bluuebunny/crossref_metadata_2025 huggingface dataset:
Sovereign and Individual Official Immunity
Authors: Bradley Curtis A
Published: December 2020

This chapter discusses four types of immunity in U.S. litigation: the immunity of foreign governments and their agencies and instrumentalities; the immunity of international organizations; the immunity of diplomats and consular officials; and the immunity of other foreign officials. Foreign governmental immunity is addressed by an extensive statute that was enacted in 1976—the Foreign Sovereign Immunities Act—and both the historical practice predating the Act and its core provisions are considered here. Among other things, the chapter describes how courts have interpreted some of the exceptions to immunity in the Act, such as for commercial activity and noncommercial torts, and also for certain acts by state sponsors of terrorism. International organization immunity is discussed in light of the Supreme Court’s 2019 decision in Jam v. Int’l Finance Corp. Diplomatic immunity and consular immunity are addressed by multilateral treaties, and this chapter describes those treaties and how they have been applied by U.S. courts. The most unsettled category of immunity concerns suits against other foreign government officials, including against sitting and former heads of state. The chapter describes how the lower courts, since the Supreme Court’s 2010 decision in the Samantar case, have been developing a common law of immunity for these cases, while also often giving deference to the views of the executive branch. The chapter also notes various unresolved issues, including issues concerning the proper level of deference and the extent to which the violation of jus cogens norms of international law can qualify as official conduct for purposes of conduct-based immunity.
Extradition and Other Means of Criminal Law
Enforcement
Authors: Bradley Curtis A
Published: December 2020

This chapter considers the extradition of criminal suspects to and from the United States, as well as other issues relating to international criminal law enforcement. The chapter begins by describing early U.S. practice relating to extradition. It then describes the respective roles of the courts and the executive branch in modern extradition cases. The chapter further describes some of the common limitations in U.S. extradition treaties, such as the dual criminality requirement, the political offense exception, and the specialty doctrine, and how these limitations have been applied by the courts. In addition, the chapter considers special issues that have arisen in some cases involving extradition to the United States where the federal government or a state government is likely to seek the death penalty. Besides extradition treaties, the chapter also discusses Mutual Legal Assistance Treaties and prisoner exchange agreements. The chapter concludes by discussing the domestic legal implications of both international abduction of criminal suspects and “extraordinary rendition” of suspects in the war on terrorism.
Foundations
Authors: Werle Gerhard , Jeßberger Florian
Published: December 2020

This chapter sets down the legal and historical foundations of international criminal law. It begins with a brief overview of the history of international criminal law, beginning with the 1919 Versailles Peace Treaty and ending with the developments after the creation of the International Criminal Court (ICC) Statute. From there, the chapter discusses the concepts, aim, and legitimacy of international criminal law before turning to the role of international criminal law within the international legal order. Afterward, the chapter turns to the sources and interpretation of international criminal law as well as universal jurisdiction, the duty to prosecute, and transitional justice. Next, the chapter considers the relationship between international and domestic courts as well as the prosecution of international crimes under international law by international and ‘internationalised’ courts. Finally, this chapter closes with a discussion on international criminal law in practice.
General Principles
Authors: Werle Gerhard , Jeßberger Florian
Published: December 2020

This chapter focuses on the general principles of international criminal law. It first develops a general theory of crimes under international law by considering the concept of crimes under international law as well as the context of organised violence. The structure of crimes under international law is also explored. Next, the chapter studies the material and mental elements of crimes under international law. Individual criminal responsibility and superior responsibility are also discussed, as are the grounds for excluding criminal responsibility. Next, the chapter covers inchoate crimes, omissions within the context of the ICC Statute, immunity, the multiplicity of offences, and finally, the requirements for prosecution.
Genocide
Authors: Werle Gerhard , Jeßberger Florian
Published: December 2020

