bluuebunny/crossref_metadata_2025_split huggingface dataset:
PATH-25. APPLICABILITY OF A NOMOGRAM INCLUDING CLINICAL AND MOLECULAR VARIABLES IN THE STRATIFICATION OF RISK GROUPS IN PEDIATRIC MEDULLOBLASTOMA
Authors: Mançano Bruna , Reis Rui , Leal Leticia , de Paula Flavia , Almeida Jr Carlos , Almeida Gisele , Matushita Marcus , Faustino Fabio , Cavalcante Carlos , Magalhães Fernanda , Oliveira Marco 
Published: November 2019

Abstract
Medulloblastoma is the most common type of malignant brain tumor that occurs during childhood and adolescence. Currently, this pathology comprises at least four different molecular tumor subtypes (WNT, SHH, group 3 or C and group 4 or D) which have their own molecular characteristics, distinct clinical presentations and are associated with different survival rates. The purpose is to evaluate the applicability of a nomogram that includes clinical and molecular variables in pediatric medulloblastomas in the routine of the Hospital de Cancer de Barretos. The series l consists of 85 pediatric patients from 0 to 18 years old, diagnosed with medulloblastoma attended at the Hospital de Cancer de Barretos (HCB), from January 2000 to December 2017. The molecular subgroups will be performed using the Nanostring technique. This research intends to implement a nomogram that uses several variables known and involved in the treatment and prognosis of patients, this nomogram with multiple variables will show the clinical and molecular effect of each variable to predict disease-free survival and survival overall in 3 and 5 years. Thus, we will have the opportunity to analyze these characteristics in order to improve survival and reduce morbidity and consequently mortality during treatment for the different subgroups of medulloblastomas.
PATH-29. POTENTIAL OF RAMAN SPECTROSCOPY IN ONCOLOGICAL NEUROSURGERY
Authors: Kleine Borgmann Felix , Husch Andreas , Slimani Redouane , Jelke Finn , Mirizzi Giulia , Klein Karoline , Mittelbronn Michel , Hertel Frank 
Published: November 2019

Abstract
Raman spectroscopy (RS) has gained increasing interest for the analysis of biological tissues within the recent years. It is a label-free, non-destructive method providing insights in biochemical properties of tumor cells. It is possible to compare RS signals with histological properties of identical tissue parts. Therefore, RS bears promising potentials in neurosurgical neurooncology. On one hand, it could potentially be used for both intraoperative tumor diagnostics and resection control. On the other hand, it could provide important knowledge on tumor biochemistry and used for a subclassification of tumors with a potential impact on personalized therapy approaches. Within our group, we analyzed over 3000 measurement points in different brain tumors ex vivo with a robotized RS system and correlated the spectral curves with histopathological results. We separated and subclassified the data by AI-based methods. Additionally, we compared the latter results with those of a handheld probe, which is potentially navigatable for in vivo, intraoperative applications. We could demonstrate, that it is possible to separate distinct tumor groups only based on RS signals, especially by using computer-based signal analysis. Furthermore, we could demonstrate the differences of the spectra of deep-frozen and formalin-fixed tissues versus non-fixed tissues. Based on our results, we will highlight the potentials of RS for intraoperative neurosurgical application in resection control for brain tumors, as well as we will focus on the potentials for brain tumor diagnostics based purely on this method or by using it as an adjunct. Those methods bear additional potentials in the field of personalized chemotherapy approaches.
PATH-31. BUILDING A RAMAN SPECTROSCOPY REFERENCE DATABASE FOR TUMOR IDENTIFICATION AND CLASSIFICATION
Authors: Kleine Borgmann Felix , Husch Andreas , Slimani Redouane , Jelke Finn , Mirizzi Giulia , Klein Karoline , Mittelbronn Michel , Hertel Frank 
Published: November 2019

