bluuebunny/crossref_metadata_2025_split huggingface dataset:
OS8.1 A phase 0/2 clinical trial of a CDK4/6 inhibitor in aggressive meningioma patients
Authors: Tien A , Li J , Bao X , DeRogatis A , Fujita Y , Pennington-Krygier C , Kim S , Mehta S , Sanai N 
Published: September 2019

Abstract

BACKGROUND
New approaches are urgently needed for aggressive meningiomas, which remain largely incurable. Forkhead Box M1 (FOXM1) has been identified as a master transcription factor in aggressive meningiomas and Cyclin D-dependent Kinases (CDK) are positive regulators of cell-cycle entry, promoting tumorigenesis through FOXM1 activation. We evaluated the tumor pharmacokinetics (PK), tumor pharmacodynamics (PD), and preliminary clinical response of ribociclib, a selective CDK4/6-inhibitor, in aggressive meningioma patients.

MATERIAL AND METHODS
Eight aggressive WHO Grade II/III meningioma patients with intact RB expression were enrolled and administered oral ribociclib daily (900mg) for 5 days prior to tumor resection. Plasma, tumor, and cerebrospinal fluid (CSF) samples were collected at 2, 8, or 24 h after the last dose. Total and unbound drug concentrations were determined using a validated LC-MS/MS method. PD effects, including RB and FoxM1 phosphorylation, were compared to matched archival tissue. Patients with PK and PD responses in tumor tissue, defined as unbound ribociclib concentration > 5-fold in vitro IC50 (0.04µM) and >20% decrease in pRB levels, respectively, were enrolled into an exploratory Phase 2 cohort.

RESULTS
The median CSF concentration of ribociclib was 0.25 µM. In tumor tissue, the median unbound ribociclib concentration was 1.36 µM and the median unbound tumor-to-plasma ratio was 5.34. Suppression of G1-to-S phase was inferred in tumors with declining FoxM1 phosphorylation (50%), RB phosphorylation (38%), and cellular proliferation (75%). Four patients demonstrated concurrent PK and PD responses and were graduated to continuous ribociclib therapy. At one year, two of these patients (one Grade II and one Grade III) demonstrate partial responses per RANO criteria.

CONCLUSION
Ribociclib achieves pharmacologically-active concentrations in aggressive meningioma tissue. Target modulation was demonstrated by a decrease in FOXM1-mediated tumor proliferation. Further investigation of ribociclib as a therapeutic strategy for aggressive meningiomas is warranted.
OS9.1 Clinical significance of hypermutation in gliomas
Authors: Touat M , Li Y , Boynton A , Spurr L , Iorglescu B , Geduldig J , Birzu C , Lim Fat M , Santagata S , Coulet F , Beuvon F , Mokhtari K , Giry M , Block S , Guillerm E , Carpentier A , Huang R , Delattre J , Hoang-Xuan K , Sanson M , Duval A , Cherniack A , Reardon D , Wen P , Idbaih A , Marabelle A , Bandopadhayay P , Beroukhim R , Bielle F , Ligon K 
Published: September 2019

Abstract

BACKGROUND
Among patients with glioma, little is known about the clinical significance of hypermutation. We sought to define the determinants of hypermutation in gliomas, and to assess the value of this biomarker for predicting response to standard of care and immune checkpoint blockade.

MATERIAL AND METHODS
We performed comprehensive molecular characterization of 2420 pediatric and adult gliomas with clinical annotation. We determined the clinical and molecular characteristics associated with hypermutation, and assessed the relationship between hypermutation and clinical response to cancer therapies.

RESULTS
Overall, 114 hypermutated gliomas were identified. Hypermutation occurred predominantly in therapy-responsive subtypes characterized by methylated MGMT promoter, IDH1/2mutation or 1p/19q co-deletion. Hypermutation was almost always associated with prior treatment with temozolomide and molecular defects in DNA mismatch repair (MMR), which were identified in one-third of IDH1/2-mutated recurrent gliomas and was associated with shorter survival in multivariate analyses (hazard ratio 2.11 [95% CI 1.24–3.6], P=0.006). The molecular mechanisms whereby gliomas undergo hypermutation during therapy with alkylating agents were dissected using patient-derived glioma models in vitro and in vivo. Outcomes of hypermutated gliomas treated with immune checkpoint blockade or with standard of care agents will be presented at the conference.

