bluuebunny/crossref_metadata_2025 huggingface dataset:
A case report of paroxysmal complete atrioventricular block in a patient with dextrocardia and repaired tetralogy of Fallot
Authors: Fujita Takeshi , Yoshida Akira , Ichikawa Minoru
Published: November 2022

Background

Some adults suffer sudden cardiac death after previous surgical repair of tetralogy of Fallot (TOF), and in such cases, ventricular tachycardia is believed to be the most frequent cause of death. However, we report a case of cardiac arrest due to paroxysmal complete atrioventricular block in an adult with dextrocardia and repaired TOF.

Case summary

A 49-year-old woman with dextrocardia and a history of surgical treatment for TOF lost consciousness three times. A previously implanted loop recorder showed a 60-second cardiac arrest, and complete atrioventricular block was diagnosed. An electrophysiological study showed prolongation of the His-ventricular interval but no ventricular tachycardia. A dual chamber pacemaker was implanted, and there has been no recurrence of syncope in the 23 months since implantation.

Discussion

There is little evidence for paroxysmal complete atrioventricular block in patients with repaired TOF. This case suggests that paroxysmal complete atrioventricular block can occur late after surgical repair of TOF, and research needs to elucidate whether it is the cause of sudden cardiac death in some patients with TOF.
Seasonal dynamic of diazotrophic activity and environmental variables affecting it in the Gulf of Riga, Baltic Sea
Authors: Liepina-Leimane Ineta , Barda Ieva , Jurgensone Iveta , Labucis Atis , Suhareva Natalija , Kozlova Vendija , Maderniece Agita , Aigars Juris
Published: November 2022

The semi-enclosed Baltic Sea experiences regular summer blooms of diazotrophic cyanobacteria. Previously, it has been conclusively demonstrated that in open nitrogen-limited parts of the Baltic Sea, cyanobacteria successfully fix atmospheric N2. At the same time, diazotrophic activity is still poorly understood in Baltic Sea sub-regions where nitrogen and phosphorus are co-limiting primary production. To address this gap in research, we used the15 N tracer method for in situ incubations and measured the N2-fixation rate of heterocyst-forming cyanobacteria and picocyanobacteria in the Gulf of Riga, Baltic Sea, from April to September. Physicochemical variables and phytoplankton community composition were also determined. Our results show that the dominant species of cyanobacteria for this region (Aphanizomenon flosaquae) was present in the phytoplankton community during most of the study period. We also establish that the N2-fixation rate has a strong correlation with the proportion of A. flosaquae biomass containing heterocysts (r = 0.80). Our findings highlight the importance of a heterocyst-focused approach for an accurate diazotrophic activity evaluation that is one of the foundations for future management and protection of the Baltic Sea.
Periostin Plasma Levels and Changes on Physical and Cognitive Capacities in Community-Dwelling Older Adults
Authors: Sánchez-Sánchez Juan Luis , Ader Isabelle , Jeanson Yannick , Planat-Benard Valérie , Vellas Bruno , Casteilla Louis , de Souto-Barreto Philipe
Published: November 2022

Periostin, involved in extracellular matrix development and support, has been shown to be elevated in senescent tissues and fibrotic states, transversal signatures of aging. We aimed to explore associations between plasma periostin and physical and cognitive capacity evolution among older adults. Our hypothesis was that higher levels of plasma periostin will be associated with worse physical and mental capacities along time. Analyses included 1 096 participants (mean age = 75.3 years ± 4.4; 63.9% women) from the Multidomain Alzheimer Preventive Trial. Periostin levels (pg/mL) were measured in plasma collected at year 1. Periostin was used in continuous variable, and as a dichotomous variable highest quartile (POSTN+) versus lowest 3 quartiles (POSTN−) were used. Outcomes were measured annually over 4 years and included: gait speed (GS), short physical performance battery (SPPB) score, 5-times sit-to-stand test (5-STS), and handgrip strength (HS) as physical and cognitive composite z-score (CCS) and the Mini-Mental State Examination (MMSE) as cognitive endpoints. Plasma periostin as a continuous variable was associated with the worsening of physical and cognitive capacities over 4 years of follow-up, specifically the SPPB score, the 5-STS, and CCS in full-adjusted models. POSTN+ was associated with worse evolution in the physical (GS: [β = −0.057, 95% confidence interval (CI) = −0.101, −0.013], SPPB score [β = −0.736, 95% CI = −1.091, −0.381], 5-STS [β = 1.681, 95% CI = 0.801, 2.561]) as well as cognitive (CCS [β = −0.215, 95% CI = −0.335, −0.094]) domains compared to POSTN− group. No association was found with HS or the MMSE score. Our study showed for the first time that increased plasma periostin levels were associated with declines in both physical and cognitive capacities in older adults over a 4-year follow-up. Further research is needed to evaluate whether periostin might be used as a predictive biomarker of functional decline at an older age.
The whole-genome assembly of an endangered Salicaceae species: Chosenia arbutifolia (Pall.) A. Skv
Authors: He Xudong , Wang Yu , Lian Jinmin , Zheng Jiwei , Zhou Jie , Li Jiang , Jiao Zhongyi , Niu Yongchao , Wang Weiwei , Zhang Jun , Wang Baosong , Zhuge Qiang
Published: November 2022

Background

As a fast-growing tree species, Chosenia arbutifolia has a unique but controversial taxonomic status in the family Salicaceae. Despite its importance as an industrial material, in ecological protection, and in landscaping, C. arbutifolia is seriously endangered in Northeast China because of artificial destruction and its low reproductive capability.

