bluuebunny/crossref_metadata_2025 huggingface dataset:
A SHEPWM-based wireless information and power transfer system using a single inverter
Authors: Liu Jianping , Zhang Bochen , Fan Li , Zhang Hongli , Feng Kai , Li Yuegong
Published: October 2024

Considering the special structure of a wireless power transfer system, there is no direct electrical connection between the sending module and the receive module. To increase the system interoperability, it is necessary to realize the information transfer during power transmission. In this paper, Selected Harmonic Elimination PWM (SHEPWM) is applied to make a single inverter generate two controlled frequency components. During normal power transmission, the proposed WPT system can also realize information without any high-frequency signal sources. For information transmission, an additional coil is applied to build an information transmission channel without a tightly coupled transformer. Besides, the corresponding information modulation and demodulation methods are redesigned. Finally, a simulation case based on this proposed WPT system is carried out. The rate of information transfer is 42.5 kbps.
Improved radar signal sorting algorithm based on density-peak-clustering approach
Authors: Ren Biao , Deng Lianwen , Xie Haipeng , Liao Congwei , Shi Junping
Published: October 2024

This paper proposes improved radar pulse sorting signals by the Density-Peak (DP) algorithm. In this study, we propose finding a density threshold within the entire density interval to distinguish radar pulse signals and noise pulse signals, leading to higher sorting accuracy. Through MATLAB simulations, we compared the performance of the improved DP algorithm with the original Density Peak algorithm, as well as the traditional K-means and FCM algorithms. Our results verify that the proposed DP algorithm outperforms these other methods by sorting accuracy and Adjusted Rand Index (ARI). The accuracy of this work can reach 98.30%, and the ARI of this work can reach 0.9627, which verifies excellent performance.
Maritime 5G channel properties along the ferry route at the N41 band
Authors: Zhang Shuo , Yang Kun , Xu Beining , Wu Jianming , Zeng Hao , Lin Jinglong
Published: October 2024

With the improvement of diverse maritime infrastructures, the efficient utilization of constrained wireless resources to deliver enhanced data rates has emerged as a pivotal focus in maritime communication. Multiple-input, multiple-output (MIMO) wireless communication technology offers a promising solution to this challenge. In order to investigate the performance of MIMO wireless communication technology in maritime environments, we conducted tests spanning from Changzhi island to Liuheng island. Through rigorous practical experimentation and meticulous data analysis, we determined that the average received signal strength of maritime MIMO wireless communication along the specified route was measured at -91.89 dBm, with an average received signal quality of -13.94 dB.
Beam management strategy of MIMO phased array antenna based on the topology of LEO constellation network
Authors: Liu Keyu , Jiang Li , Deng Sicheng , Chen Boyan , Cui Zhaoyun , Li Biao
Published: October 2024

In recent years, the launch and operation of large-scale LEO communication satellites has been a development trend and research hotspot in the field of satellite communication. However, large-scale satellite networking will inevitably lead to the waste of beam and frequency resources, thus reducing the efficiency of the system and increasing the energy consumption of the satellites. In this paper, a beam management strategy based on LEO constellation topology is proposed and simulated by using the Iridium generation constellation system as model input. The simulation results show that the proportion of C/I greater than 16 dB in the global region has increased from 84.57% to 98.89%.
Study of load cell calibration based on adaptive kalman filter algorithm
Authors: Liu Kai , He Chuchao , Zhao Xiangmo , Di Ruohai , Li Xiaoyan , Sun Mengyu
Published: October 2024

Nowadays, load cells are widely used. However, the influence of the external environment, the degradation of the sensor performance, and other issues may result in measuring sensor deviation, thus affecting the accuracy of the measurement results. An adapted Kalman filter algorithm calibration algorithm is designed. Firstly, it compares the output of the sensor with the real value to get the observation residual. Secondly, based on the residuals and predefined noise and covariance matrices, the calculation of the gain matrix is performed, and finally, the estimate and matrix are updated. In the updating process, to address the issue of sensor output anomaly, adaptive adjustment of the parameters of the Kalman filter is used. Experiments show that the calibration algorithm based on adaptive Kalman filtering can run well on the embedded platform with good accuracy and stability. After calibration, the accuracy of the sensor is improved from 0.05% F.S to 0.01% F.S.
Research on state perception data acquisition technology for PV modules based on dual-mode communication technology
Authors: Lin Fantao , Zhu Enguo , Liu Yan , Zheng Guoquan , Li Congcong , Jing Zhen
Published: October 2024

A photovoltaic (PV) module state perception data acquisition technology based on high-speed carrier and high-speed micropower wireless dual-mode communication technology (DMCT) networking is proposed, which realizes real-time perception of the operating status of distributed PV DC side modules by the electric energy data acquisition system (EEDAS), effectively solving the problem of fine monitoring and control of PV modules. The experimental results show that the one-time acquisition success rate of PV module status sensing data is more than 90%, and the minute-level acquisition success rate is more than 99%, which meets the communication reliability and timeliness requirements of EEDAS for low-voltage distributed PV acquisition and monitoring.
Signal simulation based on improved doppler filter
Authors: Zhen Mengyang , Qi Chundong , Sun Mengsu
Published: October 2024

In satellite communication, the signal is transmitted through a wireless channel, and distorted signals will appear under the influence of the actual environment. In this paper, an improved Doppler filter is proposed by mathematically fitting the actual signals, and the similarity of the time-frequency map of the signals output by this improved filter reaches 94.357% of the standard value, realizing the simulation of a kind of aberration appearing in the actual environment on the time-frequency image and finally realizing the self-adaptation.
Towards Defining Climate Adaptation Literacy in the Context of Urban Resilience
Authors: Khoja Ahmed , Felicioni Licia , Danylenko Olena
Published: October 2024

