bluuebunny/crossref_metadata_2025 huggingface dataset:
Sex hormone-binding globulin and heart failure hospitalizations in patients with dysglycemia - Experiences from the Outcome Reduction with an Initial Glargine Intervention (ORIGIN) trial
Authors: Wang Gottlieb A , Gerstein H , Hess S , Lee S , Mellbin L , Ryden L
Published: November 2023

Background

Sex hormone-binding globulin (SHBG), which binds most of the circulating testosterone in blood, is linked to both dysglycemia and a variety of cardiovascular (CV) events. However, few studies have investigated the link between SHBG and heart failure.

Purpose

To investigate the relationship between SHBG levels and heart failure hospitalizations in men and women with dysglycemia.

Methods

The Outcome Reduction with an Initial Glargine Intervention (ORIGIN) trial followed individuals with dysglycemia (impaired fasting glucose, impaired glucose tolerance or diabetes) and high cardiovascular risk for a median of 6.2 years. Incident CV events, including heart failure hospitalizations (defined as heart failure requiring overnight stay at hospital or attendance in an acute care setting) were collected and adjudicated. A subset of patients (n = 8,494) in whom blood samples were stored had SHBG levels analysed. Cox regression was used to estimate hazard ratios (HRs) of heart failure hospitalizations per standard deviation increase of SHBG. Adjustments were made for age, comorbidities, biochemical data (including testosterone) and pharmacological treatment. Analyses were performed separately in men and women.

Results

A total of 5,553 men and 2,848 women were included in whom heart failure hospitalizations were reported in 349 men and 123 women. Median SHBG levels were 35 nmol/L (25-47) in men and 39 nmol/L (27-55) in women. The primary outcome was more frequent in men with SHBG levels above median (n = 208/349 [59.6 %]; p<0.01) whilst no difference was seen for women (n = 69/123 [56.1%]; p = 0.24). A higher SHBG was associated with increased risk of heart failure hospitalizations in men (adjusted HR 1.15, 95% CI 1.03-1.28; p = 0.011) but not in women (adjusted HR 1.13; 95% CI 0.96-1.39; p = 0.14).

Conclusions

In this biomarker substudy within the ORIGIN trial comprising patients with dysglycemia and at high CV risk, increasing levels of SHBG were associated with heart failure hospitalizations independent of testosterone levels in men but not in women.
Echocardiographic assessment of right heart function in the presence of TR: Is right heart strain the answer?
Authors: Curtis E , Lemarchand L , L'official G , Bourg C , Oger E , Donal E
Published: November 2023

Background

Right heart function is challenging to assess with echocardiography due to the complex anatomy and load dependence. To complicate the assessment, significant tricuspid regurgitation flatters the right ventricle. These complexities have led to the need for other modalities and invasive measures of RV function to complement clinical decision-making and risk profiling. Speckle tracking can assess subtle anomalies and appears to be promising for right heart assessment.

We assessed right heart strain against classic echocardiographic measures of RV function (TAPSE, RVS’ and fractional area change (FAC)) and invasive measures of RV function (right ventricular stroke work index (RVSWI) and Pulmonary Artery Pulsatility index (PAPi)), in patients with severe TR and without, to see strain reclassifies the assessment of RV function from "normal" to impaired and to assess the prognostic value of right heart strain.

Methods

A single-centre retrospective analysis of data from 262 consecutive patients (age 74 ±11.2 years old; male 53%) with both right heart catheterization (RHC) and TTE. Clinical data was gathered from patient files, and outcomes of heart failure hospitalisation or death were recorded. Echocardiographic evaluation was completed on commercially available GE ultrasounds and data was stored on a dedicated workstation for offline analysis (EchoPAC version 112.99). Statistical analysis was performed using SAS 15.1.

Results

Over a median follow up of 34 ±15 months 99 events occurred. 53% of patients had severe TR. RV free wall strain reclassified RV function as impaired in 73% of patients with "normal" RV function as determined by FAC (p value 0.005), and in 71% of patients with normal RVS’ (p value 0.03) with severe TR. Using invasive measures, RVSWI reclassified RV function as abnormal when compared to TAPSE in 53% of patients (p value 0.02). PAPi reclassified RV function as impaired compared to TAPSE in 53% of patients (p value of 0.009).

