bluuebunny/crossref_metadata_2025 huggingface dataset:
Non-invasive localization of post-infarct ventricular tachycardia exit sites to guide ablation planning: a computational deep learning platform utilizing the 12-lead electrocardiogram and intracardiac electrograms from implanted devices
Authors: Monaci Sofia , Qian Shuang , Gillette Karli , Puyol-Antón Esther , Mukherjee Rahul , Elliott Mark K , Whitaker John , Rajani Ronak , O’Neill Mark , Rinaldi Christopher A , Plank Gernot , King Andrew P , Bishop Martin J
Published: November 2022

Aims

Existing strategies that identify post-infarct ventricular tachycardia (VT) ablation target either employ invasive electrophysiological (EP) mapping or non-invasive modalities utilizing the electrocardiogram (ECG). Their success relies on localizing sites critical to the maintenance of the clinical arrhythmia, not always recorded on the 12-lead ECG. Targeting the clinical VT by utilizing electrograms (EGM) recordings stored in implanted devices may aid ablation planning, enhancing safety and speed and potentially reducing the need of VT induction. In this context, we aim to develop a non-invasive computational-deep learning (DL) platform to localize VT exit sites from surface ECGs and implanted device intracardiac EGMs.

Methods and results

A library of ECGs and EGMs from simulated paced beats and representative post-infarct VTs was generated across five torso models. Traces were used to train DL algorithms to localize VT sites of earliest systolic activation; first tested on simulated data and then on a clinically induced VT to show applicability of our platform in clinical settings. Localization performance was estimated via localization errors (LEs) against known VT exit sites from simulations or clinical ablation targets. Surface ECGs successfully localized post-infarct VTs from simulated data with mean LE = 9.61 ± 2.61 mm across torsos. VT localization was successfully achieved from implanted device intracardiac EGMs with mean LE = 13.10 ± 2.36 mm. Finally, the clinically induced VT localization was in agreement with the clinical ablation volume.

Conclusion

The proposed framework may be utilized for direct localization of post-infarct VTs from surface ECGs and/or implanted device EGMs, or in conjunction with efficient, patient-specific modelling, enhancing safety and speed of ablation planning.
Mitochondrial Dysfunction and Intrinsic Capacity: Insights From a Narrative Review
Authors: Aragoni da Silva Jaqueline , Rolland Yves , Martinez Laurent O , de Souto Barreto Philipe
Published: November 2022

Mitochondrial dysfunction occurs during aging and may play a role, by distinct mechanisms, in the loss of intrinsic capacity (IC), operationalized through 5 domains: locomotion, psychological, cognition, vitality/nutrition, and sensory (hearing, vision). The objective of this review is to provide an overview of the associations between mitochondrial function and IC domains. This study is a narrative review of original investigations (any study design) on the relationship of mitochondrial function in humans with locomotion (eg, gait speed), psychological (eg, depressive symptoms), cognition (eg, global cognitive function), vitality (eg, handgrip strength), and/or sensory (hearing and vision acuity) domains. The IC domains were considered from the perspective of the Integrated Care for Older People (ICOPE), according to the World Health Organization guidelines. The results show that there is still limited evidence regarding the associations between mitochondrial function and IC domains. Most studies were cross-sectional and involved small samples. The tissues/cells most often investigated in the original studies were skeletal muscle and peripheral blood mononuclear cells. The available evidence, although limited, indicates that mitochondrial function, in particular, the mitochondrial DNA copy number, is associated with all IC domains. The evidence is more robust for locomotion and less abundant for hearing. In conclusion, this review supports the notion that mitochondrial function is correlated with IC domains by distinct mechanisms. Future studies are needed to confirm whether mitochondria play a role in maintaining optimal function and preventing/delaying the onset of disability during aging, which could ultimately contribute to healthy aging.
Effects of misreporting landings, discards, and Catch Per Unit of Effort index in state-space production models: the case of black hake in northwest Africa
Authors: Soto María , Fernández-Peralta Lourdes , Pennino Maria Grazia , Kokkalis Alexandros , Rey Javier , Salmerón Francisca , Liébana María , Meissa Beyah , Kell Laurie
Published: November 2022

Recently, various state-space implementations of surplus production models (SPMs) have been developed for data-limited stocks. Often, catches and fishing effort are underestimated and discards are ignored. This results in biased estimates of stock status and reference points. Therefore, we conduct a sensitivity analysis for different under-reporting scenarios (due to non-declared landings, by-catch, and discards) on model estimates and thus advice for the black hake species in northwest Africa. Two modelling frameworks were used, namely a stochastic SPM in continuous time (SPiCT) and Just Another Bayesian Biomass Assessment (JABBA). A common set of diagnostics was developed to allow comparison across modelling frameworks. Scenarios correspond to hypotheses about misreporting and assumptions and priors that were kept consistent. The ratio of current fishing mortality over the fishing pressure that gives the maximum sustainable yield, F/FMSY, is most affected by under-reporting. Results are sensitive to the prior assumed for the initial depletion level, B0/K, and research is needed. If the misreporting is changing over time, relative quantities (e.g. F/FMSY) and trends are biased, while if misreporting (or at least a part of misreporting) is constant, relative quantities are unbiased. Therefore, the nature of any trend in misreporting should be investigated.
Smooth Points of the Space of Plane Foliations with a Center
Authors: Gavrilov Lubomir , Movasati Hossein
Published: November 2022

We prove that a logarithmic foliation corresponding to a generic line arrangement of $d+1 \geq 3$ lines in the complex plane, with pairwise natural and co-prime residues, is a smooth point of the center set of plane foliations (vector fields) of degree $d$.
EQUAL CPA Score 2022: a tool to measure guideline adherence for chronic pulmonary aspergillosis
Authors: Sprute Rosanne , Van Braeckel Eva , Flick Holger , Hoenigl Martin , Kosmidis Chris , Agarwal Ritesh , Davidsen Jesper R , Laursen Christian B , Cornely Oliver A , Seidel Danila
Published: November 2022

Background

Chronic pulmonary aspergillosis (CPA) can complicate underlying pulmonary diseases, and clinical management of CPA is challenging. Guidelines support clinicians but due to the complexity of the disease they can be difficult to adhere to.