The climate crisis intensifies rapidly, straining the urban environment and society. Addressing climate change requires collaborative efforts, integrating physical resilience with knowledge empowerment. Formal and informal knowledge are vital for effective adaptation. In the updated Intergovernmental Panel on Climate Change (IPCC) AR6 Report an emphasis on knowledge and its role in reducing response risk was highlighted. At the urban scale, adaptation knowledge is essential, bridging social and technical systems. Here, community knowledge evolves from a passive component within a greater adaptation strategy to an active, integral element. This paper develops a unique definition of climate adaptation literacy for the urban built environment based on an extensive literature review on urban climate adaptation, guided by the PISA (Program for International Student Assessment) 2025 Framework. The results of this work highlight existing gaps in climate adaptation knowledge and present urban climate adaptation literacy as a means to measure the response risk. These insights aid the formulation of resilience policies and urban adaptation strategies and contribute to the safety, resilience, sustainability, and functionality of the material and non-material values of the urban environment
Sound & Music Projects for Eurorack and Beyond
Authors: Edstrom Brent
Published: October 2024

Sound & Music Projects for Eurorack and Beyond explores the intersection of music, electronics, and computer science, and provides a path for musicians and sound designers to envision and create custom electronic instruments. Throughout the book, examples are built on Teensy® microcontrollers, which provide a musician-friendly platform for combining code and circuitry. The book explores these concepts in the context of Eurorack, a popular framework for mounting and interconnecting electronic instruments. Hands-on projects introduce core technologies including microcontroller programming, electronic circuits, and fabrication of custom instruments. Culminating Eurorack projects include an audio mixer, audio effects unit, MID to voltage control module, and Eurorack synthesizer.
Wavetable Synthesis
Authors: Edstrom Brent
Published: October 2024

This chapter explains that wavetable synthesis is a category of music synthesis useful for producing realistic sounds. With wavetable synthesis, a table of samples is stored in a memory block and played back at a periodic rate to recreate a sound. The wavetable project is a simple synthesizer that uses two potentiometers to control the attack and release of an envelope. The chapter then discusses how to use potentiometers to interact with the audio system and incorporate USB to process MIDI Note-On and Note-Off messages. It elaborates on how the wavetable object’s output can be processed by other objects in the library, such as filters and digital signal processors.
FM Synthesis
Authors: Edstrom Brent
Published: October 2024

This chapter examines the extent of FM synthesis and how it can be achieved with Teensy microcontrollers. It introduces Frequency Modulation (FM) as a category of synthesis popularized by Yamaha’s DX7 in the 1980s. The core concept of FM synthesis revolves around one periodic signal that is used to modulate another signal called the carrier wave or modulated signal. The chapter then details how to create sidebands at frequencies equal to the carrier frequency plus and minus integer multiples of the modulator frequency. It explains that hands-on experimentation will provide a good foundation for more advanced applications even though the FM synthesizer project is relatively simple.
Additive Synthesis
Authors: Edstrom Brent
Published: October 2024

This chapter looks into the process and components of additive synthesis. It explains that additive synthesis uses sine waves of differing frequencies and amplitudes to create a unique harmonic spectrum. The additive synthesizer project consists of four rotary encoders with integrated pushbuttons and an OLED display and is built around a Teensy 4 with an Audio Adapter Board. The chapter also explores the interplay between additive synthesis and the structures and elements of a user interface. It then provides an overview of how to marry components created in the Audio System Design Tool with code to create an interactive and expressive additive synthesizer.
Genetic Step Sequencer
Authors: Edstrom Brent
Published: October 2024

This chapter provides an overview on the genetic step sequencer. It explains how Evolutionary Algorithms provide a fascinating avenue of exploration for electronic musicians. Thus, genetic algorithms, a subclass of evolutionary algorithms, are modeled on natural systems and utilize stochastic search techniques. The chapter then elaborates on the use of genetic algorithms to drive a MIDI step sequencer with ever-changing genetic modifications, while also considering that microcontroller technology provides an opportunity for innumerable variations. It cites that the pseudo-Darwinian model forms the basis for the genetic step sequencer and will guide the creation of a virtual habitat for the algorithms to adapt and flourish.
Powering Eurorack Modules
Authors: Edstrom Brent
Published: October 2024

This chapter discusses how to power Eurorack modules. Some manufacturers offer Eurorack cases with built-in power supplies, but prices can be prohibitively expensive. The chapter then explains that Eurorack projects are built around a reliable power source, such as a voltage regulator to provide +5V and a shunt to provide a stable reference voltage. Another reliable power source includes using diodes to prevent damage from reverse polarity. The chapter offers the option of using a DC wall in conjunction with a switching regulator, while also warning about the real danger of electrocution whenever mains power is involved with DIY power supplies.
Voltage Control, Gates, and Triggers
Authors: Edstrom Brent
Published: October 2024

This chapter covers the significance of voltage control, gates, and triggers. While MIDI has many advantages over voltage control, including support for polyphonic performance, using voltage to control synthesizers can open to new expressive opportunities. Voltage is also used for triggers, gates, and clock pulses, but voltage control can provide unique opportunities for creative application including using a voltage source to modulate another voltage source. The chapter then looks into how MIDI to Control Voltage converters provide a useful addition to a Eurorack setup. It also mentions the possible enhancements like support for polyphonic output or USB MIDI input.
MIDI to Control-Voltage Converter
Authors: Edstrom Brent
Published: October 2024

This chapter tackles how the MIDI to Control-Voltage Converter project provides a useful addition to any Eurorack setup. It cites that the MIDI to control voltage conversion opens the door to using computers, MIDI keyboards, and other devices as sources of voltage control. Essentially, the converter is comprised of a modest collection of circuits and code and includes CV/octave and gate/trigger output, onboard 5-volt power supply, and MIDI input. Moreover, the modular approach to the MIDI to CV backpack enables its use in a variety of projects such as custom sequencers, arpeggiators, or real-time controllers. The chapter considers several enhancements and creative applications to the MIDI to Control-Voltage Converter.
Myeloid sarcomas with CBFA2T3
:
GLIS2 fusion: clinicopathologic characterization of 4 cases mimicking small round cell tumors
Authors: Malik Faizan , Eldomery Mohammad K , Wang Wei , Gheorghe Gabriela , Khanlari Mahsa
Published: October 2024

Objectives

Acute myeloid leukemia with CBFA2T3::GLIS2 fusion can initially present as extramedullary lesions (myeloid sarcoma), leading to a misdiagnosis of nonhematologic pediatric solid tumors.