Abstract
Brain tumor resection requires careful assessment of the nature and malignancy of the tumor tissue during intervention, as this is the basis for the decision as to how radical surgery has to be. Typically, there is no tissue available for analysis prior to the surgery. Intraoperative histopathological examination of tumor samples is time consuming and puts the patient to a significant amount of strain due to ongoing anesthesia and prolonged surgery, thus there is a need to develop faster methods for thorough diagnostics. Raman spectroscopy allows for a fast analysis of samples without the need for labeling and sample preparation, making it a useful tool for peri- and intrasurgical application. We collect Raman spectra and correlated histopathological results to build a database of different tumor types. As intrasurgical use of Raman spectroscopy will typically be applied to native specimens, the respective database has to be based on native samples as well. We collected several thousands of measurements from more than 100 patients and continue to assemble a native database. Tumors that do not occur with a high frequency are not sufficiently represented in the database. Therefore, we investigate whether it is possible to integrate fixed and frozen specimens in the collection of Raman spectra and the classifier. Fixation results in characteristic changes to the biochemistry of biological tissues. We collect pairs of spectra from native and fixed as well as from native and frozen specimens and use the difference of the spectra to create an algorithm for filtering of the specific changes in the spectra. These data can be used to train a classifier for the identification of native samples. This opens the way for assessing large collections of pathological samples in fixed and frozen state to cover any type of neoplastic disease in the database.
PATH-32. GENOMIC LANDSCAPE AND BIOLOGY OF MEDULLOBLASTOMA IN ADULTS
Authors: Goschzik Tobias , zur Mühlen Anja , Dörner Evelyn , Waha Andreas , Friedrich Carsten , Hau Peter , Pietsch Torsten 
Published: November 2019

Abstract

BACKGROUND
Medulloblastoma (MB) is a rare disease in adults. Only few cohorts have been studied so far.

METHODS
Histological features were evaluated and tumors were annotated to WNT-MB, SHH-MB, and non-WNT/non-SHH-MB by immunohistochemistry. Copy number alterations were analyzed by genome-wide molecular inversion probe array. MB-related genes were screened by NGS panel and Sanger sequencing in WNT- and SHH-MB.

RESULTS
The cohort of 117 tumors contained 14.5% WNT-MB, 63.2% SHH-MB, and 22.2% non-WNT/non-SHH-MB. Classic histology was found in WNT-MB, non-WNT/non-SHH-MB and 22% of SHH-MB; 78% of SHH-MB showed desmoplastic/nodular histology. In WNT-MB, CTNNB1 mutations were found in 88.2% and monosomy 6 in 52.9% of cases. In SHH-MB, PTCH1 mutations were present in 40% of cases and chromosome 9q loss including the PTCH1 locus was the most frequent copy number event in SHH-MB (50%), while SMO and SUFU mutations were found only in 15.4% and 7.7%, respectively. TERT promoter mutations were present in 92.3% of SHH-MBs. Only 2 (3%) of SHH-MB were TP53-mutated (1.7% of whole cohort). In non-WNT/non-SHH-MB, isochromosome 17q was the most frequent chromosomal alteration (84.6%). A previously published whole chromosomal aberration (WCA) signature with ≥1 WCA was found in 69.2% of cases. For 87 cases, survival data were available. WNT-MB, SHH-MB with wildtype TP53 and non-WNT/non-SHH-MB showed similar outcomes (5-year OS: 75%, 78.1% and 69.1%, respectively). Both SHH-MB patients with mutant TP53 died of disease. Patients with non-WNT/non-SHH-MB characterized by the cytogenetic WCA phenotype showed – as described in pediatric standard-risk MB – significant better overall survival compared to patients with tumors lacking WCA (p=0.02).

