bluuebunny/crossref_metadata_2025_split huggingface dataset:
P08.06 Clinical value scores for treatment of newly diagnosed glioblastoma with TTFields
Authors: Kelly J , Proescholdt C 
Published: September 2019

Abstract

BACKGROUND
High quality and value of recommended treatments is of specific importance in cancer care. ESMO, ASCO and NCCN have developed tools intended to help assessing the clinical value of cancer treatments in a standardised way, allowing for a comparative discussion. Tumor treating fields (TTFields) is a novel, device based cancer treatment, that was recently demonstrated to be effective in newly diagnosed glioblastoma (GBM). This new modality augments the treatments discussed with glioblastoma patients today.

MATERIAL AND METHODS
ESMO and ASCO frameworks each calculate a score for the clinical value of a cancer treatment, called Magnitude of Clinical Benefit Scale (MCBS) by ESMO and the Net Health Benefit (NHB) by ASCO. NCCN self reports “evidence blocks” which are assessed by clinician panels and were recently published for the first line treatment of newly diagnosed GBM with TTFields. We apply and compare the ESMO, ASCO and NCCN tools for TTFields treatment of newly diagnosed GBM.

RESULTS
The resulting ASCO NHB score for TTFields treatment of newly diagnosed GBM is 56. ESMO MCBS scores for TTFields in GBM are resulting in A/5, these being the highest achievable scores for this framework. All frameworks value the increase in overall survival by TTFields and the moderate toxicity profile. ESMO additionally values quality of life, while ASCO values palliation and treatment free intervals. NCCN’s specific focus is on the quality and consistency of the evidence. NCCN evidence blocks also contain an affordability score.

CONCLUSION
All three frameworks consider the clinical efficacy of a treatment and it’s toxicity profile in their clinical value assessment. Beyond that, their respective focus is on slightly different aspects and their definition of clinical value therefore varies in detail. However, all value scores suggest that TTFields treatment of newly diagnosed GBM provides a substantial clinical benefit. The high ESMO and ASCO scores are based on the significantly extended progression free and overall survival for TTFields treated patients, without adding systemic toxicities. The NCCN evidence blocks strongly support the NCCN category 1 recommendation for the use of TTFields in newly diagnosed GBM.
P09.05 177Lu-DOTATATE therapy in progressive meningioma
Authors: Müther M , Roll W , Zinnhardt B , Schäfers M , Rahbar K , Brokinkel B , Stummer W 
Published: September 2019

Abstract

BACKGROUND
Progressive meningioma is a challenging condition with a decreasing number of treatment options over the course of disease. Neurovascular involvement and multifocal disease often complicate surgical management. In addition, repeated radiotherapy carriers a risk of side effects. In somatostatin receptor expressing meningioma, peptide receptor radiotherapy (PPRT) with 177Lu-DOTATATE poses a promising alternative. However, current evidence is scarce. Hereby we present our single center experience of (PPRT) with 177Lu-DOTATATE in progressive meningioma.

METHODS
Eight patients (median age: 71 years; range 56–77) with progressive meningioma underwent PRRT using 177Lu-DOTATATE were included in this retrospective analysis. Response to therapy was assessed by interim and post-therapy 68Ga-DOTATATE-PET-CT and MRI. 177Lu-DOTATATE scintigraphies 48h p.i. were evaluated according to Krenning scale. Additionally, clinical outcome and follow up imaging were analyzed for progression free interval times.

RESULTS
Eight patients were included: Six patients with grade II and two patients with grade I meningiomas, according to the 2016 WHO classification. Six of eight patients harbored multifocal disease. One patients suffered systemic metastatic disease. Patients received a median of three cycles (range: 1 - 5) of PRRT with 177Lu-DOTATATE (mean injected dose 7.1 GBq) between 1/2015 and 1/2019. Tumor uptake in 48h p.i. 177Lu-Scintigraphies was heterogeneous (Krenning scale; median: 3; range: 1–4). Post-therapy imaging scheduled eight weeks after completion of therapy showed progressive disease in five patients, three patients had stable disease. Median follow-up post therapy response evaluation was 24 months in patients with stable disease. Median time to progression was 10 months.

