bluuebunny/crossref_metadata_2025_split huggingface dataset:
Part VIII: Final Provisions
Authors: Hobér Kaj 
Published: December 2020

Abstract
This concluding chapter assesses Part VIII, ‘Final Provisions’, of the Energy Charter Treaty. Article 38 of the ECT states that the ECT was open for signature only for States which had signed the European Energy Charter. Article 39 is entitled ‘Ratification, Acceptance or Approval’. The ECT is open for ratification, acceptance, and approval to States which have signed the Treaty as per Article 38. Article 40 builds on Article 29 of the Vienna Convention, which deals with the territorial scope of treaties. Similarly, Article 41 mirrors Article 15 of the Vienna Convention, which deals with consent by a State to be bound by a treaty expressed by accession. Article 42 sets forth the procedure to be followed to amend the Treaty. Meanwhile, pursuant to Article 43 of the ECT, the Charter Conference may authorize the negotiation of association agreements with a view to pursuing the objectives and principles of the European Energy Charter and the ECT. The provisions of Article 44 determine when the Treaty enters into force. Article 45 concerns provisional application, while Article 46 concerns reservations. Article 47 regulates withdrawals from the Treaty, the procedure thereof, and the effect of withdrawals. Article 48 is entitled ‘Status of Annexes and Decisions’; Article 49 states that the Government of the Portuguese Republic shall be the Depositary for the ECT; and Article 50 is entitled ‘Authentic Texts’.
BIOM-01. TYROSINE KINASE INHIBITORS AS A TREATMENT OF SYMPTOMATIC CNS METASTASES IN ONCOGENE-DRIVEN NSCLC
Authors: Benouaich-Amiel Alexandra , Gal Omer , Dudnik Elizabeth , Rotem Ofer , Finket Inbar , Peretz Idit , Zer Alona , Mandel Jacob , Siegal Tali , Bar Jair , Yust-Katz Shlomit 
Published: December 2020

Abstract

BACKGROUND
Central nervous system (CNS) metastases occur frequently in oncogene-driven non-small cell lung cancer (NSCLC). Standard treatment (i.e surgery, whole brain radiation therapy or stereotactic radiosurgery) approaches can potentially delay systemic treatment and/or result in neurocognitive impairment. Recently, next generation tyrosine kinase inhibitors (TKIs) have demonstrated a remarkable intracranial activity. However, most clinical trials did not enroll patients with neurological symptoms. Our study aims to assess the CNS activity of targeted therapy in this patient population.

METHOD
We present a case series of nine NSCLC patients with either EGFR mutation of ALK rearrangement and symptomatic CNS metastases that were treated with TKIs, without radiation therapy or surgery. Clinicopathological characteristics, treatment and outcome were analyzed.

RESULTS
Most patients presented with symptomatic CNS metastases at time of metastatic disease presentation (6/9 patients). Additionally, the majority of patients had leptomingeal disease (6/9 patients) and multiple parenchymal metastases. Patients presented with a variety of CNS symptoms with the most common being nausea, vomiting, headache and confusion. Five patients were treated with Osimertinib. One patient with ALK rearrangement was treated with Lorlatinib. The remaining 3 patients received either Gefitinib or Afatinib. Most patients (6/9 patients) responded rapidly both clinically and radiographically to the targeted treatment, with a marked correlation between systemic and intracranial radiographic response.

CONCLUSION
Upfront use of next generation TKIs in patients with oncogene-driver NSCLC with symptomatic CNS metastases is associated with reasonable intracranial activity and represents a valuable treatment option.
BIOM-03. INVASIVE HISTOPATHOLOGY DRIVES POOR OUTCOMES IN SURGICALLY RESECTED BRAIN METASTASES
Authors: Dankner Matthew , Caron Maxime , Al-Saadi Tariq , Yu WenQing , Ouellet Veronique , Ezzeddine Rima , Annis Matthew G , Le Phuong Uyen , Nadaf Javad , Neubarth Noah S , Savage Paul , Zuo Dongmei , Couturier Charles P , Monlong Jean , Djambazian Haig , Altoukhi Huda , Bourque Guillaume , Ragoussis Jiannis , Diaz Roberto J , Park Morag , Guiot Marie-Christine , Lam Stephanie , Petrecca Kevin , Siegel Peter M 
Published: December 2020

Abstract

BACKGROUND
Surgery as a single modality for the treatment of brain metastases (BrM) results in local recurrence (LR) in 60% of patients. These failure rates are reduced by half with post-operative radiotherapy. The non-invasive nature of BrM has led to the assumption that local recurrence is caused by spillage of cancer cells into the surgical cavity at the time of surgery. We present evidence suggesting that invasion of metastatic cancer cells into the adjacent brain is present in the majority of BrM and is associated with LR, leptomeningeal metastasis (LM), and overall survival (OS).