Methods

We characterized the clinicopathologic features of 4 cases of CBFA2T3::GLIS2 fusion-positive myeloid sarcoma in pediatric patients where the sarcoma presented either without leukemic involvement (isolated myeloid sarcoma; 3/4 [75%]) or had concurrent leukemic disease (1/4 [25%]).

Results

All cases mimicked nonhematopoietic tumors at morphologic and immunophenotypic levels, so the initial evaluation did not raise suspicion for acute myeloid leukemia/myeloid sarcoma. After extensive workup, however, including molecular studies, the diagnosis of myeloid sarcoma with CBFA2T3::GLIS2 fusion was rendered.

Conclusions

This study highlights the need for a high suspicion index of GLIS2-rearranged myeloid sarcoma in the differential diagnosis of pediatric small round cell tumors in tissue biopsies and the application of adequate workup to avoid misdiagnosing this entity.
Characterizing metabolomic signatures related to coffee and tea consumption and their association with incidence and dynamic progression of type 2 diabetes: A multi-state analysis
Authors: Zheng Guzhengyue , Ran Shanshan , Zhang Jingyi , Qian Zhengmin (Min) , Tian Fei , Shi Hui , Elliott Michael , Tabet Maya , Yang Yin , Lin Hualiang
Published: October 2024

Our study aimed to investigate the impact of tea and coffee consumption and related metabolomic signatures on dynamic transitions from diabetes-free status to incident type 2 diabetes (T2D), and subsequently to T2D-related complications and death. We included 438,970 participants in the UK Biobank who were free of diabetes and diabetes complications at baseline. Of these, 212,146 individuals had information on all metabolic biomarkers. We identified tea- and coffee-related metabolomic signatures using elastic net regression models. We examined associations of tea and coffee intake and related metabolomic signatures with the onset and progression of T2D using multi-state regression models. We observed that tea and coffee consumption and related metabolomic signatures were inversely associated with the risk of five T2D transitions. For example, HRs (95% CIs) per SD increase of the tea-related metabolomic signature were 0.87 (0.85, 0.89), 0.97 (0.95, 0.99), 0.91 (0.90, 0.92), 0.92 (0.91, 0.94), and 0.91 (0.90, 0.92) for transitions from diabetes-free state to incident T2D, from diabetes-free state to total death, from incident T2D to T2D complications, from incident T2D to death, and from T2D complications to death. These findings highlight the benefit of tea and coffee intake in reducing the risk of occurrence and progression of T2D.
The metabolomic composition of the oviductal fluid is controlled by the periovulatory hormonal context in Bos indicus cows
Authors: Gonella-Diaza Angela , Sponchiado Mariana , Rodrigues França Moana , Liu Lihe , Pugliesi Guilherme , Guimarães Lo Turco Edson , Peñagaricano Francisco , Binelli Mario
Published: October 2024

In cattle, oviductal function is controlled by the ovarian sex-steroids estradiol and progesterone. Here, we tested the hypothesis that the exposure to contrasting sex-steroid milieus differentially impacts the oviductal fluid composition. Estrous cycles of non-lactating, multiparous Nelore cows were pre-synchronized and then synchronized with a protocol designed two induce ovulation of large or small follciles. Larger preovulatory follicle (day 0) and corpora lutea (day 4) and greater estradiol (day 0) and progesterone (day 4) concentrations were observed in the large follciles group. Four days after induced ovulation, oviductal fluid was collected post-mortem. Quantitative mass spectrometry was used to determine the concentration of amino acids, biogenic amines, acylcarnitines, phosphatidylcholines, lysophosphatidylcholines, sphingomyelins, hexoses, prostaglandins, and related compounds. Multivariate analyses (orthogonal projections to latent structures discriminant analysis) were conducted to compare the metabolomic signatures of oviductal fluids. Correlation network analysis was conducted to measure the strength and hierarchy of associations among metabolites. Of the 205 metabolites quantified, 171 were detected in at least 50% of the samples and were included in further data analysis. After orthogonal projections to latent structures discriminant analysis analysis, samples of the large follciles and small follciles were divided clearly into two non-overlapping clusters. Twenty metabolites had different or tended to have different concentrations in the oviductal fluid when comparing groups. Seven of these 20 analytes had greater concentrations in large follciles cows. Moreover, total sum of biogenic amines, phosphatidylcholines, and prostaglandins were higher in the small follciles group. The correlation network showed that the large follciles group metabolites’ concentrations were highly intercorrelated, which was not observed in the small follciles group. We concluded that the periovulatory endocrine milieu regulates the composition of the oviductal fluid.
Functional principal component analysis with informative observation times
Authors: Sang Peijun , Kong Dehan , Yang Shu
Published: October 2024