This chapter covers genocide. It first examines the phenomenon of genocide, particularly in the context of the Holocaust, the history and structure of the crime, and how the criminalisation of genocide seeks to protect certain groups' right to exist. The chapter then explores the material and mental elements of the crime, before discussing the incitement to commit genocide. Here, the structure of the crime of genocide is explored, alongside its material and mental elements. To conclude, the chapter explores the multiplicity of offences in genocide. Typically, numerous acts are involved in carrying out the crime of genocide, each of which in itself fulfils the requirements for genocide. As such, it is necessary to decide whether these individual acts should be seen as legally separate crimes or as one single crime.
War Crimes
Authors: Werle Gerhard , Jeßberger Florian
Published: December 2020

This chapter turns to war crimes. Here, the chapter narrows the definition of ‘war crimes’ to a violation of a rule of international humanitarian law that creates direct criminal responsibility under international law. It then proceeds to examine the historical development of war crimes as part of international humanitarian law as well as criminal sanctions, war crimes in non-international armed conflict, protected interests, and categories of war crimes. Afterward, the chapter describes the overall requirements for an offence to be deemed a war crime. Next, the chapter explores war crimes against persons, against property and other rights, and against humanitarian operations. It also discusses prohibited methods of warfare and the use of prohibited means of warfare. The chapter ends with a coverage of the multiplicity of offences.
International Survey on Legal Reasoning
Authors: Strong SI
Published: December 2020

This chapter discusses results from a large-scale, international survey of judges and arbitrators, focusing on the beliefs and behaviors associated with legal reasoning. This study seeks to identify general practices and motivations regarding legal reasoning to determine whether and to what extent conventional wisdom in this field is correct. Many questions in the survey mirror those asked in the semi-structured interviews, which allows a certain amount of validity testing across the two studies. The survey also addresses issues considered in the quantitative (coding) exercise, thereby allowing further triangulation of results.
Semi-Structured Interviews on Legal Reasoning
Authors: Strong SI
Published: December 2020

This chapter involves a series of semi-structured interviews of judges and arbitrators covering the same types of issues addressed by the survey. The chapter begins with methodological and definitional information before moving to the substantive results from the interviews, which focused not only on what judges and arbitrators do, but why they do it. Topics include use of legal authorities, the use of factual authorities (evidence), the reasoning process, and the drafting process as well as judicial and arbitral education.
Historical Background
Authors: Butler William E
Published: December 2020

This chapter traces the history of the Russian treaty from its inception during the Kievan Rus to Soviet applications of the instrument. The precise origins of the "treaty" in Kievan practice has not been determined. However, it was from this early period that concepts such as treaty ratifications and "confirmation" were conceived in early Russian law. From there, the chapter follows Russian treaties through post-medieval times, including the inclusion of international treaties within the 1825 Complete Collection of Laws of the Russian Empire. The chapter also takes a look at the so-called "internal treaties," by examining the differences between "international" treaties and "constitutional" treaties given Russia's historic borders and its relationships with neighboring states. Finally, the chapter outlines Soviet treaty policy and its doctrinal philosophies.
Sources of the Russian Law of Treaties
Authors: Butler William E
Published: December 2020

This chapter considers what Russian legislation, judicial practice, and doctrinal views regulate the conclusion, ratification, entry into force, or termination of treaties under Russian law. In other words, it asks how Russian law interacts with and/or implements the international law of treaties. Here, the sources of Russian law generally are also the sources of Russian foreign relations law, including the Russian law of treaties. The latter refers to a body of legislation, judicial practice, and doctrinal literature which determines how treaties are to be concluded, ratified, confirmed, approved, or provisionally applied by relevant State agencies, terminated, denounced, or suspended if necessary, and otherwise procedurally dealt with under Russian law. Furthermore, as the chapter shows, the sources of the Russian law of treaties are also the same sources of other branches or rules of Russian law.
Contemporary Treaty-Making in the Russian Federation
Authors: Butler William E
Published: December 2020