METHODS
We assessed the histopathological growth pattern (HGP) of 164 surgically resected BrM. HGP was correlated with LR, LM and OS. Single-cell transcriptomics (scRNAseq) was performed on 15,615 cells from metastasis center (MC) and surrounding brain (SB) adjacent to the tumor. N=30 orthotopic patient-derived xenograft models (OPDX) were established from BrM.

RESULTS
56/164 (34%) BrM specimens showed a minimally invasive (MI) HGP between the tumor and adjacent brain while 108/164 (66%) showed significant invasion of tumor lobules or single-cells into the brain (HI-HGP). HI-HGP was associated with LR, LM and shortened OS in BrM patients. scRNAseq identified abundant cancer cells in SB that overexpressed pathways and genes involved in cell survival and stress adaptation compared to matched cancer cells in MC. Validation of these targets with immunohistochemistry in patient and OPDX tissues revealed cold-inducible RNA binding protein (CIRBP) overexpression in HI-HGP patient and OPDX BrM. Modulation of CIRBP expression in OPDX and cell line models of HI-HGP BrM delayed BrM progression and extended OS.

CONCLUSION
HI-HGP is a poor prognostic indicator in patients with surgically resected BrM, establishing HGP as an important prognostic factor that should be considered by clinicians treating BrM patients. We identify CIRBP as a functional mediator of this process.
BIOM-12. CIRCULATING TUMOR DNA IN ADULTS WITH GLIOMA: A SYSTEMATIC REVIEW AND META-ANALYSIS OF BIOMARKER SENSITIVITY
Authors: McMahon James , Studer Matthew , Ulrich Bryan , Pradilla Gustavo 
Published: December 2020

Abstract

BACKGROUND
Circulating tumor DNA (ctDNA) has emerged as a promising non-invasive biomarker to capture tumor genetics in patients with primary brain tumors. Research into its clinical utility, however, has not been standardized, as performance statistics of ctDNA remain undefined and optimal ctDNA assay and biospecimen sources for its evaluation have not been conclusively identified. We sought to determine a pooled sensitivity of the detection ctDNA in both CSF in plasma when compared to detecting the same mutant DNA in tumor tissue of gliomas. We then sought to compare ctDNA sensitivity between these two reservoirs, as well as between individual WHO grades of glioma.

METHODS
Following PRISMA guidelines, systematic review and meta-analysis was performed using published studies that assessed circulating tumor DNA in either plasma or CSF among adult patients with histopathology-confirmed glioma. Weighting of individual studies was conducted to reach an overall pooled sensitivity of ctDNA detection in both CSF and plasma. Chi-squared tests of independence were performed to compare overall sensitivity of ctDNA in CSF versus plasma, as well as to estimate the sensitivity of ctDNA for each WHO grade of glioma.

RESULTS
The overall reported sensitivity of ctDNA in CSF was found to be 77.4%, significantly higher than the 38.8% sensitivity in plasma (p&lt; 0.0001). Sensitivity was significantly higher for high grade (82.8%) than low grade (60.5%) tumors in CSF (p=0.0023), and sensitivity was found to sequentially increase with increasing WHO grade. Qualitative analysis revealed evidence of greater sensitivity among single-allele PCR or small targeted next generation sequencing (NGS) panels, and increased sensitivity among larger tumors and those in proximity to cisternal or ventricular CSF.

CONCLUSION
Circulating tumor DNA is potentially a highly sensitive non-invasive biomarker among adults with gliomas. To maximize its sensitivity, CSF should be studied with targeted genetic analysis platforms, particularly in suspected high-grade gliomas.
BIOM-15. SUBVENTRICULAR ZONE INVOLVEMENT IS ASSOCIATED WITH WORSE OUTCOME IN GLIOMA WHO GRADE II INDEPENDENT OF MOLECULAR MARKERS
Authors: Karschnia Philipp , Weller Jonathan , Blobner Jens , Stoecklein Veit M , Dorostkar Mario M , Rejeski Kai D , Forbrig Robert , Niyazi Maximilian , von Baumgarten Louisa , Dietrich Jorg , Tonn Joerg-Christian , Thon Niklas 
Published: December 2020

Abstract

BACKGROUND
The subventricular zone represents a niche of adult neural stem cells. Involvement of the subventricular zone is associated with decreased survival in malignant glioma. We aimed to determine whether a similar association applies to low-grade gliomas.