Results

To clarify its phylogenetic relationships with other Salicaceae species, we assembled a high-quality chromosome-level genome of C. arbutifolia using PacBio High-Fidelity reads and Hi-C sequencing data, with a total size of 338.93 Mb and contig N50 of 1.68 Mb. Repetitive sequences, which accounted for 42.34% of the assembly length, were identified. In total, 33,229 protein-coding genes and 11,474 small noncoding RNAs were predicted. Phylogenetic analysis suggested that C. arbutifolia and poplars diverged approximately 15.3 million years ago, and a large interchromosomal recombination between C. arbutifolia and other Salicaceae species was discovered.

Conclusions

Our study provides insights into the genome architecture and systematic evolution of C. arbutifolia, as well as comprehensive information for germplasm protection and future functional genomic studies.
Quality classification and inversion of receiver functions using convolutional neural network
Authors: Gan Lu , Wu Qingju , Huang Qinghua , Tang Rongjiang
Published: November 2022

Convolutional neural network (CNN) is presented to implement quick quality classification and inversion for teleseismic P-wave receiver functions (RF). For the first case, a CNN is trained using field measured RFs from NE margin of the Tibetan Plateau to efficiently predict the quality of each input waveform. Signal-to-noise ratio and correlation are introduced to quantitatively determine the quality label of RF, avoiding the subjectivity of manual labelling. The trained network reduces the time needed for data processing and has higher accuracy and efficiency than conventional methods. Its good performance is confirmed by comparing it with manually selected data from NE of the Tibetan Plateau. The second case is an example of joint inverting teleseismic P-wave RF and surface wave dispersions for the estimation of earth S-wave structure and associated uncertainties. We train a UNet based on synthetic global Crust 5.1 models and standard earth models, as well as associated perturbed models to ensure enough generalization capacity. We find that the UNet inversion is robust and has a better performance to reconstruct subsurface ${V}_s$ distributions than the damping least-squares method, but at the expense of slightly higher data misfits. The pre-trained network can predict subsurface ${V}_s$ models and associated uncertainties beneath NE of the Tibetan Plateau, which is consistent with the published models.
Micromechanics of rock damage and its recovery in cyclic loading conditions
Authors: Brantut Nicolas , Petit Léo
Published: November 2022

Under compressive stress, rock ‘damage’ in the form of tensile microcracks is coupled to internal slip on microscopic interfaces, such as pre-existing cracks and grain boundaries. In order to characterize the contribution of slip to the overall damage process, we conduct triaxial cyclic loading experiments on Westerly granite, and monitor volumetric strain and elastic wave velocity and anisotropy. Cyclic loading tests show large hysteresis in axial stress–strain behaviour that can be explained entirely by slip. Elastic wave velocity variations are observed only past a yield point, and show hysteresis with incomplete reversibility upon unloading. Irrecoverable volumetric strain and elastic wave velocity drop and anisotropy increase with increasing maximum stress, are amplified during hydrostatic decompression, and decrease logarithmically with time during hydrostatic hold periods after deformation cycles. The mechanical data and change in elastic properties are used to determine the proportion of mechanical work required to generate tensile cracks, which increases as the rock approaches failure but remains small, up to around 10 per cent of the net dissipated work per cycle. The pre-rupture deformation behaviour of rocks is qualitatively compatible with the mechanics of wing cracks. While tensile cracks are the source of large changes in rock physical properties, they are not systematically associated with significant energy dissipation and their aperture and growth is primarily controlled by friction, which exerts a dominant control on rock rheology in the brittle regime. Time-dependent friction along pre-existing shear interfaces explains how tensile cracks can close under static conditions and produce recovery of elastic wave velocities over time.
Progress across empire: entanglements between Indian and European reformers before the First World War
Authors: Deroo Florian , Verbruggen Christophe
Published: November 2022

This article argues that the field of social reform was a flourishing sphere of encounter between progressive Indian and European intellectuals in the years leading up to the First World War. By building personal networks, sharing intellectual reference points and exchanging information in internationally oriented journals, reformers could develop the sense that they belonged to a globe-spanning vanguard of like-minded intellectuals who, by identifying and addressing social issues in a local context, were allied to a range of analogous initiatives abroad. The expectation of a mutually beneficial bridging of ‘East’ and ‘West’ stimulated the personal entanglements of these intellectuals, yet they would become harder to maintain after the mechanized violence of the First World War cast doubts on the civilizing offensive.
Decreased cyclic-AMP caused by ATP contributes to fosfomycin heteroresistance in avian Escherichia coli
Authors: Zhao Bing , Han Han , He Kun , Hou Wen-Fei , Liang Yu-Lei , Cui Jun-ling , He Dan-Dan , Hu Gong-Zheng , Liu Jian-Hua , Yuan Li
Published: November 2022

Background

Fosfomycin is an important broad-spectrum bactericidal antibiotic to treat multidrug-resistant bacteria infections. It is generally accepted that heteroresistant bacteria are an intermediate stage in the formation of drug resistance, but there are few studies on the formation mechanism underlying fosfomycin heteroresistance (FHR).

Objectives

To reveal the characteristics and formation mechanisms of FHR in Escherichia coli isolates obtained from chickens.

Methods

We identified the FHR according to the population analysis profile (PAP) test and in vitro time–kill assay. Growth curves for FHR E. coli and their subpopulations were measured. Also, the subpopulations were repeatedly cultured in fosfomycin-free medium for 5–20 overnight incubation periods. The formation mechanisms of FHR in E. coli isolates were identified through accumulation assay, carbohydrate utilization testing, real-time relative quantitative PCR analysis, DNA sequencing, transcriptomic analysis, intracellular ATP and cAMP-level assessment.

Results

Four of six E. coli strains were confirmed to show FHR, with a total of six subpopulations. The subpopulations restored phenotypic susceptibilities to fosfomycin within 5–20 overnight incubation sessions, but four of six subpopulations still maintained FHR characteristics. Differing from their parental isolates, the uptake of fosfomycin in the subpopulations through GlpT was reduced remarkably. Further studies identified that the low expression of glpT was due to the decrease of intracellular cAMP levels in the subpopulations, which was caused by the decreased ATP levels in cells.