CONCLUSIONS
Adult MB represents four defined biological/genomic entities. While in our cohort WNT-MB and SHH-MB-TP53wt were standard risk, non-WNT/non-SHH-MB patients could be divided into two risk-groups according to the presence or absence of WCA in the tumors as previously published for childhood standard-risk MB.
PATH-34. CLINICOPATHOLOGIC, MOLECULAR AND IMMUNOLOGICAL CHARACTERIZATION OF DIFFUSE MIDLINE GLIOMAS: IS THERE A PROGNOSTIC SIGNIFICANCE?
Authors: Manjunath Niveditha , Jha Prerna , Raheja Amol , Suri Vaishali , Suri Ashish , Garg Ajay , Kaur Kavneet , Sarkar Chitra 
Published: November 2019

Abstract
H3K27M Diffuse Midline Gliomas (DMGs) are amongst the most fatal cancers, considered WHO grade IV irrespective of the histological features. Treatment modalities have been ineffective in prolonging survival. The aim was to determine the clinico-pathologic, molecular and immunological characteristics of DMGs in children and adults. Genetic (H3K27M, ATRX, IDH1, p53) and immune (CD3,CD8 and PD-L1) profile of 126 DMGs identified over 10 years was studied with immunohistochemistry (IHC). Sanger sequencing performed for IDH1 and H3K27M mutation. Clinico-radiologic characteristics were reviewed and survival analysis performed. Of the 126 DMGs, 49.2% H3K27M mutant and 50.8% wildtype cases (mean age 21.27 years vs. 36.23 years). 75.68% of pediatric whereas 38.20% of adults were H3K27M mutant. Brainstem (46%) was commonest site in H3K27M mutant pediatric cases while majority of adults (62%) were thalamic. H3K27M was mutually exclusive with IDH mutation in 92.5% cases, whereas p53, ATRX mutation was 56.4% and 30.6% respectively. IHC showed 95% concordance with Sanger sequencing for H3K27M mutation. PD-L1 expression was greater in elderly (>50 years), than young adults and pediatric cases (p=0.002). CD8 expression was greater in adult then pediatric cases (p=0.0001). Overall survival (OS) was not statistically significant in mutant versus wildtype cases in children (p=0.45) as well as adults (p=0.65). Tumor location showed no correlation with OS. Tumor resection independently or on correlation with H3K27M did not influence OS (p=0.505 and p=0.470). Adjuvant therapy impacted survival significantly in adults (p=0.0009) than in pediatric patients (p=0.0669) The study highlights the differences in frequency and location of pediatric and adult H3K27M mutant DMGs. Dismal prognosis in both age groups of H3K27M mutant and wild type DMGs. IHC for H3K27M mutation is an excellent substitute to Sanger sequencing. Our analysis emphasises the role of molecular characterisation for the development of effective therapeutic strategies, for different DMG subgroups.
PATH-46. DETECTING MISDIAGNOSED ATYPICAL TERATOID/RHABDOID TUMOR (ATRT) BY DNA METHYLATION-BASED TUMOR CLASSIFICATION
Authors: Hsiao Meng-Chang , Holinka Lauren , Peracchio Michael , Kelly Kevin , Hesse Andrew , Lau Ching , Reddi Honey 
Published: November 2019

