bluuebunny/crossref_metadata_2025 huggingface dataset:
Israeli COVID lockdowns mildly reduced overall use of preventive health services, but exacerbated some disparities
Authors: Rose Adam J , Ein mor Eliana , Krieger Michal , Ben-yehuda Arie , Cohen Arnon D , Matz Eran , Bar-Ratson Edna , Bareket Ronen , Paltiel Ora , Calderon-Margalit Ronit
Published: September 2022

Background

During 2020, Israel experienced two COVID-19-related lockdowns that impacted the provision of primary and secondary preventive care.

Methods

We examined the month-by-month performance of selected preventive care services using data from Israel’s national Quality Indicators in Community Healthcare program. Process of care measures included hemoglobin A1c (HbA1c) testing, cholesterol testing, colon cancer screening and mammography. Intermediate outcome measures included low-density lipoprotein control and HbA1c control. Measures were stratified by sex and by area-level socioeconomic position (SEP). Diabetes and mammography are presented in this abstract due to space limitations.

Results

Annual HbA1c testing among persons with diabetes decreased from 90.9% in 2019 to 88.0% in 2020. Performance of HbA1c tests during lockdown months was as low as half the usual amount. There were compensatory increases in testing during post-lockdown months that did not quite make up for the missed tests. In 2019, 9.0% of Israelis with diabetes had poor glycemic control (HbA1c ≥ 9.0); in 2020, it was 8.8%. In total, 4.5% fewer mammograms were performed in 2020 compared with 2019. Women in the lowest SEP level performed 10.4% fewer mammograms in 2020 than in 2019, while women in the highest SEP level performed 3.1% more mammograms.

Conclusions

Prolonged COVID lockdowns in 2020 were associated with marked decreases in the performance of preventive health services during those months. Compensatory spikes following the end of lockdowns partly, but did not completely, make up for the missed care. COVID lockdowns may have exacerbated socioeconomic disparities in some preventive health services.
Assessment of current practice for β-lactam therapeutic drug monitoring in French ICUs in 2021: a nationwide cross-sectional survey
Authors: Tritscher Perrine , Delannoy Matthieu , Agrinier Nelly , Charmillon Alexandre , Degand Nicolas , Dellamonica Jean , Roger Claire , Leone Marc , Scala-Bertola Julien , Novy Emmanuel
Published: September 2022

Background

Current guidelines and literature support the use of therapeutic drug monitoring (TDM) to optimize β-lactam treatment in adult ICU patients.

Objectives

To describe the current practice of β-lactam monitoring in French ICUs.

Methods

A nationwide cross-sectional survey was conducted from February 2021 to July 2021 utilizing an online questionnaire that was sent as an email link to ICU specialists (one questionnaire per ICU).

Results

Overall, 119 of 221 (53.8%) French ICUs participated. Eighty-seven (75%) respondents reported having access to β-lactam TDM, including 52 (59.8%) with on-site access. β-Lactam concentrations were available in 24–48 h and after 48 h for 36 (41.4%) and 26 (29.9%) respondents, respectively. Most respondents (n = 61; 70.1%) reported not knowing whether the β-lactam concentrations in the TDM results were expressed as unbound fractions or total concentrations. The 100% unbound fraction of the β-lactam above the MIC was the most frequent pharmacokinetic and pharmacodynamic target used (n = 62; 73.0%).

Conclusions

Despite the publication of international guidelines, β-lactam TDM is not optimally used in French ICUs. The two major barriers are β-lactam TDM interpretation and the required time for results.
Population pharmacokinetic/pharmacodynamic study suggests continuous infusion of ceftaroline daily dose in ventilated critical care patients with early-onset pneumonia and augmented renal clearance
Authors: Chauzy Alexia , Gregoire Nicolas , Ferrandière Martine , Lasocki Sigismond , Ashenoune Karim , Seguin Philippe , Boisson Matthieu , Couet William , Marchand Sandrine , Mimoz Olivier , Dahyot-Fizelier Claire
Published: September 2022

Objectives

Ceftaroline could be suitable to treat early-onset ventilator-associated pneumonia (VAP) because of its antibacterial spectrum. However, augmented renal clearance (ARC) is frequent in ICU patients and may affect ceftaroline pharmacokinetics and efficacy. The objective of the study was to explore the impact of ARC on ceftaroline pharmacokinetics and evaluate whether the currently recommended dosing regimen (600 mg every 12 h) is appropriate to treat VAP in ICU patients.

Methods

A population pharmacokinetic model was developed using pharmacokinetic data from 18 patients with measured creatinine clearance (CLCR) ranging between 83 and 309 mL/min. Monte Carlo simulations were conducted to determine the PTA and the cumulative fraction of response (CFR) against Streptococcus pneumoniae and MRSA for five dosing regimens. Study registered at ClinicalTrials.gov (NCT03025841).

Results

Ceftaroline clearance increased non-linearly with CLCR, with lower concentrations and lower probability of reaching pharmacokinetic/pharmacodynamic targets when CLCR increases. For the currently recommended dosing regimen, the probability of having unbound ceftaroline concentrations above the MIC over the entire dose range is greater than 90% for MICs below 0.125 mg/L. Considering the distribution of MICs, this regimen would not be effective against MRSA infections (CFR between 21% and 67% depending on CLCR), but would be effective against S. pneumoniae infections (CFR >86%).