Conclusions

Our findings revealed the formation mechanism of E. coli isolates showing FHR obtained from chicken in China and characterized the dynamic change traits in vitro of the subpopulations.
Temperature-dependent Functional Response of the Arboreal Rove Beetle,Oligota flavicornis(Coleoptera: Staphylinidae), a Voracious Predator ofTetranychus urticae(Acarina: Tetranychidae)
Authors: Lin Tao , Chen Yixin , Chen Yong , Lin Shuo , Hu Jinfeng , Zhao Jianwei , Yang Guang , Yang Fenghua , Wei Hui
Published: November 2022

The functional responses of Oligota flavicornis (Boisduval & Lacordaire) (Coleoptera: Staphylinidae) preying on the eggs of Tetranychus urticae Koch (Acarina: Tetranychidae) were examined at seven constant temperature settings (12, 15, 18, 22, 25, 30, and 32°C) to elucidate the predator–prey interactions between them. Logistic regression showed that O. flavicornis exhibited type II functional responses to T. urticae eggs at different temperatures. The reciprocal of handling time declined exponentially with warming, and the search rate presented a single hump-shaped relationship with temperature. For the search rate, the lower temperature thresholds were 9.1°C (linear) and 8.7°C (Briere). The optimal temperature and upper temperature threshold were 29.1 and 37.8°C for Logan and 29.7 and 35.8°C for Briere, respectively. The predation threshold window of O. flavicornis reached 27.1°C with a range of 8.7–35.8°C. The predator could consume 244.7–388.4 T. urticae eggs in a day in the optimal temperature range (18–32°C). The voracious predatory behavior of O. flavicornis against T. urticae eggs over a broad temperature range indicates that the predator shows promise as a potential biological control agent and that temperature-dependent predation could be a basis for formulating strategies to control tetranychid mites.
Serotype 19A and 6C Account for One-Third of Pneumococcal Carriage Among Belgian Day-Care Children Four Years After a Shift to a Lower-Valent PCV
Authors: Ekinci Esra , Van Heirstraeten Liesbet , Willen Laura , Desmet Stefanie , Wouters Ine , Vermeulen Helene , Lammens Christine , Goossens Herman , Van Damme Pierre , Verhaegen Jan , Beutels Philippe , Theeten Heidi , Malhotra-Kumar Surbhi ,   NP Carriage Study Group
Published: November 2022

Background

Pneumococcal conjugate vaccines (PCVs) effectively reduce infection and asymptomatic carriage of Streptococcus pneumoniae vaccine serotypes. In 2016, Belgium replaced its infant PCV13 program by a 4-year period of PCV10. Concomitantly, S. pneumoniae serotype carriage was monitored together with the carriage of other nasopharyngeal pathogens in children attending day-care centers.

Methods

From 2016 to 2019, a total of 3459 nasopharyngeal swabs were obtained from children aged 6–30 months. Culture and qPCR were used for the identification of S. pneumoniae, Haemophilus influenzae, Moraxella catarrhalis, and Staphylococcus aureus and for serotyping and antimicrobial susceptibility assessment of S. pneumoniae strains.

Results

S. pneumoniae colonization was frequent and stable over the study years. H. influenzae and M. catarrhalis were more frequently carried (P < .001) than S. pneumoniae, by, respectively, 92.3% and 91.0% of children. Prevalence of all PCV13 serotypes together increased significantly over time from 5.8% to 19.6% (P < .001) and was attributable to the increasing prevalence of serotype 19A. Coincidently, non-vaccine serotype 6C increased (P < .001) and the overall pneumococcal non-susceptibility to tetracycline and erythromycin. Non-susceptibility to cotrimoxazole decreased (P < .001).

Conclusions

The switch to a PCV program no longer covering serotypes 19A, 6A, and 3 was associated with a sustained increase of serotypes 19A and 6C in healthy children, similarly as in invasive pneumococcal disease. This resulted in a re-introduction of the 13-valent conjugate vaccine during the summer of 2019.
Distinct chromosomal “niches” in the genome ofSaccharomyces cerevisiaeprovide the background for genomic innovation and shape the fate of gene duplicates
Authors: Stavropoulou Athanasia , Tassios Emilios , Kalyva Maria , Georgoulopoulos Michalis , Vakirlis Nikolaos , Iliopoulos Ioannis , Nikolaou Christoforos
Published: November 2022

Nearly one third of Saccharomyces cerevisiae protein coding sequences correspond to duplicate genes, equally split between small-scale duplicates (SSD) and whole-genome duplicates (WGD). While duplicate genes have distinct properties compared to singletons, to date, there has been no systematic analysis of their positional preferences. In this work, we show that SSD and WGD genes are organized in distinct gene clusters that occupy different genomic regions, with SSD being more peripheral and WGD more centrally positioned close to centromeric chromatin. Duplicate gene clusters differ from the rest of the genome in terms of gene size and spacing, gene expression variability and regulatory complexity, properties that are also shared by singleton genes residing within them. Singletons within duplicate gene clusters have longer promoters, more complex structure and a higher number of protein–protein interactions. Particular chromatin architectures appear to be important for gene evolution, as we find SSD gene-pair co-expression to be strongly associated with the similarity of nucleosome positioning patterns. We propose that specific regions of the yeast genome provide a favourable environment for the generation and maintenance of small-scale gene duplicates, segregating them from WGD-enriched genomic domains. Our findings provide a valuable framework linking genomic innovation with positional genomic preferences.
MODL-15. BRINGING PRECISION MEDICINE TO GLIOBLASTOMA PATIENTS BY MODELING MOLECULAR TUMOR SUBTYPES IN IMMUNOCOMPETENT SWINE FOR THERAPEUTIC AND BIOMARKER DEVELOPMENT
Authors: Watson Adrienne , Korpela Derek , Koes Nicholas , Taisto Mandy , Corbiere Stanislas , Tschida Barbara
Published: November 2022

