bluuebunny/crossref_metadata_2025_split huggingface dataset:
P14.03 Shifting trends and entity-specific aspects in patients with brain metastasis: real-life analysis from 6031 individuals over an observation period of 30 years
Authors: Steindl A , Brunner T J , Heimbach K , Schweighart K , Moser G M , Niziolek H M , Moor E , Kreminger J , Starzer A M , Dieckmann K , Gatterbauer B , Widhalm G , Preusser M , Berghoff A S 
Published: September 2021

Abstract

BACKGROUND
We aimed to investigate the changing clinical characteristics of patients with brain metastases (BM) over the last three decades as the foundation for modern BM specific clinical trial planning.

MATERIAL AND METHODS
6031 patients with newly diagnosed BM from different solid tumors treated between 1986–2020 were identified from the Vienna Brain Metastasis Registry.

RESULTS
The fraction of BM originating from the most common BM causing primary tumors (lung cancer, breast cancer and melanoma) was stable over the observation period from 1986–2020. BM from renal cell carcinoma, colorectal cancer and cancer of unknown primary (CUP) decreased over time (p&lt;0.001). Synchronous diagnosis of BM and primary tumor was more frequently observed in lung cancer and CUP patients compared to breast cancer patients (p&lt;0.001). An increasing fraction of patients presented with asymptomatic BM (1986–1999: 20.2% vs. 2010–2020: 30.4%; p&lt;0.001), specifically in lung cancer (p&lt;0.001), melanoma (p&lt;0.001) and renal cell cancer (p=0.004). A decrease of neurosurgical procedures (1986–1999: 39.3% vs. 2010–2020: 20.4%) and an increase of radiation treatments (1986–1999: 56.5% vs. 2010–2020: 73.0%) and systemic therapies (1986–1999: 0.6% vs. 2010–2020: 2.4%; p&lt;0.001) was observed. Furthermore, median overall survival significantly increased across entities (1986–1999: 5 months vs. 2010–2020: 7 months; p=0.001). Intracranial progression as the cause of death increased across entities (p&lt; 0.001). The prognostic DS-GPA (Hazard ratio [HR] 1.42; p&lt; 0.001) and the Lung-molGPA (HR 1.67; p&lt;0.001) could be validated.

CONCLUSION
We observed changes of BM presentation and clinical parameters during the observation period depending on primary tumor origins. Future BM studies should follow an entity-specific approach and address the characteristics of modern BM cohorts.
P14.18 Patient and Public Involvement to define patient-centred outcomes from National Cancer Datasets
Authors: Pakzad-Shahabi L , Cherrington C , Brassil N , Even P , Gardner D , Fulcher W , Le Calvez K , Mauricaite R , Williams M 
Published: September 2021

Abstract

BACKGROUND
GlioCova uses linked national cancer data on all 51 000 adult patients with a primary brain tumour in England (2013 - 2018) to understand patterns of care, treatment, and outcomes in patients with glioma (http://wwwf.imperial.ac.uk/blog/gliocova/). A key aim is the use of patient and carer input in defining patient-centered outcomes. We have held multiple Patient & Public Involvement (PPI) sessions with patients and carergivers and data analysts to understand what patient and caregivers want to know about brain tumours.

MATERIAL AND METHOD
We used a modified Delphi method. The online PPI sessions (Zoom) consisted of two presentations, open discussions, and Q&As. We made the sessions as interactive as possible by using Mentimeter and an interactive online white board (Explain Everything). Pre-reading material was circulated via email. Attendees (6–14 per session) covered a wide range of ages (30–75), diagnoses (GBM, recurrent gliomas, low grade gliomas, ependymoma); patients, caregivers, neuro-oncology staff, data analysts and basic scientists. Work was conducted in line with the INVOLVE PPI guidance.

RESULTS
We identified four questions that were of interest to patients and had correlates in the data:
Patients and caregivers were also interested in the impact of diet, quality of life, social life, and exercise. However, these data cannot be answered using the current national data.