Objectives

To map current guideline recommendations for the clinical management of CPA into a scoring tool to facilitate and quantify guideline adherence in clinical practice.

Methods

Recommendations for diagnosis, treatment and follow-up of CPA presented in the current ESCMID/ERS/ECMM and CPAnet guidance documents were assembled and weighed on the basis of their strength of recommendation and level of evidence.

Results

Twenty-seven recommendations were identified, resulting in a total maximum EQUAL CPA Score of 51. For diagnostics (ScoreMax = 27), a strong emphasis on expert consultation, culture, direct microscopy, histopathology, serology and imaging was reflected in respective points, whereas molecular techniques and susceptibility testing count into the diagnostics score to a lesser extent.

Ten treatment recommendations (ScoreMax = 14), including antifungal therapy, therapeutic drug monitoring and treatment duration, were identified. Surgery, where indicated, adds three points. For refractory disease or intolerance of first-line antifungal treatment, optimal second-line treatment added another two points.

During follow-up (ScoreMax = 10), response assessment via imaging gave three points, while culture and serology added two points each to the ScoreMax.

Conclusion

The EQUAL CPA Score intents to be used as a comprehensive tool for measuring guideline adherence. If adherence to current guidelines is associated with clinical outcome, this will be assessed in future studies.
Attempted Suicide by Burning: A Cross-sectional Analysis at a Regional Burn Center in Germany
Authors: Obed Doha , Dastagir Nadjib , Salim Mustafa , Bucher Florian , Gruber Lisa , Schröter Andreas , Panayi Adriana C , Knoedler Samuel , Dastagir Khaled , Vogt Peter M
Published: November 2022

Attempted suicide by self-immolation or burning constitutes an uncommon form of attempted suicide in high income countries, presenting substantial challenges to burn units. The aim of this study was to analyze the epidemiologic characteristics and outcomes in intensive care burn patients treated for attempted suicide by burning. For this purpose, we examined intensive care burn patients admitted to a single major burn unit between March 2007 and December 2020. Demographic, clinical, epidemiological, and mortality data were collected and analyzed. Major psychiatric comorbidities were evaluated according to ICD-9 and ICD-10 classifications. A total of 1325 intensive care unit burn patients were included. Suicide by burning was attempted in 45 cases (3.4%). Attempted suicide victims presented with significantly higher burn severity, reflected by higher abbreviated burn severity index scores, and larger TBSA affected. Burned TBSA ≥30% and inhalation injuries were observed more frequently in suicidal patients. These patients also experienced prolonged hospital and intensive care unit length of stay, required surgical interventions and mechanical ventilation more frequently, and had significantly longer periods on ventilation, causing an overall higher mortality rate (24.4%). Psychiatric comorbidities were present in 75.6% of patients who attempted suicide. Despite the low prevalence, burn severity and mortality are considerably high in patients who attempted suicide by burning, presenting a significant challenge for healthcare providers. The majority of patients had a history of psychiatric disorder, highlighting the importance of identifying patients at high-risk who may profit from increased psychiatric intervention.
Best Management Practices Increase Profitability of Small-Scale US Beekeeping Operations
Authors: Tubene Stephan , Kulhanek Kelly , Rennich Karen , vanEngelsdorp Dennis
Published: November 2022

Little is known about the economics of small-scale beekeeping, due in part because many of these beekeepers are motivated by personal enjoyment and not profit. These beekeepers, however, represent more than 90% of US beekeeping population, so economic analysis of this majority group is warranted. Understanding how management practices impact colony profitability in small apiaries can inform beekeeper management decisions. Best management practices (BMPs) can increase colony productivity and survival, but often require additional labor and materials compared to less intensive beekeeping practices. Here, we investigate the impact of BMPs on the profitability of small-scale beekeeping. We found that BMPs required higher costs in labor and materials, but that they also produced higher revenue from honey and nucleus colony production. As a result, after three years, BMP apiaries were 8 times more profitable than less intensively managed apiaries. The increased profitability in BMP apiaries is largely attributed to improved colony health and survival due to more active Varroa management and reduced Varroa and viral loads. These results can inform small scale beekeeper budgeting and management, and also support extension efforts to increase BMP adoption.
Resistance to Beta-cypermethrin, Azadirachtin, and Matrine, and Biochemical Characterization of Field Populations of Oedaleus asiaticus (Bey-Bienko) in Inner Mongolia, Northern China
Authors: Gao Shujing , Tan Yao , Han Haibin , Guo Na , Gao Haiyan , Xu Linbo , Lin Kejian
Published: November 2022