CONCLUSION
This study establishes that mutation burden and mutation signatures are clinically and biologically significant biomarkers that can be used to predict therapy response and guide treatment decisions in gliomas.
OS9.5 Evidence that adult glioblastoma adapts to standard therapy though chromatin remodeling
Authors: Rippaus N , Manning J , Droop A , Al-Jabri M , Care M , Bruns A F , Jenkinson M D , Brodbelt A , Chakrabarty A , Ismail A , Short S , Stead L F 
Published: September 2019

Abstract

BACKGROUND
Glioblastoma (GBM) tumours recur following standard treatment in almost all cases. We use ‘omics technologies to simultaneously profile pairs of primary and matched recurrent GBM to specifically identify and characterise the cells that resisted treatment, with the aim of determining how to more effectively kill them.

MATERIAL AND METHODS
We have analysed high coverage RNAseq data from pairs of GBM tumours: primary de novo tumour and matched local recurrence from patients that underwent standard therapy. Our original cohort constituted 23 pairs and our validation cohort was an additional 22 pairs. We also cultured two plates of spheroids directly from a patient’s GBM, treating one with radiation and temozolomide. We monitored growth and captured and sequenced RNA from single cells at two time-points: one week post-treatment when the deviation between untreated and treated spheroid growth curves was most pronounced; and three weeks post-treatment when the growth rate of treated spheroids had recovered. We investigated differential gene expression between primary and recurrent pairs, and single cells pre- and post-treatment, and performed a bespoke per patient gene set enrichment analysis.

RESULTS
Differential gene expression analysis in 23 tumour pairs indicated a treatment-induced shift in cell states linked to normal neurogenesis and prompted us to develop a novel gene set enrichment analysis approach to identify gene regulatory factors that may orchestrate such a shift. This revealed the significant and universal dysregulation of genes, through therapy, that are targeted by a specific chromatin remodeling machinery. This finding was validated in an independent cohort of 22 further GBM pairs. To understand the therapeutic potential of this finding we must determine whether genes are dysregulated through therapy owing to a) their fixed expression in inherently treatment resistance cells in the primary tumour which get selected during therapy to increase the signal of that profile, or b) changes in expression during the process of cells acquiring treatment resistance. To inspect this, we analysed single cell gene expression data from GBM spheroids pre- and post-treatment. We found that there was significant dysregulation of the genes associated with the chromatin remodeling complex but only at the three-week post-treatment time-point.

CONCLUSION
Our results indicate that GBM cells are being transcriptionally reprogrammed in response to treatment; the mechanism of which may represent a therapeutic opportunity.
OS9.6 Diagnosis of pseudoprogression using FET PET radiomics
Authors: Lohmann P , Elahmadawy M A , Werner J , Rapp M , Ceccon G , Fink G R , Shah N J , Langen K , Galldiks N 
Published: September 2019

Abstract

BACKGROUND
Radiomics derived from different imaging modalities is gaining increasing interest in the field of neuro-oncology. Besides MRI, amino acid PET radiomics may also improve the to date challenging, clinically relevant diagnostic problem of differentiating pseudoprogression (PsP) from tumor progression (TP). To this end, we here explored the potential of O-(2-[18F]fluoroethyl)-L-tyrosine (FET) PET radiomics to discriminate between PsP and TP.

MATERIAL AND METHODS
Thirty-five newly diagnosed IDH-wildtype glioblastoma patients with MRI findings suspicious for TP within 12 weeks after completion of chemoradiation with temozolomide underwent an additional dynamic FET PET scan. FET PET tumor volumes were segmented using a tumor-to-brain ratio (TBR) ≥ 1.6. The static PET parameters TBRmax and TBRmean, as well as the dynamic parameter time-to-peak (TTP), were calculated. For radiomics analysis, the number of datasets for model generation was increased using data augmentation techniques. Subsequently, 70 datasets were available for model generation. Prior to further processing, patients were randomly assigned to a discovery and a validation dataset in a ratio of 70/30, with balanced distribution of PsP and TP diagnoses. Forty-two radiomics features (4 shape-based, 6 first- and 32 second-order features) were obtained using the software LifeX (lifexsoft.org). Afterwards, a z-score transformation was performed for data normalization. For feature selection, recursive feature elimination using random forest regressors was performed. For the final model generation, the number of parameters was limited to three to avoid data overfitting. Different algorithms for model calculation were compared, and the diagnostic accuracy was assessed using leave-one-out cross-validation. Finally, the resulting models were applied to the validation dataset to evaluate model robustness.