Conclusions

The recommended dosing regimen of ceftaroline seems sufficient for covering S. pneumoniae in ICU patients with ARC, but not for MRSA. Among the dosing regimens tested it appears that a constant infusion (50 mg/h) after a loading dose of 600 mg could be more appropriate for MRSA infections.
Five-year analysis of the in vitro activity of tedizolid against a worldwide collection of indicated species causing clinical infections: results from the Surveillance of Tedizolid Activity and Resistance (STAR) programme
Authors: Carvalhaes Cecilia G , Sader Helio S , Streit Jennifer M , Mendes Rodrigo E
Published: September 2022

Objectives

The Surveillance of Tedizolid Activity and Resistance (STAR) programme monitored the tedizolid activity against Staphylococcus aureus, Enterococcus faecalis, Streptococcus pyogenes, Streptococcus agalactiae and Streptococcus anginosus group. We evaluated the antimicrobial susceptibility of 47 400 unique Gram-positive clinical isolates from the STAR programme collected from USA (21 243), Europe (17 674), Asia-Pacific (4954) and Latin America (3529) medical centres (2015–19).

Methods

All isolates were tested for susceptibility by reference broth microdilution method. WGS and in silico analysis were performed on linezolid-non-susceptible (NS) isolates.

Results

Tedizolid was active against ≥99.9% of S. aureus (100.0% of MSSA and >99.9% of MRSA), E. faecalis, S. pyogenes, S. agalactiae and S. anginosus group isolates, with MIC50 values ranging from 0.12 to 0.25 mg/L and MIC90 values of 0.25 mg/L. Linezolid, vancomycin and daptomycin were also active agents against these organisms. Tedizolid inhibited all VRE and 73.1% of linezolid-NS E. faecalis isolates. Ampicillin and daptomycin retained 100.0% activity against VRE and linezolid-NS E. faecalis isolates. Linezolid-NS E. faecalis isolates carried mostly the optrA gene. G2576T alterations in the 23S rRNA were observed in one linezolid-NS S. aureus isolate and one linezolid-NS E. faecalis isolate.

Conclusions

No resistance trends were observed for tedizolid during the study period.
MDR Shigella sonnei in Spain: an ever-evolving emerging threat?
Authors: Ortiz de la Rosa José Manuel , Rodríguez-Villodres Ángel , Casimiro-Soriguer Carlos S , Ruiz-Pérez De Pipaón Maite , Briones Eduardo , Aznar Fernández María , Lepe José Antonio
Published: September 2022

Background

Seven CTX-M-27-producing Shigella sonnei strains were isolated at the University Hospital Virgen del Rocío (Seville, Spain) microbiology service from October to November 2021.

Objectives

To offer extensive information on the microbiological and molecular epidemiology results of the seven S. sonnei isolates and compare them with other previously documented CTX-M-27-producing S. sonnei associated with MSM transmission.

Methods

S. sonnei isolated from stool samples of patients with acute diarrhoea were identified through biochemical and serological typing. Whole characterization of the seven isolates was performed by sequencing with MinION Mk1C followed by genomic and molecular analysis.

Results

All the isolates were resistant to penicillins, cephalosporins, fluoroquinolones, cotrimoxazole and azithromycin. Sequencing showed the presence of several resistance determinants, outstanding blaCTX-M-27, azithromycin resistance genes [ermB and mph(A)], qnrB19 and mutations in the QRDRs. All isolates belonged to the same hierarchical clustering of cgMLST (HierCC) with five allele distance (HC5) scheme v1 from EnteroBase. However, they presented differences in plasmid composition, with all seven isolates harbouring IncFII, IncB/O/K/Z and ColE1-like while SH2, SH6 and SH7 had IncFIB only. Our isolates were closely related to others from Spain (HC5; 98748), Australia (HC5; 98748) and the UK (HC5; 98748), which were also associated with MSM transmission. Nevertheless, the structure of the non-chromosomal genetic elements and the genetic context of blaCTX-M-27 presented a certain variability compared with isolates from other countries and among them.

Conclusions

This study confirms the emergence of CTX-M-27-producing S. sonnei (ST152) associated with MSM transmission in Spain, adding it to the Europe outbreak list and reinforcing the necessity of active surveillance and control of this high-risk clone.
Impact of patient portal-based self-scheduling of diagnostic imaging studies on health disparities
Authors: Ganeshan Smitha , Pierce Logan , Mourad Michelle , Judson Timothy J , Kohli Marc D , Odisho Anobel Y , Brown William
Published: September 2022

While many case studies have described the implementation of self-scheduling tools, which allow patients to schedule visits and imaging studies asynchronously online, none have explored the impact of self-scheduling on equitable access to care.1 Using an electronic health record patient portal, University of California San Francisco deployed a self-scheduling tool that allowed patients to self-schedule diagnostic imaging studies. We analyzed electronic health record data for the imaging modalities with the option to be self-scheduled from January 1, 2021 to September 1, 2021. We used descriptive statistics to compare demographic characteristics and created a multivariable logistic regression model to identify predictors of patient self-scheduling utilization. Among all active patient portal users, Latinx, Black/African American, and non-English speaking patients were less likely to self-schedule studies. Patients with Medi-Cal, California’s Medicaid program, and Medicare insurance were also less likely to self-schedule when compared with commercially insured patients. Efforts to facilitate use of patient portal-based applications are necessary to increase equitability and decrease disparities in access.
Kolmogorov and Kuroda translations into basic predicate logic
Authors: Ardeshir Mohammad , Ruitenburg Wim
Published: September 2022