CONCLUSION
Our PPI work has helped us to identify and prioritise questions to ask of the data. Ongoing PPI work will provide a wider perspective and identify knowledge gaps for future research. Patients and caregivers report feeling empowered, being part of a team, feeling like they had given something back and done something meaningful for the research community and other patients. Patients and caregivers also felt that they had an enriched understanding of the data that is collected. As this process is an iterative process, we will hold more PPI sessions to identify and prioritise topics to analyse.
P14.23 Relation between neurological deficits and location of postsurgical ischemia in glioma resection
Authors: van der Boog A T J , David S , Steennis A M M , Dankbaar J W , Snijders T J , Verhoeff J J C , Robe P A 
Published: September 2021

Abstract

BACKGROUND
Postoperative ischemia is a known complications of glioma resection and can lead to neurological deficits. New or worsened postoperative deficits are often transient, but some patients experience persisting effects after surgery. Neuroanatomical location of ischemia is suspected to play an important role in the development as well as persistence of neurological deficits. Therefore, the aim of this study was to investigate the spatial relation between postoperative ischemia and short-term and long-term neurological deficits.

MATERIAL AND METHODS
Postoperative ischemia was defined as new confluent areas of diffusion restriction on DWI in a retrospective database of 144 adult WHO grade II-IV supratentorial glioma patients, who received MRI within 3 days after resection in 2012–2014. New or worsened neurological deficits of any grade at discharge and after 3 months was assessed in relation to postoperative ischemia by an experienced neuro-oncologist. We manually delineated ischemic lesions and spatially normalized these to stereotaxic MNI space. Next, we performed voxel-based analysis (VBA) to identify locations of ischemia associated with new or worsened neurological deficits and corrected for multiple comparisons using family-wise error correction to eliminate false positive results. Delineations were labeled using the Harvard-Oxford cortical and subcortical atlases and a white matter atlas (XTRACT).

RESULTS
Any new or worsened neurological deficits were present in 44 (30.5%) cases at discharge and in 27 (20.9%) cases after 3 months, of which respectively 26 (18%) and 21 (16.3%) were related to ischemia. Volume of ischemia was significantly associated with deficits at discharge (P = 0.003) and after 3 months (P = 0.039). No areas of ischemia were associated with a lack of new or worsened deficits. A statistically significant cluster of 42.96cc was associated with deficits at discharge and encompassed the right frontal, insular and tempo-occipital regions. Voxels associated only with deficits at discharge included lateral occipital cortices and supramarginal gyri. A cluster of 17.68cc in the right frontal and insular lobes was significantly associated with deficits after 3 months. Overlapping areas included the right thalamus, caudate nucleus, putamen, globus pallidum, insular cortex, middle and inferior temporal gyri, corticospinal tract and superior thalamic radiation.

CONCLUSION
Transient and persisting new or worsened deficits after glioma resection were significantly associated with volume of postoperative ischemia. Ischemic lesions in right frontal and insular regions, including the basal nuclei, corticospinal tract and superior thalamic radiation were significantly associated with persisting neurological deficits after 3 months, while temporo-occipital lesions were associated with transient deficits only found at discharge.
P14.65 Survival in a consecutive series of 467 glioblastoma patients: impact of prognostic factors and recurrent treatment at two independent institutions
Authors: Blakstad H , Brekke J , Rahman M A , Arnesen V S , Brandal P , Lie S A , Chekenya M , Goplen D 
Published: September 2021

Abstract

BACKGROUND
Glioblastoma (GBM) is an aggressive primary brain tumor with median overall survival (OS) of less than one year in unselected adult patients. There is no standard therapy at recurrence. We aimed to evaluate OS in a consecutive series of GBM patients from Norway’s two largest regional health authorities, compare the effect of physicians’ choice of antineoplastic treatment upon recurrence and identify prognostic and predictive factors.

MATERIAL AND METHODS
Clinicopathological data from n=467 patients with histologically confirmed GBM diagnosed and treated at Haukeland and Oslo university hospitals from January 2015 to December 2017 was retrospectively collected. Data included tumor location, methylation status of the methylguanine-DNA methyltransferase (MGMT) promoter and mutation of the isocitrate dehydrogenase (IDH) genes, patient age and sex, extent of tumor resection at primary diagnosis, and treatment at first, second and third tumor recurrences. Cox-proportional hazards regression with pairwise analyses adjusted for multiple testing with Scheffé’s post-hoc test were used to adjust effect of multiple risk factors on mortality.