Glioblastoma (GBM) is an aggressive primary brain tumor with no effective cure. Standard of care treatment offers dismal prognoses for patients with a median survival time of only 15.6 months, and no new drugs have been approved in 15 years. Contributing factors include tumor heterogeneity, high mutation rates, infiltrative growth, a complex tumor-immune microenvironment, and the blood-brain barrier, all of which are obstacles clinicians and researchers must overcome to improve patient outcomes. Research to identify novel therapeutic strategies are ongoing, but treatments that show promise in preclinical studies often do not pass Phase 2 and 3 clinical trials. These costly failures are attributable to a lack of predictive preclinical models that translate to human application, low patient availability for numerous and robust clinical trials, and an “all-comer” approach to clinical trial design where patients are enrolled based on disease presence and not molecular features of the tumor. To advance treatments for GBM, Recombinetics has pioneered somatic gene-editing technologies to the same genetic changes seen in patient tumors in GBM-initiating cells in an immune-competent swine model. These models rapidly and reproducibly develop GBM tumors that resemble human GBMs genetically, clinically and histologically. In addition to the physiological, immunological, and metabolic parallels between swine and humans, the molecular data collected from our swine mesenchymal and classical subtypes of GBM validate accurate disease modeling and we are pursuing additional GBM subtypes. Using RNA-sequencing, we are characterizing molecular profiles of these tumors, as well as identifying and validating drug targets. Studies are ongoing to characterize the tumor immune microenvironment of our models for improved immune-oncology therapeutic development. These large animal models of GBM will usher in a new era of pre-clinical testing that predicts the efficacy of a variety of therapeutic approaches, using precision medicine to bring novel, safe, and effective therapies to patients.
CTIM-07. PHASE II RANDOMIZED, BLINDED, PLACEBO-CONTROLLED TRIAL TESTING PP65 CMV MRNA DENDRITIC CELL VACCINE AND TETANUS-DIPHTHERIA TOXOID FOR NEWLY DIAGNOSED GBM (ATTAC II, NCT02465268)
Authors: Rahman Maryam , Ghiaseddin Ashley , Deleyrolle Phuong , Peters Katherine B , Archer Gary , Sampson John , Mitchell Duane
Published: November 2022

INTRODUCTION

Immunotherapy is limited in efficacy for glioblastoma (GBM). The objective of this study was to evaluate the efficacy and immune effects of the pp65 mRNA dendritic cell (DC) vaccine with the use of lysosomal-associated membrane protein (LAMP) in two different formulations (full-length (fl) and short-length (sh).

METHODS

Patients who underwent resection of newly diagnosed GBM were enrolled and randomized to one of 3 arms: Arm 1) pp65-shLAMP mRNA DC with GM-CSF, Arm 2) pp65-flLAMP mRNA DC with GM-CSF, Arm 3) Unpulsed peripheral blood mononuclear cells (PBMC). After surgery, patients underwent leukapheresis for PBMC isolation and vaccines generation. Patients were treated with standard radiation and temozolomide followed by dose intensified adjuvant temozolomide at 75-100 mg/m2 x 21 days (aged less than 70) or standard dose at 150-200 mg/m2 x 5 days (patients 70 and older). Immunization started days 22-24 of cycle #1 with vaccines 1-3 delivered at 2 week intervals. All patients received tetanus-toxoid booster prior to vaccine 1. Patients continued to receive monthly vaccines for up to 10 vaccines with tetanus-diphtheria toxoid skin prep prior to vaccines 3, 6 and 9 (arms 1 and 2). Safety, efficacy and immune labs were evaluated.

RESULTS

Overall DC vaccines were well-tolerated with 2 SAEs possibly attributed to DC vaccination that met criteria as DLTs. Of recorded grade 2 or lower AEs, 2 were possibly attributable to DC vaccination. One patient was removed from the study due to failure to produce DC vaccines that met QA/QC release criteria.

CONCLUSION

In a large randomized and blinded patient cohort, delivery of CMV LAMP pp65 mRNA DC vaccines is feasible and safe in a multi-institutional setting. The primary endpoint of survival will be analyzed at the conclusion of the study.
CTIM-24. NUTMEG: A RANDOMIZED PHASE II STUDY OF NIVOLUMAB AND TEMOZOLOMIDE VERSUS TEMOZOLOMIDE ALONE IN NEWLY DIAGNOSED ELDERLY PATIENTS WITH GLIOBLASTOMA
Authors: Sim Hao-Wen , Lwin Zarnie , Barnes Elizabeth , McDonald Kerrie , Yip Sonia , Verhaak Roel , Heimberger Amy , Hall Merryn , Wong Matthew , Jennens Ross , Ashley David , Rosenthal Mark , Hovey Elizabeth , Ellingson Benjamin , Tognela Annette , Gan Hui , Back Michael , Koh Eng-Siew , Long Anne , Cuff Katharine , Begbie Stephen , Gedye Craig , Mislang Anna , Le Hien , Johnson Margaret , Kong Benjamin , Simes John , Khasraw Mustafa
Published: November 2022

BACKGROUND

Nivolumab is a PD-1 inhibitor with known safety profile. An increase in mutations as we age is well documented in glioblastoma and other cancers. Higher mutational load is associated with increased response to nivolumab in extracranial malignancies. NUTMEG examined the activity of nivolumab added to temozolomide in glioblastoma patients aged ≥ 65 years.