CONCLUSION
In this cohort of eight progressive meningioma patients 177Lu-DOTATATE therapy showed heterogeneous efficacy.
P10.02 Differentiating microglia and tumour associated macrophages in high grade glioma
Authors: Woolf Z , Swanson M , Park T , Brooks A , Dragunow M 
Published: September 2019

Abstract

BACKGROUND
Glioblastoma multiforme (GBM) is the most common primary brain tumour that affects adults. This aggressive tumour is invariably fatal, carrying a rapid progression and a dismal median survival period of only 15 months despite multimodal treatment approaches. Central to GBM pathogenesis is the immunosuppressive profile of these tumours. The two cell types that are highly abundant in these tumours and play critical roles in the immunosuppressive niche are the brain’s resident microglia and their peripheral counterparts - tumour associated macrophages (TAMs). Despite microglia and TAMs being ontogenetically distinct, these cells have largely been grouped together in research owing to the previous lack of cell-specific markers. Recent evidence has suggested that although TAMs may hold a predominantly pro-tumoral role, microglia may adopt a more anti-tumoral phenotype. Therefore, the differentiation of these two cell types is critical in elucidating the potentially characteristic roles of these two cell types in GBM pathogenesis.

MATERIAL AND METHODS
Tissue sections from resected low- and high-grade glioma tumours, along with epilepsy tissue (control), were used for immunohistochemistry (IHC) staining of macrophage pan-makers (Iba1, CD45, PU.1) and microglial-specific markers (TMEM119, P2RY12). Marker co-localisation was then used to differentiate microglia from TAMs. We further investigated a wider subset of cell-specific markers using multicolour flow cytometry and immunocytochemical staining of isolated cells from patient tissue samples.

RESULTS
Immunofluorescent staining of glioma and epilepsy tissue revealed two clear populations of cells; one population displayed long processes and co-labelling for both pan- and microglial-specific markers, whilst the other population displayed an amoeboid phenotype with only pan-maker staining. Preliminary analysis comparing microglia/TAM populations in low-grade, high-grade and epilepsy tissue suggests a clear difference in the proportions of these cells.

CONCLUSION
Our work complements RNA-Seq studies, showing that TMEM119 and P2RY12, alongside other markers, can indeed identify two distinct myeloid cell populations within glioma tissue. This provides a strong basis for further study where we aim to elucidate the respective roles of microglia and TAMs within tumours. Ultimately, this may hold the potential for differential targeting of these cells using immunotherapies.
P10.04 Incidence and characteristics of neurological adverse events secondary to immunotherapy with checkpoint inhibitors
Authors: Velasco R , Argyriou A , Bruna J , Anastopoulou G G , Alemany M , Simó M , Piulats J M , Nadal E , Kalofonos H P 
Published: September 2019

Abstract

BACKGROUND
To explore the incidence and clinical phenotype of serious neurological adverse events (NAEs) in cancer patients who received immunotherapy with checkpoint inhibitors (ICIs) at two institutions.

MATERIAL AND METHODS
We reviewed files of cancer patients who were treated with ICIs from 2010 to 2018 and then searched for ICIs-related NAEs.

RESULTS
We identified 1185 ICIs-treated patients. Males and females were 63.7% and 36.3%, respectively, with a mean age of 63.4±7.3 years-old. Nivolumab was given to 536 (45.2%) patients, Pembrolizumab to 301 (25.4%) patients, Atezolizumab to 135 (11.4%), Ipilimumab to 104 (8.8%), Durvalumab-Tremelimumab to 77 (6.5%), and other ICIs to 32 (2.8%). Of those patients, 24 (2%) developed a ICI-related NAE. No differences were identified in age, sex, tumor type and class of ICIs between patients who developed neurotoxicity compared to those without neurologic adverse events. The distribution of NAE by agent was: Nivolumab (2.1%), Pembrolizumab (2%), Atezolizumab (1.5%), Ipilimumab (1%), Durvalumab-Tremelimumab (3.9%), and others (2.8%). The median number of cycles received before NAEs onset were 4.5 (1–10), and the median time was 110 days. PNS involvement was evident in 14 patients (58.3%) and CNS involvement in 41.7%, while 2 patients with aseptic meningitis also presented polyradicular involvement. Among PNS complications, there were 5 cases (20.8%) with axonal sensory neuropathies, 4 (16.7%) with Guillain-Barre-like syndromes, 4 (16.7%) with muscle involvement (myositis and myasthenias), and one with other syndromes. Seven patients (50%) with PNS-related NAEs were treated with steroids, 2 (14.3%) with IVIG, and 5 (35.7%) remained untreated. In general the outcome was good after ICIs discontinuation, with about half of patients improving or completely resolving NAEs.