This chapter discusses Russia's standard procedures for entering into an international treaty. The 1969 Vienna Convention on the Law of Treaties and Russian international legal doctrine offer general guidance. In addition, certain requirements are imposed by the 1993 Russian Constitution, 1995 Law on treaties, edicts of the President and decrees or regulations of the Government, other federal laws, and subordinate legal acts of the Russian Federation. Aside from these, the chapter describes how, within a vast government, uniformity of approach and understanding is achieved with respect to treaty-making and how institutional memories are preserved with respect to past practices. As such, the chapter examines subjects ranging from the power to conclude treaties, to draft decisions and treaty proposals, to submissions to government, treaty signatures, and even the termination of a treaty's application.
Publication and Registration of Treaties in Russia
Authors: Butler William E
Published: December 2020

This chapter focuses on the publication of treaties-a major concern in Russia during the Soviet and post-Soviet eras. This was to prevent the Russian government from engaging in secret diplomacy, as it had been caught doing during World War I. From then on, secret diplomacy was abolished and the secret treaties whose texts were found in Imperial Russian State archives were published, to the discomfiture and embarrassment of the parties on both sides in the War. Soviet international lawyers considered the introduction of the registration and publication of treaties to be a significant contribution of their country to international law. However, the early Soviet legislation on the conclusion, ratification, and denunciation of treaties contained no provisions regarding their publication until 1924. Aside from the history of treaty publication, the chapter also outlines some treaty-relevant legislation.
International Treaties in Russian Judicial and Arbitral Practice
Authors: Butler William E
Published: December 2020

This chapter explores the role of Soviet and post-Soviet Russian courts in interpreting and applying international treaties. It is clear that Soviet courts dealt more frequently with treaties than the scanty published judicial practice of that period suggests. This early body of treaties may also have contributed to the emergence in the early 1960s of priority being accorded to Soviet treaties insofar as they contained rules providing otherwise than Soviet legislation. Whatever the volume of cases involving treaties that were considered by Soviet courts prior to 1991, the inclusion of Article 15(4) in the 1993 Russian Constitution transformed the situation. A further transformation occurred when the Russian Federation acceded to the 1950 European Convention on Human Rights and Fundamental Freedoms and began to participate in the deliberations of the European Court for Human Rights in Strasbourg.
The Energy Charter Treaty
Authors: Hobér Kaj
Published: December 2020

This chapter provides an overview of the Energy Charter Treaty. Developed on the basis of the European Energy Charter of 1991, the Energy Charter Treaty is a multilateral treaty dealing with inter-governmental co-operation in the energy sector. It covers five broad areas in the energy sector: trade; investment protection; transit; environmental protection and energy efficiency; and settlement of disputes. The trade provisions of the Treaty were designed to import fundamental GATT principles, such as non-discrimination, national treatment, most-favoured-nation treatment, and transparency. The provisions on investment protection are found in Part III of the Treaty. In particular, Article 13 in Part III deals with expropriation, while Article 10 deals with various standards of treatment of foreign investments. The rules for facilitating transit of energy through the participating States are laid down in Article 7. The transit regime is based on freedom of transit and the principle of non-discrimination. Meanwhile, Article 19 of the ECT sets forth a number of ‘best efforts’ obligations of the Contracting Parties with respect to environmental protection and energy efficiency. Lastly, the ECT includes two binding dispute settlement mechanisms: investor-State arbitration for investment disputes (Article 26) and state-to-state arbitration for basically all disputes that may arise under the ECT (Article 27), with the exception for disputes concerning competition (Article 6(7)) and environment (Article 27(2)). The chapter then looks at the Energy Charter Conference, an inter-governmental organization established by the ECT and the governing and decision-making body for the Energy Charter Process.
Rules of Attribution
Authors: Hobér Kaj
Published: December 2020

This chapter focuses on the rules of attribution. The State is not responsible for all acts and omissions of its nationals, but only for those which can be attributed to the State. It is thus necessary to establish this link between the State and the person, or persons, committing an unlawful act or omission. The legal principles used to establish this link are usually referred to as rules of attribution. The rules of attribution form part of the law of state responsibility, which, to a large part, is reflected in the work of the International Law Commission (ILC) of the United Nations. At its fifty-third session in 2001, the ILC adopted its final version of the ILC Articles on Responsibility of States for Internationally Wrongful Acts. The ILC Articles are intended to cover all aspects of state responsibility under international law. The rules of attribution are laid down in Chapter II of the ILC Articles. From an Energy Charter Treaty perspective, Articles 4—8 are the most relevant ones. The central provision with respect to attribution is Article 4, which confirms the well-established principle of international law that the State is responsible for the acts of its own organs acting in the capacity of the State.
The Preamble
Authors: Hobér Kaj
Published: December 2020