METHODS

NUTMEG was an international multicenter phase II trial for newly diagnosed glioblastoma patients aged ≥ 65 years, randomized 2:1 to experimental (40Gy/15 fractions with temozolomide 75mg/m2, then 6 cycles of temozolomide 150-200mg/m2 D1-5 Q28D + nivolumab 240mg D1,15 Q28D C1-4 and 480mg D1 Q28D C5-6) versus standard arm (40Gy/15 fractions with temozolomide 75mg/m2, then 6 cycles of temozolomide alone 150-200mg/m2 D1-5 Q28D), stratified by age, ECOG status, MGMT status and resection extent.

RESULTS

103 patients were enrolled (69 in experimental arm, 34 in standard arm). Median age was 73 years, 36% ECOG 0, 57% MGMT-unmethylated and 51% gross macroscopic resection. Median follow-up is 31 months to date, with 77 deaths (surviving patients to continue follow-up and final results will be presented). Median overall survival was 11.8 months in the experimental arm versus 12.0 months in the standard arm (HR 0.95 95%CI 0.59-1.53 for experimental relative to control). Six-month progression-free survival rate using mRANO was 64% in the experimental arm versus 49% in the standard arm (HR 0.81 95%CI 0.51-1.26). Grade 3/4 adverse events were reported in 46% of experimental arm (7% lung infection, 7% thromboembolic events, 6% fatigue, 6% muscle weakness) and in 29% of control arm (9% fatigue, 6% seizure, 6% thromboembolic events).

CONCLUSIONS

There was insufficient evidence of clinical benefit with nivolumab in this population. No new safety signals were identified. Central imaging review is underway and correlative studies will characterize the immune landscape, including mutational load, neoantigen and other immune markers. NCT04195139.
CTIM-27. AUTOLOGOUS TUMOR LYSATE-LOADED DENDRITIC CELL VACCINATION IMPROVES SURVIVAL IN PATIENTS WITH NEWLY DIAGNOSED AND RECURRENT GLIOBLASTOMA: SURVIVAL RESULTS FROM A PHASE 3 TRIAL
Authors: Liau Linda M , Ashkan Keyoumars , Brem Steven , Campian Jian , Trusheim John , Iwamoto Fabio , Tran David , Anstass George , Cobbs Charles , Heth Jason , Salacz Michael , D'Andre Stacy , Aiken Robert , Moshel Yaron , Nam JooYeon , Pillainayagam Clement , Wagner Stephanie , Walter Kevin , Chaudary Rekha , Goldlust Samuel , Lee Ian , Bota Daniela , Elinzano Heinrich , Grewal Jai , Lillehei Kevin , Mikkelsen Tom , Walbert Tobias , Abram Steve , Brenner Andrew , Ewend Matthew , Khagi Simon , Lovick Darren , Portnow Jana , Kim Lyndon , Loudon William , Martinez Nina , Thompson Reid , Avigan David , Fink Karen , Geoffroy Francois , Giglio Pierre , Gligich Oleg , Krex Dietmar , Lindhorst Scott M , Lutzky Jose , Meisel Hans-Joerg , Nadji-Ohl Minou , Sanchin Lhagva , Sloan Andrew , Bosch Marnix
Published: November 2022

BACKGROUND

Standard of care (SOC) and patient survival in glioblastoma have changed little in the past 17 years. We evaluated in a phase 3 trial whether adding an autologous tumor lysate-loaded dendritic cell vaccine (murcidencel) to SOC extends survival. Patients and

METHODS

Newly diagnosed glioblastoma patients were randomized 2:1 to either murcidencel or placebo. Under a crossover design, all patients could receive murcidencel following tumor recurrence. All parties remained blinded regarding treatments before recurrence. Patients thus received murcidencel at new diagnosis (nGBM) or at recurrence (rGBM) following crossover from placebo. The primary and secondary endpoints compare overall survival (OS) with contemporaneous, matched external controls. Four sets of analyses were conducted to ensure rigorous matching of the controls, reduce biases, and confirm the robustness of the results.

RESULTS

331 patients were enrolled. With the crossover, 89% received murcidencel. Median OS (mOS) for nGBM patients (n = 232) was 19.3 months from randomization (22.4 months from surgery) with murcidencel vs. 16.5 months from randomization in the controls (HR = 0.80, p = 0.002). Survival at 48 months from randomization was 15.7% vs. 9.9%, and at 60 months was 13% vs. 5.7%. For rGBM (n = 64), mOS was 13.2 months from relapse vs. 7.8 months in the controls (HR = 0.58, p < 0.001). Survival at 24 months post-recurrence was 20.7% vs. 9.6%, and at 30 months post-recurrence was 11.1% vs 5.1%. In nGBM patients with methylated MGMT (n = 90), mOS was 30.2 months from randomization (33 months from surgery) with murcidencel vs. 21.3 months from randomization in the controls (HR = 0.74, p = 0.027). The treatment was well tolerated, with only 5 serious adverse events deemed at least possibly related to the vaccine.

CONCLUSION

Clinically meaningful and statistically significant survival extension was seen in both nGBM and rGBM patients treated with murcidencel and SOC compared with contemporaneous, matched external controls who received SOC alone.
CTNI-39. FIGHT-209: A PHASE 2, OPEN-LABEL, MULTICENTER STUDY OF PEMIGATINIB IN PATIENTS WITH PREVIOUSLY TREATED GLIOBLASTOMA OR OTHER PRIMARY CENTRAL NERVOUS SYSTEM TUMORS WITH ACTIVATING FGFR1-3 ALTERATIONS
Authors: Ahluwalia Manmeet , Franceschi Enrico , Veronese Luisa , Oliveira Natalia , Li Xin , van den Bent Martin
Published: November 2022