Kolmogorov established the principle of the double negation translation by which to embed Classical Predicate Logic ${\operatorname {CQC}}$ into Intuitionistic Predicate Logic ${\operatorname {IQC}}$. We show that the obvious generalizations to the Basic Predicate Logic of [3] and to ${\operatorname {BQC}}$ of [12], a proper subsystem of ${\operatorname {IQC}}$, go through as well. The obvious generalizations of Kuroda’s embedding are shown to be equivalent to the Kolmogorov variant. In our proofs novel nontrivial techniques are needed to overcome the absence of full modus ponens in Basic Predicate Logic. In [3] we argued that ${\operatorname {IQC}}$ is not the logic of constructive mathematics. Our doubts were far from new. New was that we put forward an alternative, ${\operatorname {BQC}}$. One concern is that ${\operatorname {BQC}}$ is too weak for serious mathematics, or even trivial. This paper is one step to alleviate such concerns.
Race, Ethnicity, and Health Disparities in US Children With COVID-19: A Review of the Evidence and Recommendations for the Future
Authors: Vicetti Miguel Claudia P , Dasgupta-Tsinikas Shom , Lamb Gabriella S , Olarte Liset , Santos Roberto P
Published: September 2022

Coronavirus disease 2019 (COVID-19) is an important cause of morbidity in children in the United States (U.S.). Moreover, the U.S. has witnessed significant disparities affecting American Indian/Alaska Native, Black, and Hispanic/Latino children, stemming from systemic racism and social-structural inequalities and not differences in innate biological susceptibility. We review what is known on COVID-19 and health disparities in disease burden, access to care, pharmaceutical interventions, and clinical research in children, with a focus on the U.S. context. In addition, we propose strategies to communicate scientific data in ways that do not promote racism and biological susceptibility themes, and to address pediatric disparities in clinical infectious diseases research.
Hemophilia B acquired after cadaveric liver transplantation: a case report
Authors: Machado e Silva Gomide Larissa , Weihermann Viktoria , de Oliveira Isabella Corrêa , Nissel Maria Alice Zarate , Valejo Igor Raphael Mathias , da Silva Wolff Lucas , de Aguiar Alan Junior , Verona Dunia , Degraf Ygor , de Carvalho Arouca Julianna Storace , Barros Sanches João Paulo , Cabral Rodrigo Rezende Silva , Kampa Katia Cristina , de Freitas Alexandre Coutinho Teixeira , Tefili Nertan Luiz
Published: September 2022

Hemophilia B is a recessive hereditary disease, and manifestations result from coagulation factor IX deficiency. Although improbable, as factor IX is produced exclusively in the liver, the possibility of developing the disease after transplantation represents an infrequent but potentially morbid complication. Standard laboratory tests may be insufficient to determine the probability of transmission of this pathology. This report describes the case of a patient who developed hemophilia B after liver transplantation whose donor had no prior knowledge of the disease.
A feeding jejunostomy causing an intussusception – case report and literature review
Authors: Tian Jane , Bhatia Shubham , Mourad Youssef , Hall Philip , Louis Martine A , Khan Noman
Published: September 2022

Use of enteral nutrition has increased dramatically over the past two decades due to improved nutritional formulas, better quality feeding tubes and the ability to use less invasive endoscopic, fluoroscopic and laparoscopic techniques. Intussusception accounts for 1–5% of adult intestinal obstructions, with feeding tubes acting as a lead point in < 1% of cases. Since intussusception is rare, especially in adults, it is not always considered in the initial differential diagnosis of patients presenting with abdominal pain, nausea, vomiting or constipation. If left untreated, intussusception can eventually lead to bowel compromise, poor outcomes and even death. Therefore, prompt recognition and correction are necessary. We present a case of small bowel obstruction in an elderly male secondary to a tube-related intussusception. A review of the signs, symptoms and treatment recommendations is provided.
Dynamic switching of crotonylation to ubiquitination of H2A at lysine 119 attenuates transcription–replication conflicts caused by replication stress
Authors: Hao Shuailin , Wang Ya , Zhao Yuqin , Gao Wen , Cui Wei , Li Youhang , Cui Jian , Liu Yu , Lin Lixiu , Xu Xingzhi , Wang Hailong
Published: September 2022

The reversible post-translational modification (PTM) of proteins plays an important role in many cellular processes. Lysine crotonylation (Kcr) is a newly identified PTM, but its functional significance remains unclear. Here, we found that Kcr is involved in the replication stress response. We show that crotonylation of histone H2A at lysine 119 (H2AK119) and ubiquitination of H2AK119 are reversibly regulated by replication stress. Decrotonylation of H2AK119 by SIRT1 is a prerequisite for subsequent ubiquitination of H2AK119 by BMI1. Accumulation of ubiquitinated H2AK119 at reversed replication forks leads to the release of RNA Polymerase II and transcription repression in the vicinity of stalled replication forks. These effects attenuate transcription–replication conflicts (TRCs) and TRC-associated R-loop formation and DNA double-strand breaks. These findings suggest that decrotonylation and ubiquitination of H2A at lysine 119 act together to resolve replication stress-induced TRCs and protect genome stability.
Interpreting alignment-free sequence comparison: what makes a score a good score?
Authors: Swain Martin T , Vickers Martin
Published: September 2022