Oedaleus asiaticus (Bey-Bienko) is an economically devastating locust species found in grassland and pastoral areas of the Inner Mongolia region of northern China. In this study, resistance to three frequently used insecticides (beta-cypermethrin, matrine, and azadirachtin) was investigated in six field populations of O. asiaticus using the leaf-dip bioassay method. The inhibitory effects of synergists and the activities of detoxification enzyme activities in the different populations were determined to explore potential biochemical resistance mechanisms. The results showed that the field populations SB (resistance ratio [RR] = 7.85), ZB (RR = 5.64), and DB (RR = 6.75) had developed low levels of resistance to beta-cypermethrin compared with a susceptible control strain. Both the SB (RR = 5.92) and XC (RR = 6.38) populations had also developed low levels of resistance against matrine, with the other populations remaining susceptible to both beta-cypermethrin and matrine. All field populations were susceptible to azadirachtin. Synergism analysis showed that triphenyl phosphate (TPP) and diethyl-maleate (DEM) increased the toxicity of beta-cypermethrin significantly in the SB population, while the synergistic effects of TPP, piperonyl butoxide (PBO), and DEM on the toxicity of matrine were higher in SB (SR 3.86, 4.18, and 3.07, respectively) than in SS (SR 2.24, 2.86, and 2.29, respectively), but no synergistic effects of TPP, PBO, and DEM on azadirachtin were found. Biochemical assays showed that the activities of carboxylesterases (CarEs) and glutathione-S-transferases (GSTs) were significantly raised in all field populations of O. asiaticus, with a significant positive correlation observed between beta-cypermethrin resistance and CarE activity. The activities of cytochrome P450 monooxygenases (P450) and multi-function oxidases (MFO) were elevated in all six field populations, and P450 activity displayed strong positive correlations with the three insecticides. Our findings suggest that resistance to beta-cypermethrin in O. asiaticus may be mainly attributed to elevated CarE and GST activities, while P450 plays an important role in metabolizing matrine and azadirachtin. Our study provides insights that will help improve insecticide resistance management strategies.
Social media use in the context of the Personal Social Media Ecosystem Framework
Authors: Carter Michael C , Cingel Drew P , Ruiz Jeanette B , Wartella Ellen
Published: November 2022

The rapid proliferation and maturation of social media platforms have led to numerous challenges in understanding the correlates of social media use among users. To advance this research, the present article proposes a new way to think about social media with the Personal Social Media Ecosystem Framework (PSMEF). This perspective defines social media as a user-centric digital environment made up of a central set of individual, yet interrelated digital spaces (e.g., in-app pages) that are themselves embedded within a broader ecology (e.g., operating system, the Internet, offline contexts). By leveraging the PSMEF and data from focus groups involving adolescent participants (N = 59), we identify a core subset of salient environmental contexts within participants’ PSMEs that can generalize across platforms, which are differentially associated with popular social media platforms. The theoretical and practical implications of this work are discussed.
Dynamic architectural responses of morphological traits to emergence timing inAbutilon theophrasti(Malvaceae)
Authors: Wang Shu , Zhou Dao-Wei
Published: November 2022

Architectural plasticity in traits should be useful for understanding morphological and allocation plasticity at the whole-plant level and associated growth strategies of plants in dealing with variation in emergence time. To investigate how plants respond to emergence timing via dynamic architectural plasticity, we conducted a field experiment by sowing plants of Abutilon theophrasti on different dates to make them emerge in spring, late spring, summer and late summer, as four treatments of emergence time (ET1–ET4), and measured a series of mass and morphological traits in different vertical layers (with an inter-distance of 10 or 20 cm per layer) of plants at three stages. The ‘vertical arch’ and ‘inverted-cone’ shapes displayed at reproductive stage by plants emerged between spring and summer (ET1–ET3) and in late summer (ET4), respectively, revealed that they had contrasting timing schemes for vegetative and reproductive growth. Plants emerged earlier had relatively isolated vegetative and reproductive stages, while late-summer emerged plants had overlapped vegetative and reproductive stages due to accelerated leaf and reproductive growth simultaneously, as a result of shortened lifetime. In spite of this, plants emerged earlier were still able to adopt different optimal strategies in dealing with their corresponding circumstances. Architectural analysis should be a useful approach to better understanding diverse plant strategies in the context of varying environmental conditions.
On all pure three-valued logics
Authors: Pailos Federico
Published: November 2022

We investigate the class of all pure three-valued logics that result from choosing the eight subsets of $\{0, 1, \frac {1}{2}\}$ as designated values on the strong Kleene schema, including the sets that are not (order) filters. We present some of their main characteristics and show some formal relations between these logics. We also suggest a recipe to build philosophical interpretations for most of these logics and show why it is not easy to apply this account to the last two logics in the list.
Origin of highly r-process-enhanced stars in a cosmological zoom-in simulation of a Milky Way-like galaxy
Authors: Hirai Yutaka , Beers Timothy C , Chiba Masashi , Aoki Wako , Shank Derek , Saitoh Takayuki R , Okamoto Takashi , Makino Junichiro
Published: November 2022

The r-process-enhanced (RPE) stars provide fossil records of the assembly history of the Milky Way (MW) and the nucleosynthesis of the heaviest elements. Observations by the R-Process Alliance (RPA) and others have confirmed that many RPE stars are associated with chemo-dynamically tagged groups, which likely came from accreted dwarf galaxies of the MW. However, we do not know how RPE stars are formed. Here, we present the result of a cosmological zoom-in simulation of an MW-like galaxy with r-process enrichment, performed with the highest resolution in both time and mass. Thanks to this advancement, unlike previous simulations, we find that most highly RPE (r-II; [Eu/Fe] > +0.7) stars are formed in low-mass dwarf galaxies that have been enriched in r-process elements for [Fe/H] $\lt -2.5$, while those with higher metallicity are formed in situ, in locally enhanced gas clumps that were not necessarily members of dwarf galaxies. This result suggests that low-mass accreted dwarf galaxies are the main formation site of r-II stars with [Fe/H] $\, \lt -2.5$. We also find that most low-metallicity r-II stars exhibit halo-like kinematics. Some r-II stars formed in the same halo show low dispersions in [Fe/H] and somewhat larger dispersions of [Eu/Fe], similar to the observations. The fraction of simulated r-II stars is commensurate with observations from the RPA, and the distribution of the predicted [Eu/Fe] for halo r-II stars matches that observed. These results demonstrate that RPE stars can be valuable probes of the accretion of dwarf galaxies in the early stages of their formation.
Structural basis of direct and inverted DNA sequence repeat recognition by helix–turn–helix transcription factors
Authors: Fernandez-Lopez Raul , Ruiz Raul , del Campo Irene , Gonzalez-Montes Lorena , Boer D Roeland , de la Cruz Fernando , Moncalian Gabriel
Published: November 2022