Functional principal component analysis has been shown to be invaluable for revealing variation modes of longitudinal outcomes, which serve as important building blocks for forecasting and model building. Decades of research have advanced methods for functional principal component analysis, often assuming independence between the observation times and longitudinal outcomes. Yet such assumptions are fragile in real-world settings where observation times may be driven by outcome-related processes. Rather than ignoring the informative observation time process, we explicitly model the observational times by a general counting process dependent on time-varying prognostic factors. Identification of the mean, covariance function and functional principal components ensues via inverse intensity weighting. We propose using weighted penalized splines for estimation and establish consistency and convergence rates for the weighted estimators. Simulation studies demonstrate that the proposed estimators are substantially more accurate than the existing ones in the presence of a correlation between the observation time process and the longitudinal outcome process. We further examine the finite-sample performance of the proposed method using the Acute Infection and Early Disease Research Program study.
Apelin levels in patients with polyuria-polydipsia syndrome upon copeptin stimulation tests
Authors: Bizzozero Chiara Angela , Monnerat Sophie , Chapman Fiona A , Dhaun Neeraj , Refardt Julie , Christ-Crain Mirjam
Published: October 2024

Objective

Differentiating between arginine vasopressin deficiency (AVP-D) and primary polydipsia (PP) requires a copeptin stimulation test. We aimed to characterize changes in apelin, an endogenous hormone antagonizing AVP, upon copeptin stimulation tests.

Design

Post hoc secondary analysis of a multi-centric cross-over diagnostic study (NCT03572166).

Setting

Outpatients included at the University Hospital Basel.

Participants

Patients with AVP-D and PP.

Interventions

Copeptin stimulation tests with hypertonic saline and arginine infusion.

Outcomes and Measures

The primary outcome was the absolute difference in apelin between baseline and peak of copeptin stimulation tests. Secondary objectives included the diagnostic ability of apelin.

Results

Thirty-eight patients were analysed, 23 (60%) had PP and 15 (40%) had AVP-D. No difference was seen between baseline median (IQR) apelin levels in PP and AVP-D (1079 [912, 1225] and 910 [756, 1039] pmol/L, respectively). Upon hypertonic saline, apelin decreased by −241 (−326, −124) pmol/L in PP and −47.2 (−198, 5.86) pmol/L in AVP-D (P = .022). The area under the curve (AUC) to differentiate PP from AVP-D was 97.1% (95% CI, 90.5-100) for copeptin and 49.3% (95% CI, 30.4-68.1) for apelin (P < .001). Upon arginine, apelin decreased by −39.2 (−96.4, 39.8) pmol/L in PP and increased by 25.8 (2.8, 113.0) pmol/L in AVP-D (P = .1). The AUC was 97.1% (95% CI: 79.6-98.0) for copeptin and 60.5% (95% CI: 39.8-80.0) for apelin (P = .007).

Conclusions and Relevance

Our findings suggest that apelin decreases to a greater extent in PP compared with AVP-D upon copeptin stimulation tests. However, copeptin remains the best marker to differentiate AVP-D from PP.
Low Anti-Tumor Necrosis Factor Levels During Maintenance Phase Are Associated With Treatment Failure in Children With Crohn’s Disease
Authors: Moses Jonathan , Adler Jeremy , Saeed Shehzad A , Firestine Ann M , Galanko Joseph A , Ammoury Rana F , Bass Dorsey M , Bass Julie A , Bastidas Monique , Benkov Keith J , Bousvaros Athos , Cabrera José M , Chun Kelly Y , Dorsey Jill M , Ebach Dawn R , Gulati Ajay S , Herfarth Hans H , Ivanova Anastasia , Jester Traci W , Kaplan Jess L , Kusek Mark E , Leibowitz Ian H , Linville Tiffany M , Margolis Peter A , Minar Phillip , Molle-Rios Zarela , Niklinska-Schirtz Barbara Joanna , Olano Kelly K , Osaba Lourdes , Palomo Pablo J , Pashankar Dinesh S , Pitch Lisa , Samson Charles M , Sandberg Kelly C , Steiner Steven J , Strople Jennifer A , Sullivan Jillian S , Tung Jeanne , Wali Prateek , Wohl David A , Zikry Mike , Boyle Brendan M , Kappelman Michael D
Published: October 2024

Background

Higher drug levels and combination therapy with low-dose oral methotrexate (LD-MTX) may reduce anti-tumor necrosis factor (TNF) treatment failure in pediatric Crohn’s disease. We sought to (1) evaluate whether combination therapy with LD-MTX was associated with higher anti-TNF levels, (2) evaluate associations between anti-TNF levels and subsequent treatment failure, and (3) explore the effect of combination therapy on maintenance of remission among patients with therapeutic drug levels (>5 µg/mL for infliximab and >7.5 µg/mL for adalimumab).

Methods

We conducted a post hoc analysis of the COMBINE trial, which compared anti-TNF monotherapy to combination therapy with LD-MTX. We included participants who entered maintenance therapy and provided a serum sample approximately 4 months from randomization.

Results

Among 112 infliximab and 41 adalimumab initiators, median drug levels were similar between combination therapy and monotherapy (infliximab: 8.8 vs 7.5 μg/mL [P = .49]; adalimumab: 11.1 vs 10.5 μg/mL [P = .11]). Median drug levels were lower in patients experiencing treatment failure (infliximab: 4.2 vs 9.6 μg/mL [P < .01]; adalimumab: 9.1 vs 12.3 μg/mL [P < .01]). Among patients treated with infliximab with therapeutic drug levels, we observed no difference in treatment failure between participants assigned monotherapy or combination therapy. Among patients treated with adalimumab, a trend towards reduced treatment failure in the combination therapy arm was not statistically significant (P = .14).