Alignment-free methods are alternatives to alignment-based methods when searching sequence data sets. The output from an alignment-free sequence comparison is a similarity score, the interpretation of which is not straightforward. We propose objective functions to interpret and calibrate outputs from alignment-free searches, noting that different objective functions are necessary for different biological contexts. This leads to advantages: visualising and comparing score distributions, including those from true positives, may be a relatively simple method to gain insight into the performance of different metrics. Using an empirical approach with both DNA and protein sequences, we characterise different similarity score distributions generated under different parameters. In particular, we demonstrate how sequence length can affect the scores. We show that scores of true positive sequence pairs may correlate significantly with their mean length; and even if the correlation is weak, the relative difference in length of the sequence pair may significantly reduce the effectiveness of alignment-free metrics. Importantly, we show how objective functions can be used with test data to accurately estimate the probability of true positives. This can significantly increase the utility of alignment-free approaches. Finally, we have developed a general-purpose software tool called KAST for use in high-throughput workflows on Linux clusters.
SIQ: easy quantitative measurement of mutation profiles in sequencing data
Authors: van Schendel Robin , Schimmel Joost , Tijsterman Marcel
Published: September 2022

With the emergence of CRISPR-mediated genome editing, there is an increasing desire for easy-to-use tools that can process and overview the spectra of outcomes. Here, we present Sequence Interrogation and Quantification (SIQ), a simple-to-use software tool that enables researchers to retrieve, data-mine and visualize complex sets of targeted sequencing data. SIQ can analyse Sanger sequences but specifically benefit the processing of short- and long-read next-generation sequencing data (e.g. Illumina and PacBio). SIQ facilitates their interpretation by establishing mutational profiles, with a focus on event classification such as deletions, single-nucleotide variations, (templated) insertions and tandem duplications. SIQ results can be directly analysed and visualized via SIQPlotteR, an interactive web tool that we made freely available. Using insightful tornado plot visualizations as outputs, we illustrate that SIQ readily identifies sequence- and repair pathway-specific mutational signatures in a variety of model systems, such as nematodes, plants and mammalian cell culture.
KS04.5.A Development of a somatostatin receptor type 2 (SSTR2)-targeted probe for near infrared fluorescence guided meningioma surgery
Authors: Fürtjes G , Weitzenberg M , Arús B , Rolbieski H , Mawrin C , Goldbrunner R , Plettenburg O , Bruns O , Neuschmelting V
Published: September 2022

Background

Meningioma mostly recur at the primary resection bed requiring improvement in the intraoperative tumor visualization and surgical technique. This study aims to develop a highly specific and sensitive optical probe for intraoperative meningioma imaging to guide the tumor resection. Fluorescent dyes in the near infrared (NIR I, 700-1000nm) and shortwave infrared (NIR II, 1000-2000nm) allow detection by suitable cameras up to few millimeters in depth in real time. Our objective is to invent a fluorescent NIR I and II probe specifically targeting the somatostatin receptor type 2 (SSTR2) reliably overexpressed in meningioma independently of WHO grade and subtype.

Material and Methods

By linking a somatostatin analogue (TATE, Tyr(3)Thr(8)-Octreotid) to a new developed dye (sNIR), we synthesized a SSTR2 specific probe. Its optical properties are comparable to indocyanine green and stability as well as bleaching kinetic were observed in vitro. The probe was intravenously injected in native mice to evaluate pharmacokinetics and biodistribution and detected by a custom-built camera setup focusing on physiologically highly expressing SSTR2 tissues validated by immunohistochemistry (IHC). As proof-of-principle fluorescence guided tumor resection was performed in an ectopic and orthotopic meningioma IOMM-Lee mouse model.

Results

The SSTR2-sNIR probe is stable in aqueous solution up to 12h with favorable optical properties regarding kinetics, biodistribution and photostability compared to its IRDye800 analogue. In vivo, we observed a highly specific physiological signal uptake in the gastric epithelium, the pancreas and pituitary (they are highly expressing SSTR2 on IHC) compared to autofluorescence and negative controls (unlabeled dye and scrambled version). Given the moderate SSTR2 expression in the preclinical meningioma model we could still detect a mean tumor-to-brain ratio of 6.12 (n = 5; SD 1.8) in the orthotopic meningioma mouse model, allowing the fluorescence guidance to be feasible.

Conclusion

Our preclinical results demonstrate that the innovative SSTR2-targeted fluorescent probe is stable in various biological media over time and capable of specifically targeting the SSTR2 in vitro and in vivo potentially enabling sensitive and specific meningioma fluorescent guided surgery in the future.
KS05.6.A Oral DNA vaccination targeting VEGFR2 combined with the anti-PD-L1 antibody avelumab in patients with progressive glioblastoma - final results. NCT03750071
Authors: Wick W , Wick A , Chinot O , Sahm F , von Deimling A , Jungk C , Mansour M , Podola L , Lubenau H , Platten M
Published: September 2022

Background

Vascular endothelial growth factor receptor (VEGFR)2 overexpression on glioblastoma endothelia serves as a target for VEGFR2 primed T cells using VXM01 DNA vaccine encoding for VEGFR2. VXM01 is delivered in a bacterial Ty21a carrier suitable for oral administration. A previous phase I/II study in 14 patients with progressive glioblastoma showed a positive correlation of of VEGFR2 specific T cells as well as altered intra-tumoral immunity with prolonged overall survival. One partial response was reported with VXM01 alone. The current trial aimed at intensifying the efficacy signal and testing the co-administration of a checkpoint inhibitor.