Some transcription factors bind DNA motifs containing direct or inverted sequence repeats. Preference for each of these DNA topologies is dictated by structural constraints. Most prokaryotic regulators form symmetric oligomers, which require operators with a dyad structure. Binding to direct repeats requires breaking the internal symmetry, a property restricted to a few regulators, most of them from the AraC family. The KorA family of transcriptional repressors, involved in plasmid propagation and stability, includes members that form symmetric dimers and recognize inverted repeats. Our structural analyses show that ArdK, a member of this family, can form a symmetric dimer similar to that observed for KorA, yet it binds direct sequence repeats as a non-symmetric dimer. This is possible by the 180° rotation of one of the helix–turn–helix domains. We then probed and confirmed that ArdK shows affinity for an inverted repeat, which, surprisingly, is also recognized by a non-symmetrical dimer. Our results indicate that structural flexibility at different positions in the dimerization interface constrains transcription factors to bind DNA sequences with one of these two alternative DNA topologies.
Multiple-low-dose therapy: effective killing of high-grade serous ovarian cancer cells with ATR and CHK1 inhibitors
Authors: Golder Anya , Nelson Louisa , Tighe Anthony , Barnes Bethany , Coulson-Gilmer Camilla , Morgan Robert D , McGrail Joanne C , Taylor Stephen S
Published: November 2022

High-grade serous ovarian cancer (HGSOC) is an aggressive disease that typically develops drug resistance, thus novel biomarker-driven strategies are required. Targeted therapy focuses on synthetic lethality—pioneered by PARP inhibition of BRCA1/2-mutant disease. Subsequently, targeting the DNA replication stress response (RSR) is of clinical interest. However, further mechanistic insight is required for biomarker discovery, requiring sensitive models that closely recapitulate HGSOC. We describe an optimized proliferation assay that we use to screen 16 patient-derived ovarian cancer models (OCMs) for response to RSR inhibitors (CHK1i, WEE1i, ATRi, PARGi). Despite genomic heterogeneity characteristic of HGSOC, measurement of OCM proliferation was reproducible and reflected intrinsic tumour-cell properties. Surprisingly, RSR targeting drugs were not interchangeable, as sensitivity to the four inhibitors was not correlated. Therefore, to overcome RSR redundancy, we screened the OCMs with all two-, three- and four-drug combinations in a multiple-low-dose strategy. We found that low-dose CHK1i-ATRi had a potent anti-proliferative effect on 15 of the 16 OCMs, and was synergistic with potential to minimise treatment resistance and toxicity. Low-dose ATRi-CHK1i induced replication catastrophe followed by mitotic exit and post-mitotic arrest or death. Therefore, this study demonstrates the potential of the living biobank of OCMs as a drug discovery platform for HGSOC.
BIOM-11. ROR1 MRNA EXPRESSION IN GLIOMA - A NOVEL PROGNOSTIC BIOMARKER
Authors: Madani Daniel , John Miya , Satgunaseelan Laveniya , Shivalingam Brindha , Ford Caroline
Published: November 2022

BACKGROUND

Glioblastoma is the most common and aggressive primary brain tumor in adults. Despite maximal surgical resection followed by concomitant chemo-/radiotherapy, the three-year survival remains less than 5%. Receptor tyrosine kinase-like orphan receptor 1 (ROR1) overexpression is associated with poor prognosis in several cancers. ROR1 therapeutics are in Phase I/II clinical trials making it an exciting novel target with translational potential to explore for glioblastoma treatment. The aim of this study was to examine the association between ROR1 mRNA expression and overall survival, by applying the WHO 2021 classification to transcriptomic glioma datasets.

METHODS

Clinical, histological, and molecular data was extracted from The Cancer Genome Atlas (TCGA), Chinese Glioma Genome Atlas (CGGA), Repository for Molecular Brain Neoplasia (REMBRANDT), and GSE16011 (GRAVENDEEL) projects via the GlioVis portal. Using the WHO 2021 classification, the dataset was appropriately re-classified. Only confirmed cases of astrocytoma, oligodendroglioma, or glioblastoma, and ROR1 mRNA expression data were included in the analysis, which included a total of 2,303 cases. 981 cases comprised the low-grade glioma cohort and 1322 cases were included in the high-grade glioma cohort. ROR1 mRNA expression from the four datasets was normalized within each dataset, combined, and divided into high and low expression groups. ROR1 expression and survival correlations were estimated with Kaplan-Meier survival analysis and Mantel-Cox test using GraphPad Prism v9.

RESULTS

Those with high ROR1 expression had an overall median survival of 4.5 months, as compared to 21.4 months in the low ROR1 expression cohort (p< 0.0001). High-grade gliomas had the highest ROR1 mRNA expression across the consortium when compared to the low-grade glioma cohort (p< 0.0001).