Fibroblast growth factor receptor (FGFR) signaling plays a role in progression of gliomas. Pemigatinib is a potent selective inhibitor of FGFR1-3, with demonstrated antitumor activity in patients with cholangiocarcinoma harboring FGFR2 fusions/rearrangements. The FIGHT-209 study will evaluate pemigatinib treatment for patients with glioblastoma or other primary central nervous system tumors harboring activating FGFR mutations or fusions/rearrangements. Eligible patients are adults with a radiologically measurable and histologically or molecularly confirmed recurrent glioblastoma, other diffuse glioma, or circumscribed astrocytic tumors harboring a FGFR1-3 gene alteration or fusion/rearrangement. Patients must have Karnofsky performance status ≥ 60, life expectancy ≥ 12 weeks, and documented disease progression after prior therapy with no available therapy likely to provide clinical benefit. Exclusion criteria include prior treatment with FGFR or VEGF/VEGFR inhibitors (other than bevacizumab for radiation necrosis), evidence of corneal or retinal disorder, or history of calcium or phosphate homeostasis disorder. Patients will be assigned to 1 of 3 cohorts based on genomic testing: A: glioblastoma with FGFR1-3 fusions/rearrangements; B: other CNS tumors with FGFR1-3 fusions/rearrangements; C: glioblastoma or other CNS tumors with FGFR1-3 activating mutations. Patients will receive pemigatinib 13.5 mg administered orally QD on a 21-day treatment cycle (2 weeks on/1 week off). Hyperphosphatemia, an on-target pharmacologic effect of FGFR inhibition, will be managed with diet modification, phosphate binders, diuretics, or dose reduction. Treatment will continue until disease progression or unacceptable toxicity. Primary endpoints are objective response rate (ORR) in cohorts A and B based on response assessment in neuro-oncology and assessed by ICR. Secondary endpoints include ORRs in cohorts A and B combined, in all cohorts, and in cohort C alone and the following endpoints for cohorts A and B individually: disease control rate, progression-free survival, duration of response, and overall survival. Safety and tolerability will also be assessed. Clinical trial information: NCT05267106
INNV-17. EXTRANEURAL METASTASES OF MYXOPAPILLARY EPENDYMOMA TREATED WITH DOSE-DENSE TEMOZOLOMIDE AND LAPATINIB
Authors: Riegel Devon , Connelly Jennifer
Published: November 2022

Myxopapillary ependymomas (MPEs) are recently reclassified WHO grade II tumors that usually affect the sacral spinal cord. MPEs have a high recurrence rate, especially if gross total resection (GTR) is not achieved. Recurrence tends to be local, but distant CNS metastases are not uncommon. Rarely, MPEs can metastasize to extraneural locations, including the lungs. Patient outcomes are worse with recurrence, and there is an absence of consensus for the best treatment approach for extraneural MPE metastases. The standard of care for initial MPE diagnosis is GTR, or subtotal resection (STR) with radiotherapy. Systemic treatment has shown inconclusive results regarding improvement of MPE outcomes. A recent phase II clinical trial demonstrated the efficacy of using dose-dense temozolomide (TMZ) and lapatinib for the treatment of metastatic, recurrent ependymoma. We present a case of a 35-year-old female with a history of MPE status post GTR who developed extraneural metastases 11 years after her initial resection. Sites of metastases included multiple bilateral intrapulmonary and pleural based masses with pleural effusion and pelvic mass. Her original site of disease had no evidence of recurrence and imaging of the neuro-axis was negative. Biopsy of the lung mass and pelvic mass confirmed metastatic MPE. She proceeded with dose-dense TMZ and lapatinib and had a positive radiographic response after 3 cycles of treatment. This is the first known case of extraneural metastases of MPE to demonstrate response to dose-dense TMZ and lapatinib.
INNV-20. INCORPORATING EXPERT OPINIONS INTO THE DEVELOPMENT OF FEARLESS: A PSYCHOTHERAPEUTIC INTERVENTION TARGETING FEAR OF CANCER RECURRENCE IN THOSE WITH BRAIN TUMORS
Authors: Loughan Ashlee , Braun Sarah , Lanoye Autumn , Willis Kelcie
Published: November 2022

INTRODUCTION

A brain tumor diagnosis brings about emotional distress, including significant fear of cancer recurrence (FCR). Three evidence-based interventions that target FCR exist, but all excluded patients with brain tumors (PwBT) from their efficacy trials. Preliminary evidence suggests that FCR may be categorically different in PwBT compared to other cancer populations, thereby necessitating tailored intervention development. For these reasons, we convened a neuro-oncology Expert Advisory Board (EAB) to assist in the creation of a psychotherapeutic intervention targeting FCR in PwBT.

METHODS

The EAB included neuro-oncology professionals, patients, and caregivers (N=7). To facilitate open dialogue, the patients and caregivers (n=3) met separately from the professionals (n=4). The EAB met virtually over five consecutive weeks to discuss three evidence-based FCR manuals, identify topic applicability, determine medical relevance, and discuss necessary adaptations to meet the specific needs of PwBT. Readings were provided in advance, two moderators (ARL & SEB) led group discussions, and all sessions were recorded following consent.

RESULTS

The EAB determined the content contained in the three FCR intervention required tailoring to meet the distinct needs of PwBT. Hypervigilance patterns were determined to be unique for PwBT (e.g., headache, fatigue, word-finding, auras). Language surrounding uncertainty of progression and inclusion of healthcare providers in therapy were less relevant in PwBT. Strategies and skills to enhance acceptance of existential themes were spotlighted. Mindfulness practices were requested. Results called for a blend of three therapeutic orientations: cognitive behavioral therapy, existential therapy, and mindfulness-based therapy. Professionals promoted group intervention delivery, whereas patients and caregivers promoted individual or dyadic sessions. Caregiver participation was unanimously supported.