Material and Methods

A multicentre, open-label phase I/II study (EudraCT 2017 003076 31) included 28 patients (25 non-resectable, 3 resectable) with progressive glioblastoma after standard chemoradiotherapy. VXM01 was administered on day 1, 3, 5, 7 followed by boostings q4w. Avelumab (800 mg) was given intravenously q2w. Treatment continued up to week 96 followed by a 2-year observation period. Endpoints included safety and tolerability, objective response rate (ORR), clinical response using immune-response assessment in Neurooncology criteria (iRANO), and immunological assays like ELISpot, FACS, and tumor immune biomarkers.

Results

Treatment with VXM01 106 or 107 CFU plus avelumab was completed in all patients. No treatment-related toxicities were observed. Three partial responses (according to iRANO) with tumor reductions of 58, 81 and 95% to baseline, respectively, were reported in the non-resectable patients (Objective response rate (ORR) was 12% (3/25)). Two of these patients were progression-free > 12 months. Best response in 3 additional non-resectable patients was SD including one patient progression-free > 6 months. In one resected patient, tumor shrinkage of 30% each was observed after initial treatment before resection as well as subsequent to incomplete resection, associated with survival > 18 months, and accompanied by an increase of intratumoral CD8+ T-cells.

Conclusion

VXM01 in combination with avelumab was safe and produced detectable peripheral VEGFR-2-specific immune responses. Three non-resected patients had an objective response, three more patients experienced best response stable disease. For future studies a patient enrichment strategy based on immune biomarkers might be envisaged.
JS09.5.A Is Radiation Dose to Sleep-relevant Brain Structures Associated with Lower Sleep Quality in Adults with Primary Brain Tumors?
Authors: Amidi A , Haldbo-Classen L , Kallehauge J , Wu L , Lukacova S , Lassen Y , Zachariae R , Hoyer M
Published: September 2022

Background

Sleep plays a central role in optimal brain health and daily functioning, and poor sleep is associated with impaired cognitive functioning and reduced quality of life. Despite improved precision of modern radiotherapy (RT) for brain tumors, radiation to healthy tissue, including brain structures relevant for sleep/wake regulation, is often inevitable. In the present study, we investigate whether radiation dose to sleep/wake-relevant brain structures is associated with poorer patient-reported sleep quality in primary brain tumor patients.

Material and Methods

Patients who had received RT for non-glioblastoma primary brain tumors between 2006 and 2016 were included. They completed the Pittsburg Sleep Quality Index (PSQI) and mean radiation doses to sleep/wake-relevant structures (i.e., brainstem, thalamus, hypothalamus, and the pituitary and pineal glands) were calculated based on planning CTs and contrast-enhanced MR-images. Mean radiation dose (Dmean) to brain structures were compared between patients with and without impaired sleep outcomes using bootstrapped independent t-tests. Differences with effect sizes (ES, Cohen’s d) exceeding ± 0.3 are reported.

Results

A total of 78 patients (glioma, grade 1-3 = 28; meningioma = 22, pituitary = 16, other = 12) were included. Median time since RT was 4.6 years (range = 8.4 years). Mean global PSQI score was 5.13 (SD = 3.1). No differences were observed between tumor types, F (3,74) = 0.37, η 2= .02. Clinical sleep disturbance (PSQI > 5) was reported by 37.2% (n=29). Compared with patients without sleep disturbance, those with sleep disturbance had received a higher radiation dose to the pituitary gland, Dmean = 26.11 Gy, SE = 2.59, versus 34.57 Gy, SE = 3.43, ES(d) = - 0.46, 95% CI [-0.93, 0.003]. Furthermore, compared with patients reporting normal sleep latency (SL), those with poor SL had received a higher radiation dose to the pituitary gland, Dmean = 24.55 Gy, SE = 3.71, versus 32.60 Gy, SE = 2.48, ES(d) = - 0.44, 95% CI [-0.90, 0.03], and the brain stem, Dmean = 15.32 Gy, SE = 2.71, versus 20.20 Gy, SE = 2.01, ES(d) = -3.44, 95% CI [-0.80, 0.12]. Finally, compared with patients with a high sleep efficiency (>85%), those with a low sleep efficiency had received a higher radiation dose to the thalamus, Dmean = 18.11 Gy, SE = 2.36, versus 24.55 Gy, SE = 4.43, ES(d) = -0.35, 95% CI [-0.83, 0.15], and the pineal gland, Dmean = 16.20 Gy, SE = 2.48, versus 23.10 Gy, SE = 4.25, ES(d) = -0.36, 95% CI [-0.85, 0.13].

Conclusion

The prevalence of clinical sleep disturbances in patients with primary brain tumors was high (37%). Our results indicated that higher radiation doses to the pituitary gland, brain stem, thalamus, and pineal gland may be risk factors for poor sleep quality in patients with a primary brain tumor.
OS02.5.A Alzheimer-type neuropathological changes in glioblastoma-adjacent cortex
Authors: Greutter L , Miller-Michlits Y , Klotz S , Miller-Michlits A , Roetzer-Pejrimovsky T , Baumann B , Kiesel B , Kovacs G G , Stepper P , Woehrer A
Published: September 2022

Background

Glioblastoma (GBM) is an aggressive type of brain cancer that is prevalent and fatal in the elderly. Age is not only the most common risk factor for brain cancer but also for neurodegenerative diseases, and previous studies have indicated an excess risk of co-occurrence of both diseases. Here, we aim to map Alzheimer (AD)-related pathology in GBM-adjacent cortex.