CONCLUSION
ICIs-related NAE although rare overall, might be severe, and are mostly represented by neuromuscular complications. Early discontinuation of ICIs and possibly treatment with immune-modulating therapies should early be initiated to achieve a favourable neurological outcome
P11.05 Reappraisal of CNS embryonal tumors, not otherwise specified and RELA fusion negative supratentorial ependymomas using immunohistochemistry and sequencing for BCOR
Authors: Nambirajan A , Gurung N , Sashidharan A , Sharma A , Kedia S , Garg A , Suri V , Sarkar C , Sharma M 
Published: September 2019

Abstract

BACKGROUND
BCl2 co-repressor (BCOR) gene internal tandem duplications have recently been identified as the defining molecular alteration in a subset of central nervous system (CNS) high grade neuroepithelial tumors (CNS-HGNET). Their clinicopathological profile is yet to be fully elucidated with available data being largely derived from case reports and small case series. Reported cases presented in young children with a male preponderance, were located predominantly in the posterior fossa, and sometimes but not always showed an ependymoma-like morphology. BCOR protein overexpression and exon 15 internal tandem duplications were characteristic. These tumors associated with a poor overall survival.

MATERIAL AND METHODS
We designed a retrospective study (2002–2019) wherein all cases of CNS embryonal tumors, not otherwise specified (NOS), by definition lacking C19MC locus amplification and Lin28A protein expression, and supratentorial ependymomas (ST-EPN), NOS, lacking RELA and YAP1 fusions and L1CAM protein expression were retrieved and subject to immunohistochemistry for BCOR. Those tumors showing nuclear expression of BCOR were subject to sequencing of exon 15 of BCOR gene.

RESULTS
A total of 19 CNS embryonal tumors, NOS, constituting 86% of all CNS embryonal tumors other than medulloblastomas and atypical teratoid rhabdoid tumors, and 11 ST-EPN, NOS constituting 30% of all ST EPNs, were included. Diffuse nuclear staining for BCOR was seen in 6 tumors, including two patients with CNS embryonal tumor, NOS (10 year old male with spinal cord mass; 5-year-old female with left frontal mass) and 4 patients with ST-EPN-NOS (median age 15 years, ranging from 10–28 years, all females). While the CNS embryonal tumors showed high grade small round cell morphology, the remaining showed ependymoma-like morphology, but with increased cellularity and focal to diffuse membranous expression of epithelial membrane antigen and cytokeratins unlike ependymomas. Among these four patients, one was disease free at last follow-up at 17 months, while the remaining suffered recurrences within a median time duration of 26 months after diagnosis (24 months - 36 months).

CONCLUSION
The clinicopathological spectrum of BCOR-altered CNS tumors appears to be wider than that described in literature. We describe BCOR alterations in a subset of ependymoma-like tumors in older children and young adults with a striking female preponderance. BCOR alterations need to be studied on a broad spectrum of pediatric and adults CNS tumors to aid in better understanding of its true prevalence and biological significance.
P11.07 LAPTM5 functions as a tumor suppressor via CD40 - NFêB pathway inhibition and represents a potential biomarker for temozolomide sensitivity in CD40 proficient glioblastoma
Authors: Berberich A , Bartels F , Tang Z , Pusch S , Hucke N , Kessler T , Dong Z , Wiestler B , Winkler F , Platten M , Wick W , Abdollahi A , Lemke D 
Published: September 2019

Abstract

BACKGROUND
Glioma therapy is challenged by the invasive nature of glioma resulting in tumor recurrence and treatment resistance. Lysosomal protein transmembrane 5 (LAPTM5) was identified to inhibit invasion by screening for invasion-associated genes in glioma. The aim of this study was to decipher the function of LAPTM5 in glioblastoma and its interaction with the CD40 receptor which was shown to be highly expressed in up to 40% of glioblastoma.