This chapter examines the Preamble of the Energy Charter Treaty. The Preamble draws heavily on the ideas and philosophy underlying the European Energy Charter. The Charter constitutes a political commitment to co-operation in the energy sector based on the idea of open and efficient energy markets. It foresees the creation of conditions stimulating private investment based on non-discrimination and respect for state sovereignty over natural resources. The signatories to the Concluding Document agreed to pursue the objectives and principles of the European Energy Charter and to transform them into binding international legal commitments which eventually lead to the Energy Charter Treaty. The signatories are desirous of sustainable energy development—improving energy security and maximising the efficiency of production, conversion, transport, distribution, and use of energy—to enhance safety and to minimize environmental problems, on an acceptable economic basis. Within the framework of state sovereignty and sovereign rights over energy resources and in a spirit of political and economic cooperation, they undertake to promote the development of an efficient energy market throughout Europe and a better functioning global market, in both cases based on the principle of non-discrimination and on market-oriented price formation, taking due account of environmental concerns.
Part I: Definitions and Purpose
Authors: Hobér Kaj
Published: December 2020

This chapter assesses Part I of the Energy Charter Treaty, which deals with definitions and the purpose of the treaty. Central to the functioning and proper understanding of the ECT, Article 1 sets forth relatively detailed definitions of key terms and concepts used in the ECT. In particular, there are two defined terms which are important: Article 1(6), which defines ‘Investment’; and Article 1(7), which defines ‘Investor’. These two concepts have been argued in practically every ECT award rendered so far. Article 1 also defines other key terms used in the ECT such as ‘Contracting Party’ (paragraph 4), ‘Energy Materials and Products’ (paragraph 5), and ‘Area’ (paragraph 10). Meanwhile, Article 2 is titled ‘Purpose of the Treaty’. Proceeding from the rules of treaty interpretation laid down in the Vienna Convention, Article 2 of the ECT is relevant when determining the object and purpose of the ECT. It should be noted that Article 2 refers to the European Energy Charter, which is also relevant when determining the object and purpose of the ECT.
PART II: Commerce
Authors: Hobér Kaj
Published: December 2020

This chapter addresses Part II of the Energy Charter Treaty, which deals with commerce and trade in the energy sector. Article 3 addresses general questions concerning access to international markets relating to Energy Materials and Products and Energy Related Equipment. Articles 4 and 5 deal with trade-related matters in the energy sector, with particular emphasis on the relationship between the ECT and the WTO Agreement. Stated in general terms, the objective is to ensure that trade-related matters under the ECT are compatible with the rights and obligations of the WTO Agreements. Meanwhile, Article 6 deals with competition matters and Article 7 with transit. The guiding principle laid down in Article 7 is the freedom of transit. Article 7 also has detailed provisions addressing the settlement of transit disputes. Lastly, Articles 8 and 9 deal with transfer of technology and access to capital respectively.
Part IV: Miscellaneous Provisions
Authors: Hobér Kaj
Published: December 2020

This chapter studies Part IV of the Energy Charter Treaty, which is entitled ‘Miscellaneous Provisions’. Article 18, dealing with sovereignty over natural resources, is the first article in Part IV of the ECT. This is significant, because the placement of Article 18 outside of Part III of the ECT means that the provisions in Article 18 cannot be made the subject of the dispute settlement mechanism in Article 26 of the ECT, which requires that there be an alleged breach of an obligation under Part III of the ECT. Meanwhile, Article 19 deals with environmental aspects and Article 20 with transparency. Article 21, concerning taxation, has a complex structure such that interpretation based on the Vienna Convention may be required. Article 22 deals with a Contracting Party's obligations in relation to the conduct of state enterprises (paragraphs 1 and 2); the conduct of entities which it has entrusted with governmental authority (paragraph 3); and the conduct of entities which have been granted exclusive or special privileges (paragraph 4). Article 23 addresses the responsibility of Contracting Parties for acts of all organs of government, be they at the national, regional, or local level. Article 24 sets forth a number of general exceptions to the obligations set out in the ECT. Lastly, Article 25 sets forth a separate exception related to most-favoured-nation treatment for members of an economic integration agreement (EIA).
Part VII: Structure and Institutions
Authors: Hobér Kaj
Published: December 2020