Material and Methods

To this end, we have screened a cohort of 99 individuals with 200 tissue samples comprising tumor and adjacent cortex, including longitudinal samples in 13 patients. The samples were provided by the Division of Neuropathology and Neurochemistry, Medical University of Vienna from 2002 to 2021. Age and tumor location were abstracted from clinical data where available. All samples were stained for A-beta, tau-AT8 and NeuN using immunohistochemistry. Whole slide scans were segmented and protein deposits were quantified with QuPath. Further statistical analyses were conducted with R. Tau pathology was recorded as neurofibrillary tangles, neuropil threads, and astroglial pathology. Likewise, amyloid pathology was assessed as plaques and/or cerebral amyloid angiopathy (CAA). For both proteins, deposits were grouped into: absent, mild, moderate, and severe.

Results

In the total cohort, median age was 67.5 ys (range 20-92 ys), the female-to-male ratio 0.68. Overall 44.4 % (n=44/99) showed any type of A-beta and/or taupathology, which was strongly correlated with age (R=0.26, p= 0.001). Among them, 38.6 % (n=17/44) had combined pathology, while 36.4 % (n=16/44) displayed pure amyloid-beta, and 25 % (n=11/44) only tau pathology. A-beta pathology comprised plaques in 74.4 % (n=29/39) and CAA in 28.2 % (n=11/29). Consistent with the spatiotemporal evolution of AD, neurofibrillary tangle load was highest in the temporal lobe (42.9 % n=21/49), while plaque load was most prevalent in the occipital lobe (62.5 % n=5/8). This pattern was accentuated in patients above age 65, while it deviated in those below age 65. Over time, the AD-type pathology increased in 38.4 % (n=5/13) and remained stable in 53.8 % (n=7/13) of recurrent tumors. Total cell densities in tumor-infiltrated cortex ranged from 474 to 7,540 cells/mm2, being similar across all lobes. Higher cell density correlated with decreased neuronal counts (R= -0.46, p<0.0001) and decreased AD-load (R= -0.25, p= 0.002).

Conclusion

Collectively, our results establish frequent co-occurrence of Alzheimer disease neuropathological changes in the GBM-adjacent cortex. They prompt further investigation of shared pathogenic mechanisms and seek to raise awareness for synergistic effects on cognitive decline.
OS07.3.A Phase 1/2 clinical trial of blood-brain barrier opening with the SonoCloud-9 implantable ultrasound device in recurrent glioblastoma patients receiving IV carboplatin
Authors: Idbaih A , Sonabend A , Stupp R , Chinot O , Dufour H , Ducray F , Menei P , de Groot J , Desseaux C , Carpentier A
Published: September 2022

Background

Low intensity pulsed ultrasound (LIPU) in combination with microbubbles is a promising approach for brain drug delivery. A phase 1/2 clinical study (NCT03744026) was initiated to demonstrate the safety and efficacy of blood-brain barrier (BBB) disruption over a large volume using an implantable ultrasound system (SonoCloud-9) in patients with recurrent glioblastoma receiving carboplatin chemotherapy.

Material and Methods

The SonoCloud-9 device (Carthera, Paris, France) was placed at the end of tumor resection and replaced the bone flap. The device was activated 9-14 days after surgery for a duration of 270 seconds every 4 weeks until progression or treatment completion, concomitantly with IV DEFINITY microbubbles (10 μl/kg, Lantheus, Billerica, US). The Phase 1 cohort consisted of an escalation of BBB disruption volume by activation of 3 (n=3), 6 (n=3), then 9 (n=3) emitters of the device. Dose limiting toxicity (DLT) was assessed during the first 2 weeks after the 1st sonication. A subsequent expansion cohort consisted of patients treated with 9 emitters in which the primary endpoint was assessment of BBB opening on MRI using gadolinium (<1 hr after sonication). All patients received carboplatin either after (n=21) or before (n=12) device activation to disrupt the BBB. In addition, a sub-study was performed to investigate carboplatin concentration enhancement in the peritumoral region with sonication at time of device implantation.

Results

Study accrual is complete with 38 patients enrolled and 33 patients having been implanted and received at least one sonication+carboplatin. A total of 101 sonications were performed (range=1-10 sonication sessions/patient). No DLTs were observed. A total of 14 SAEs were observed including five events considered as possibly treatment related. BBB disruption was confirmed by gadolinium enhancement after sonication. In an analysis of 60 treatments in 27 patients that had all nine emitters active, 90% of activated emitters led to BBB opening in gray and/or white matter with good repeatability of BBB opening. In 3 patients who underwent intraoperative sonication and carboplatin administration, a 7.58-fold increase in brain/plasma drug levels was demonstrated. Updated and mature outcome results will be presented.

Conclusion

These results confirm the safety and feasibility of repeated BBB disruption using an implantable ultrasound system. LIPU substantially increases drug levels in the peritumoral brain.
OS07.7.A Rate and type of recurrence of lower-grade gliomas submitted to functional neurosurgical approach: the impact of the extent of resection
Authors: Gay L , Rossi M , Conti Nibali M , Sciortino T , Bello L
Published: September 2022

Background

In the last decade, different published studies enlightened the extent-of-resection (EOR) as an independent factor for progression-free-survival (PFS) in patients with lower-grade gliomas (LGG). Aim of this study was to evaluate the impact of resections extending beyond FLAIR MRI abnormalities (supratotal), and eventual predictive factors and characteristics of recurrences.