METHODS
LAPTM5 expression was correlated with clinical outcome of glioma patients. Knockdown of LAPTM5 was performed in different glioma cell lines to analyze the impact on clonogenicity, invasiveness, sensitivity to temozolomide chemotherapy and tumorigenicity in-vitro and in-vivo in a subcutaneous xenograft mouse model. Expression array was used to elucidate the underlying pathways. CD40 knockdown and overexpression was induced to prove the crosstalk of LAPTM5 and CD40.

RESULTS
LAPTM5 expression correlated with better overall survival in high grade glioma patients and acted as a tumor suppressor in CD40 positive glioblastoma cells. LAPTM5 inhibited CD40-mediated NFκB activation resulting in anti-invasive, anti-clonogenic and temozolomide sensitizing effects in-vitro and in-vivo. Vice-versa, knockdown of LAPTM5 enhanced tumorigenicity by activation of the NFκB pathway which was overcome by NFκB inhibition. Importantly, CD40 expression was required for LAPTM5-mediated tumor suppressive activity.

CONCLUSION
LAPTM5 conveyed tumor suppressive and temozolomide sensitizing effects in CD40-positive glioblastoma by inhibition of CD40-mediated NFκB activation and thereby might provide a reasonable biomarker for sensitivity to temozolomide in CD40-positive glioblastoma.
P11.11 Circulating Pro-Angiogenic Cells and Proteins in Patients with Glioma and Acute Myocardial Infarction: Differences in Neovascularization between Neoplasia and Tissue Regeneration
Authors: Huizer K , Sacchetti A , Dik W , Kros J M , Mustafa D 
Published: September 2019

Abstract

BACKGROUND
Although extensive angiogenesis takes place in glial tumors, anti-angiogenic therapies have remained without the expected success. In the peripheral circulation of glioma patients increased numbers of endothelial precursor cells (EPCs) are present, potentially offering targets for anti-angiogenic therapy (Zheng et al., Ann Neurol, 2007). However, for an anti-angiogenic therapy to be successful, the therapy should specifically target glioma-related EPC subsets and secreted factors. Here we compared the EPC subsets and plasma factors in the peripheral circulation of patients with gliomas to acute myocardial infarctions (representing fysiologic regeneration).

MATERIAL AND METHODS
We investigated the five most important EPC subsets and 21 angiogenesis-related plasma factors in peripheral blood samples of 29 patients with glioma, 14 patients with myocardial infarction and 20 healthy people as controls, by an advanced FACS protocol (Huizer et al., PlosOne 2018) and Luminex assay.

RESULTS
In GBM patients all EPC subsets were elevated as compared to healthy subjects. In addition, HPC and KDR+ cell fractions were higher than in MI, while CD133+ and KDR+CD133+ cell fractions were lower. There were differences in relative EPC fractions between the groups: KDR+ cells were the largest fraction in GBM while CD133+ cells were the largest fraction in MI. An increase in glioma malignancy grade coincided with an increase in the KDR+ fraction while the CD133+ cell fraction decreased relatively. Most plasma angiogenic factors were higher in GBM than MI patients. In both MI and GBM, the ratio of CD133+ HPCs correlated significantly with elevated levels of MMP9. In the GBM patients MMP9 correlated strongly with levels of all HPCs.

CONCLUSION
In conclusion, the data demonstrate that EPC traffic in patients with glioma is different from that in normal tissue regeneration. Therefore, the effects of glioma extent beyond the brain, and future therapies aimed at lowering KDR+ cells and HPCs may add to effective treatment.
P11.17 Splicing dysregulation drives glioblastoma malignancy: SRSF3 as a potential therapeutic target to impair glioblastoma progression
Authors: Fuentes-Fayos A C , Vázquez-Borrego M C , Jiménez-Vacas J M , Bejarano L , Blanco-Acevedo C , Sánchez-Sánchez R , Solivera J , Blasco M A , Castaño J P , Luque R M 
Published: September 2019

