bluuebunny/crossref_metadata_2025_split huggingface dataset:
P13.18 Inhibition of epidermal growth factor receptor and platelet-derived growth factor receptor-alpha exerts synergistic efficacy in glioblastoma
Authors: Noch E , Alnahhas I , Palma L , Cantley L 
Published: September 2021

Abstract

BACKGROUND
Despite our understanding of the genetic changes that precipitate gliomagenesis, targeted therapy has failed in glioblastoma (GBM) with median survival not significantly improved over the past two decades. Epidermal growth factor receptor (EGFR) alterations, including amplification and activating mutations, are among the most common genetic changes in GBM, occurring in more than half of cases. EGFR is located on Chr. 7, and Chr. 7 gain is one of the earliest events precipitating gliomagenesis. Various EGFR inhibitors, including tyrosine kinase inhibitors, monoclonal antibodies, vaccines, and CAR-T cells have failed in GBM due to intrinsic heterogeneity and receptor tyrosine kinase bypass pathways that mediate therapeutic resistance. New targeted therapeutic approaches to leverage synergistic combinations are desperately needed to improve GBM prognosis. Using the TCGA and other GBM databases, we have previously demonstrated that the presence of PDGFRAamplification in patients with EGFR-amplified GBM carries significantly worse survival. EGFR and PDGFRA co-expression occur in more than one-third of GBM patients. The PDGFRA ligand PDGFA is also located on Chr. 7, and its expression is significantly increased with Chr. 7 gain and EGFR copy number increase. Therefore, Chr. 7 gain inherently leads to co-activation of both EGFR and PDGFRA signaling pathways.

MATERIALS AND METHODS
We used models of patient-derived glioblastoma cells to test combined inhibition of epidermal growth factor receptor and platelet-derived growth factor receptor-alpha in vitro.

RESULTS
Using patient-derived GBM models with Chr. 7 gain, we found that combined inhibition of both EGFR and PDGFRA using a variety of FDA-approved EGFR-targeted agents (Erlotinib, Gefitinib, Dacomitinib, Neratinib, and Osimertinib) and Crenolanib, respectively, leads to synergistic cytotoxicity in vitro. We found that inhibition of either EGFR or PDGFRA alone led to receptor cross-activation, and EGF and PDGF-AA-induced receptor tyrosine kinase activation was blocked by Neratinib and Crenolanib. Immunoprecipitation experiments and proximity ligation assays demonstrated that combined inhibition prevents EGFR and PDGFRA heterodimerization and pathways of therapeutic resistance. This combined inhibition led to decreased activation of downstream signaling pathways, including phosphatidylinositol 3-kinase and mitogen-activated protein kinase.

CONCLUSIONS
We show that combined inhibition of EGFR and PDGFRA exerts synergistic cytotoxicity in GBM and prevents resistance pathways that emerge during single-agent targeted therapy against these receptor tyrosine kinases. These pathways are targetable with FDA-approved agents that could be used in patients with GBM with Chr. 7 gain.
P14.02 The Natural History of a Residual Intracranial Meningioma- Volumetric Growth and Predictors of Progression
Authors: Gillespie C S , Richardson G E , Mustafa M A , Islim A I , Keshwara S M , Taweel B A , Bakhsh A , Kumar S , Millward C P , Mehta S , Rathi N , Chavredakis E , Brodbelt A R , Mills S J , Jenkinson M D 
Published: September 2021

Abstract

BACKGROUND
Resection of meningioma leaves residual solid tumour in ~25% of patients. Selection for further treatment and follow-up strategy may benefit from knowledge of volumetric growth and associated prognostic factors.

MATERIAL AND METHODS
Growth rates were assessed using a linear mixed effects model, in a retrospective adult cohort that underwent subtotal resection of meningioma (2004–2018). Endpoints were re-treatment, end of follow-up or death. Cox regression analysis was used to identify prognostic factors for progression, defined using the Response Assessment in Neuro-Oncology (RANO) volumetric criteria.