Conclusions

LD-MTX combination was not associated with higher drug levels, but higher drug levels were associated with reduced risk of treatment failure. Among patients with therapeutic drug levels, we observed no benefit of LD-MTX for patients treated with infliximab. A nonsignificant trend towards reduced treatment failure with the addition of LD-MTX patients treated with adalimumab warrants further investigation.
MultiShape: a spectral element method, with applications to Dynamic Density Functional Theory and PDE-constrained optimization
Authors: Roden Jonna C , Mills-Williams Rory D , Pearson John W , Goddard Benjamin D
Published: October 2024

A new numerical framework is developed to solve general nonlinear and nonlocal PDEs on complicated two-dimensional domains. This enables the solution of a wide range of both steady and time-dependent problems on nonstandard geometries, as well as providing the ability to impose nonlinear and nonlocal boundary conditions (typical of those arising in the modelling of physical phenomena) in a flexible and automated way. This spectral element methodology, which we called MultiShape, is compatible with other state-of-the-art numerical methods, such as differential–algebraic equation solvers and optimization algorithms. MultiShape is an open-source Matlab library, in which the numerical implementation is designed to be user-friendly: the problem set-up and computations are done automatically through intuitive operator definitions and notation. Validation tests are presented, before we showcase the power and versatility of MultiShape with three motivating examples in Dynamic Density Functional Theory and PDE-constrained optimization.
Conceptual Decolonization, Conceptual Justice, and Religious Concepts
Authors: Burley Mikel
Published: October 2024

Calls for decolonization are on the rise in social and academic life, but ‘decolonization’ can mean various things. This article expounds and critically evaluates the programme of conceptual decolonization, chiefly as promulgated in relation to African philosophy by Kwasi Wiredu. The programme involves both resisting the unreflective acceptance of non-indigenous concepts and constructively utilizing indigenous conceptual resources to address philosophical questions. Examining recent objections from Olúfẹ́mi Táíwò and giving particular attention to Wiredu’s treatment of religious concepts, I concur with Wiredu that conceptual decolonization can encourage conceptual enlargement but argue that care is needed to avoid oversimplifying the non-indigenous concepts that are subjected to scrutiny.
PL02.2.A TRAMETINIB IN NEUROFIBROMATOSIS TYPE 1 RELATED SYMPTOMATIC PLEXIFORM NEUROFIBROMAS: ONE-YEAR FOLLOW-UP OF THE TRAIN STUDY
Authors: Noordhoek D C , van Dijk S A , French P J , Wiemer E A C , Hanff D F , Manintveld O C , Taal W
Published: October 2024

BACKGROUND

Plexiform neurofibromas (PN) are present in 50% of the patients with neurofibromatosis type 1 (NF1). They can cause pain, neurological deficit and cosmetic problems. Recent phase 2 clinical trials have shown promising results of treatment of inoperable PN with MEK inhibitors, especially in pediatric patients. Our aim was to evaluate the effect of the MEK inhibitor trametinib in adult NF1 patients.

MATERIAL AND METHODS

The TRAIN study is an open-label, single arm, phase 2 trial with trametinib 2 mg daily in 30 patients with NF1 and at least one symptomatic inoperable PN. The primary outcome measure is tumor volume decrease of the pre-defined target PN lesion(s) as measured by 3D volumetric analysis on 6-monthly MR imaging. A decrease of >20% in total tumor volume is considered treatment response. Secondary outcome measures are pain, safety and tolerability.

RESULTS

Thirty patients have been enrolled since July 2020. The last patient completed one year follow-up end of May 2024. The current median follow-up is 29 months (range 12-46 months). Average age at study registration was 44 years (range 19-67 years). Eleven patients (37%) discontinued study treatment within the first year: 8 patients due to toxicity, 2 because of symptom progression and one patient because of a new contraindication for trametinib. Twenty-seven patients completed 12 months follow-up with MR imaging. The response rate was 48% within the first year of study treatment. Volume decrease ranged from: 21% to 57%. The remaining 52% of the patients had stable disease. The average Numeric Pain Rating Scale (NPRS) decreased from 5.2 at baseline to 3.5 at one year follow-up (p=0.027). The most common adverse events were acneiform rash, diarrhea, fatigue, asymptomatic anemia and hypoalbuminemia. Four severe adverse events (grade 3) occurred: pneumonitis (n=1), rhabdomyolysis (n=1) and erysipelas (n=2).

CONCLUSION

Approximately half of the adult NF1 patients with inoperable PNF showed a treatment response with trametinib within the first year. The average NPRS decreased significantly. However, adverse events are common and therefore more research is needed to select patients that will benefit the most from MEK inhibition.
KS01.5.A A BRAIN CANCER CELL ATLAS REVEALS SHARED ASTROCYTE-LIKE STEM CELL STATES DRIVE INTRATUMOURAL HETEROGENEITY AND SHAPE IMMUNE DYNAMICS IN ADULT-TYPE DIFFUSE GLIOMAS
Authors: Zaman A , Muskovic W , Holton E , Pandya M , Zakanovic R , Chin V , Lam E , Yeung J , Sughrue M , Teo C , Powell J
Published: October 2024

BACKGROUND

Adult-type diffuse gliomas pose significant clinical challenges due to their complex cellular makeup and evolving nature. Understanding this heterogeneity is crucial for developing effective targeted therapies.

MATERIALS AND METHODS

To understand glioma heterogeneity, we performed single-cell and single-nucleus RNA sequencing on 66 tumours (single surgery) and 54 paired (two surgeries) longitudinal samples. This dataset comprises approximately 900,000 cells, enabling us to investigate both the conserved cellular landscape and dynamic cellular evolution across different glioma subtypes.

