bluuebunny/crossref_metadata_2025_split huggingface dataset:
Ethics consultations in patients with neuro-oncologic diseases.
Authors: Sener Ugur , Neil Elizabeth C. , Carver Alan , Diamond Eli L. , Voigt Louis 
Published: May 2019

e13519 Background: In patients with cancer, ethical issues regarding patient autonomy, surrogate decision making, and end-of-life care often arise. Ethics consultation can help clarify perspectives of different stakeholders involved in a patient’s care, facilitate communication, and resolve conflicts. Neurologic manifestations of cancer can cause impairment of cognition, communication, and functional independence. Ethical conflicts in the specific context of neuro-oncologic diseases have yet to be characterized. Methods: In this retrospective study, we reviewed 50 cases where ethics consultation was requested for patients with neurologic malignancies or neurologic complications of cancer treated at Memorial Sloan Kettering Cancer Center (MSK). Results: Of 50 patients (ages 4-76, 56% female) reviewed, 27 had a primary central nervous system (CNS) malignancy, 21 had CNS metastasis, one had a vascular malformation, and one had no clear diagnosis. Neurologic issues contributing to patients’ clinical status included toxic metabolic encephalopathy (14), leptomeningeal disease (10), intracerebral hemorrhage (10), hydrocephalus (9), seizures (6), cord compression (5), and ischemic stroke (3). At the time of ethics consultation, 39 patients lacked decision-making capacity, 47 did not have an advance directive, and 38 did not have a do not resuscitate (DNR) order. Ethical issues identified included surrogate decision making (20), DNR (18), capacity (6), refusal of treatment (5), futility (4), brain death (4), and research ethics (2). Contextual issues included staff-family conflict (22), cultural or religious considerations (10), intra-family conflict (7), intra-staff conflict (6), and physician attitude toward treatment (3). Conclusions: Neuro-oncologic diseases present a unique constellation of ethical conflicts, particularly about end-of-life care. Language and cognitive deficits, impaired decision-making, and sudden neurological decline are factors that shape ethical conflicts in this clinical setting. Further study of ethical issues in neuro-oncology may help patients receive care that is consistent with their goals and values.
RNA-sequencing and bioinformatic analysis to pre-assess sensitivity to targeted therapeutics in recurrent glioblastoma.
Authors: Kim Ella L , Buzdin Anton , Sorokin Maxim , Poddubskaya Elena , Poddubskiy Artem , Kantelhardt Sven R , Kalasauskas Darius , Sprang Bettina , Bikar Sven Ernoe , Giese Alf 
Published: May 2019

e13533 Background: This study developed molecular guided tools for individualized selection of chemotherapeutics for recurrent glioblastoma (rGB). A consortium involving clinical neurooncologists, molecular biologists and bioinformaticians identified gene expression patterns in rGB and quantitatively analyzed pathways involved in response to FDA approved oncodrugs. Methods: From2016 to 2018 biopsies from GB were collected using a multisampling approach. Biopsy material was used to isolate glioma stem-like cells and examined by RNA-sequencing. RNA-seq results were subjected to differential expression (DE) analysis and Oncobox analysis – a bioinformatic tool for quantitative pathway activation analysis. Results for newly diagnosed (nGB) and rGB (tissue samples and cell cultures) were compared. Oncobox analysis was further used to examine differential activation of pathways involved in response to existing chemotherapeutics. Results: 128 tissue samples and 28 cell cultures from a total of 44 GBs including 23 nGB, 19 rGB and 2 second-recurrent GBs were analyzed. 14 patient-matched pairs of nGB and rGB were obtained. DE analysis of nGB and rGB, showed a distinct “signature” associated with rGB. Oncobox analysis found down regulation of pathways related to cell cycle and DNA repair and upregulation of immune response pathways in rGB vs corresponding nGB. Specifically, pathways targeted by temozolomide, which is the first line chemotherapy for GB, were found down regulated in rGB. Among the top pathways upregulated in rGB were the pathways targeted by durvalumab and pomalidomide currently under investigation in phase II or III trials for GB. Conclusions: Specific pathway analysis revealed regional and clinical stage-associated differences in the transcriptional landscapes of nGB and rGB. Our results support a concept of treatment-induced resistance to cytotoxic therapeutics and indicate that temozolomide and radiation treatment have important impacts on gene expression changes associated with GB recurrence. Systematic molecular profiling of rGB is a promising avenue towards predicting sensitivity to targeted therapeutics in rGBs on an individual basis.
Mutations of H3.3 and H3.1 in a large cohort of glioma tumors.
Authors: Sumrall Ashley Love , Xiu Joanne , Eschbacher Jennifer M , Mittal Sandeep , Gatalica Zoran , Pandey Manjari K , Phuphanich Surasak , Korn Wolfgang Michael , Fuller Gregory N. , Heimberger Amy B. 
Published: May 2019