RESULTS
Median OS was 12.1 months and 21.4 % and 6.8 % of patients were alive at 2 and 5 years, respectively. Treatment at recurrence varied between institutions but did not impact OS (p=0.201). Median time to progression was 8.2 months. Age, MGMT promoter methylation, tumor location and extent of tumor resection were all independent prognostic factors for OS. Patients receiving radiotherapy to 60 Gray with concomitant and adjuvant temozolomide at primary diagnosis had best outcome with median OS of 16.1 months and 9.3% were alive at 5 years. At first recurrence patients eligible for gammaknife/stereotactic radiosurgery (GK/SRS) or surgery, alone or combined with chemotherapy, had superior survival compared to chemotherapy alone (p&lt;0.0001 and p=0.014, respectively). On Scheffé’s post-hoc analyses only GK/SRS was superior to chemotherapy (p=0.01). At second and third recurrence none of the antineoplastic strategies came across as superior or inferior to each other using Cox. On Scheffé’s post-hoc analyses chemotherapy alone and combined with bevacizumab were superior at second recurrence (p=0.008 and p=0.042, respectively) and chemotherapy combined with bevacizumab was superior at third recurrence (p=0.043), compared to no antineoplastic treatment. Our retrospective study is limited by small sample sizes and heterogeneous treatment groups, especially at second and third recurrences, as well as patient selection.

CONCLUSION
Recurrence treatment differed between the two institutions but there was no difference in OS. Our findings underline the lack of standard therapy upon GBM recurrence and the urgent need for novel therapeutic strategies.
P14.69 Trends in postoperative chemoradiotherapy for Glioblastoma patients: a Danish cohort study
Authors: Trip A K , Veluppillai V K , Dahlrot R H , Guldberg T L , Muhic A , Høyer M , Lukacova S 
Published: September 2021

Abstract

BACKGROUND
Postoperative chemoradiotherapy (CRT), using conventional radiotherapy (convRT), has a key role in the treatment of glioblastoma (GBM) supported by level 1A evidence. In the past decade, evidence supporting hypofractionated radiotherapy (HFRT) has emerged. However, GBM patients in clinical trials are highly selected. Consequently, real-world patients may not be able to undergo evidence-based treatments. The aim of this retrospective Danish cohort study was to evaluate the utilisation of and compliance with postoperative CRT in real-world GBM patients over time.

MATERIAL AND METHODS
All adults (≥18 years) with newly diagnosed GBM (histology confirmed) between 2011 and 2018 were identified via the Danish Neuro-Oncology Registry, which was furthermore used to extract all data. Radiotherapy (RT) was classified as convRT (≤2 Gy/fr, planned dose 44–66 Gy) or HFRT (&gt;2 Gy/fr, planned dose 34 or 40 Gy). The utilisation of and compliance with CRT (only concomitant treatment assessed) was measured by intended and administered treatment, respectively. To assess trends, patients were grouped per year of diagnosis. Multivariable logistic regression was used to analyse the association of age (&lt;/≥70), sex, performance status (PS) before surgery and RT, tumour focality, extent of surgery, concomitant chemotherapy (CT), hospital (4 University Hospitals), and year of diagnosis, with convRT or HFRT.

RESULTS
The cohort consisted of 2153 patients. For the entire period, postoperative RT was planned in 1743 patients: utilisation of 81%, over time fluctuating between 77 and 84%. ConvRT was planned in 1428 patients (66%), with a steadily decreasing utilisation from 73% in 2011 to 52% in 2018. Of those, 1346 (94%) could complete RT as planned (over time fluctuating between 88–97%). In this group, the utilisation of and compliance with concomitant CT was 86% (fluctuating between 80–93%) and 73% (fluctuating between 47–84%), respectively. HFRT was planned in 315 patients (15%), with a utilisation of up to 26% in 2018, after a more pronounced increase since 2014. The compliance with HFRT was 93%, fluctuating between 85–100%. In this group, the utilisation of and compliance with concomitant CT was 33% (fluctuating between 0–47%) and 78% (fluctuating between 33–100%), respectively. The utilisation of HFRT compared to convRT was significantly associated with higher age, poorer PS before RT, multifocal tumour, less extensive surgery, less frequent concomitant CT, one hospital of RT treatment, and more recent diagnosis years.

CONCLUSION
The increased utilisation of HFRT is in line with emerging evidence during the cohort period. However, while HFRT was developed as a more convenient schedule for those with a poorer PS and older age, the overall utilisation of postoperative RT did not increase. Nor did the compliance with CRT increase in real-world Danish GBM patients.
P16.06 Immunophenotyping of tumor-infiltrating T cells in primary CNS lymphoma
Authors: Schliffke S , Maire C , Holz M , Bokemeyer C , Westphal M , Lamszus K , Mohme M 
Published: September 2021

Abstract

BACKGROUND
Primary CNS lymphoma represents a malignant disease with dismal prognosis. Standard of care is high dose chemotherapy and radiation. However, this combination cannot be applied to the elderly and fragile population. Immunotherapy holds great promise to be effective in these patients. This study therefore aims to explore the phenotype of tumor-infiltrating lymphocytes (TIL) in order to analyze the potential for immune checkpoint inhibition.