Abstract
Brain tumor diagnostics is achieved by combining morphology assessment and biomarker identification. However, the inter-observer variability of the histopathological diagnosis and lack of distinctive biomarkers makes these diagnoses particularly challenging. Recently, the potential for methylation-based characterization has been developed for brain tumors. To provide accurate and efficient brain tumor diagnostics, The Jackson Laboratory developed a DNA methylation array (Illumina Infinium HD Methylation EPIC), combining the “Classifier” established by the German Cancer Research Center (DKFZ), which can identify 82 distinct central nervous system tumors. Here we present a pediatric patient referred to us for medulloblastoma subtype classification by the methylation profile. Surprisingly, the array classified the tumor type as atypical teratoid/rhabdoid tumor (ATRT), subclass SHH. Also, the CNV profile indicated the SMARCB1/INI1 heterozygous deletion as part of the chromosome 22q deletion typically seen in ATRT, and absent was the isochromosome 17q commonly associated with medulloblastoma. Immunohistochemistry confirmed the loss of SMARCB1/INI1 expression leading to ATRT. Additionally, our NGS panel found a novel SMARCB1/INI1 frameshift variant c.1150delG (p.Ala384fs) in the last exon (exon 9). Although this variant is not expected to induce nonsense-mediated mRNA decay, it is located in the ATP-dependent nucleosome-remodeling complex domain Sfh1/SNF5 (IPR017393), which is associated with cell proliferation and differentiation. In addition, ClinVar reported several pathogenic/likely pathogenic variants in this domain, further supporting SMARCB1/INI1 c.1150delG which, together with the SMARCB1/INI1 deletion, may contribute to the loss of SMARCB1/INI1 expression, resulting in ATRT. We have identified the ATRT misclassification by the methylation profile and characterized a novel SMARCB1/INI1 variant c.1150delG most likely contributing to ATRT. We further propose that the DNA methylation profile will significantly improve the brain tumor diagnostics for cases with ambiguous, or contradictory histology and molecular profiles.
PATH-49. CLINICAL UTILITY OF PLASMA CELL-FREE DNA IN ADULT PATIENTS WITH NEWLY DIAGNOSED GLIOBLASTOMA – A PILOT PROSPECTIVE STUDY
Authors: Bagley Stephen , Nabavizadeh Seyed , Mays Jazmine , Till Jacob , Yee Stephanie , Ware Jeffrey , Guiry Samantha , Nasrallah MacLean , Levy Scott , Sarchiapone Whitney , Hussain Jasmin , Prior Timothy , Cucciara Andrew , Binder Zev , O’Rourke Donald , Brem Steven , Desai Arati , Carpenter Erica 
Published: November 2019

Abstract

BACKGROUND
Liquid biopsy has been not been widely utilized in patients with glioblastoma (GBM) compared to other solid tumors. However, the clinical utility of plasma cell-free DNA (cfDNA) in GBM has not been assessed prospectively or at the time of initial diagnosis.

METHODS
We conducted a prospective cohort study of patients with newly diagnosed GBM. Whole blood was collected in Streck® tubes at baseline prior to initial surgical resection and longitudinally during the course of adjuvant chemoradiotherapy. Plasma cfDNA concentration (ng/mL) was quantified by qPCR for a 115 bp amplicon of the human ALU repeat element, correlated with radiographic tumor burden by volumetry at multiple time points using Spearman rank correlation, and assessed for its impact on progression-free (PFS) and overall survival (OS) by Cox regression.

RESULTS
Prior to initial resection, GBM patients (N=42) had higher plasma cfDNA concentration compared to age-matched healthy controls (N=42) (mean 13.43 vs. 6.70 ng/mL, p< 0.001). Plasma cfDNA concentration was correlated with radiographic tumor burden on subjects’ first post-radiation MRI scan (r=0.77, p=0.003) and tended to rise prior to or concurrently with radiographic tumor progression. Pre-operative plasma cfDNA concentration above the mean (>13.4 ng/mL) was associated with inferior PFS (median 4.9 vs. 9.5 months, p=0.038) and OS (median 8.9 vs. 14.8 months, p=0.078). The impact on PFS persisted after adjusting for age, extent of resection, performance status, MGMT promoter methylation, and IDH1/2 mutational status (HR 2.48, 95% CI 1.1–6.1, p=0.046).

CONCLUSIONS
Plasma cfDNA may be an effective prognostic tool and noninvasive surrogate of tumor burden in newly diagnosed GBM. Tumor tissue samples from our cohort have been subjected to targeted next generation sequencing (NGS), and baseline plasma samples have been sent to Guardant Health for NGS. Plasma NGS results and concordance with matched tissue NGS will be included at time of presentation.
PATH-56. PYROSEQUENCING METHOD FOR RAPID DETECTION OF KIAA1549-BRAF FUSION GENES IN PEDIATRIC BRAIN TUMORS
Authors: Shimizu Yuzaburo , Adachi Satoshi , Suzuki Mario , Akiyama Osamu , Ogino Ikuko , Kondo Akihide 
Published: November 2019

Abstract

BACKGROUND
Fusion genes driving tumorigenesis have drawn the attention of oncologists and researchers. Recently, independent genomic researchers have identified a tandem duplication of BRAF at 7q34 that leads to several KIAA1549-BRAF gene exon fusions in the majority of pilocytic astrocytoma (PA). Because KIAA1549-BRAF fusion transcripts are usually absent in diffuse astrocytoma, these genetic alterations may have diagnostic value. Despite the importance of such molecular alterations, there are no comprehensive reproducible methods to detect these fusion genes.