e13540 Background: Mutations in the histone genes H3.3 and H3.1 are driver events in pediatric and adult gliomas and carry diagnostic and prognostic importance for tumors originating from midline structures. Patients with tumors affected by these mutations are notoriously difficult to treat, and the prevalence and molecular correlates of H3 mutations in a large glioma population have not been systematically reported. We aim to survey a large cohort of gliomas for H3-mutations. Methods: Consecutive gliomas submitted for tumor profiling at Caris Life Sciences from 2015- 2018 were analyzed. NextGen sequencing was done on 592 genes (NextSEQ Illumina); MGMT promoter methylation was tested by pyrosequencing; and EGFRvIII and gene fusions were tested by RNA-sequencing (ArcherDx FusionPlex). Results: Of the 1763 tumors analyzed, 41 harbored H3F3A alterations, including 33 with the K27M mutation (4 arose from the spinal cord, 1 from cerebellum, 1 from brain stem, 4 from thalamus, and 23 from brain, NOS). Eight G34R mutations were identified. A HIST1H3B-K27M was detected in a tumor from the brain stem. Overall, H3 mutations were more prevalent in pediatric tumors (8 of 26, 31%) than adult tumors (34 of 1737, 2%). All H3 mutations seen in pediatric tumors were from grade IV tumors. Among the 34 H3-mutated adult tumors, histology differed. There were 2 grade II tumors (diffuse astrocytoma), 1 low grade glioma from the spinal cord, 1 anaplastic ganglioglioma and 2 anaplastic astrocytomas. In the investigated cohort, H3-mutations were mutually exclusive of IDH1/2 mutations and EGFR alterations. Significantly higher mutation rates were seen in H3-mutated tumors for TP53 (69%. Vs. 37%), ATRX (46% vs. 24%), NF1 (23% vs. 12%) , PDGFRA (17% vs. 1%), FGFR1 (12% vs. 1%), FBXW7 (5% vs. 0), BLM (3% vs. 0) and TSC2 (2% vs.0) compared with H3-WT (p < 0.05). The H3-WT tumors were more enriched for MGMT-methylation (53% vs. 26%) and PTEN mutation (22% vs. 7%) (p < 0.05). In H3-mutated tumors that were MGMT-methylated (n = 10), most H3-mutations seen were G34R (n = 8) while K27M (n = 2) was largely exclusive. Conclusions: This survey of a large cohort of gliomas revealed a heterogeneous distribution of H3 mutations. The co-occurring molecular alterations seen in H3-mutated tumors further support the hypothesis that these tumors are a distinct molecular entity. By better characterizing these associations, we are closer to developing more insight into novel treatment strategies for a class of tumors with historically dismal prognosis.
Assessment of neurocognitive function in illiterate patients of high-grade glioma treated with chemoradiation.
Authors: Malik Monica , Valiyaveettil Deepthi , Ashalatha G , E Prathyusha , Joseph Deepa M. 
Published: May 2019