CONCLUSION

The results of this study indicate an association between overall survival in glioma and ROR1 expression. In addition, targeting ROR1 could hold translational importance for novel putative treatment in glioblastoma patients.
BIOM-14. SYSTEMIC BIOMARKERS OF TUMOR BURDEN IN GLIOBLASTOMA PATIENTS
Authors: Chabot Peter , Fontaine Dominique , del Genio Carmen , Shentu Yujia , Gaur Arti
Published: November 2022

Glioblastomas (GBM) are Grade IV gliomas that are highly aggressive, lethal primary brain tumors. They are extremely heterogenous tumors both at a cellular and molecular level, harboring diverse oncogenes and mutated tumor suppressor genes with both inter- and intra-tumor variability in expression patterns. Currently, the presence of GBM cannot be predicted and they are diagnosed post-surgical resection by histologic evaluation of tumor tissue. There is an urgent, unmet need for the discovery of GBM-specific biomarkers that could precisely predict and monitor the presence of tumors in GBM patients. Over the last seven years we have carried out a prospective, multi-center, clinical study to longitudinally analyze tumor and plasma samples from GBM patients. We have characterized expression levels of microRNAs, mRNAs and proteins isolated from plasma samples collected from GBM patients throughout their treatment and compared these data to clinical and pathological reports for each patient. Our research has identified a set of systemic microRNAs and their targets that can be correlated to tumor burden in GBM patients. Data will be presented to demonstrate how specific sets of molecular markers and secreted proteins can track disease in GBM patients. This study provides insights into how systemically expressed biomarkers in GBM patients can be used in the development of methods for the precise assessment of disease progression and treatment efficacy while being minimally invasive and cost-effective. Combining clinicopathological findings and biomarker profiling will predict treatment outcomes and provide oncologists precise readouts for tumor burden and response to treatment. Furthermore, this research will also provide critically needed criteria for rigorous monitoring of efficacy of all new therapeutic trials for GBM.
BIOM-23. MOLECULAR MARKER TESTING AND REPORTING COMPLETENESS FOR ADULT-TYPE DIFFUSE GLIOMAS IN THE UNITED STATES
Authors: Neff Corey , Cioffi Gino , Waite Kristin , Kruchko Carol , Barnholtz-Sloan Jill , Ostrom Quinn , Iorgulescu Bryan
Published: November 2022

BACKGROUND

A newly developed brain molecular marker (BMM) data item was implemented by U.S. cancer registries for individuals diagnosed with brain tumors in 2018—including IDH and 1p/19q-codeletion statuses for adult-type diffuse gliomas. We thus investigated the testing/reporting completeness of BMM in the U.S.

METHODS

Cases of histopathologically-confirmed glioblastoma, astrocytoma, and oligodendroglioma diagnosed in 2018 were identified in the National Cancer Database. Adjusted odds ratios (ORadj) and 95% confidence intervals (95CI) of BMM testing/reporting were evaluated for association with selected patient, treatment, and facility-level characteristics using multivariable logistic regression. As a secondary analysis, predictors of MGMT promoter methylation testing/reporting among IDH-wildtype glioblastoma individuals was assessed.

RESULTS

Among 7,370 histopathologically-diagnosed adult-type diffuse gliomas nationally, the overall BMM testing/reporting completeness was 81%. Compared to biopsy-only cases, the odds of testing/reporting increased for increased for subtotal (ORadj= 1.38 [95CI: 1.19-1.61], p< 0.001) and gross total resection (ORadj=1.53 [95CI: 1.33-1.77], p< 0.001). Furthermore, the odds of testing/reporting completeness were lowest at community centers (hospitals (65.8%; ORadj=0.33 [95CI: 0.24-0.44], p< 0.001) and highest at academic/NCI-designated comprehensive cancer centers (85.3%; referent). By geographical location, BMM testing/reporting completeness ranged from a high of 86.9% at New England (referent) to a low of 75.2% in the West South Central region (ORadj=0.55 [95CI: 0.39-0.76]; p< 0.001). Extent of resection, facility type, and facility location were additionally significant predictors of MGMT testing/reporting among IDH-wildtype glioblastoma cases.

CONCLUSION

Initial BMM testing/reporting completeness for individuals with adult-type diffuse gliomas in the U.S. were favorable, although patterns varied by hospital attributes and extent of resection.
BIOM-27. PROGNOSTIC SIGNIFICANCE OF EXTENT OF RESECTION IN GLIOMA ACCORDING TO THE 2021 WHO CLASSIFICATION
Authors: Saito Kuniaki , Sasaki Yuta , Shimizu Saki , Nagai Jun , Yamagishi Yuki , Sasaki Nobuyoshi , Kobayashi Keiichi , Shiokawa Yoshiaki , Nakatomi Hirofumi , Nagane Motoo
Published: November 2022

BACKGROUND

In the updated 2021 WHO classification, diffuse gliomas were strictly reclassified by molecular statuses. In glioblastoma (GBM), the prognostic significance of the resection has been shown, but the excision rate to be achieved in the new classification has not been defined. Moreover, the correlation between the extent of resection (EOR) and the prognosis is still controversial for other gliomas.

METHODS

IDH 1/2 mutations and TERT promoter mutations were analyzed by Sanger sequencing, 1p/19q co-deletion by microsatellite or MLPA, and EGFR amplification and CDKN2A deletions by MLPA. The correlation between the resection rate and prognosis of each tumor type in the 2021/2016 WHO classification was analyzed retrospectively.