METHODS
A retrospective institutional database search was performed for patients with glioma WHO grade II according to the 2016 classification. Demographic data, histology and molecular signature, imaging, and therapy were recorded and outcome was analysed for tumors with and without infiltration of the subventricular zone.

RESULTS
182 patients with glioma WHO grade II were identified, including 97 oligodendrogliomas and 85 astrocytomas. 78 of 182 patients (43%) presented with subventricular zone involvement. Demographics, histopathology, and molecular signature did not differ between patients with and without subventricular zone involvement. First-line management included surgery, chemotherapy, radiotherapy, brachytherapy, and wait-and-scan approaches. Median follow-up was 43 months. Median time to malignant progression was 122 months; median overall survival was not reached. Subventricular zone involvement was a negative prognostic marker for time to malignant progression (p = 0.002) and overall survival (p = 0.023) in the entire cohort as well as in the subgroup of patients who were managed with wait-and-scan approaches. Among patients in which early therapy was provided, subventricular zone involvement was not prognostic for overall survival but for time to malignant progression. In multivariate analysis, subventricular zone involvement was associated with worse prognosis independent of molecular markers or treatment approaches including use of resection.

CONCLUSION
Subventricular zone involvement represents a key risk factor for worse outcome in glioma WHO grade II. Early first-line therapy may improve outcome in such patients.
BIOM-24. IDENTIFYING VULNERABILITY SIGNATURES THROUGH MACHINE LEARNING IN AN UMBRELLA TRIAL FOR GLIOBLASTOMA
Authors: Lee Matthew , Tang Nanyun , Ahluwalia Manmeet , Fonkem Ekokobe , Fink Karen , Dhruv Harshil , Berens Michael , Peng Sen 
Published: December 2020

Abstract
Glioblastoma is characterized by intra- and inter-tumoral heterogeneity. An umbrella trial tests multiple treatment arms depending on corresponding biomarker signatures. A contingency of an umbrella trial is a suite of preferably orthogonal molecular biomarkers to classify patients into the likely-most-beneficial arm. Assigning thresholds of molecular signatures to classify a patient as a “most-likely responder” for one specific treatment arm is a crucial task. Gene Set Variation Analysis (GSVA) of specimens from a GBM clinical trial of methoxyamine associated differential enrichment in DNA repair pathways activities with patient response. The 44 DNA-repair related pathways confound confident “high” enrichment of responder, as well as obscuring to what degree each feature contributes to the likelihood of a patient’s response. Here, we utilized semi-supervised machine learning, Entropy-Regularized Logistic Regression (ERLR) to predict classification. By first training all available data using semi-supervised algorithms we transformed unclassified TCGA GBM samples with highest certainty of predicted response into a self-labeled dataset. In this case, we developed the predictive model which has a larger sample size and potential better performance. Our umbrella trial design currently includes three treatment arms for GBM patients: arsenic trioxide, methoxyamine, and pevonedistat. Each treatment arm manifests its own signature developed by the above (or similar) machine learning pipeline based on selected gene mutation status and whole transcriptome data. By expansion to three, independent treatment arms within a single umbrella trial, a “mock” stratification of TCGA GBM patients binned 56% of all cases into a “high likelihood of response“ arm. Predicted vulnerability using genomic data from preclinical PDX models placed 4 out of 6 models into a “high likelihood of response” regimen. Our utilization of multiple vulnerability signatures in an umbrella trial demonstrates how a precision medicine model can support an efficient clinical trial for heterogeneous diseases such as GBM.
BIOM-34. CLINICAL, RADIOGRAPHIC, AND PATHOLOGIC PREDICTORS OF RESPONSE TO ANTI-PD-1 AND ANTI-PD-L1 THERAPY IN IDH-WILDTYPE GLIOBLASTOMA PATIENTS
Authors: Iorgulescu Bryan , Lim-Fat Mary Jane , Qin Lei , Grant Gareth , Huang Raymond , Young Geoffrey , Reardon David 
Published: December 2020

Abstract

BACKGROUND
Although monoclonal antibodies targeting PD-1 and its ligand PD-L1 have improved overall survival (OS) for many cancers, recent trials of anti-PD-(L)1 in glioblastoma revealed no OS benefit. However, a small subset of patients appears to benefit, warranting evaluation of predictive markers of improved survival.