e13543 Background: Although the role of chemo-radiation (CRT) in gliomas has been studied extensively, its effects on neurocognitive function (NCF) remain elusive. Assessment of NCF in illiterate patients is a challenge. Methods: Illiterate adults with histopathologically proven high grade gliomas planned for CRT following maximal safe resection were included. Temozolomide based CRT using standard protocols was planned. Neurocognitive function was assessed using the Addenbrooke’s Cognitive Examination (ACE-III) questionnaire prior to the start of CRT and at 3 and 6 months post RT. The subventricular zones (SVZ) and hippocampus were contoured using standard guidelines. The NCF scores were compared using the paired t test. Results: 32 patients were recruited. The median age was 40 years. M:F ratio was 1:1.16. IMRT to a dose 60 Gy with concurrent and adjuvant temozolomide was planned. Overall there was no significant difference in scores at 3 months and a significant decline in visuospatial scores at 6 months (p < 0.001). Mean doses to the ipsilateral and contralateral SVZ were 49.5 Gy and 35 Gy respectively. Based on mean ipsilateral SVZ dose, patients were divided into: Group I < 50 Gy (n = 18), group II ≥ 50 Gy (n = 14). At 3 months there was significant improvement in scores in Group I whereas a decline in scores in Group II. At 3 months, memory (18.73 vs 21.93; p = 0.021) and fluency (10.20 vs 11.67; p = 0.042) showed improvement in group I patients. In group II there was decline in visuospatial scores (14.41 vs 13.71; p = 0.016) at 3 months. At six months, there was improvement in memory (17.94 vs 22.94; p = 0.002), attention (14.78 vs 16.39; p = 0.031), fluency (10.11 vs 11.67; p = 0.018) and total ACE scores (80.83 vs 89.94; p = 0.008) in group 1 patients and a significant decline in visuospatial function, attention, memory and language scores in group II patients. Higher contralateral SVZ doses (> 35 Gy) correlated with a significant decline in visuospatial scores at 3 and 6 months. Lower mean dose to ipsilateral hippocampus (< 40 Gy) correlated significantly with improved memory scores. Doses to contralateral hippocampus did not correlate with scores. Conclusions: The Addenbrooke’s Cognitive Examination (ACE-III) questionnaire can be used to assess NCF in patients with gliomas including illiterate patients. Lower mean doses to the ipsilateral and contralateral SVZ and hippocampus resulted in improvement/preservation of memory, attention and fluency whereas higher doses were associated with a decline in scores.
Factors influencing the intracellular exposure of gemcitabine triphosphate in children with CNS tumors.
Authors: Campagne Olivia , Zhong Bo , Selvo Nicholas , Owens Thandranese S , Gajjar Amar J. , Robinson Giles W. , Stewart Clinton F. 
Published: May 2019

e13547 Background: Gemcitabine (dFdC), a cytosine analog, is currently being evaluated as a therapy to treat children and young adults with central nervous systems (CNS) tumors in two clinical trials (NCT01878617 and NCT03434262). Once in the cell, dFdC undergoes complex and highly variable conversion to gemcitabine triphosphate (dFdCTP), which is responsible for its cytotoxic effects. Our objective is to identify the factors influencing dFdC and dFdCTP exposures in children. Methods: As part of treatment, patients with newly diagnosed medulloblastoma and patients with recurrent/refractory medulloblastoma or ependymoma receive 28-day cycles of dFdC, as a 30-minute IV infusion at 750, 1000 or 1250 mg/m2 on days 1 and 15 of each cycle. Patients with recurrent/refractory disease also receive concomitant ribociclib. Pharmacokinetic (PK) studies were performed after one dose of dFdC alone (day 1) and with ribociclib (day 15). dFdC and dFdCTP concentrations were measured in plasma and in peripheral blood mononuclear cells respectively, for up to 4h post-dose, using validated LC-MS/MS methods. The concentrations were analyzed using a population PK model. A preliminary covariate analysis was performed to evaluate the impact of factors (e.g., patient demographics and infusion rate) on dFdC and dFdCTP exposure (area under the curve). Results: dFdC and dFdCTP concentrations were fitted with a three-compartment linear model. dFdC infusion rate significantly influenced the drug exposures with a faster plasma dFdC elimination and higher dFdCTP formation observed at the lower infusion rate. On average, patients receiving dFdC as 25 or 33 mg/m2/min had a dFdCTP exposure of 526 µM·h vs 205 µM·h with a rate of 42 mg/m2/min (p < 0.001). Patient with lower body surface area also showed higher dFdC clearance. Significant intra-patient differences were observed in dFdCTP concentrations measured on days 1 and 15. Conclusions: This preliminary PK analysis shows a saturable formation of dFdCTP in children with CNS tumors, and suggests the need for longer infusion duration with higher dFdC dosages. Future work will evaluate potential drug-drug interaction with ribociclib and the effect of genotypic variants on dFdCTP exposure.
The prognosis of diffuse midline glioma H3 K27M mutant.
Authors: KIM Donghwan , Chung Chun Kee 
Published: May 2019