RESULTS
Eighteen patients were diagnosed with TP, and 17 patients had PsP. Diagnoses were based on a neuropathological confirmation or clinicoradiological follow-up (26% and 74%, respectively). The diagnostic accuracy of the best single FET PET parameter was 75% (TBRmax). Combining TBRmax and TTP increased the diagnostic accuracy to 83%. Other combinations of static and dynamic FET PET parameters, however, did not further increase the accuracy. The highest diagnostic accuracy of 92% was achieved by a three-parameter model combining the FET PET parameter TTP with two radiomics features. The model demonstrated its robustness in the validation dataset with a diagnostic accuracy of 86%.

CONCLUSION
The results suggest that FET PET radiomics improves the diagnostic accuracy for discerning PsP and TP considerably. Given the clinical significance of differentiating PSP and TP, prospective multicenter studies are warranted.

FUNDING
Wilhelm-Sander Stiftung and the DAAD GERSS Program, Germany
OS12.1 Editing of IDH1 R132H mutation in human induced pluripotent stem cells to investigate tumor genesis in glioma
Authors: Köpp A , Preussler M , Richter S , Heide M , Marrone L , Sterneckert J , Schöler A , Capper D , Schröck E , Klink B 
Published: September 2019

Abstract

BACKGROUND
Low grade gliomas and secondary glioblastomas are characterised by a hot-spot mutation in the Isocitrate dehydrogenase 1 (IDH1). The mutation causes a new catalytic function of the enzyme resulting in the production of 2-Hydroxyglutarat (2-HG), which is known as an oncometabolite. To this day, the pathomechanism by which IDH1 mutation promotes tumorigenesis is not completely understood and the tumour cell of origin for glioma is not known. Moreover, reliable cell models reflecting the patient ́s situation are not available. Thus, we aim at creating human induced pluripotent stem cells (hiPSC) carrying the IDH1 R132H mutation. We will utilize this cell model to investigate how the mutation influences stem cell properties and cell differentiation in neuronal progenitor cells.

MATERIAL AND METHODS
For designing the cell model, we applied the novel CRISPR/Cas9 based genome editing tool Base Editor 3 and 4. We transiently transfected the cells with two plasmids containing the Cas9 enzyme and sgRNA respectively. To determine editing efficiency, cells were investigated using the T7 Endonuclease 1 assay and Next Generation Sequencing. Single cell clones were picked to analyse allele status using allele-specific PCR with subsequent Sanger Sequencing.

RESULTS
Using fluorescence-activated cell sorting we measured a transfection efficiency in iPSCs for one plasmid of 33.8% ± 5.92%. Out of 96 picked clones one clone showed the IDH1 mutation. Thus, the overall editing efficiency was about 1%. We confirmed expression of mutated IDH1 R132H by Western Blot. Measurement of the tricarboxylic acid cycle metabolites using liquid chromatography tandem mass spectrometry (LC-MS/MS) showed a forty times increased concentration of 2-HG in IDH-mutated compared to the wildtype iPSCs, proving that the mutated enzyme is functional. To investigate effects of the IDH1 R132H on cell differentiation, we generated cerebral organoids from our iPSC-models. The IDH1 R132H mutation did not inhibit the cell differentiation in maturation of cerebral organoids. However, we observed differences in the growth between mutated and wildtype brain organoids. We additionally characterized our cell models using genome wide methylation arrays and RNA-Seq; these results will also be presented.