METHODS
We evaluated 108 patients managed at Dana-Farber Cancer Institute for IDH-wildtype glioblastoma, who received anti-PD-(L)1 therapy and had complete clinical, pathologic, and radiographic data. OS was measured from anti-PD-(L)1 initiation to death or censored at last follow-up. Predictors of OS were evaluated by multivariable Cox regression, adjusted for age at diagnosis, sex, disease setting (newly-diagnosed vs. recurrent), MGMT status, chemotherapy and bevacizumab before/during anti-PD-(L)1, extent of resection prior to anti-PD-(L)1, and, at anti-PD-(L)1 initiation: KPS, dexamethasone use, absolute lymphocyte count (ALC), ADC mean value, FLAIR volume, T1 post-contrast volume.

RESULTS
Of 108 patients, 28 (25.9%) were newly-diagnosed, 80 (74.1%) were treated in the recurrent setting, and 100 died (92.3%). In multivariable analysis, unmethylated MGMT (HR 2.31, 95%CI: 1.38–3.88, p=0.002), and, at the time of anti-PD-(L)1 initiation, baseline dexamethasone use (HR 1.79, 95%CI: 1.07–3.00, p=0.03), lower ADC mean values (reference 2nd quartile [1,130-1,262 10-6mm2/s]; 3rd quartile [1,268–1,388] HR 0.32, 95%CI: 0.15–0.67, p=0.002; 4th quartile [1,402–11,966] HR 0.30, 95%CI: 0.14–0.66, p=0.003), and higher T1 post-contrast volumes (reference 2nd quartile [4,121–8,157mm3]; 3rd quartile [8,701–14,663mm3] HR 2.08, 95%CI: 1.03–4.19, p=0.04; 4th quartile [15,566-64,362mm3] HR 3.15, 95%CI: 1.49–6.69, p=0.003) independently predicted worse OS. Older age (HR 1.02/year, 95%CI: 1.00–1.05, p=0.07) and lower ALC (HR 0.66/unit, 0.40–1.10, p=0.11) trended towards worse OS.

CONCLUSION
Unmethylated MGMT, and, at the time of starting anti-PD-(L)1, baseline dexamethasone, low ADC mean value, and high T1 post-contrast volume may be predictive of worse OS in IDH-wildtype glioblastoma patients treated with anti-PD-(L)1. These findings may help better select patients who could benefit from PD-(L)1 inhibitors.
BIOM-35. MULTI ANALYTE ASSAY FOR NON-INVASIVE DIAGNOSIS OF BRAIN TUMORS
Authors: Akolkar Dadasaheb , Patil Darshana , Fulmali Pooja , Puranik Sneha , Apurwa Sachin , Patil Revati , Fulmali Pradip , Adhav Archana , Mene Priti , Paranjape Pratik , Golar Snehal , Puranik Swapnil , Patel Shoeb , Ranjan Vishal , Chougule Rohit , Khan Shabista , Dhasarathan Raja , Datta Vineet , Sims Cynthe , Srinivasan Ajay , Datar Rajan 
Published: December 2020

Abstract
The diagnosis of Central Nervous System (CNS) malignancies such as Gliomas in individuals presenting with Intracranial Space Occupying Lesions (ICSOL) is based on histopathological examination (HPE) of tumor tissue obtained by an invasive brain biopsy. However, brain biopsies are resource intensive and are associated with procedural risks such as haemorrhage, morbidity and mortality. The present study evaluated a non-invasive approach for diagnosis of CNS-M in symptomatic individuals based on evaluation of circulating tumor analytes in peripheral blood. The non-invasive multi-platform approach for diagnosis of CNS-M included Immunocytochemistry (ICC) profiling and Fluorescence in situ Hybridization (FISH) of Circulating Tumor Cells (CTCs) and Digital Droplet PCR (ddPCR) of cell-free tumor DNA (ctDNA) and exosomal mRNA. Performance characteristics of each platform were evaluated using blood and tissue samples from 445 individuals including 227 known cases of CNS-M, 47 known cases of benign CNS conditions (CNS-B), 141 known cases of other cancers with brain metastases (OTH-M) and 30 asymptomatic individuals (ASYM). In a set of 37 samples from individuals with radiological ICSOL, suspected of malignancy (CNS-S) complete diagnostic work-up was performed with ICC, FISH and ddPCR. Glial CTCs were detected in 88.8% of 227 CNS-M and undetectable in 89.4% of 47 CNS-B or 100% of 141 OTH-M, indicating high sensitivity and specificity, respectively. The multi-analyte approach discerned CNS-M from CNS-B as well as OTH-M with 91.7% accuracy and accurately inferred lineage in 84.6% of cases. This non-invasive multi-analyte approach can diagnose CNS-M with an accuracy not inferior to standard HPE, can substitute invasive biopsies in most cases and is particularly helpful in cases where a biopsy is not viable.
BIOM-37. INITIAL RADIOGRAPHIC ASSESSMENT OF ADC VALUES IN PEDIATRIC PATIENTS TREATED WITH DAY101 FOR RECURRENT OR PROGRESSIVE LOW-GRADE GLIOMAS (LGGs) HARBORING MEK/ERK PATHWAY ALTERATIONS
Authors: Krzykwa Emily , Korn Ronald , Blackman Samuel , Wright Karen 
Published: December 2020