CONCLUSION

The development of a psychotherapeutic intervention targeting FCR in PwBT offers a distinct opportunity for interdisciplinary and community collaboration. Results from the EAB were overwhelmingly informative, and recommendations will be incorporated into the newly developed FCR intervention for PwBT: FearLess.
INNV-32. COMPARING THE MONTREAL COGNITIVE ASSESSMENT (MOCA) FULL AND 5-MINUTE PROTOCOLS IN MILD COGNITIVE IMPAIRMENT SCREENING OF ADULT CNS TUMOR PATIENTS
Authors: Kim Yeonju , Rogers James , Jammula Varna , Vera Elizabeth , Christ Alexa , Leeper Heather , Acquaye Alvina , Boris Lisa , Briceno Nicole , Burton Eric , Choi Anna , Grajkowska Ewa , Komlodi-Pasztor Edina , Levine Jason , Lindsley Matthew , Lollo Nicole , Panzer Marissa , Penas-Prado Marta , Pillai Valentina , Polskin Lily , Reyes Jennifer , Roche Kayla , Smith-Cohn Matthew , Theeler Brett , Wu Jing , Gilbert Mark , Armstrong Terri
Published: November 2022

BACKGROUND

Mild cognitive impairment (MCI) commonly occurs in primary CNS tumor patients (PCTP). Our group and others have reported on the Montreal Cognitive Assessment (MoCA) as an MCI screening tool. Several abbreviated MoCA protocols have been developed for telehealth administration in other neurological diseases, with varied literature on scoring and clinical utility. We compared MoCA Full and 5-minute scores to assess utility in neuro-oncology.

METHODS

71 PCTP completed the MoCA Full (abnormal: < 26/30) assessing: visuospatial/executive functioning, naming, memory, attention, language, abstraction, delayed recall, and orientation. Full scores were retrospectively recoded to the Pendlebury MoCA 5-minute protocol (abnormal: < 10/12) assessing: memory, delayed recall, and orientation. Correlation was assessed using Pearson’s coefficient. Disagreements between tests were examined using t-test and chi-square test.

RESULTS

Patients were primarily White (83%), college-educated (71%) males (54%) diagnosed with glioblastoma (20%), with average age of 43 years (range: 19-75), KPS > 80 (57%), prior radiation treatment (78%), and imaging surveillance at time of testing (79%). MoCA Full and 5-minute mean scores were 25.3 (SD: 4.8) and 9.9 (SD: 2.3), respectively. MCI was indicated in 32% (n= 23) of patients using MoCA Full and 27% (n= 19) using MoCA 5-minute. Where the protocols disagreed, MCI was detected only by MoCA Full in 6 patients (8%), and MoCA 5-minute in 2 patients (3%). Visuospatial/executive (p= 0.025) and abstraction (p< 0.001) subdomain scores, unique to MoCA Full, were significantly associated with MCI detected only by the MoCA Full; other subdomains, patient characteristics, and total score were not significant. The MoCA versions were highly correlated (r= 0.90).

CONCLUSION

High correlation and agreement between MoCA Full and 5-minute scores in this neuro-oncology patient population highlight potential telehealth utility of the MoCA 5-minute. Future prospective assessment of the MoCA 5-minute is warranted to describe optimal scoring threshold and utility in neuro-oncology.
SURG-19. PROGNOSTIC VALIDATION OF A NEW CLASSIFICATION SYSTEM FOR EXTENT OF RESECTION IN GLIOBLASTOMA: A REPORT OF THE RANO RESECT GROUP
Authors: Karschnia Philipp , Young Jacob S , Dono Antonio , Häni Levin , Sciortino Tommaso , Bruno Francesco , Jünger Stephanie T , Teske Nico , Morshed Ramin A , Haddad Alexander F , Zhang Yalan , Stöcklein Sophia , Weller Michael , Vogelbaum Michael , Beck Juergen , Tandon Nitin , Hervey-Jumper Shawn L , Molinaro Annette , Rudà Roberta , Bello Lorenzo , Schnell Oliver , Esquenazi Yoshua , Ruge Maximilian I , Grau Stefan J , Berger Mitchel S , Chang Susan M , van den Bent Martin , Tonn Joerg-Christian
Published: November 2022

BACKGROUND

Terminology to describe extent of resection in glioblastoma is inconsistent across clinical trials. A surgical classification system was previously proposed based upon residual contrast-enhancing (CE) tumor. We aimed to (I) explore the prognostic utility of the classification system and (II) define how much removed non-CE tumor translates into a survival benefit.

METHODS

The international RANO resect group retrospectively searched the databases from seven neuro-oncological centers in the USA and Europe for patients with newly diagnosed glioblastoma per WHO 2021 classification. Clinical and volumetric information from pre- and post-operative MRI were collected.

RESULTS

We collected 1021 patients with newly diagnosed glioblastoma, including 1008 IDHwt patients. 744 IDHwt glioblastomas were treated with radiochemotherapy per EORTC 26981/22981 (TMZ/RT→TMZ) following surgery. Among such homogenously treated patients, lower absolute residual tumor volumes (in cm3) were favorably associated with outcome: patients with ‘maximal CE resection’ (class 2) had superior outcome compared to patients with ‘submaximal CE resection’ (class 3) or ‘biopsy’ (class 4) (median OS: 19 versus 15 versus 10 months; p=0.001). Extensive resection of non-CE tumor (≤ 5 cm3 residual non-CE tumor) provided an additional survival benefit in patients with complete CE resection, thus defining class 1 (‘supramaximal CE resection’) (median OS: 24 versus 19 months; p=0.008). The prognostic value of the resection classes was retained on multivariate analysis when adjusting for molecular and clinical markers including MGMT promotor status. Relative tumor reduction (in percentage) was not prognostic for outcome on multivariate analysis, and inter-rater agreement for CE and non-CE tumor on post-operative MRI was sufficient.