RESULTS

According to the 2021 classification, 293 patients with GBM, IDH-wild type, 68 with astrocytoma, IDH-mutant (2/3/4 22/26/20), and 58 with oligodendroglioma, IDH-mutant and 1p/19q co-deleted were identified. Based on the 2016 classification, they were diagnosed as 314 GBM, 106 astrocytoma (Gd II/III 37/69), and 59 oligodendroglioma. For GBM, IDH-wild type (2021 classification), a prolonged OS benefit was observed with >25% removal (p=0.042), whereas, more than 20% of tumor removal for patients with GBM (2016 classification) resulted in OS prolongation. EOR was a significant favorable prognostic factor for grade II/III astrocytoma by the 2016 classification, but not for astrocytoma, IDH-mutant (grade 2/3) in the 2021 classification. When analyzed only in patients with astrocytoma, IDH-mutant by the 2021 classification, EOR was not significantly prognostic, suggesting that poorer prognosis of patients with unresectable IDH-wild type astrocytomas (2016 classification) might have a negative impact on the outcome.

CONCLUSION

There was a strong correlation between EOR and prognosis in patients with GBM, and >25% removal was considered significant according to the 2021 classification. For astrocytoma in the 2021 classification, EOR did not show a prognostic significance, but further validation including grading effect is warranted.
BIOM-29. THE PROGNOSTIC AND PREDICTIVE SIGNIFICANCE OF PARTIAL MGMT PROMOTER METHYLATION FOR IDH-WILDTYPE GLIOBLASTOMA PATIENTS
Authors: Torre Matthew , Iorgulescu Bryan
Published: November 2022

BACKGROUND

Glioblastoma patients showing hypermethylation of the promoter of the O6-methylguanine-methyltransferase (MGMT) gene have significantly improved survival when treated with temozolomide compared to patients with hypomethylated MGMT promoters. However, the prognostic and predictive significance of partial MGMT promoter methylation is unclear.

METHODS

The National Cancer Database was queried for patients newly diagnosed in 2018 with histopathologically-confirmed IDH-wildtype glioblastoma. MGMT promoter methylation status was correlated with overall survival (OS) using multivariable Cox regression with Bonferroni correction for multiple testing (p< 0.008 was significant).

RESULTS

3,663 patients were identified with newly diagnosed, histopathologically-confirmed IDH-wildtype glioblastoma and known MGMT promoter methylation. Of the 2,807 patients who received single agent chemotherapy (i.e. likely temozolomide), the MGMT promoter was unmethylated, partially methylated, hypermethylated, and methylated not otherwise specified (NOS) in 57.9%, 5.0%, 3.1%, and 34.0% of cases, respectively, with the later group likely consisting predominantly of hypermethylated cases. Multivariable analysis demonstrated that among patients receiving temozolomide, those with unmethylated MGMT promoters had significantly worse OS than patients with partially methylated MGMT promoters (hazard ratio (HR) 1.94; 95% confidence interval (CI), 1.54-2.44; p< 0.001). However, the OS of hypermethylated patients (HR 1.02; 95% CI, 0.72-1.46; p=0.9) and methylated NOS patients (HR 0.99; 95% CI, 0.78-1.26; p=0.928) were not statistically different from the OS of partially methylated patients.

CONCLUSIONS

IDH-wildtype glioblastoma patients with partial methylation of the MGMT promoter treated with temozolomide have improved OS compared to their unmethylated counterparts, supporting the use of temozolomide therapy in these patients.
BIOM-35. A NEW PRECISION-MEDICINE APPROACH TO PREDICT TUMOR TREATMENT RESPONSE IDENTIFIES IN GLIOBLASTOMA A 17 GENE SIGNATURE PROGNOSTIC OF TMZ RESPONSE AND SURVIVAL WITH ROBUST PREDICTIVE VALUE
Authors: Morelli Mariangela , Stefano Anna Luisa Di , Picca Alberto , Lessi Francesca , Santonocito Orazio , Menicagli Michele , Pasqualetti Francesco , Franceschi Sara , Aretini Paolo , Sanson Marc , Mazzanti Chiara Maria
Published: November 2022

The Glioblastoma (GB) field has been experiencing a therapeutic standstill since 2005, primarily due to ineffective preclinical approaches to test anti-cancer treatments. Therefore, better treatment screening approaches are required. We developed a NADH FLIM-based functional precision medicine approach, that within one week after surgery identified two groups of TMZ Responder and Non-Responder tumors. A 17 gene molecular signature able to classify with 100% precision the TMZ responder and non-responder samples was discovered and identified by Kaplan Meier analysis, a Low-Risk and a High-Risk survival group, interrogating the TCGA GB database (Hazard Ratio = 1.87 p=0.00098,n=148) and TCGA LGG database (Hazard Ratio = 7.66 p=1.197e−35, n=660). Same results were obtained in the CCGA datasets. The 17 gene signature power for independently predicting prognosis (Hazard Ratio = 1.9, p=0.002) was then confirmed by direct RNAseq analysis of a separate clinically characterized cohort of 235 GB patients. Then, we combined the methylation status of the MGMT promoter to analyze the survival status of patients. The survival analysis based on the 17 gene risk signature and MGMT promoter methylation status demonstrated remarkable stratification of the clinical courses into four subgroups. Patients with MGMT promoter unmethylation and 17 gene High-Risk score had the worst prognosis, while patients with MGMT promoter methylation and 17 gene Low-Risk score had the best prognosis. In the latter group, a significant 24-month increase in survival was observed with 10% of 100 months Long Survivors with a difference of 35 months compared to the other groups. Our data indicate a new statistically strong RNAseq-based prognostic survival and TMZ response tool for patients with malignant glioma. The accuracy of this functional precision medicine approach allowed the development of a new prognostic gene signature that can improve the clinical management of GB patients. The approach could be implemented on other cancers as well.
BIOM-43. THE GENOMIC, TRANSCRIPTOMIC, AND EPIGENOMIC LANDSCAPE OF ISOCITRATE DEHYDROGENASE WILD TYPE GLIOBLASTOMA ACROSS THE AGE CONTINUUM
Authors: Johnson Margaret , Bell April , Shah Yajas , Viets-Layng Kayla , Mauer Elizabeth , Xiu Joanne , Elemento Olivier , Glantz Michael , Walker Phillip , Chen Clark , Dunbar Erin , Fonkem Ekokobe , Kesari Santosh , Brenner Andrew , Newton Herbert , Low Justin , Sumrall Ashley , Korn Wolfgang , Ashley David , Wainwright Derek
Published: November 2022

BACKGROUND

Older age is a poor prognostic factor for glioblastoma (GBM) patients. We tested whether the intrinsic molecular landscape of the tumor may contribute to this poor prognosis.