RESULTS

Employing a novel phylogeny-based approach, we showed that the astrocyte-like glioma stem cell (GSC) is the origin of diverse glioma lineages. This finding represents a paradigm shift in our understanding of glioma development, highlighting the GSC as a potential therapeutic target. The GSC’s resemblance to healthy adult neural stem cells provides insight into the roots of glioma heterogeneity and suggests a shared origin for intratumoral diversity. Our analysis revealed a consistent cellular architecture spanning astrocytomas, oligodendrogliomas, and glioblastomas (GBMs). This architecture comprises seven recurring malignant cell states: neuro-, oligo-, neuro-oligo-lineage, cycling (G1/S, G2/M), hypoxia-associated, and a quiescent astrocyte-like GSC. Notably, the proportions of these cell states differ among glioma subtypes. We further show that GBMs exhibit significantly higher T-cell and myeloid cell infiltration than IDH-mutant gliomas. Paradoxically, this correlates with a worse prognosis, suggesting profound T-cell dysfunction and a complex interplay between myeloid cells and the tumour. Longitudinal analysis underscored the evolving nature of the glioma’s malignant cell populations and immune landscape. We identified subtype-specific T-cell and myeloid gene expression profiles, including targets like PARD6G (GBM) and CXCL13 (astrocytoma), which offer a foundation for developing targeted immunotherapies and prognostic biomarkers.

CONCLUSION

Our study provides a model of glioma heterogeneity and evolution. This model integrates a shared astrocyte-like GSC driving cellular diversity alongside distinct, dynamic immune landscapes across different glioma subtypes. These findings offer unprecedented potential for developing transformative treatment strategies. Future research functionally validating the GSC and its impact on tumour dynamics will be crucial for translating these insights into improved patient outcomes.
KS02.7.A LONGITUDINAL SINGLE-CELL ANALYSES IDENTIFY DRIVERS OF GENETIC, EPIGENOMIC, AND CELLULAR EVOLUTION IN IDH-MUTANT GLIOMA
Authors: Johnson K C , Spitzer A , Varn F S , Nomura M , Garofano L , Chowdhury T , Anderson K J , D’Angelo F , Bussema L , Gritsch S , Oh Y , Moon H , Paek S , Bielle F , Laurenge A , Di Stefano A , Mathon B , Picca A , Sanson M , Lipsa A , Hertel F , Zhao Z , Wang Q , Jiang T , Hermes B , Sanai N , Golebiewska A , Niclou S P , Huse J , Yung W , Lasorella A , Suvà M L , Iavarone A , Tirosh I , Verhaak R G
Published: October 2024

BACKGROUND

Hotspot mutations in the IDH genes serve as tumor-initiating events that define a subset of adult diffuse glioma that can further be divided into either oligodendroglioma or astrocytoma subtypes. Despite standard treatment, IDH-mutant gliomas inevitably recur. Previous studies suggest that therapeutic resistance may result from a combination of intratumoral cellular heterogeneity, epigenetic evolution, and acquired genetic alterations. However, how these multilayered molecular features interact to influence the evolutionary paths of IDH-mutant gliomas remains incompletely understood.

MATERIAL AND METHODS

To chart this evolution, 75 glioma samples were longitudinally collected from 35 patients (n = 13 oligodendroglioma, n = 22 astrocytoma) and profiled using single nucleus RNA sequencing, ATAC sequencing, and bulk DNA sequencing.

RESULTS

Analysis of 331,016 nuclei (snRNA) revealed eight tumor microenvironment cell types and five pan-IDH-mutant malignant cellular states. The malignant states were distributed along a cellular hierarchy of stem-like populations (neural progenitor cell-like, oligodendrocyte progenitor cell-like, and undifferentiated) and more differentiated populations (mesenchymal-like and astrocyte-like) with cycling cells enriched in the stem-like populations. Joint open chromatin accessibility data (snATAC) was available for a subset of malignant cells (71,088 nuclei) and state-specific differentially accessible peaks supported that these states are epigenetically encoded. Across both subtypes, higher tumor grade was associated with reduced malignant cell differentiation and increased cycling populations. Between the two time points, we identified that there was a longitudinal increase in the cycling, undifferentiated, and mesenchymal-like populations with a corresponding decrease in the astrocyte-like population. Longitudinal genetic analysis revealed that 19 of 35 tumors acquired at least one of the following genetic alterations: treatment-associated hypermutation, cell cycle alteration, or large changes in copy number alterations. Importantly, tumors that acquired these key genetic alterations demonstrated significant shifts towards reduced differentiation and increased cycling populations while those tumors that did not had more stable malignant profiles.

CONCLUSION

Collectively, our results suggest a common cellular hierarchy across IDH-mutant gliomas with a shift towards reduced differentiation, increased cycling populations during disease progression that is driven by acquired genetic alterations.
KS03.4.A PATTERNS OF CARE AND CLINICAL OUTCOMES OF PATIENTS WITH GLIOBLASTOMA IN THE UNITED STATES FROM 2005-2020: A REAL-WORLD ANALYSIS
Authors: Jayram D , Bellur S , Ozair A , Ahmad S , Hodgson L , Frias Perez N , Podder V , Ganiyani M , Ahluwalia M
Published: October 2024

BACKGROUND

Survival for glioblastoma (GBM) remains low, with disparities affecting outcomes. Standard of care (SoC) includes surgery and adjuvant chemoradiation. This study explores the demographics, treatment patterns, and outcomes of GBM pts in the United States (US).

MATERIAL AND METHODS

We conducted a retrospective study with the US National Cancer Database (NCDB), capturing more than 70% of newly diagnosed patients in US, for GBM pts diagnosed in 2005-2020 according to ESMO Guidance for Reporting Oncology Real-World (GROW). Trends were analyzed with descriptive statistics and X2-test between time periods: 2005-08, 2009-12, 2013-16, and 2017-20. Predictors of SoC receipt were analyzed with multivariate logistic regression. Kaplan-Meier method and log-rank test were used to estimate and compare median overall survival (mOS) for univariate association and Cox proportional-hazards analysis for multivariate modelling. Adjustment was made using demographic, socioeconomic, and clinical factors. Associations were reported as (Odds Ratio [OR]/Hazard Ratio [HR] 95% CI) per STROBE guidelines.