CONCLUSION
We successfully established a heterozygous IDH1 R132H mutated hiPSC cell line, which represents a promising cell model for future studies of early glioma genesis.
OS12.2 Targeting epigenetic pathways in the treatment of recurrent high-grade glioma
Authors: Hau A , Houben L , Klein E , Oudin A , Stieber D , Flies B , Kaoma T , Azuaje F , Fritah S , Bjerkvig R , Hertel F , Mittelbronn M , Golebiewska A , Niclou S P 
Published: September 2019

Abstract

BACKGROUND
High grade glioma (HGG) patients develop resistance to standard treatment leading to disease progression and limited life expectancy. Advances in the molecular characterisation of treatment-naïve HGGs based on next-generation sequencing and DNA methylation analyses have led to a better delineation of HGG subtypes and the identification of distinct genomic abnormalities. Furthermore, using large patient cohorts of longitudinal tumor samples, comprehensive genomic profiling studies emerged to investigate therapy-associated evolution of gliomas. All together, those studies point out the need for personalised treatment strategies, where applied drugs will be adapted to the unique patient-specific genetic abnormalities.

MATERIAL AND METHODS
We collected fresh samples of more than 800 brain tumors containing almost 300 glioma specimen with approximately 100 longitudinal samples of initial and recurrent tumors from 43 matched patients. By now, we have successfully established 34 patient-derived orthotopic xenografts (PDOXs) in mice. We performed comprehensive molecular profiling using array comparative genomic hybridisation, DNA methylation analysis and targeted DNA sequencing on patient specimen and their derivatives such as 3D tumor organoids and PDOXs. The custom-design sequencing panel comprises 234 genes that reflect both established genetic identifiers for individual glioma subtype classification and novel genes encoding mainly epigenetic effector genes. Based on patient-derived material we carried out drug response screening on 3D tumor organoids using a compound library matching the majority of genes that were assessed by targeted sequencing.

RESULTS
We succeeded in generating a live biobank of HGG patient-derived xenografts and 3D organoids that neatly recapitulates the mutational spectrum including structural DNA variation and methylation-based subtypes of gliomas. A highlight is the generation of 19 PDOXs of paired initial and relapse HGGs from a total of 9 glioma patients. A detailed analysis of the paired longitudinal samples indicated that PDOX models closely recapitulate the evolutionary trajectory of the parental tumors. Targeted sequencing of longitudinal HGG PDOXs suggests that relapse tumors accumulate somatic mutations in epigenetic effectors compared with the Initial. Differential drug responses between initial and relapse tumors were observed after screening of in vitro 3D tumor organoids.

CONCLUSION
Response assessment of naïve initial gliomas and recurrences provides crucial information on the differential sensitivity between initial and relapsed HGGs and offers novel personalised therapeutic options in the relapse setting. Furthermore, in depth correlation of the profiled somatic molecular landscape with drug response will enable pharmacogenomic predictions of potential inhibitors in the clinical setting.
OS12.4 In vivo dynamics and targeting of vessel co-option in glioma
Authors: Seano G , Griveau A , Shelton S , Krishnan S , Wang N , Kloepper J , Huillard E , Batchelor T , Stemmer-Rachamimov A , Aghi M , Jain R , Rowitch D 
Published: September 2019

Abstract

BACKGROUND
Gliomas comprise heterogeneous malignant glial and stromal cells. While blood vessel co-option is a potential mechanism to escape anti-angiogenic therapy, the relevance of glial phenotype in this process is unclear.

MATERIAL AND METHODS
Here, we intravitally study preclinical syngenetic models of glioma as well as patient-derived cells transplanted orthotopically. Moreover, we profoundly confirm our preclinical results with histological studies on patient specimens.

RESULTS
We show that Olig2+ oligodendrocyte precursor-like glioma cells invade by single-cell vessel co-option and preserve the blood-brain barrier (BBB). Conversely, Olig2-negative glioma cells form dense perivascular collections and promote angiogenesis and BBB breakdown, leading to innate immune cell activation. Experimentally, Olig2 promotes Wnt7b expression, a finding that correlates in human glioma profiling. Targeted Wnt7a/7b deletion or pharmacologic Wnt inhibition blocks Olig2+ glioma single-cell vessel co-option and enhances responses to temozolomide. Finally, Olig2 and Wnt7 become upregulated after anti-VEGF treatment in preclinical models and patients.