In patients with TR 3+, right atrial strain reclassified presence of right heart dysfunction in 91% of patients compared to TAPSE >17 (p value 0.01) and in 95% of patients compared to RVS’ (p value 0.004).

In patients with moderate or less TR, RV strain reclassified 66% as having RV dysfunction with normal FAC (p value 0.003) and reclassified 61% of patients with RV dysfunction in patients with a normal RVS (p value 0.03). Invasive measures did not reclassify RV function assessment in patients with moderate or less TR. In patients with and without TR, RV strain and invasive measures were in accordance.

Abnormal RV strain (>-23%) was associated with an adverse prognosis HR 3.63 (1.43 – 9.22).

Conclusion

In the presence of severe TR, right heart strain helps to reclassify RV function, comparable to invasive measures. Abnormal right heart strain is strongly associated with prognosis and its utility should be confirmed in prospective studies.
Predicting heart failure and cardiovascular mortality after myocardial infarction: UCCS-HF risk score
Authors: Trifunovic Zamaklar D , Veselinovic A , Andjelkovic M , Petrovic O , Jovanovic I , Paunovic I , Vratonjic J , Boricic Kostic M
Published: November 2023

In spite of the current effective management of acute myocardial infarction, post-infarction heart failure (post-MI HF) continues to be a significant medical problem, with high morbidity and mortality. The robust risk score based on readily available clinical and echocardiographic data might help to recognize patients at risk and initiate early preventive/treatment strategies for post-MI HF.

The aim of the work: identify clinical and echocardiographic independent predictors of MACE (post-MI HF hospitalization or cardiovascular death) and develop a simplified risk score to predict MACE.

Material and methods

the retrospective study, 330 post-MI patients were initially included. Clinical (age, diabetes mellitus-DM, atrial fibrillation-Afib, chronic kidney diseases-CKD, cerebrovascular insult-CVI and gastro-bleeding) and standard echocardiographic parameters were analyzed.

Results

104 patients have complete data set for analysis and represent final cohort. During the follow-up period (median: 57 months), 24% of them experienced MACE. Significant clinical MACE predictors were: chronic kidney diseases (CKD: HR 1.95, 95% CI 1.124-3.394, p = 0.017) and atrial fibrillation (Afib: HR 2.66, 95% CI 1.522-4.647, p = 0.001). Significant echocardiographic MACE predictors were: left ventricular ejection fraction (EF<40%: HR 2.40, p = 001), right ventricular systolic pressure (RVSP≥33mmHg: HR 4.043, 95% CI 2.104-7.767, p<0.001), left atrial volume (LAVi≥46ml/m2: HR 4.377, 95%CI 1.852-10.348, p = 0.001), deceleration time of transmitral E wave (Dct≤188 ms: HR 4.00, 95%CI 1.739-9.201, p = 0.001), right ventricular diameter (RVd≥26mm: HR 2.056, 95%CI 1.221-3.462, p = 0.007), the systolic velocity of tricuspid annuli (Sm<9.3 cm/sec: 2.068, 95%CI 0.954-4.485, p = 0.006), mitral regurgitation (MR≥2+: HR 3.657, 95% CI 2.079-6.433, p<0.001) and tricuspid regurgitation (TR≥2+: HR 2.824, 95%CI 1.669-4.778, p<0.001). A risk score for post-MI HF or CV mortality (UCCS-HF score) of 10 variables was defined with good discrimination (c-statistic 0.85) (Picture 1).

Conclusion

nearly 1/4 of post-MI patients experienced HF hospitalization or CV death within 5 years after MI. A simplified risk score (UCCS-HF score) merging clinical risk factors (CKD and Afib), and echo variables (parameters of LV systolic function, LV diastolic properties, and RV systolic pressure and function) is a potentially easy, helpful, and robust tool to predict post-MI HF hospitalization and CV death. External validation and on larger patient population is needed.
Impact of diaphragm atrophy in elderly patients with heart failure: a multicenter prospective cohort study
Authors: Kagiyama N , Kamiya K , Toki M , Saito H , Iwata K , Matsue Y , Yoshioka K , Saito K , Murata A , Hayashida A , Kitai T , Maekawa E
Published: November 2023

Background

The diaphragm plays an important role in cardiac and respiratory functions. However, the importance of diaphragm atrophy in patients with heart failure (HF) has not been well described.