CONCLUSION

The proposed “RANO categories for extent of resection in glioblastoma” are highly prognostic and may serve for stratification of clinical trials. Removal of non-CE tumor beyond the CE tumor borders translates into additional survival benefit, providing a rationale to explicitly denominate such a ‘supramaximal CE resection’.
The (Un)fairness of Vaccination Freeriding
Authors: Verweij Marcel
Published: November 2022

For contagious diseases like measles a successful immunization program can result in herd protection. Small outbreaks may still occur but fade out soon, because the possibilities for the pathogen to spread in the ‘herd’ are very small. This implies that people who refuse to participate in such a program will still benefit from the protection it offers, but they don’t do their part in maintaining protection. Isn’t that a case of freeriding—and isn’t that unfair towards all the people who do collaborate? If so, that might be considered an additional ground for making vaccination mandatory or compulsory.

In this paper I argue that vaccination refusal can be considered as freeriding, but that this might not be unfair. The public good of herd protection is a peculiar public good because it supervenes on private benefits that are enjoyed by all who do opt for vaccination. For vaccinated individuals, the additional benefit of herd protection comes about, as it were, for free, and hence they can’t complain that others benefit without sharing in the burdens. There are however still other grounds for making vaccination compulsory or at least for seeing refusal as a morally wrong choice.
Twists of rational Cherednik algebras
Authors: Bazlov Y , Jones-Healey E , Mcgaw A , Berenstein A
Published: November 2022

We show that braided Cherednik algebras introduced by Bazlov and Berenstein are cocycle twists of rational Cherednik algebras of the imprimitive complex reflection groups $G(m,p,n)$, when m is even. This gives a new construction of mystic reflection groups which have Artin–Schelter regular rings of quantum polynomial invariants. As an application of this result, we show that a braided Cherednik algebra has a finite-dimensional representation if and only if its rational counterpart has one.
Cataract surgery in adult eyes with short axial length
Authors: Elhusseiny Abdelrahman M. , Sallam Ahmed B.
Published: November 2022

Purpose of review

Cataract surgery in eyes of patients with short axial length (AL) can be technically challenging and is associated with a high risk of intra- and postoperative complications. Several technical and surgical strategies have been proposed to optimize the visual outcome and decrease the rate of surgical complications and it is important to understand their applications in these cases

Recent findings

Traditional intraocular lens (IOL) measurement formulas in eyes with short AL have reduced reliability. Novel formulas such as the Kane formula provide a better refractive prediction. Surgery can be difficult in short eyes due to the crowdedness of the anterior chamber (AC) and the associated scleral abnormalities increasing the risk of uveal effusion. Surgical techniques such as prophylactic scleral incisions, limited pars plana anterior vitrectomy, and modified hydrodissection, have been shown to facilitate surgery in extremely short eyes and decrease the rate of operative complications. Although cataract surgery improves vision in these cases, short AL and shallow AC have been associated with worse visual outcomes.

Newer 4th generation IOL formulas have improved the refractive outcomes of cataract surgery in eyes with short AL. There are multiple evolving surgical strategies for optimizing surgery in these eyes. However, studies on the surgical and visual outcomes of cataract surgery in eyes with short AL are limited by their design and sample size. With further research and continued clinical experiences, we hope to develop evidence-based algorithms for the management of these complex cases.
Long-Term Safety and Outcomes of β-radiation for Trabeculectomy
Authors: Murdoch Ian , Puertas Renata , Hamedani Mehran , Khaw Peng Tee
Published: November 2022

Précis:

β-radiation is a neglected antiscarring therapy with past concerns for safety. This report found it safe and efficacious when used as an adjuvant to trabeculectomy surgery in 101 people (135 eyes) over 20 years

Purpose:

β-radiation has been used as an adjunct to prevent scarring in trabeculectomy surgery for many decades. Safety concerns were raised with the use of high doses on the bare sclera. Moorfields Eye Hospital has a large cohort of patients who have received β-radiation therapy. We report a review of the long-term safety and efficacy.

Methods:

Cases undertaken between August 1992 and August 1996 were reviewed. Those with records available for postoperative review of more than 5 years were included. Failure (reintervention/>21 mm Hg on 2 successive occasions) and any complication previously reported in association with β-radiation were the primary outcomes.

Results:

In total, 292 operations using β-radiation were recorded and 101 people (135 eyes) with trabeculectomy surgery and postoperative follow-up for over 4.5 years were included. The median follow-up period was 22.5 years. At the final follow-up, 48 (48%) single eyes per person had failed and 20/51 (51%) eyes with primary open angle glaucoma had cataract surgery. Other complications were rare and associated with copathology.

Conclusion:

In glaucoma patients at risk of scarring and failure after trabeculectomy, as an antiscarring adjuvant, a 750 cGY dose of β-radiation was found to be safe and efficacious in the long term.
An update on the diagnosis and treatment of adrenoleukodystrophy
Authors: Gujral Jasmine , Sethuram Swathi
Published: November 2022

Purpose of review

The present review summarizes recent advances in the diagnosis and management of patients with X-linked adrenoleukodystrophy (ALD).

Recent findings

Although ALD screening has been on the list of Recommended Uniform Screening Panel since 2016, only 30 states in the United States are currently testing their newborns for this disease. Hematopoietic stem cell transplant (HSCT) remains the only successful treatment option available for early cerebral ALD but does not reverse neurological changes or affect the course of adrenal insufficiency. There remains a significant knowledge gap in our understanding and treatment of this disease. Novel therapies such as gene therapy and gene editing have shown promising results in animal models and are exciting potential treatment options for the future.

Recently, the American Academy of Neurologists released their consensus guidelines on the diagnosis, surveillance, and management of ALD.

Early diagnosis and HSCT are key to improving the morbidity and mortality associated with ALD. The implementation of universal newborn screening for ALD and rigorous investigations of novel diagnostic and therapeutic agents is the need of the hour.