Material and Methods

We retrospectively analysed 460 patients submitted to surgery between 2007 and 2016 with a presumptive diagnosis of LGG, i.e., harbouring a mass lesion with no enhancement on contrast-administered T1-weighted MRI-sequences. All resections were performed according to functional boundaries determined by brain mapping/monitoring technique, without any patient or tumor a priori selection. The EOR was defined by analyzing pre- and post-operative volumetric FLAIR images.

Results

The median pre-operative tumor volume was 43,7 cm3. A supratotal resection (SPR) was achieved in 31.4%, a gross-total (GTR) in 41.1%, a subtotal (STR) in 27.5%. WHO grade II/III gliomas were diagnosed in 347 cases (319 IDH-mutant, 28 IDH-wildtype). Median follow-up was 60 months. SPR versus other EOR was associated to increased PFS (log rank test, p=.000) and malignant PFS (p=.000). Data were confirmed also after IDH status stratification. Rate of immediate and permanent post-op deficits among different EOR were comparable. Pre-op tumor volume, parietal and insular sites, eloquent location and dominant hemisphere tumors, and astrocytoma histology were associated to recurrence (p<.05). In 95.1% of cases recurrences were peri-cavitary. Lesions invading the corpus callosum presented minor rate of relapse; recurrences were most frequently diffuse and at distant sites. After SPR most common radiological appearance of recurrence was solid, while after GTR and STR percentages of solid and diffuse patterns were similar. Occurrence of distant recurrences, away from the resection cavity, were most associated to SPR.

Conclusion

Our preliminary data suggests the dramatic impact in LGG of resections extending beyond FLAIR abnormalities on PFS and malignant PFS and on the characteristics of tumor recurrence.
OS07.8.A Prognosis in IDH-mutant glioma: the role of extent-of-resection, age and tumor grade
Authors: van der Vaart T , Wijnenga M M J , van Garderen K A , Dubbink H , French P J , Smits M , Dirven C M F , Kros J M , Vincent A P J E , van den Bent M J
Published: September 2022

Background

Evidence suggests that smaller residual tumor volumes after initial surgery are associated with longer survival in patients with astrocytoma, IDH-mutant, grade II. For IDH-mutant glioma of higher grade but also for oligodendroglioma, IDH-mutant, and 1p/19q codeleted, the impact on survival of more residual tumor is unclear. This could be related to the limited follow-up of patients with oligodendroglioma that typically have long overall survival. We expanded a previously published series of patients increase the duration of follow-up and the spectrum of tumor grades.

Material and Methods

Single center observational cohort study of patients with adult-type diffuse glioma, IDH-mutant, all WHO-2021 grades, from 2003 to 2021 . Molecular characteristics were assessed by next-generation targeted sequencing. Tumor volumes were calculated by semi-automatic 3D segmentation on pre- and postoperative MRI-scans. Associations between prognostic factors and survival were assessed using univariate and multivariate Cox proportional hazards models.

Results

384 patients with IDH-mutant glioma (174 oligodendroglioma, 212 astrocytoma) were followed for a median of 7 years. Median age at diagnosis was 41 years (IQR 33 - 55). Significant prognostic factors for survival were Karnofsky performance status, 1p19q-status and post-operative tumor volume. Smaller post-operative tumor volume was associated with better survival, both in astrocytoma and oligodendroglioma. Age, tumor grade and MRI-contrast enhancement were not associated with survival.

Conclusion

Lower residual tumor volume after first surgery is a strong prognostic factor in all IDH-mutant glioma subgroups, even in patients with very small residual tumor. Importantly, age and histological tumor grade were not significantly associated with survival. The data serves as further support for optimal initial resections of tumors suspected for IDH-mutant glioma, also in oligodendroglioma.
P07.05.A Implantable electrophoretic devices for local treatment of inoperable brain tumours
Authors: Ahmed M H , Naegele T , Hilton S , Malliaras G
Published: September 2022

Background

Glioblastoma (GBM) is the most malignant primary brain tumour in adults, with a median overall survival of fewer than 18 months after initial diagnosis. For over five decades, research has been focused on developing new anticancer therapies for GBM, including anti-neoplastic agents, molecular targeted drugs, immunotherapeutic approaches, and angiogenesis inhibiting compounds; however, the prognosis of patients has hardly improved and temozolomide remains the only chemotherapy shown to improve patient survival in randomized clinical trials. A fundamental limitation of the success of chemotherapy in brain cancer therapies is the blood-brain barrier which significantly reduces the concentration of chemotherapeutic agents delivered into a tumour.

Material and Methods

Therapeutic strategies that control drug release spatially and temporally represent a significant step forward in terms of reducing side effects and improving treatment efficacy and will thus have a significant clinical impact. Electrophoretic drug delivery devices, which use electric fields to enhance drug transport, represent one such strategy.

Results

Here, we present an implantable device that enables highly spatially selective delivery of charged drug molecules directly into brain tumours. Our device combines a microfluidic system for drug transport with embedded electrodes which enable electrophoretic transport of drug molecules into the target tissue. This allows delivery of chemotherapeutic agents without transport of bulk solvent preventing issues arising from intracranial pressure gradients. We have shown that the device can be implanted safely without any limitation. We have tested the device's capabilities to deliver a wide range of small, medium, and large chemotherapeutic agents without limitations. Currently, we are investigating the delivery of cisplatin in GBM-bearing mice.