Purpose

To assess the feasibility of ultrasound-based assessment of the diaphragm and its prognostic impact in elderly patients with HF.

Methods

We conducted a multicenter prospective cohort study enrolling patients hospitalized with HF aged ≥65 years. Diaphragm thickness at rest and during inspiration was measured with ultrasound before discharge by certified observers, and interobserver variability was assessed using 90 images.

Results

Of the 599 enrolled patients (median 81 [74 - 86] years old, 55% female), mean diaphragm thickness at rest and during inspiration were 1. 9 ± 0.6 and 3.1 ± 1.2 mm, respectively. Interobserver variability was small with an intraclass correlation coefficient of 0.84 (0.76 – 0.89). Patients with thin (< 1.9 mm) diaphragm at rest (n = 304) had smaller body mass index (20.9 ± 3.6 vs 22.2 ± 4.0 kg/m2, p < 0.001), higher NYHA class (class II or higher 78% vs 61%, p < 0.001), lower % forced expiratory volume in 1 second (83.2 ± 22.3% vs 88.7 ± 23.7%, p = 0.013), and lower handgrip strength (18.1 ± 7.3 vs 19.8 ± 8.0 kg, p = 0.009). During the median follow-up of 663 [456 - 882] days, 160 patients died. Kaplan-Meier curve analysis showed significant stratification by quartile groups of diaphragm thickness at rest. After adjustment for the established MAGGIC risk score, diaphragm thickness was significantly associated with all-cause death (hazard ratio 0.56 [0.41 – 0.71] /mm, p < 0.001).

Conclusions

Diaphragm atrophy was prevalent in elderly patients with HF and had a strong association with all-cause death. Further studies are necessary to evaluate the efficacy of interventions.
The effect of sglt-2 inhibitor dapagliflozin on adropin serum levels in patients with chronic heart failure and concomitant type 2 diabetes mellitus
Authors: Berezin A , Fuschtey I M , Berezin A A
Published: November 2023

Background

adropin plays a protective role in cardiac remodeling through supporting energy metabolism and water homeostasis and suppressing inflammation. Low circulating levels of adropin were positively associated with the risk of cardiovascular diseases and type 2 diabetes mellitus (T2DM). We hypothesized that sodium–glucose linked transporter 2 (SGLT2) inhibitor dapagliflosin might represent cardiac protective effects in T2DM patients with known chronic heart failure (HF) through the modulation of adropin levels.

Methods

The study was an open-label, multicenter non-randomized cohort investigation. Patients of both sexes were included from October 2020 to July 2022 who were aged ≥18 years and had established T2DM with HbAc1 <6.9%, hemodynamically stable HF (I-III NYNA functional classes), and written consent to participate in the study. According to these criteria, we prospectively enrolled 417 patients with T2DM and HF. The eligible patients were treated with the recommended guided HF therapy according to their HF phenotypes, including the consumption of SGLT2 inhibitor dapagliflozin at a dose of 10 mg OD orally, along with standard therapy of HF. Anthropometry, clinical data, echocardiography / Doppler examinations, and measurements of biomarkers were performed at the baseline and over a 6-month interval of SGLT2 inhibitor administration.

Results

Over a 6-month period after the initial prescription of SGLT2 inhibitor dapagliflozin, the levels of adropin in the entire group demonstrated a significant increase of up to 26.6% (from 2.37 [25–75% IQR = 1.91–2.75] ng/mL to 3.00 [25−75% IQR = 2.68–3.36] ng/mL, p = 0.042). In the female subgroup, the increase in the circulating levels of adropin was sufficiently higher (Δ% = 35.6%, from 2.69 [25–75% IQR = 2.31–2.99] ng/mL to 3.65 [25–75% IQR = 3.40–3.89] ng/mL, p = 0.010)when compared with those of the male subgroup (Δ% = 22.7%, from 2.11 [25–75% IQR = 1.90–2.37] ng/mL to 2.60 [25–75% IQR = 2.07–3.21] ng/mL, p = 0.161). A multivariate linear regression analysis of the entire group showed that the relative changes (Δ) in the left ventricular (LV) ejection fraction (LVEF), left atrial volume index (LAVI), and E/e` were significantly associated with increased adropin levels. In the female subgroup, but not in the male subgroup, ΔLVEF (p = 0.046), ΔLAVI (p = 0.001), and ΔE/e` (p = 0.001) were independent predictive values for adropin changes.