Abstract

BACKGROUND
Calculated from a diffusion-weight image (DWI), the apparent diffusion coefficient (ADC) is a quantitative measure that reflects observed net movement of water and correlates to tumor cellularity. We examine the changes in ADC values in patients with LGG treated with dimeric, pan-RAF inhibitor DAY101 (formerly TAK-580/MLN2480).

METHODS
Focusing on ADC change with treatment, we reviewed historical, baseline, and on-treatment brain MRIs for 9 patients enrolled on our institutional, IRB-approved phase 1 trial of DAY101 in children and young adults with radiographically recurrent or progressive LGG harboring MEK/ERK pathway alterations. De-identified DICOM MRI files were independently reviewed. Time points selected included baseline, first follow-up and best response. The pmod molecular image software package was utilized for data processing of ADC estimates. ADC changes were displayed as a histogram with mean values. Results were based upon a single read paradigm.

RESULTS
A shift to lower ADC values for solid components of these tumors was observed, reflecting cellularity and organization; while necrosis correlated with a shift toward higher ADC values. DWI results show reduced ADCs in responding patients, with greater percent change in ADC from baseline associated with deeper responses among treated patients. DWI for treated patients with resultant stable disease showed no significant change in ADC values from baseline while a shift toward higher ADC values was evident in treated, progressing tumors.

CONCLUSION
Preliminary DWI analysis reveals that a reduction in ADC values may correlate with treatment response and a shift toward more normal cellularity in tumors treated with DAY101. This method will be applied to a larger cohort of patients in an ongoing phase 1 trial (NCT03429803) and a planned phase 2 trial.
BIOM-39. ESTABLISHMENT OF A CONNECTIVITY SIGNATURE FOR GLIOMAS
Authors: Kessler Tobias , Hai Ling , Hoffmann Dirk , Xie Ruifan , Mandelbaum Henriette , Jung Erik , Schlesner Matthias , Winkler Frank , Wick Wolfgang 
Published: December 2020

Abstract
Recent studies have demonstrated extensive cell-to-cell connectivity between tumor cells of gliomas with considerable relevance for tumor progression and therapy resistance. Tumor microtubes (TMs) are neurite-like tumor cell extensions that build these tumor cell networks. Measuring the extent of connectivity in individual tumors has been challenging and depended on anatomical parameters that are difficult to evaluate in patient samples. We performed bulk and single-cell (sc)RNA sequencing of connected vs. unconnected tumor cells from patient-derived xenograft tumors using a newly developed technology that exploits SR101 dye transfer within tumor cell networks. scRNA sequencing was performed with 17 human glioblastoma tumor samples. Three diffuse glioma cohorts from The Cancer Genome Atlas (n = 648), the Chinese Glioma Genome Atlas (n = 668) and the NCT Neuro Master Match (n = 38, IDH-wildtype only) were used to assess clinical properties. A connectivity signature both from bulk and scRNA sequencing data of xenografted primary glioblastoma tumor cells was established. Comparative analysis showed better performance and higher biological relevance of the single-cell derived signature that involves 71 genes. Most of the genes are related to neurogenesis and neural tube development, including several previously recognized TM-relevant genes. Highest connectivity was observed in astrocytic-like and mesenchymal-like tumor cells. Induction of connectivity in vitro was accompanied with increase of the connectivity signature. The connectivity signature was higher in astrocytic as compared to oligodendrocytic gliomas, and highest in IDH-wildtype gliomas. In accordance, connectivity correlated strongly with dismal survival in all three glioma cohorts. The connectivity signature established here is biologically plausible and associates with prognostically relevant glioma subtypes. It provides the first proof-of-principle that tumor cell connectivity is relevant for the clinical course of patients with gliomas, and at the same time serves as a robust biomarker that can be used for future studies, including prospective clinical trials.