Conclusion

While electrophoretic drug delivery was first described in the early 20th century and has been used since primarily for transdermal drug delivery, we believe that our approach is one of the first times this has been demonstrated for brain cancer therapy.
P11.37.B When to resect or biopsy for patients with supratentorial glioblastoma: a multivariable prediction model
Authors: Kommers I O , Eijgelaar R S , Barkhof F , Bouget D , Pedersen A , Ardon H , Bello L , Berger M S , Bouwknegt W , Conti Nibali M , Furtner J , Han S J , Han S J , Hervey-Jumper S , Hervey-Jumper S , Idema A J S , Kiesel B , Kloet A , Nandoe Tewarie R , Mandonnet E , Reinertsen I , Robe P A , Rossi M , Sciortino T , Solheim O , van den Brink W A , Vandertop P W , Wagemakers M , Widhalm G , Witte M G , Zwinderman A H , De Witt Hamer P C
Published: September 2022

Background

The prospects of a patient with suspected glioblastoma may rely heavily on the indication for surgical resection versus biopsy only. Biopsy percentages vary considerably across hospitals and guidelines for treatment of glioblastoma lack criteria for surgical decision-making. To identify patient and tumor characteristics associated with the decision to resect or biopsy a glioblastoma and to develop and validate a prediction model for decision support.

Material and Methods

Clinical data and pre-operative MRI scans were collected for adults who underwent first-time surgery for supratentorial glioblastoma from a registry-based cohort study of 12 hospitals from the Netherlands, Germany, France, Italy, and the United States between 1st of January 2007 and 31st of December 2011. The main outcome was the type of surgical procedure: surgical resection or biopsy only. Predictors were patient- and tumor-related characteristics. Radiological factors were extracted from MRI using an automated tumor segmentation method. A prediction model was constructed using multivariable logistic regression analysis. The model was cross-validated and externally validated with a leave-one-hospital-out approach.

Results

Out of 1053 patients treated for glioblastoma, 28% underwent biopsy only. Biopsy rates varied from 15-40% across hospitals. The prediction model showed excellent discrimination with an average area under the curve of 0.86. Of the patient-related characteristics, younger age was associated more with resection and Karnofsky Performance Score of 60 or less with biopsy. Of the tumor-related characteristics, a location in the right hemisphere, unifocality, no tumor midline crossing, and no involvement of the cortical spinal tract, were associated with resection, as well as a high expected resectability index, a location in the right occipital lobe, and a higher percentage of tumor in Schaefer’s dorsal or ventral attention, limbic, and default networks. External validation proved acceptable to outstanding discrimination with areas under the curve ranging between 0.79 and 0.92 for hospitals.

Conclusion

A prediction model is presented and validated to support the decision to resect or to biopsy a patient with a suspected supratentorial glioblastoma. In this prediction model, tumor-related characteristics were more informative than patient-related factors. This may support surgical decision-making for individual patients, or facilitate comparisons of patient cohorts between surgeons or institutions.
P11.64.A Long-term follow up and translational data from the ReoGlio phase Ib trial of GM-CSF and intravenous pelareorep (Reovirus) alongside standard of care in GBM
Authors: Short S , Kendall J , West E , Chalmers A , McBain C , Melcher A , Collinson F , Phillip R , Brown S , Samson A
Published: September 2022

BACKGROUND

We previously reported safety data from a phase Ib, open-label study of intravenous oncolytic virus pelareorep with GM-CSF alongside standard chemoradiotherapy in newly diagnosed glioblastoma confirming that the combination is well tolerated. We now report on long-term follow up and analysis of translational samples from tumour and blood in a subset of patients.

METHODS

15 patients with newly diagnosed GBM were treated with GM-CSF 50μg subcutaneously on days 1-3 and intravenous pelareorep on days 4-5 in weeks 1 and 4 of chemoradiotherapy, and subsequently in week 1 of each adjuvant temozolomide course: 7 patients received 1x1010TCID50 (dose level 1); 8 received 3x1010TCID50 (dose level 2). The primary objective was to determine the maximum tolerated dose of pelareorep and GM-CSF with standard chemoradiotherapy. Following a protocol amendment we also collected survival data in all patients up to August 2021. Serial blood samples were taken from three patients, at baseline, during chemoradiotherapy and in the first adjuvant cycle. Peripheral blood mononuclear cells were analysed for immune checkpoint expression by flow cytometry, RNAseq gene expression and T-cell receptor clonality, whilst plasma cytokines were quantified by Luminex.

RESULTS

This combination was well tolerated with 87% of patients completing treatment as planned. Survival data analysis showed that median OS was 12.6 months in dose level 1 and 16.1 months in dose level 2, median OS for all patients was 13.1 months. The 24-month survival estimate for all patients was 25.0%, 16.7% for dose level 1 and 33.3% for dose level 2. One patient in dose level 1 remains alive at 43 months post registration without further treatment. Laboratory data showed that pelareorep infusion resulted in inflammatory cytokine and chemokine secretion, immune checkpoint modulation, and upregulation of inflammatory pathways. There was also increased peripheral clonal tumour-specific T-cell proliferation following pelareorep infusion.

CONCLUSION

Although based on small numbers, these long-term follow up data suggest this may be an active combination in a subset of GBM patients. Translational data confirm that pelareorep potentially activates tumour-targeting immune pathways in GBM, with consequential immune checkpoint modulation. These data support a combination clinical trial of pelareorep, radiotherapy and immune checkpoint blockade in GBM.