Conclusion

the levels of adropin seem to be a predictor for the favorable modification of hemodynamic performances during SGLT2 inhibition, independent of N-terminal brain natriuretic pro-peptide levels.
Oral anticoagulation in heart failure complicated by atrial fibrillation: a nationwide routine data study
Authors: Pudasaini S , Jeschke E , Baberg H T , Levenson B , Malzahn J , Mansky T , Michels G , Gunster C , Mockel M
Published: November 2023

Background/Introduction

Heart failure (HF) is frequently complicated by atrial fibrillation (AF). The co-occurrence of both conditions worsens the overall patient prognosis (1). To reduce the risk of thromboembolic complications, current guidelines highly recommend an oral anticoagulant (OAC) therapy in the majority of patients affected (2).

Purpose

Aim of this study was to evaluate whether a permanent OAC therapy in patients with HF and AF leads to favourable outcomes. Additional benefits of new oral anticoagulants (NOACs), compared to vitamin K antagonists (VKA), were further assessed.

Methods

Anonymous routine data of patients who were medically insured at the largest German health insurance provider and had a claims record for hospitalisation with the main diagnosis of HF and AF (2017-2019) were included. Admission due to HF in the previous year, incomplete medication data within 90 days after hospital stay as well as the diagnoses of congenital anomaly, transplantation, asthma, and age under 30 years were exclusion criteria. The endpoints of mortality and readmission rate for all-cause and stroke/intracranial bleeding (ICB) 91-365 days after the index hospitalisation were analysed. For this, information about the medications was taken from the pharmacy database. Kaplan-Meier survival curves and multivariable Cox regression models were used to evaluate the impact of medication on outcome. Adjusted hazard ratios (HRs) and 95% confidence intervals (95% CIs) were calculated. Patient age, sex, and comorbidities were evaluated as independent factors, including all variables of the CHA2DS2-VASc score.

Results

We included n = 180,316 cases (see figure 1). The median age was 81 years (interquartile range of 76-86) with 55.6% of the patients being female. 96.81% had a CHA2DS2-VASc score of ≥ 2. We found OAC prescription in 80.6% (VKA: 21.7%; direct factor Xa inhibitors (FXaI): 60.0%; direct thrombin inhibitors (DTI): 3.4%). In 8,087 cases, more than one OAC was prescribed. The mortality rate was 19.1%, readmission rate was 29.9% and stroke/ICB occurred in 1.9% during the observed time span. As presented in figure 2, the risk of death was lower with any OAC (HR 0.77, 95% CI 0.75-0.79) but without significant differences in OAC type (VKA: HR 0.73, 95% CI 0.71-0.76; FXaI: HR 0.77, 95% CI 0.75-0.78; DTI: HR 0.71, 95% CI 0.66-0.77). The total readmission rate (HR 0.97, 95% CI 0.94-0.99) and readmission for stroke/ICB (HR 0.71, 95% CI 0.65-0.77) was likewise lower with OAC use.

Conclusion(s)

Routine data confirm the beneficial outcome of OAC therapy in patients with HF complicated by AF regarding mortality and readmission for all-cause as well as for stroke/ICB. No additional benefits were visible with the use of NOACs.Figure 1.Patient selection criteria.Figure 2.Kaplan-Meier survival (OAC).
Sex differences for the efficacy of sodium-glucose cotransporter 2 inhibitors on cardiorenal outcomes: a systematic review and meta-analysis
Authors: Yamashita I , Fujisaki T , Romeo F J , Fujisue K , Sueta D , Usuku H , Yamamoto E , Tsujita K
Published: November 2023

Background

It is unclear if sex differences affect the efficacy of sodium-glucose cotransporter 2 (SGLT2) inhibitors to improve cardiorenal outcomes in patients with increased risks of cardiovascular diseases.