This chapter examines Part VII of the Energy Charter Treaty, which is entitled ‘Structure and Institutions’. Any signatory to the European Energy Charter may participate in negotiations envisioned in Article 33, ‘Energy Charter Protocols and Declarations’. A State or a Regional Economic Integration Organization may not, however, become a party to a Protocol or Declaration unless it becomes a Contracting Party to the ECT. Article 34 establishes the Energy Charter Conference, which is the principal decision-making body of the ECT. The Energy Charter Conference—at which each Contracting Party is entitled to have one representative—has political responsibility for the European Energy Charter, the ECT, and related instruments. Meanwhile, Article 35 is entitled ‘Secretariat’; The Secretariat organizes and administers the Charter Conference and its various bodies. Article 36 sets forth the voting rules at the meetings of the Charter Conference, while Article 37 concerns the funding principles. The activities of the Charter Conference and the Secretariat are funded by the Contracting Parties.
Part VIII: Final Provisions
Authors: Hobér Kaj
Published: December 2020

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

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

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

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< 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

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

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

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

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

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

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.
BIOM-40. ANALYSIS OF SERUM MIRNA IN GLIOBLASTOMA PATIENTS: TARGETED ENRICHMENT OF EXTRACELLULAR VESICLES ENHANCES SPECIFICITY FOR PROGNOSTIC SIGNATURE
Authors: Tzaridis Theophilos , Weller Johannes , Bachurski Daniel , Schäfer Niklas , Schaub Christina , Hallek Michael , Scheffler Björn , Glas Martin , Hartmann Gunther , Herrlinger Ulrich , Wild Stefan , Coch Christoph , Reiners Katrin
Published: December 2020

Glioblastoma is a devastating disease, for which biomarkers allowing a prediction of prognosis are urgently needed. microRNAs have been described as potentially valuable biomarkers in cancer. Here, we studied a panel of microRNAs in extracellular vesicles (EV) from the serum of glioblastoma patients and also in total serum without prior EV separation, and evaluated their correlation with the survival of these patients. Our study included 55 patients in total, 26 (47.3%) of which were treated within the multicenter Phase III CeTeG/NOA-09 trial and 29 (52.7%) in the Division of Clinical Neurooncology of the University Hospital of Bonn, as well as 10 healthy volunteers (HV). Blood was drawn from patients during the adjuvant chemotherapeutic treatment. A panel of 15 microRNAs was studied by quantitative real-time PCR in EV that were separated by size-exclusion chromatography, followed by CDxx* immunoprecipitation (SEC+CDxx*), and compared with those from total serum of glioblastoma patients and HV. Comparing SEC+CDxx* to total serum, we found evidence for enrichment of miR-21-3p and miR-106a-5p and, conversely, lower levels of miR-15b-3p in SEC+CDxx* EV. miR-15b-3p and miR-21-3p were upregulated in serum of glioblastoma patients compared to healthy subjects. Significant correlation with survival of the patients was found for levels of miR-15b-3p in total serum and miR-15b-3p, miR-21-3p, miR-106a-5p and miR-328-3p in SEC+CDxx* EV. Combining miR-15b-3p in serum or miR-106a-5p in SEC+CDxx* EV with any one of the other three microRNAs in SEC+CDxx* EV allowed for a prognostic stratification of glioblastoma patients. We have thus identified four microRNAs whose levels, in combination, can predict the prognosis for these patients. *=Cluster of Differentiation xx (CDxx); Molecule cannot be specifically mentioned due to pending patent.