e13548 Background: Diffuse Midline Glioma is rare spinal cord primary tumor. Unfortunately it is known that the prognosis is poor, and it was added to the WHO guidelines in 2016 as a grade IV. It is so rare that the prognosis of the diffuse midline glioma in spinal cord is not well known yet. So we want to analyze the prognosis of the spinal cord diffuse midline glioma and find out about the molecular profile. Methods: We retrospectively reviewed of 10 diffuse midline glioma H3-K27M mutant patients who underwent surgery in a single institute, 2015.09~2018.04. We analyzed the demographic data, overall survival, progression free survival and molecular profile which includes PTEN, BRAF, EGFR, MGMT methylation status, c-MET, IDH1, 1p/19q deletion. Results: Mean age was 44.8 yr; male to female ratio was 5:5. Tumor was located conus medullaris (8), CT Junction(1), Cervical(1). One was given gross total resection and the other was a partial resection or biopsy. All patient were treated with CCRT. Medial overall survival was 47.8 months, and median progression free survival was 21 months. One case each was found for BRAF, C-MET, IDH1, PTEN and EGFR. Conclusions: This study was conducted on patients collected for a relatively short period. This study reported survival analysis and molecular profile. These mutations are known to be mainly associated with MAPK pathway. So there may be a correlation between H3-K27M and MAPK pathway. Results indicating the association of MAPK and H3K27M can be found in some literature. Further research is needed.
DDR1 may be a good biomarker for brain tumors.
Authors: Erdem Dilek , Büyüksimsek Mahmut , Gunaldi Meral , Sahin Nilgun 
Published: May 2019

e13557 Background: There are two important hardness in the treatment of central nerve system tumors; first of it is tumor heterogenity while the second is biomarker deficiency which can be target in the tumor tissue. For the reason we aimed to examine discoidin domain receptor (DDR1), a tyrosine kinase receptor , which may be thought to be effective in cell adhesion. Methods: 38 brain tumor were evaluated for tissue DDR1 messenger ribonucleic acid and blood DDR1 levels. We compared these with 10 control group tissue and blood levels of DDR1. Results: All brain tumor and control group tissues and blood samples were found DDR1 value positive. DDR1 levels of brain tumor tissues and blood samples were statistically higher when compared with DDR1 levels of control group tissue and blood samples. Conclusions: DDR1, found statistically higher among brain tumor tissues and blood samples may be a useful biomarker for the therapy and management of these patients.
Targeting of CD317 by the immunotoxin HM1.24-ETA’ to allow immunotherapy in glioblastoma patients.
Authors: Gramatzki Dorothee , Szabo Emese , Gramatzki Martin , Peipp Matthias , Weller Michael 
Published: May 2019

e13560 Background: Glioblastoma is the most common primary malignant brain tumor with a poor prognosis. CD317 (HM1.24) is a transmembrane protein and may exist in differently spliced variants. It is highly expressed on plasma cells in multiple myeloma, as well as in certain solid tumor types. While several antibody drug conjugates are already in clinical practice, small immunotoxins with a different intracellular mode of action are only established in hairy cell leukemia. The immunotoxin HM1.24-ETA’ protein is a CD317 single chain Fv (scFv) antibody fused to a truncated version of Pseudomonas aeruginosa exotoxin A (ETA’). Methods: In vivo CD317 mRNA expression in human glioma of different grades and survival probabilities of glioblastoma patients based on CD317 mRNA expression were analyzed using the database of the Cancer Genome Atlas network (TCGA). CD317 protein expression was analyzed by immunohistochemistry in a human tissue microarray (TMA). In vitro CD317 mRNA expression was assessed by RT-PCR and CD317 protein levels by flow cytometry in several human glioblastoma cell lines. A cytotoxicity assay after treatment with HM1.24-ETA’ immunotoxin was performed in human glioblastoma cell lines. Results: Data on mRNA expression from the TCGA database demonstrated, that CD317 was upregulated in human glioblastomas compared to lower grade gliomas. In the group of glioblastoma patients increased CD317 mRNA expression was associated with decreased probability of survival ( p< 0.001). CD317 protein levels correlated directly with the tumor grade of astrocytic gliomas in the TMA. CD317 was expressed heterogeneously on mRNA and protein levels in the tested cell-lines in vitro. HM1.24-ETA’ induced cytotoxicity in CD317-positive glioblastoma cells in a concentration-dependent manner. Animal experiments currently performed suggest activity in glioblastoma xenografted mice. Conclusions: These data highlight CD317 as an interesting target antigen and HM1.24-ETA’ immunotoxin as a strategy for immunotherapy of glioblastoma patients.
Radiomics-based identification of peritumoral infiltration in de novo glioblastoma imaging presents targets amenable for potential targeted extended resection: A neurosurgical survey.
Authors: Sloan Andrew E. , Shukla Gaurav , Rathore Saima , Akbari Hamed , Gondi Vinai , Davatzikos Christos 
Published: May 2019