RESULTS

Of 104,697 GBM pts, 42.5% were female. 91.2% White, 5.7% Black, and 2.0% were Asian. 5.3% were Hispanic. Median age was 65 (IQR 57-73). Percentage of pts ≥ 65 years increased from 48.8% in 2005-08 to 54.0% in 2017-20. 56.5% of pts received SoC. SoC receipt rose over time: 2009-12 (OR 1.26, CI 1.21-1.31, P<0.001) vs 2013-16 (OR 1.36, CI 1.31-1.42, P<0.001) vs 2017-20 (1.51, CI 1.45-1.57, P<0.001). Older pts were less likely to receive SoC compared to pts aged <50: 50-64: (OR 0.81, CI 0.77-0.86, p<0.001), 65-74: (OR 0.59, CI 0.55-0.62, p<0.001) vs >74: (OR 0.23, CI 0.22-0.25, p<0.001). Females (OR 0.91, CI 0.89-0.93 P<0.001), Black (OR 0.81, CI 0.77-0.86, P<0.001), and Hispanics (OR 0.91, CI 0.86-0.97, P=0.004) were less likely to receive SoC than males, White, and non-Hispanics. Privately insured were more likely to receive SoC than with Medicare (OR 0.83, CI 0.80-0.87, P<0.001), Medicaid (OR 0.67, CI 0.64-0.71, P<0.001), and uninsured pts (OR 0.60, CI 0.55-0.64, P<0.001). SoC recipients had mOS of 14.6 months (CI 14.5-14.8) vs 4.8 (CI 4.7-4.9) for non-recipients (P<0.001). Compared to 2005-08, pts were more likely to survive in 2017-20 (HR 0.84, CI 0.82-0.85, P<0.001) followed by 2013-16 (HR 0.88, CI 0.86-0.89, P<0.001) and 2009-12 (HR: 0.93, CI 0.91-0.94, P<0.001).

CONCLUSION

Receipt of SoC has increased with significant improvement in OS. However, female, Black and Hispanic pts were less likely to receive SoC. Targeted efforts are warranted to mitigate disparities and increase receipt of SoC.
KS04.5.A DIFFERENCES IN COGNITIVE FUNCTIONING BETWEEN PATIENTS WITH IDH1-MUTANT OLIGODENDROGLIOMA AND ASTROCYTOMA BEFORE AND AFTER SURGERY
Authors: Landers-Wouters M , Butterbrod E , Brouwers B , Rutten G
Published: October 2024

BACKGROUND

Alongside differences in growth rate, IDH1-mutant oligodendroglioma and astrocytoma exhibit differences in growth pattern. Whereas oligodendroglioma seem to infiltrate subcortical tracts, astrocytoma tend to displace them. Tracts traversing a tumor are more likely to be damaged during surgical resection than displaced tracts, possibly resulting in a (temporary) worse cognitive outcome. This study explored differences in cognitive functioning before and after surgery between patients with IDH1-mutant astrocytoma and oligodendroglioma.

MATERIAL AND METHODS

Patients who underwent surgery for confirmed IDH1-mutant, WHO grade 2 or 3 oligodendroglioma (1p19-codeleted) or astrocytoma were included. Cognition was assessed with computerized and paper-and-pencil tests before surgery, and 3 and 12 months after. Test scores were standardized. Diagnostic groups were compared on sociodemographics, tumor location, awake vs. asleep surgery, type of mapping, extent of resection (EOR), adjuvant treatment and baseline cognition. We performed longitudinal mixed models (LMM) to investigate differences in performances over time in the total sample and stratified according to surgical modality (awake or asleep), α=.05. We first examined the effect of diagnosis only, and subsequently with correction for group differences.

RESULTS

Compared to astrocytoma patients (n=95), those with oligodendroglioma (n=67) were significantly older, more often harbored a tumor located in the frontal lobe, and less often in the temporal lobe. Gross total resection (vs. subtotal) was more frequently achieved in oligodendroglioma surgery. Diagnosis was not related to any baseline test performance, but WHO grade (3 vs 2) was. In univariable LMM, oligodendroglioma patients performed worse than astrocytoma patients on cognitive flexibility over time. This effect was most apparent in the first time interval (astrocytoma: B= -0.45, oligodendroglioma: B=-0.84), after which both groups improved (B=0.23, B=0.24). Stratification showed no effect of diagnosis on longitudinal performances in the awake surgery group, but there was a difference between diagnoses on cognitive flexibility in the asleep surgery group, where astrocytoma patients remained stable (B=-0.01) while oligodendroglioma declined significantly (B=-0.55). Differences were not significant after correcting for baseline differences and EOR. Age and EOR were associated with multiple performances.

CONCLUSION

Differences in cognitive trajectories between patients with IDH1-mutant oligodendroglioma and astrocytoma seem explained by other patient and tumor characteristics or surgical factors rather than tumor type. Studies directly linking pre- and postoperative tract integrity to test performances can enhance understanding of the interplay between tumor growth pattern, surgical resection and cognitive outcome.
JS07.5.A CORRELATION BETWEEN TUMOR-INFILTRATING LYMPHOCYTE DISTRIBUTION AND CLINICAL OUTCOME IN PHASE I/II CLINICAL TRIAL OF DENDRITIC-CELL BASED IMMUNOTHERAPY IN GLIOBLASTOMA PATIENTS
Authors: Pellegatta S , Di Ianni N , Anghileri E , Facciolla M , Cuccarini V , Milani M , Patane M , Acquino D , Pollo B , DiMeco F , Silvani A , Eoli M
Published: October 2024

BACKGROUND

Despite the first classification of glioblastoma as an immunologically “cold” tumor, accumulating evidence suggests that this cancer type is susceptible to T cell infiltration, providing a glimmer of hope for the development of effective immunotherapy approaches that until now had limited success in brain tumors. To explore the contribution of biomarkers that could identify groups of patients showing durable response to immunotherapy, we examined several clinical and biological finding in 69 newly-diagnosed glioblastoma patients treated with dendritic cell (DC) immunotherapy added to standard treatment (DENDR1 NCT04801147).