MATERIAL AND METHODS
We performed ex vivo multicolor flow-cytometry on surgical specimens of nine patients with intracerebral lymphoma, including seven with primary CNS lymphoma after isolation of TILs following standard protocols. Data was analyzed using a Fortessa LSR flow cytometer and Diva software. The study was approved by the local ethics committee (PV4904).

RESULTS
Our ex vivo phenotyping demonstrated a predominant infiltration of CD8+ T cells, which outnumber CD4+ T cells by a ratio of 2:1 (p&lt;0.01). Regulatory T cells (Tregs) were not increased in the tumor microenvironment and the NK cell frequency was reduced compared to the peripheral blood. While CD4+ T helper cells displayed significantly increased surface expression of multiple activation and checkpoint markers, including TIGIT, PD-1, Tim3 and CD57, cytotoxic CD8+ T cells predominantly expressed only TIGIT and PD-1. On average 70% and 80% of CD8+ T cells expressed PD-1 and TIGIT, respectively, compared to 35% and 60% of PD-1 and TIGIT on CD4+ T cells (p&lt;0.05). CD8+ T cells furthermore showed an increased expression of CD39 and a simultaneous downregulation of CD73, both ectoenzyms involved in the modulation of intratumoral ATP, thereby indicating a metabolic immune modulation by the tumor.

CONCLUSION
Taken together, our study demonstrates a strong infiltration of cytotoxic CD8+ T cells into cerebral lymphoma, which potentially can be disinhibited using checkpoint immunotherapy. Our profiling suggests that PD-1 and TIGIT present appealing targets for such kind of immune disinhibition.
Genomic diversity and post-admixture adaptation in the Uyghurs
Authors: Pan Yuwen , Zhang Chao , Lu Yan , Ning Zhilin , Lu Dongsheng , Gao Yang , Zhao Xiaohan , Yang Yajun , Guan Yaqun , Mamatyusupu Dolikun , Xu Shuhua 
Published: September 2021

Abstract
Population admixture results in genome-wide combinations of genetic variants derived from different ancestral populations of distinct ancestry, thus providing a unique opportunity for understanding the genetic determinants of phenotypic variation in humans. Here, we used whole-genome sequencing of 92 individuals with high coverage (30–60×) to systematically investigate genomic diversity in the Uyghurs living in Xinjiang, China (XJU), an admixed population of both European-like and East-Asian-like ancestry. The XJU population shows greater genetic diversity, especially a higher proportion of rare variants, compared with their ancestral source populations, corresponding to greater phenotypic diversity of XJU. Admixture-induced functional variants in EDAR were associated with the diversity of facial morphology in XJU. Interestingly, the interaction of functional variants between SLC24A5 and OCA2 likely influences the diversity of skin pigmentation. Notably, selection has seemingly been relaxed or canceled in several genes with significantly biased ancestry, such as HERC2–OCA2. Moreover, signatures of post-admixture adaptation in XJU were identified, including genes related to metabolism (e.g. CYP2D6), digestion (e.g. COL11A1), olfactory perception (e.g. ANO2) and immunity (e.g. HLA). Our results demonstrated population admixture as a driving force, locally or globally, in shaping human genetic and phenotypic diversity as well as in adaptive evolution.
Impact of Changes of the 2020 Consensus Definitions of Invasive Aspergillosis on Clinical Trial Design: Unintended Consequences for Prevention Trials?
Authors: Wingard John R , Alexander Barbara D , Baden Lindsey R , Chen Min , Sugrue Michele W , Leather Helen L , Caliendo Angela M , Clancy Cornelius J , Denning David W , Marty Francisco M , Nguyen M Hong , Wheat L Joseph , Logan Brent R , Horowitz Mary M , Marr Kieren A 
Published: September 2021

Abstract

Background
Consensus definitions for the diagnosis of invasive fungal diseases (IFDs) were updated in 2020 to increase the certainty of IFD for inclusion in clinical trials, for instance by increasing biomarker cutoff limits to define positivity. To date, there is a paucity of data as to the impact of the revised definitions on clinical trials.