e13573 Background: Radiomics-based machine learning tools have been developed to analyze preoperative multiparametric MR images of patients with glioblastoma (GBM) to predict various outcomes of clinical interest, such as survival, molecular mutation status, and subclinical peritumoral infiltration, all before initial surgical resection. Preoperative identification of regions containing the highest probability of subclinical tumor infiltration presents an opportunity for targeted extended resection in the setting of a clinical trial, but the willingness of neurosurgeons to perform such a procedure is not known. Methods: We selected five neurosurgeons from high volume centers ( > 20 GBM surgeries per year) and performed an in silico study of anonymized preoperative images of patients with GBM, with radiomics-based infiltration maps depicting high probabilities of peritumoral infiltration. With regards to these regions beyond the enhancing tumor, we surveyed them on their willingness to attempt biopsy, and asked them to rate whether they felt such a region could be resected. Results: Preoperative maps of 20 patients with GBM, containing 26 regions of interest depicting high-risk peritumoral infiltration regions (distributed among frontal, temporal, occipital, parietal, cerebellar, and deep loci) were presented to five expert neurosurgeons from different institutions. Of the 20 patients, a median of 90% were deemed to be safe to biopsy; a median of 55% were felt to be definitely resectable, and median 35% to be possibly resectable. 85% of the 20 subjects were felt to be good candidates for participation in a clinical trial assessing the feasibility, safety, and efficacy of targeted extended resection. Conclusions: In selected patients, experienced neurosurgeons are willing to attempt targeted extended resection using radiomics-based maps of peritumoral infiltration in the context of a clinical trial. Proceeding with development of such a trial is warranted.
Genomic characterization of brain metastases (BM) in high-grade serous ovarian cancer (HGSOC).
Authors: Duchnowska Renata , Supernat Anna Maria , Pęksa Rafał , Łukasiewicz Marta , Stokowy Tomasz , Umińska Monika , Iżycka-Świeszewska Ewa , Kowalczyk Anna , Och Waldemar , Rucinska Monika , Olszewski Wojciech P , Mandat Tomasz , Jarosz Bozena , Bieńkowski Michał , Biernat Wojciech , Jassem Jacek 
Published: May 2019

e13580 Background: BM are a rare occurrence in ovarian cancer (OC) and their molecular characteristics is virtually unknown. DNA damage repair (DDR) deficiency is prevalent in OC, and co-mutated TP53 and any DDR denotes high tumor mutation burden (TMB). We genetically characterized a unique series of high-grade serous ovarian cancer (HGSOC) patients who developed BM to identify alterations of potential clinical relevance. Methods: Whole-exome sequencing (2x150bp, SureSelectXT Library Prep Kit, Illumina’s NovaSeq platform) was performed in matched BM, primary tumors (PT) and normal tissue. DNA was extracted from FFPE samples using QIAamp DNA FFPE Tissue Kit (Qiagen, Germany). All mutations were checked with Catalogue of Somatic Mutations in Cancer (COSMIC) and Integrative Genomics Viewer (IGV). Results: Study group included 10 HGSOC patients (International Federation of Gynecology and Obstetrics classification (FIGO) II-IV, mean age at diagnosis 48 years, range 35-59). Median time from primary HGSOC diagnosis to BM was 38 months (range, 18 to 149). TP53 somatic mutations were found in both primary tumor (PT) and BM in 8 patients. The other 2 cases harbored TP53 mutations not reported in COSMIC catalogue: p.S60L and intronic TP53 mutation preceding p.I322 (IGV). In 9 cases TP53 mutations coexisted with germline or somatic DNA damage repair deficiency. Four cases contained BRCA1 mutations (all germline), and none harbored germline BRCA2 mutation. Other mutated genes included MLH1 (2 somatic, 2 germline), ATR (4 germline, 1 somatic), AMT (1 somatic), RAD50 (1 somatic), ERCC4 (1 somatic), FANCD2 (1 somatic) and RPA1 (1 germline). Three mutation signatures defined in the COSMIC database were indentified in BM: 6, 20 and 30. In 6 cases these mutations were shared in PT, and in another 4 their presence in PT could not be determined due to technical reasons. Median survival from BM was 31 months (range, 5 to 184). Conclusions: Genomic analysis of BM provides an opportunity to identify potentially clinically informative alterations. Mutational profiles in PT are generally reflected in BM. Detected genetic alterations suggest their potential sensitivity to PARP inhibitors and immunotherapy.