MATERIAL AND METHODS

Patients with post-surgery volume ≤10 cc underwent leukapheresis before radiotherapy and chemotherapy with temozolomide (TMZ). Three intradermal injections of mature DC loaded with whole tumor lysate were administrated before and four after adjuvant TMZ. In all patients peripheral immune effector subsets were assessed including T and NK cells,, In all tumor samples MGMT methylation status was evaluated, and in 36 cases an immunohistochemistry (IHC) analysis was performed on tumor specimen collected before DC immunotherapy.

RESULTS

After a median follow-up of 23months (mo) median progression-free survival (PFS) was 12 mo (CI 95%10.34-13.6) and median overall

survival (OS) was 22.6 mo (CI 95%18.7-24.5) comparing favorably with OS expected from the literature. MGMT status and expansion of NK cells positively impacted PFS and OS. Furthermore, our preliminary results suggest an association between the density and localization of specific Tumor Infiltrating Lymphocytes (TILs) and patients’ response to immunotherapy. TIL spatial patterns revealed either an immune-excluded, or an immune-infiltrated scenario with either scattered, clustered, or widespread T cell infiltration. Notably, an abundant widespread infiltration of CD8 TILs was correlated with prolonged survival of DENDR1 patients (PFS 18.0 vs. 8.9; OS 33.6 vs. 11.0; p< 0.005 compared with excluded CD8+ TIL distribution), supporting that distribution can be predictive of immunotherapy responsiveness.

CONCLUSION

These findings suggest that in DENDR-1 improved clinical outcomes correlate with an increase in the number of active NK cells, MGMT status, and abundant widespread infiltration of CD8+ TILs.
OS03.4.A REPEATED INTRACRANIAL ADMINISTRATION OF ANTI-PD-1 ALONE OR IN COMBINATION WITH ANTI-CTLA-4 IMMUNE CHECKPOINT-BLOCKING MONOCLONAL ANTIBODIES IN PATIENTS WITH RECURRENT HIGH-GRADE GLIOMA
Authors: Lescrauwaet L , Dirven I , Del’haye J , Geens W , Geeraerts X , Stevens L , Brock S , Kockx M , Seynaeve L , Everaert H , Vanbinst a , Tuyaerts S , Neyns B , Duerinck J
Published: October 2024

BACKGROUND

Recurrent high-grade glioma (rHGG) is an invariably fatal malignancy, currently lacking life-prolonging treatment options. Systemic administration of PD-1 and CTLA-4 immune checkpoint blocking monoclonal antibodies has shown limited efficacy. In the Glitipni multi-cohort dose finding phase I clinical trial, the primary aim is to establish safety and feasibility of intra- followed by postoperative intracranial (iCran) administration of nivolumab (NIVO), with or without ipilimumab (IPI), in patients with rHGG amenable for a maximal safe resection (MSR) or stereotactic core needle biopsy (SCNB).

MATERIAL AND METHODS

Sixty-one patients were enrolled (across 3 cohorts), receiving 10 mg NIVO IV within 24h prior to MSR or SCNB. Forty-three patients underwent MSR, followed by intracerebral (iCer) injection of NIVO (10 mg) and IPI (5 mg) in the brain tissue lining the resection cavity. Among them, 27 received an additional intracavitary injection of NIVO (10 mg) and IPI (1-, 5-, or 10 mg) (iCav, via an Ommaya reservoir) at the end of the neurosurgical procedure. Sixteen patients underwent SCNB followed by the intratumoral (iTum) injection of NIVO (10 mg) and IPI (5 mg). Postoperative iCav administrations were repeated bi-weekly for a maximum of 11 cycles, concurrently with 10 mg NIVO IV. Postoperatively, 1-, 5-, or 10 mg NIVO iCav was administered as a single agent in 28 patients. In the third cohort, postoperative administration of 10 mg NIVO iCav was combined with 1-, 5- or 10 mg IPI iCav in 22 patients.

RESULTS

No unexpected adverse events (AE) occurred related to the perioperative treatment. Dose limiting toxicity consisted of transient symptomatic grade 3 aseptic neutrophilic pleocytosis in 1- and 3 patients receiving iCav administration of 5- and 10 mg iCav IPI, respectively. The most frequent reported treatment related AE was fatigue (n=49,80%); no grade 5 AE occurred. PFS did not differ between cohorts. OS was superior in patients who underwent a MSR versus SCNB; but was not improved by the addition of iCav IPI (median OS: 15- [95% CI 0-53] vs. 42- [26-57] vs. 35 [29-40] weeks; 1y OS-rate: 12% [95% CI 0-28] vs. 37% [14-60] vs. 29% [12-46]). OS of pts who underwent a MSR compared favorable against a pooled historical control cohort (n=469) treated with VEGF(R)-inhibitors (log rank p.015).

CONCLUSION

This first-in-human, multi-cohort, phase I clinical trial on intracranial CTLA-4/PD-1 blockade in patients with rHGG, demonstrates that intra- and postoperative iCran administration of NIVO with or without IPI up to a bi-weekly postop iCav dose of 1 mg IPI and 10 mg NIVO can be safely performed. Promising survival is documented in patients amenable for resection.