RESULTS
236 patients were included. Mean age at surgery was 56.3 years (SD=13.7) and 73.7% were female. WHO grades were 1 (n=195, 82.6%), 2 (n=40, 16.9%) and 3 (n=1, 0.5%). Adjuvant fractionated radiotherapy (fRT) was administered to 34 patients (14.4%), with no propensity towards higher WHO grade or residual volume. Median pre-operative meningioma and post-operative residual volumes were 34.0cm3 (IQR 16.0–63.0) and 2.0cm3 (IQR 0.8–5.2), respectively. Median follow-up was 64 months (IQR 42–104). Median absolute growth rate (AGR) and relative growth rate (RGR) were 0.1cm3/year and 4.3%/year, respectively. According to RANO criteria, 132 (55.9%) patients progressed, of which 13 (9.8%) developed symptoms. Median progression-free survival was 56 months (95% CI 43.1–69.0). Multivariable analysis identified adjuvant fRT (HR 1.7, [95% CI 1.0–2.8], P=0.046), skull base location (HR 1.5, [95% CI 1.0–2.4], P=0.047) and Ki-67 index (HR 3.7 [95% CI 1.3–10.8], P=0.017) as prognostic factors for volumetric progression. WHO grade was not significant (HR 1.0, [95% CI 0.5–1.7], P=0.905). Forty-nine patients who progressed (37.1%) underwent further treatment: fRT (n=19), re-operation (n=15), Stereotactic radiosurgery (SRS) (n=10) and surgery+adjuvant fRT (n=5). Of those, 8 (16.3%) progressed further (after re-operation [n=6] and SRS [n=2]). Seven were treated with a 2nd re-operation (n=3), fRT (n=3), and SRS (n=1). One patient progressed after a 2nd reoperation and was treated with SRS, after which they remained stable. Median survival was not reached. 5- and 10-year overall survival (OS) was 96% and 86% respectively.

CONCLUSION
Growth rates of a residual meningioma vary with a dichotomy observed in progression rates. Half of patients with a residual meningioma showed radiological progression requiring multiple treatment to control the tumour. The other half demonstrate a more indolent course. Skull base location and higher Ki67 are important prognostic factors for progression and therefore, should be considered to stratify patients for adjuvant radiotherapy.
P14.33 Preoperative Lactate Dehydrogenase levels as a predictor of venous thromboembolism development in glioblastoma patients
Authors: Jacquerie A , Huijs S , Moers-Hornikx V M P , van der Heijden-Montfroy A M H G , van Goor M P J , Pasmans R C O S , Anten M H M E , Verduin M , Broen M P G 
Published: September 2021

Abstract

BACKGROUND
Venous thromboembolism (VTE) is a common complication in patients with glioblastoma. Despite high incidence of up to 30% per year, concerns about bleeding complications have limited the use of primary anticoagulant prophylaxis. Finding a suitable biomarker to assess the risk of occurrence is therefore of utmost clinical interest. We performed an exploratory study of preoperative routinely used haematological markers as predictor for the development of VTE in glioblastoma patients.

MATERIAL AND METHODS
Data was retrospectively collected from an existing database of 307 patients diagnosed with glioblastoma by the Oncology Network South-East Netherlands (OnzoZON) between 2006 and 2020. Collected preoperative haematological markers included: haemoglobin, platelets, lactate dehydrogenase, neutrophils, lymphocytes, albumin and derived ratios. In addition, type and date of VTE were retrieved from medical records. Receiver operating curve was used to identify the optimal cut-off values of the preoperative haematological markers. Univariate and multivariate logistic regression analyses were performed to predict VTE for each haematologic marker independently. Variables included in the multivariate analyses were age, gender, type of surgery, Karnofsky performance score, MGMT status, weight, height and BMI, already available from the primary database.

RESULTS
In the total dataset, 45 patients (15%) suffered from a VTE, most common pulmonary embolism (51%) followed by deep vein thrombosis (31%). Mean time from diagnosis until VTE was 4.3 months (SD = 5.5). Preoperative haemoglobin value was available for analyses in 265 patients, platelets value in 226, lactate dehydrogenase in 98, neutrophils in 133, lymphocytes in 133 and albumin in 56 patients. A preoperative lactate dehydrogenase value &gt; 243 U/L was found to increase the risk of VTE in both univariate and multivariate analysis (P &lt;0.05). Seventeen out of 98 patients of whom lactate dehydrogenase level was available suffered from a VTE, most common pulmonary embolism (59%), followed by deep vein thrombosis (29%) and cerebral venous sinus thrombosis (12%). An elevated lactate dehydrogenase in serum increased the odds for getting a VTE by 3.2 (1.1–9.4). None of the other investigated haematological markers or ratios were found to be significantly correlated with the occurrence of VTE in our study.