METHODS

In accordance with the 2021 WHO classification scheme, we included only isocitrate dehydrogenase (IDH) wild type GBM. Based on published literature, we defined older as age > 65. RNA expression, gene amplification, tumor mutational burden (TMB) and mutational profiles were analyzed in three unique datasets: Tempus (n = 1,410), Caris (n = 1,432), and TCGA (n = 557). Comparison were made between < 65 and ³ 65 year olds using Pearson’s Chi-squared tests, Fisher’s exact tests, or Wilcoxon rank-sum where appropriate.

RESULTS

From our evaluable gene sets, TERT promoter mutations were more prevalent in patients ³ 65 years old (Caris 82.64 vs 77.27%, p = 0.016; Tempus 58.0 vs 49.0%, p = 0.002). There were no significant differences in PDCD1, CD274, CD3E, TNFRSF18, CD40, CD8A, TNFRSF4, CTLA4, HAVCR2, TNFSF9, CD274, or CDKN2A; PDL-1 (by IHC); dMMR/MSI-H, TMB; CDK6 amplification, EGFR amplification, EGFR, EGFRvIII, EGFR fusions, MET fusions, PTEN, TP53, or NF-1. MGMT promoter methylation (Caris data) was more common in the older group (49.73 v 34.14%, p < 0.001). TGCA data demonstrated that gene expression, TMB, and methylation did not change significantly with age. Additionally, PCOLCE2 and SLC10A4 were differentially methylated, and missense mutations, of any type, were more common in the older group (p=0.006).

CONCLUSION

Despite worse survival outcomes for older patients with IDHwt GBM as compared to younger counterparts, the molecular landscape is similar at the genomic, transcriptomic and epigenomic levels. The key exception is TERT promoter mutations that are more common in older GBM patients. Poorer survival is therefore not likely to be attributable solely to intratumoral factors.
BIOM-45. DETERMINANTS OF GBM VULNERABILITY TO INHIBITORS OF NEDD8 ACTIVATING ENZYME (NAE)
Authors: Tang Nanyun , Hao Yue , Berens Michael
Published: November 2022

Advancing new therapeutics to FDA approval for GBM is hampered by intra- and inter-tumoral heterogeneity. Design of clinical trials to enroll patients likely to respond to a new treatment seems critical to build the arsenal of agents against this disease. Neddylation is a protein modification pathway aligned to protein degradation and cytological localization within the ubiquitin/proteasome system. Components of the neddylation pathway are frequently overexpressed or hyperactivated in GBM, and whose upregulation has been associated with glioma progression and worse survival. Among glioblastoma cell lines and patient-derived stem cells, subsets were found to be selectively susceptible to NAE inhibitors. We previously showed that PTEN signaling, DNA replication, and chromatin instability pathways are the most significant differentiators between MLN4924 sensitive vs. non-sensitive models. To test a candidate molecular “signature of vulnerability”, two subsets of PDX models (PTEN wildtype and PTEN del or mutated) were treated with a panel of 3 NAE inhibitors. 5 GBM PTENwt models were shown vulnerable to MLN4924 and TAS4464 with average EC50 values 5-10 folds lower than 6 PTENmt/del models. CDC activity was greater against PTENwt, but only 2-fold different vs PTENmt/del. Transcriptomic data mining uncovered additional determinants of response to NAE inhibitors. To disclose the relationship between constitutive expression of three gene sets: DNA Replication Fork Progressing, Replication Fork Protection, and Replication Fork Protection Complex, we found that the genes involved in these are significantly under expressed in PTENmt models when comparing to PTENwt models. The molecular determinants of drug response to NAE inhibitors will be further verified in the extended preclinical models and lead to a patient-enrollment “signature of vulnerability” to increase the likelihood of demonstrating therapeutic efficacy in the early stage of clinical trials.
BIOM-63. IDENTIFICATION OF MIRNA IN CEREBROSPINAL FLUID AND PLASMA AS A BIOMARKER TO SUPPORT MRI EVALUATION AND MONITORING OF PEDIATRIC BRAIN TUMORS
Authors: Coyle Anne , Familiar Ariana , Zhao Chao , Rathi Komal , Hollawell Madison , Choudhari Namrata , Foster Jessica , Naqvi Ammar , Bagheri Sina , Anderson Hannah , Vidal Lorenna , Vossough Arastoo , Storm Philip B , Madsen Peter , Resnick Adam C , Nabavizadeh Ali , Koptyra Mateusz
Published: November 2022