METHODS
Samples of brain tumors were selected retrospectively from our institution. 22 pediatric brain tumors of five types, namely PA, oligodendroglioma (OD), anaplastic astrocytoma (AA), glioblastoma (GBM) and, ganglioglioma (GG), were evaluated to detect KIAA1549-BRAF fusion genes using a pyrosequencing-based method following RNA isolation, cDNA synthesis and real-time polymerase chain reaction. We designed the primers to detect the three most common fusion variants: KIAA1549 ex15-BRAF ex9, KIAA1549 ex16-BRAF ex9, and KIAA1549 ex16-BRAF ex11.

RESULTS
Our method successfully detected KIAA1549-BRAF fusion in 16 out of 22 samples, that is, eleven PA, two OD, one AA, one GBM, and one GG. The entire procedure from RNA extraction to obtaining mutation data was performed within 2 hours.

CONCLUSION
A comprehensive method for detecting fusion genes in pediatric brain tumors was evaluated. This method identified KIAA1549–BRAF fusion variants quickly compared to other methods. Our results will be useful for studies on intraoperative diagnosis and classification of tumors for improving surgical decisions.
PATH-59. HISTOPATHOLOGICAL INVESTIGATION OF THE 1p/19q-CODELETED GLIOMAS RESECTED FOLLOWING ALKYLATING AGENTS CHEMOTHERAPY
Authors: Kanazawa Tokunori , Ohara Kentaro , Yoshida Kazunari , Sasaki Hikaru 
Published: November 2019

Abstract

BACKGROUND
Little is known about histopathological changes after chemotherapy in lower-grade gliomas (LrGGs).

METHODS
We investigated 15 1p/19q-codeleted gliomas resected following tumor volume decrease after alkylating agents chemotherapy in comparison with their pre-chemotherapy specimens. Histopathological changes by chemotherapy were evaluated by hematoxilyn-eosin staining and immunohistochemistry for Ki-67/MIB-1, CD68 as pan macrophage/monocyte marker, CD163 as presumed marker of M2 polarity, and nestin and CD133 as markers of glioma stem cells (GSCs).

RESULTS
Histologically, there were several presumed chemotherapy-related changes in the post-chemotherapy specimens, with the most frequent findings being sparse glial background and abundant foamy cell infiltration. The Ki-67/MIB-1 indices significantly decreased, and CD68+ cells significantly increased after chemotherapy. The increasing rate of CD68+ cells in the post-/pre-chemotherapy specimens was prone to be associated with patients’ progression-free survival (PFS) and overall survival (OS), but not tumor response. The number of CD163+ cells and the ratio of nestin+ cells and CD133+ cells significantly increased after chemotherapy. The number of CD163+ cells, the ratio of nestin+ cells and CD133+ cells, and M2 (CD163+)/M1+M2 (CD68+) ratio in the post-chemotherapy specimens were negatively correlated with patients’ PFS and OS. There was no difference between chemotherapy regimens (temozolomide versus nitrosourea-based) in the number of CD163+ cells and the ratio of nestin+ and CD133+ cells.

CONCLUSIONS
GSCs in conjunction with M2 macrophages constitute the mechanism of resistance to and recurrence after alkylating agents chemotherapy in LrGGs.
PATH-65. MOLECULAR SIGNATURE OF FAT1 RELATED MOLECULES IN GLIOMAS IN THE CONTEXT OF THE WHO 2016 CLASSIFICATION
Authors: Chosdol Kunzang , Arora Manvi , Malik Nargis , Jha Prerana , Singh Jyotsna , Suri Ashish , Sinha Subrata , Suri Vaishali 
Published: November 2019