CONCLUSION
Glioblastoma initiates locally haemostatic abnormalities, that propagate systemically though circulating mediators. Our exploratory analysis shows for the first time that preoperative lactate dehydrogenase levels might aid clinicians in identifying patients at risk for a venous thromboembolism. Ultimately this could lead to preventive measures and patient education, but larger and prospective validation of these findings is warranted.
P14.41 Cost-effectiveness of FET PET for early treatment response assessment in glioma patients following adjuvant temozolomide chemotherapy
Authors: Rosen J , Ceccon G , Bauer E K , Werner J M , Kabbasch C , Fink G R , Langen K J , Galldiks N 
Published: September 2021

Abstract

BACKGROUND
In light of increasing healthcare costs, higher medical expenses should be justified socio-economically. Therefore, we calculated the effectiveness and cost-effectiveness of PET using the radiolabeled amino acid O-(2-[18F]-fluoroethyl)-L-tyrosine (FET) compared to conventional MRI for early identification of responders to adjuvant temozolomide chemotherapy. A recent study in IDH-wildtype glioma patients suggested that after two cycles, FET-PET parameter changes predicted a significantly longer survival while MRI changes were not significant.

MATERIALS AND METHODS
To determine the effectiveness and cost-effectiveness of serial FET-PET imaging, we analyzed published clinical data and calculated the associated costs in the context of the German healthcare system.Based on a decision-tree model, FET-PET and MRI’s effectiveness was calculated, i.e., the probability to correctly identify a responder as defined by an overall survival ≥15 months. To determine the cost-effectiveness, the incremental cost-effectiveness ratio (ICER) was calculated, i.e., the cost for each additionally identified responder by FET-PET who would have remained undetected by MRI. The robustness of the results was tested by deterministic and probabilistic (Monte Carlo simulation) sensitivity analyses.

RESULTS
Compared to MRI, FET-PET increases the rate of correctly identified responders to chemotherapy by 26%; thus, four patients need to be examined by FET-PET to identify one additional responder. Considering the respective cost for serial FET-PET and MRI, the ICER resulted in €4,396.83 for each additional correctly identified responder by FET-PET. The sensitivity analyses confirmed the robustness of the results.

CONCLUSION
In contrast to conventional MRI, the model suggests that FET PET is cost-effective in terms of ICER values. Concerning the high cost of temozolomide, the integration of FET-PET has the potential to avoid premature chemotherapy discontinuation at a reasonable cost.
P14.53 Immunotherapy in the complex treatment of HGG
Authors: Rynda A , Olyushin V , Rostovtsev D 
Published: September 2021

Abstract

BACKGROUND
To improve the long-term results of complex treatment of patients with malignant gliomas

MATERIAL AND METHODS
The long-term results of treatment of 220 patients with malignant gliomas of supratentorial localization (anaplastic astrocytomas, glioblastomas, giant cell glioblastomas, gliosarcomas) were evaluated. Of these patients, in addition to standard treatment methods (surgery, radiation therapy and chemotherapy), 110 patients underwent specific antitumor immunotherapy. In 110 patients, only standard methods were used in the complex treatment structure. Follow-up results were considered follow-up data, and a relapse-free period was also evaluated.

RESULTS
The implementation of specific antitumor immunotherapy in patients with malignant gliomas was safe and did not lead to an increase in the number of complications compared with the control group. It was revealed that the use of immunotherapy based on autologous dendritic cells, in addition to standard methods of treating patients, increases the average life expectancy (in patients with anaplastic astrocytomas up to 40.5 months (p = 0.001), in patients with glioblastomas up to 21.8 months (p = 0.002)) and the value of the relapse-free period (in patients with anaplastic astrocytomas up to 17.4 months (p = 0.002), in patients with glioblastomas up to 14.3 months (p = 0.003)), provided that three or more courses are carried out. Conducting 1 or 2 courses of immunotherapy does not significantly affect the average life expectancy and median survival of patients.