MRI is the current gold standard imaging technique for diagnostic evaluation and monitoring of pediatric CNS tumors, however MRI measures are unable to fully relate to tumor biology and molecular stratification. Circulating in blood and cerebrospinal fluid (CSF), miRNAs are an abundant and stable nucleic acid which can be utilized as a tumor biomarker. Relating miRNA biomarkers and radiological tumor measurements may provide improved diagnostic and monitoring tools for pediatric brain tumors. Using a cohort of 54 pediatric brain tumors including low grade glioma, ependymoma, germ cell tumor, medulloblastoma, atypical teratoid rhabdoid tumor and high-grade glioma we attempted to combine MRI findings and circulating miRNA data. The miRNA expression was profiled in 33 CSF and 52 plasma samples using the HTG EdgeSeq platform. Clinically acquired, multi-parametric MRI scans at time-points close in proximity to liquid biopsy collection were collected retrospectively and used to generate volumetric tumor segmentations. We identified unique miRNA targets significantly correlated with MRI features, clinical findings, and patient outcomes. In both CSF and plasma, miRNA expression was identified to correlate with diagnosis and clinical features including tumor grade and survival status (p < 0.05). In CSF, miRNA expression was correlated with MRI measurements including cystic core volume, non-enhancing tumor volume, leptomeningeal disease, tumor size and location (p < 0.05). Combination of miRNA targets and radiomic tumor measurements improved diagnostic predictions between low- and high-grade tumors. In plasma, miRNA expression was correlated with MRI measurements including cystic core volume, location, and leptomeningeal disease (p < 0.05). These results demonstrate utility of miRNAs as a pediatric brain tumor biomarker which combined with imaging features can improve minimally to non-invasive diagnostics and management of pediatric brain tumors.
BIOS-03. REAL WORLD CLINICAL OUTCOMES OF PATIENTS WITH DIFFUSE MIDLINE GLIOMA IN A LONGITUDINAL OUTCOMES REGISTRY
Authors: Stuhlmiller Timothy , Wasserman Asher , Quinn Jameson , Shapiro Mark , Kesari Santosh
Published: November 2022

We utilized the longitudinal clinical outcomes registry XCELSIOR (NCT03793088) to understand real world outcomes and treatment patterns among patients with diffuse midline glioma. A total of 74 patients were identified with a diagnosis of diffuse midline glioma by pathology or imaging (36 pediatric and 38 adult patients). Median age at diagnosis was 20 years. As of 6/1/2022, 45 patients had expired. Median overall survival (mOS) of the entire cohort was 16.2 months. Cox proportional hazard ratio analysis identified age as the only significant covariate for OS (pediatric HR = 1.59, p=0.04). Pediatric patients had a mOS of 12.9 months and adult patients a mOS of 18.9 months from diagnosis. Frequency of primary tumor location in this dataset was brainstem (35%), thalamus (23%), and pons (20%). Pons location was associated with worst survival (mOS 11.4 months, n=15 patients). The most common anti-cancer interventions among all patients were ONC201 (39 patients), temozolomide (37 patients), bevacizumab (23 patients), panobinostat (8 patients), and immune checkpoint inhibitors (3 patients each, pembrolizumab and nivolumab). In this dataset, no interventions were statistically significant in a Cox proportional hazard model, but both immune checkpoint inhibitors (HR = -1.24, p=0.11) and ONC201 (HR = -0.38, p=0.27) trended toward benefit in the entire population. The subpopulation of patients treated with ONC201 whose tumor also harbored a TP53 mutation displayed a tendency toward activity (n=8); TP53-mutant patients treated with ONC201 had a mOS of 25.0 months vs. TP53 wild-type patients treated with ONC201 had a mOS of 20.3 months. Annotation of data for additional patients is ongoing and updated analyses will be presented at the meeting.
CNSC-03. NEURONAL INTERMEDIATE FILAMENT (NIF) ANTIBODY POSITIVE PARANEOPLASTIC SYNDROME IN A PATIENT WITH METASTATIC NEUROENDOCRINE PANCREATIC CARCINOMA AND TREATMENT WITH IPILIMUMAB/NIVOLUMAB
Authors: Rodriguez Karla Mora , Peguero Edwin , Pina Yolanda , Strosberg Jonathan , Verma Neha , Mokhtari Sepideh
Published: November 2022

Immune checkpoint inhibitors, such as ipilimumab (CTL-4) and nivolumab (PD-1) have shown effectiveness in many types of neoplasia. This combination has been used as salvage immunotherapy for high grade metastatic pancreatic carcinoma. Nevertheless, severe neurologic immune-mediated adverse effects can result from the use of this treatment. We present a case of a 64-year-old woman with metastatic neuroendocrine pancreatic carcinoma with abrupt left facial and oculomotor cranial nerve palsy as well spastic tetraplegia after one dose of ipilimumab/nivolumab. She had a history of sudden onset diplopia, fever and ground-level fall a few hours after her initial dose of immunotherapy. Initial laboratory assessment showed pronounced lymphocyte predominant leukocytosis and mild chronic hyponatremia. In the following hours, she developed right mydriasis, right sided fast phase nystagmus and right central facial paralysis along with weakness and spasticity in four extremities. Neuroimaging of brain, orbits and CTL spine showed enhancement of intra-orbital and intracranial optic nerves as well chiasm, linear enhancement from C4-C7 and cauda equina, as well as abnormal signal along thoracic spinal cord and conus medullaris. Routine EEG demonstrated non-etiology specific encephalopathy. Lumbar puncture had normal opening pressure, mild pleocytosis, hyper-proteinorrhachia and normal glucose. Viral panel and cytology in the CSF were negative, and myeline basic protein was elevated. She was treated with high dose steroids which improved overall strength and CN palsies. Twenty days after initial presentation, she suddenly developed hypotension, tachypnea, and altered cognition. The patient and family opted for comfort measures only. She passed away that same day. Late report of CSF antibody panels showed positive cell-based assay for heavy and light chain NIF with a titer of 1:512. This case emphasizes the importance of recognition of anti-body mediated paraneoplastic syndromes in patients treated with immunotherapy, their appropriate treatment and prognosis.