Abstract
Glioblastomas (GBMs) remain the deadliest human brain tumors, with poor prognosis despite years of research. Currently, standard therapeutic strategies to treat GBM are not efficient and common survival from diagnosis is ~12–16 months. Thus, identification of new diagnostic/prognostic/therapeutic tools to tackle GBMs is crucial. Emerging evidence indicates that the cellular machinery controlling alternative splicing is altered in tumor pathologies, leading to oncogenic splicing events linked to tumor progression. Accordingly, we aimed to determine the expression pattern of the spliceosome components (SCs) and splicing factors (SFs) in high-grade astrocytomas (HGAs), mostly GBMs, and to ascertain the potential consequences of its dysregulation on GBM development. To this end, expression levels of SCs core and selected SFs were measured using a customized-microfluidic qPCR array in a well-characterized cohort of HGAs (n=33). Our results unveiled a profound alteration in the expression of multiple SCs and SFs in HGAs compared to healthy brain control-samples, wherein levels of particular elements (SRSF3/RBM22/PTBP1/RBM3) enabled perfect discrimination between non-pathological vs. tumor human-tissues, and between proneural and mesenchymal-like GBMs vs. control samples in mouse-models. Results were confirmed in an independent validation-cohort (n=49) and available Microarray dataset (Murat), which revealed that the expression of these splicing elements was correlated with relevant tumor markers and with survival. Remarkably, SRSF3/RBM22/PTBP1/RBM3 silencing (using specific siRNAs) decreased several aggressiveness parameters in vitro (e.g. proliferation, migration, tumorsphere formation, VEGFA secretion, etc.) and induced apoptosis, being SRSF3 the most relevant element affecting these parameters. Hence, a preclinical mouse model (U87MG-xenografts) with SRSF3 silencing drastically decreased in vivo tumor development/progression (i.e. tumor size, %MKI67, mitosis number, etc.) likely through a molecular/cellular mechanism involving the regulation of PDGFRB expression and its associated oncogenic signaling pathways. Overall, our results demonstrate that there is a profound dysregulation of the splicing machinery (spliceosome core and SFs) in HGAs/GBMs, which is directly associated to the development/progression of GBMs. Furthermore, this study reveals that SRSF3 can be a novel biomarker of malignancy and a potential therapeutic target to impair GBMs progression.
P11.26 Genome-wide shRNA screen identifies candidate genes driving glioblastoma invasion
Authors: Schuster A , Neirinckx V , Klein E , Nazarov P V , Oudin A , Muller A , Azuaje F , Herold-Mende C , Klink B , Niclou S P 
Published: September 2019

Abstract

BACKGROUND
A major hallmark of glioblastoma (GBM) is its highly invasive capacity, contributing to its aggressive behaviour. Since invasive cells cannot be easily removed by surgery or irradiation, they are left behind and eventually result in lethal recurrence. Therefore, a better understanding of the invasion process and of the key molecular players underlying the invasive capacities of GBM may lead to the identification of new therapeutic targets for GBM patients.

MATERIAL AND METHODS
To identify candidate genes responsible for invasion, a genome-wide shRNA screen was performed in patient-derived GBM sphere cultures. The phenotype of the most promising candidate was validated in in vitro invasion assays, ex vivo brain slice cultures and in vivo orthotopic xenografts in mice. Gene knockdown in invasive GBM cell lines was compared with overexpression in non-invasive cells. RNA sequencing of knockdown cells, along with the generation of deletion constructs were applied to uncover the mechanisms regulating invasion.

RESULTS
Through a whole genome shRNA screen, a zinc-finger containing protein was identified as an invasion essential candidate gene. Knockdown of this gene confirmed a strong decrease in invasion capacity in two highly invasive GBM cell lines. In contrast, gene overexpression switched non-invasive GBM cells to an invasive phenotype. Deletion of either one or both zinc-finger motifs led to decreased invasion indicating that the two zinc-finger motifs are essential for regulating invasion. Mutation of the nuclear localisation signal resulted in retention of the protein in the cytoplasm and loss of the invasion phenotype demonstrating that the protein activity is required in the nucleus. Gene expression analyses revealed that invasion-related genes are significantly regulated by the candidate gene once it is localized in the nucleus.

CONCLUSION
We identified a zinc-finger containing protein as a novel driver of GBM invasion, presumably through a transcription factor activity resulting in the induction of an invasive transcriptional program. This protein and its downstream pathway may represent a novel promising target to overcome invasive capacities in GBM.