Abstract
Glioblastoma (GBM, WHO grade-IV) being the most malignant and aggressive form of glioma remains a major clinical challenge, with an overall 5-year survival rate of only 9.8%. Till recently, glioma diagnosis and grading were solely dependent on the phenotypic and histological features. However, with the advancement in the understanding of the molecular biology of glioma several molecules have been identified. The importance of these molecular/genotypic features of the tumor became evident by the inclusion of these molecular features by World Health Organization (WHO) in 2016 in glioma sub-grouping. Our lab is focused on studying the role of FAT1 gene (human ortholog of Drosophila tumor suppressor gene, fat) in glioma biology and aggressiveness. We observed FAT1 gene to have an oncogenic role in glioma where it has been found to upregulate migration/invasion, inflammatory microenvironment of the tumors, HIF1α expression/activity in the tumor-cells under severe hypoxia and in regulating EMT/stemness properties of GBM-cells under hypoxia. Here, we have characterized the molecular relationship between FAT1 related molecules and known- molecular markers of glioma with the hope of identifying glioma subgroup with a molecular signature of clinical significance by (i) analyzing the expression correlation of FAT1 and FAT1 regulated pro-inflammatroy molecules like COX2, IL1b and IL6 with the known- molecular markers of glioma like p53, IDH1, MGMT, EGFR, TERT in low-grade (grade-II) and high-grade (grade-III/IV) gliomas (n=50) by real-time PCR, sequencing, immunohistochemistry and in-silico analysis of TCGA-GBM-data (ii) Analyzed the regulatory role of FAT1 on the above known markers by siRNA mediated knockdown of FAT1 in in-vitro cell-culture system and (iii) further analyzed the identified molecular signature for their correlation with the patients prognosis/survival in the follow up patients. We observed a novel molecular signature with significant correlation with patients’ clinical outcome. Therapeutic targetting of FAT1 may benefit patients with high FAT1 expressing tumors.
NCOG-05. IMPACT OF ADDITIONAL RITUXIMAB TO STANDARD THERAPY ON COGNITIVE PERFORMANCES IN PRIMARY CENTRAL NERVOUS SYSTEM LYMPHOMA PATIENTS
Authors: van der Meulen Matthijs , Dirven Linda , Habets Esther , Bakunina Katerina , Taphoorn Martin , van den Bent Martin , Issa Samar , Doorduijn Jeanette K , Bromberg Jacoline E C 
Published: November 2019

Abstract

BACKGROUND
The goal of treatment of primary central nervous system lymphoma patients is to improve survival, without compromising neurocognitive functioning. The aim of this study was to analyze the effect of Rituximab and low-dose whole brain radiotherapy (WBRT) on cognition.

METHODS
199 patients from a phase III trial (HOVON 105/ ALLG NHL 24), randomized to standard chemotherapy (and 30Gy WBRT for patients < 61 years-old only) with or without Rituximab, were asked to participate in a short neuropsychological evaluation (NPE) before and during treatment, and up to 2 years of follow-up or until progression. A difference in z-score, corrected for sex, age and education, of ≥ 1 point was considered as clinically relevant. The primary outcome was a difference over time between the arms in multiple cognitive domains, assessed by linear mixed models (LMM). Changes in cognitive performances between baseline and 24 months after treatment were assessed for both arms in cross-sectional analyses. Effect of WBRT was analyzed in irradiated patients only.

RESULTS
105/199 patients completed at least one NPE; baseline characteristics were similar to the total trial population. Compliance was >60% at all evaluation points. No clinically relevant differences over time between the arms were seen in all domains in LMM analysis. Comparing changes from baseline to 24 months of follow-up, mean cognitive scores remained stable in both arms for attention, executive functioning (TMT B), and information processing speed. A clinically relevant improvement was seen in both arms for executive functioning (TMT A), memory and motor speed. In the irradiated patients (n=33) all scores remained stable after WBRT, up to 24 months of follow-up in all domains.

CONCLUSION
Cognitive performance remained stable or improved after treatment. Addition of Rituximab to standard treatment did not impact cognitive performance over time. After low-dose WBRT, cognition remained stable up to 2 years.