CONCLUSION
The development and use in clinical practice of specific antitumor immunotherapy based on autologous dendritic cells seems to be a very promising direction for further research, the development of which will improve the long-term results of treatment of patients.
P14.82 Glioneuronal tumors - a rare tumor entity with diagnostic and therapeutic challenges: report of two cases and review of literature
Authors: Zeitlberger A M , Neidert M C , Velez-Char N , Hundsberger T 
Published: September 2021

Abstract

BACKGROUND
The 2007 WHO classification of brain tumors first encompassed two new entities of glioneuronal tumors, including papillary glioneuronal tumors (PGNT) and rosette-forming glioneuronal tumours. The reviewed version of the 2016 WHO classification additionally included diffuse leptomeningeal glioneuronal tumours. The histopathological, genetic, and clinical understanding of glioneuronal tumors is currently evolving, however there are no guidelines for diagnostic and clinical management yet.

MATERIAL AND METHODS
We report two male patients with glioneuronal tumors and performed a review of literature.

RESULTS
The first patient was diagnosed with a PGNT (MIB-1 proliferation index = 5%) located in the right parietal lobe at the age of 33 years and received surgical resection. Two years later, the tumor recurred in the same location. A second tumor resection was performed followed by concomitant radiochemotherapy with temozolomide (60/2 Gray). A next-generation sequencing gene panel (Oncomine) confirmed the initial diagnosis of a PGNT. The patient has remained in remission for the past 10 years. The second patient developed complex partial seizures which were first misdiagnosed as anxiety disorder at the age of 26 years. An MRI scan revealed a contrast-enhancing bifrontal cystic lesions 5 years later and he received a gross total tumor resection. The diagnosis of a glioneuronal tumor was made, however molecular pathology and methylation analysis were not able to classify the tumor entity further. There was no evidence of tumor recurrence one year after surgery and he remained seizure-free with antiepileptic treatment.

CONCLUSION
Glioneuronal tumors encompass rare and heterogenous tumor entities which primarily present in young patients and often show a favorable clinical course. Although the increasing number of reports in the literature have improved our understanding of these tumors, uncertainty remains in diagnostic challenging cases and patients with progressive disease after surgery. The value of next-generation sequencing and the choice of adjuvant treatment modalities have not been systematically evaluated in this patient group.
P16.13 MenImmune: Evaluation of immune-related and prognostic biomarkers in meningioma
Authors: Truffelli M , Grassi M , Fiaschi P , Roccatagliata L , Bennicelli E , Barletta L , Cella E , Valle L , Zona G , Gaggero G 
Published: September 2021

Abstract

BACKGROUND
Meningiomas are the most common group of adult central nervous system primary tumor. The major known predictors for meningioma recurrence are extent of surgical resection and histological grade. Although grading system is the actual standard for risk classification, there are several exceptions in the clinical behavior. Recent studies have shown that meningiomas can express PD-L1, a known therapeutic target for checkpoint inhibitors. Tumor microenvironment and hormonal setting are known to influence the immune system response. The only standard therapeutic strategies nowadays are surgery and radiotherapy. Meningiomas microenvironment needs to be further studied looking for new therapeutic targets. New prognostic tools combining histological and radiological features (RF) are needed to better address the treatment strategy.

ELIGIBILITY CRITERIA
Patients diagnosed with meningioma who underwent surgery at the Department of Neurosurgery of the IRCCS Ospedale Policlinico San Martino of Genoa from 1998. - Availability of magnetic resonance imaging (MRI) at diagnosis. - Availability of histological samples.

OBJECTIVES
Identification and prevalence of immune-related biomarkers and their correlation with morphological and hormonal features. - Survival analyses in the study population and according to the different characteristics analyzed. - The identification of specific clinical, histological and RF of meningiomas and their inclusion in a prognostic signature.

STUDY DESIGN
This is a retrospective-prospective monocentric study designed to analyze clinical, radiological and histological features of meningioma patients. - Clinical data will be collected from the electronic patient records. - Analyses will be conducted on a cohort of patients enriched with higher grade meningioma to balance the proportion between high and low grade histologies. - Histological specimen will be blindly reviewed and reclassified according to histological type, morphological features and WHO 2016 criteria. - The MRI features will be analyzed at diagnosis.

