIOBLASTOMA
Authors: Their A , Baltira C , Rozing K , Beijnen J H , de Gooijer M C , van Tellingen O 
Published: September 2023

Abstract

BACKGROUND
Glioblastoma (GBM) is one of the most malignant adult brain tumors, with a median survival of only 14 months. The lack of efficient therapies so far can be traced back to issues such as resistance to treatments leading to relapses, novel drugs being unable to penetrate the blood-brain barrier (BBB) and focus on monotherapy approaches in a highly heterogeneous disease. Characterization of the genomic landscape of GBM has revealed that three major signaling pathways are co-abrogated in the majority of patients. We have previously shown proof-of-concept that targeting these pathways (PI3K-mTOR-AKT, MAPK and CDK4/6-RB) using a multi-target combination therapy (MTCT) is a promising way to treat GBM. By looking into a panel of drugs, we are screening for alternative MTCT combinations to identify those most suitable for clinical translation.

MATERIAL AND METHODS
From a panel of drugs targeting one these three pathways, we compare each drug's single-agent properties to various combinations. The synergy of the drugs is scored based on proliferation and target inhibition effects. We will establish if candidate drugs are an ABC transporter substrate with transwell assays and how well the drugs can cross the BBB in vivo using ABC transporter knock-out mouse models. Promising MTCT combinations will be further studied using in vivo orthotopic GBM models.

RESULTS
We have identified several MTCT combinations that have synergistic effects on target inhibition and cell proliferation. Transwell assays indicate that multiple drugs are to some degree ABC transporter substrates, which might affect the brain penetration of the compounds. Nonetheless, we could identify several candidate drugs targeting the PI3K or MAPK pathway that are relatively weak substrates and for which brain entry is relatively unimpeded. In contrast, finding a candidate with favorable pharmacological properties among the available CDK4/6-RB pathway inhibitors has proven to be more challenging.

CONCLUSION
Our results indicate that using an MTCT approach might be promising for treating GBM. Further research is being conducted to find the best possible MTCT combination that can access the tumor through the BBB at sufficient levels to exert its pharmacodynamic effects.
P10.34.B ONCOGENIC ASPP2KAPPA(K), A DOMINANT-NEGATIVE ISOFORM OF THE APOPTOSIS STIMULATING PROTEIN OF P53-2 (ASPP2) PROMOTES CLASSICAL HALLMARKS OF CANCER IN GLIOBLASTOMA
Authors: Hafner M , Ruiba A , Kampa L , Sommer I , Ahrens A , Kälin V , Zeitlberger A , Buchauer K , Plasswilm L , Hundsberger T , Neidert M , Schittenhelm M M , Kampa-Schittenhelm K M 
Published: September 2023

Abstract

BACKGROUND
GB is the most common, most aggressive primary brain tumor with a deleterious prognosis. ASPP2 is a tumor suppressor, directly interacting with p53. We recently identified a dominant-negative isoform of ASPP2, named ASPP2κ, lacking the important p53 binding sites and show that ASPP2κ is highly expressed and functionally active in glioblastoma, affecting all classical hallmarks of cancer.

MATERIAL AND METHODS
Grade IV glioma (n=46) were assessed for ASPP2κ expression. Isogenic GB models, stably suppressing or overexpressing ASPP2κ, were established in A-172, U-251 and T98g cell lines and from resected GB tissue. The role of ASPP2κ in induction of apoptosis, cellular proliferation, migration and invasion was assessed in vitro and in vivo. Proteome arrays allowed to study pathways involved in ASPP2κ signaling. Two ASPP2κ knock-down (KD) NOD/SCID xenotransplant mouse models were established to study ASPP2κ in tumor engraftment and progression.

RESULTS
Frequent overexpression of ASPP2κ was confirmed in virtually all patients analyzed compared to tumor-free tissue. Expression thereby varied widely in between patients (2-40 fold). Functional analyses confirm that ASPP2κ directly affects multiple cancer hallmarks in GB, resulting in a more aggressive phenotype with impaired induction of apoptosis (avg. -25 %), higher proliferation (avg. +25%), migration (avg. +65%) and invasion (avg. +70%) rates. Silencing of ASPP2κ rescues the ASPP2 wt tumor suppressor phenotype, rendering cells more susceptible towards temozolomide (TMZ, avg. +25%), γ-irradiation (avg. +40%) or combinational approaches. Upregulation of p53 phosphorylation sites (S15: 2,5x/S46: 1,5x) and cell cycle regulators (p21: 2x, p27: 3x and pRAD: 2,5x) thereby confirms restoration of important p53-mediated pathways. GB mouse models confirm attenuated tumor engraftment and progression of ASPP2κ KD tumors in vivo. Mice carrying ASPP2κ-KD tumors presented with statistically significant increased overall survival in both models (p= 0.03 and p=0.005) and attenuated tumor growth (p=0.0001). Importantly, neo-angiogenesis was strongly regulated in relation to ASPP2κ expression, impairing tumor growth and metastasis in the ASPP2κ KD models. Downregulation of pro-angiogenic (VEGF 20x, angiogenin 4x) and upregulation of anti-angiogenic (endostatin 2x, LAP 2,5x) players in ASPP2κ KD models were confirmed.

CONCLUSION
ASPP2κ is highly expressed in GB, affecting all classical hallmarks of cancer, including regulation of apoptosis, cell cycle, invasion/metastasis and angiogenesis. ASPP2κ contributes to aggressiveness of disease and resistance to therapy and silencing of ASPP2κ re-activates crucial p53-mediated tumorsuppressor pathways. Studies evaluating ASPP2κ as a target for therapy are ongoing.