Methods
In this study, we sought to determine the impact of the new definitions on classifying invasive aspergillosis (IA), the most common invasive mold disease in immunocompromised patients. We reclassified 226 proven and probable IA cases plus 139 possible IFD cases in the Aspergillus Technology Consortium (AsTeC) and in an antifungal prophylaxis trial (BMT CTN 0101) using the new criteria.

Results
Fewer cases met the more stringent diagnostic 2020 criteria after applying the reclassification criteria to define probable IA. Of 188 evaluable probable cases, 41 (22%) were reclassified to 40 possible IA and 1 probable IFD. Reclassification to possible IFD occurred in 22% of hematologic malignancy (HM) patients, 29% of hematopoietic cell transplant (HCT) patients, and in no lung transplant (LT) patients. Date of diagnosis was established a median (range) of 3 (1–105) days later in 15% of probable IA cases using the new criteria. Applying the new definitions to the BMT CTN 0101 trial, the power to detect the same odds ratio decreased substantially.

Conclusions
The updated IA consensus definitions may impact future trial designs, especially for antifungal prophylaxis studies.
Conquering COVID: How Global Vaccine Inequality Risks Prolonging the Pandemic
Authors: Oehler Richard L , Vega Vivian R 
Published: September 2021

Abstract
The development of effective vaccines during the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic has been deemed a towering achievement in modern science. Since the end of 2020, the vaccine rollout has offered the promise of vanquishing the pandemic in the United States and other developed countries. Even as the United States and other wealthier nations encounter both setbacks and successes in their coronavirus disease 2019 (COVID-19) eradication efforts, developing countries around the world are likely to face far less fortunate fates. With much of the world’s vaccine production and distribution capacity reserved by wealthier nations, impoverished countries stand to face devastating financial, social, and health-related impacts. The consequences of this disparity will resonate deeply into the collective fabric of these countries, ensuring that the economic and geopolitical imbalance between developed and developing nations will widen even more substantially. Wealthier countries must do more to eliminate the inequality that exists in widespread SARS-CoV-2 vaccine availability in less-developed nations. Like HIV, tuberculosis, malaria, and other global epidemics, COVID-19 cannot be forgotten just because the pandemic is eventually contained from the shores of wealthier nations. For as long as the pandemic rages in any corner of the globe, the world will never be truly rid of COVID-19. And all nations, rich or poor, will suffer the consequences.
Grand Strategy
Authors: Freedman Lawrence 
Published: September 2021

Abstract
A concept of “grand strategy” only emerged during the first decades of the twentieth century. Through the nineteenth century, strategy had a very narrow meaning, largely concerned with getting troops into the best position for battle. Tactics was concerned with the conduct of battle. For a number of reasons, including the importance of peacetime preparation for war, the separation between military strategy and the wider political and economic context came to be recognized as untenable. The contemporary strategy of grand strategy was developed in the UK first by the naval theorist Corbett and then by Fuller and Liddell Hart after the First World War. It referred to the nonmilitary aspects of prosecuting a war. After the Second World War, grand strategy tended to be used to refer to the higher conduct of war where the political, social, and economic came together with the military. Most use was made by historians who found it helpful as a way of discussing past politico-military conduct, even going back to the Romans. It came back into prescriptive use as the Cold War drew to a close. This encouraged the contemporary concept, which refers to the bringing together of all elements of a state power in pursuit of long-term objectives, which has been criticized for being too ambitious.
Culture, Identity, and Grand Strategy
Authors: McCourt David M. 
Published: September 2021

Abstract
What do culture and identity have to do with grand strategy—the task of matching broad national security aims to capabilities? Is grand strategy not the preserve of politics and power, and the timeless wisdom of realpolitik? This chapter argues that culture and identity are essential components of any realistic account of grand strategy, since grand strategies tell a story of who or what a country is, and should be, in world politics. Grand strategies are performative, making the world at the same time as speaking of it, and fashioning an identity for an international actor. The centrality of culture and identity in international politics are key insights from the constructivist approach to IR theory. The chapter outlines the constructivist challenge to mainstream approaches that emphasize material conceptions of power and interests. It then illustrates the ubiquity of culture and identity in the formulation of UK and US grand strategy. It explores recent developments in culturalist theorizing that caution against taking culture and identity as stable entities rather than often contradictory processes. This serves to connect the insights from this chapter to others in the volume on practice, discourse, legitimation, power, and expertise.