CONCLUSION
Here, we show that glioma is able to employ vessel co-option, i.e. the movement of tumor cells towards and along the pre-existing vasculature.
Glioma oligodendrocyte-like (OPCL) cells express Wnt7 that is necessary for vessel co-option and Wnt inhibitors significantly improve survival with temozolomide. Moreover, we demonstrated that anti-VEGF-treatment of glioma selects for Olig2/Wnt7+ cells
P03.01 Secondary central nervous system lymphoma (SCNSL) in patient with non Hodgkin lymphoma (NHL): a case report
Authors: Susanti E , Suci Rahayu N , Fuad M 
Published: September 2019

Abstract

BACKGROUND
non Hodgkin lymphoma (NHL) is a systemic cancer that originates from lymphocites. Central nervous system lymphoma is a rare form of non Hodgkin lymphoma that involve brain parenchym and spinal cord. The most common type of nervous system involvement is a leptomeningeal metastases. Whereas brain metastases is an extremely rare finding in NHL. We present a case report of NHL patient which metastasized to brain parenchym.

MATERIAL AND METHODS
Case report: a fourty two year old male patient suffered from seizure in September 2018, 7 days prior to hospitalized. severe headache and weakness on the left extremities were found in addition to seizure. A single nodule on the right frontal and another nodules on the right neck region were also found since 7 months ago. Patient was diagnosed with NHL in 2017 after a confirmed biopsy of NHL and underwent a chemotherapy procedure, but uncompleted. After head ct scan procedure in September 2018, which depicted a round mass in frontal lobe, patient underwent a complete chemotherapy procedure with CHOP regimen in September 2018. Another head ct scan was performed in January 2019 after a completed chemotherapy cycle which showed significant decrease in tumour size.

RESULTS
before and after head ct scan showed significant decrease in tumour size, from 4cmx2cm before chemotherapy and 2.5cmx1.3cm after chemotherapy

CONCLUSION
central nervous system involvement in NHL is a rare condition that carries a poor prognosis. Prophylaxis therapy still on debate about it’s efficacy to prevent this disease from spreading or relapse. Awareness of the possibility central nervous system involvement should always remain in a physician’s mind when dealing with NHL patients.
P03.06 Cavernous malformations of the brainstem: radiosurgical management with gamma knife
Authors: Abdel Karim K , El-Shehaby A M , Reda W A , Emad Eldin R M , Nabeel A , Tawadros S , Khalil P 
Published: September 2019

Abstract

BACKGROUND
About 20% of intracranial cavernous malformations (CM) occur in the brainstem. The greatest risk of brainstem CM is hemorrhage which can be devastating and even fatal in this location. The optimal management for these lesions would naturally be microsurgical resection. However, surgery in this location is associated with significant morbidity and mortality. Gamma knife radiosurgery provides a safer alternative. The purpose of this study is to investigate the efficacy of gamma knife radiosurgery for brainstem CM in preventing bleeding, as well as, assess safety with regards to radiation-induced complications. Additionally, we aimed to evaluate the feasibility and safety of volume-staged gamma knife radiosurgery for larger CM in the brainstem.

MATERIAL AND METHODS
Between September 2007 and August 2017, 48 patients with brainstem CM were treated by gamma knife. Thirty-two patients were available for follow up of at least one year. A total of 33 lesions were treated (one patient had two brainstem CM). Twenty-eight patients had at least one hemorrhagic event before radiosurgery. The patients underwent 40 gamma knife sessions. These included 28 single sessions (including two sessions for same patient for 2 different lesions in pons). Five patients had volume-staged gamma knife treatments due to the large size of the CM. The median total CM volume/lesion was 0.8 cc (0.1–30.4 cc), while the median target volume/session was 1 cc (0.1–11.5 cc). The median prescription dose was 12 Gy (10–14 Gy).

RESULTS
The mean follow up after treatment was 40 months (12–95 months). The annual hemorrhage rate (AHR) before gamma knife radiosurgery was 25.5%. After treatment there were a total of 5 hemorrhagic events with an overall AHR of 4.5%. Three hemorrhagic events occurred in the first 2 years after treatment with an AHR of 2.7% and 2 events more than 2 years after treatment with an AHR of 2.2%. No hemorrhagic events occurred among the patients treated by volume-staged radiosurgery. Clinical improvement was observed in 15 (46.9%) patients. Temporary adverse radiation events developed in 6 patients (19%).

CONCLUSION
Gamma knife radiosurgery provides an effective and safe treatment alternative to surgery for brainstem CM. Volume-staged gamma knife radiosurgery for brainstem CM appears to be a viable option for larger CM.