STUDY ANALYSIS
We retrospectively enrolled 50 patients with available radiological, histological and clinical data.- All histopathological specimens will be examined with slides obtained from material fixed in 10% neutral buffered formalin, included in kerosene, sectioned at 3 µm and stained with hematoxylin-eosin. - We will look for the presence of estrogens and progesterone receptors. - Concerning immune-related biomarkers we will further assess PD-L1 positivity (cut-off: positive 1%, negative &lt;1%), MSI status and the inflammatory infiltrate with immunohistochemistry, in particular TILs (CD45, CD3, CD4, CD8, FOXP3, CTLA4), B cell (CD20), TAM (CD68). - All histological and radiological data will be analyzed and correlated with the clinical characteristics of meningioma patients and their outcomes.
Adoptive Parenting Is More Complex Than Evolutionary Theory Would Predict
Authors: Matthews Jessica A. K. , Pinderhughes Ellen E. , Pott Martha L. 
Published: September 2021

Abstract
This chapter focuses on adoptive parenting. At face value, adoption does not fulfill one of the primary goals of evolution: survival and eventual reproduction of one’s genes. Why, then, given our evolutionary history, and the relative difficulty of adoption, is adoption so widespread and usually successful? The chapter is devoted to examining adoption from an evolutionary perspective. It traces the history of adoption and reviews many reasons why adoption has been, and still is, widespread. The human history of adoption reflects many of our evolutionary goals and biological drives. However, one of the unique capacities of humanity is the ability to rise above our baser biology to use logic and reason to overcome gut reactions rooted in animal biology. Modern adoption theory and practice seek to recognize patterns rooted in biology, history, and culture, while encouraging more equitable practices that respect each individual involved in adoption.
Research Synthesis
Authors: Guber Deborah Lynn 
Published: September 2021

Abstract
Digital trace data have the potential to offer rich insight into complex behaviors that were once out of reach, but their use has raised vital and unresolved questions about what is—or is not—public opinion. Building on the work of James Bryce, Lindsay Rogers, Herbert Blumer, Paul Lazarsfeld, and more, this essay revisits the discipline’s historical roots and draws parallels between past theory and present practice. Today, scholars treat public opinion as the summation of individual attitudes, weighted equally and expressed anonymously at static points in time through polls, yet prior to the advent of survey research, it was conceived as something intrinsically social and dynamic. In an era dominated by online discussion boards and social media platforms, the insights of this earlier “classical tradition” offer two pathways forward. First, for those who criticize computational social science as poorly theorized, it provides a strong justification for the work that data scientists do in text mining and sentiment analysis. And second, it offers clues for how emerging technologies might be leveraged effectively for the study of public opinion in the future.
Psychosocial factors correlate with adherence to medications among cardiovascular outpatient clinics in Jordan
Authors: Z Malak Malakeh , J Al-thbetat Ahlam , M AL-Amer Rasmieh 
Published: September 2021

AbstractBackgroundAdherence to medications is a significant element of self-care behaviors for patients with cardiovascular diseases (CVDs). Non-adherence to cardiovascular medications is the major risk for poor outcomes following any cardiac event. However, there is a lack of studies that addressed medication adherence among patients with CVDs attending outpatient clinics in Arabic countries, including Jordan. Thus, this study purposed to assess the psychosocial factors (e.g. depression, anxiety, stress, social support and self-esteem) and their correlation with adherence to medications among patients with CVDs attending outpatient clinics in Jordan.MethodsA total of 395 Jordanian patients attending CVDs outpatient clinics at government, military and private healthcare facilities were recruited.ResultsOur study findings showed that 31.4% of the patients reported complete adherence to their medications. The proportion of psychological reactions reported by the participants was 72.1% for depressive symptoms, 62.6% for anxiety and 50.1% for stress; 79.7% had moderate and normal social support, and 44% had low self-esteem. Depression, anxiety and stress had a significant negative correlation with adherence to medications; however, self-esteem had a significant positive relationship with adherence to medications. In addition, depression, anxiety and stress were the main predictors of adherence to medications.ConclusionOur findings might aid in paving the road for designing and developing strategies and interventions to increase adherence to medications and minimize these psychosocial problems among CVD patients in outpatient clinics.