Methods

A systematic review was performed by searching PubMed, Cochran Central, and Embase through February 2023 for randomized controlled trials (RCTs) of SGLT2 inhibitors that were performed in adults and large (≥500 participants per group). Hazard ratios (HRs) and relative risk estimates in subgroups stratified by sex were extracted from each study and were pooled using a random-effects meta-analysis. The primary outcome was a composite of cardiovascular death, myocardial infarction, or stroke. The secondary outcomes were heart failure exacerbation, adverse renal outcomes, and a composite outcome of cardiovascular death or heart failure exacerbation.

Results

This study included 10 RCTs. SGLT2 inhibitors were associated with decreased risks of the primary outcome (Female and male in total: HR, 0.80; 95% CI, 0.67-0.96, Female: HR, 0.71; 95% CI, 0.51-0.98, Male: HR, 0.90; 95% CI, 0.83-0.97). SGLT2 inhibitors were associated with decreased risks of heart failure exacerbation (Female: HR, 0.80; 95% CI, 0.69-0.94, Male: HR, 0.78; 95% CI, 0.69-0.87), adverse renal outcomes (Female: HR, 0.65; 95% CI, 0.48-0.88, Male: HR, 0.58; 95% CI, 0.46-0.72), and a composite outcome of cardiovascular death or heart failure exacerbation (Female: HR, 0.75; 95% CI, 0.67-0.84, Male: HR, 0.78; 95% CI, 0.72-0.85). There were no significant subgroup differences by sex for all outcomes (p>0.05).

Conclusions

SGLT2 inhibitor was associated with decreased risks of cardiorenal outcomes similarly in both sexes.
Two haplotype-resolved genomes reveal important flower traits in bigleaf hydrangea (Hydrangea macrophylla) and insights into Asterid evolution
Authors: Wu Xingbo , Simpson Sheron A , Youngblood Ramey C , Liu Xiaofen F , Scheffler Brian E , Rinehart Timothy A , Alexander Lisa W , Hulse-Kemp Amanda M
Published: November 2023

The Hydrangea genus belongs to the Hydrangeaceae family, in the Cornales order of flowering plants, which early diverged among the Asterids, and includes several species that are commonly used ornamental plants. Of them, Hydrangea macrophylla is one of the most valuable species in the nursery trade, yet few genomic resources are available for this crop or closely related Asterid species. Two high-quality haplotype-resolved reference genomes of hydrangea cultivars ‘Veitchii’ and ‘Endless Summer’ [highest quality at 2.22 gigabase pairs (Gb), 396 contigs, N50 22.8 megabase pairs (Mb)] were assembled and scaffolded into the expected 18 pseudochromosomes. Utilizing the newly developed high-quality reference genomes along with high-quality genomes of other related flowering plants, nuclear data were found to support a single divergence point in the Asterids clade where both the Cornales and Ericales diverged from the euasterids. Genetic mapping with an F1 hybrid population demonstrated the power of linkage mapping combined with the new genomic resources to identify the gene for inflorescence shape, CYP78A5 located on chromosome 4, and a novel gene, BAM3 located on chromosome 17, for causing double flower. Resources developed in this study will not only help to accelerate hydrangea genetic improvement but also contribute to understanding the largest group of flowering plants, the Asterids.
Control Estimates for 0th-Order Pseudodifferential Operators
Authors: Christianson Hans , Wang Jian , Wang Ruoyu P T
Published: November 2023

We introduce the control conditions for 0th-order pseudodifferential operators $\textbf{P}$ whose real parts satisfy the Morse–Smale dynamical condition. We obtain microlocal control estimates under the control conditions. As a result, we show that there are no singular profiles in the solution to the evolution equation $(i\partial _{t}-\textbf{P})u=f$ when $\textbf{P}$ has a damping term that satisfies the control condition and $f\in C^{\infty }$. This is motivated by the study of a microlocal model for the damped internal waves.
Cryopreservation and current legal problems: seeking and selling immortality
Authors: Mullock Alexandra , Romanis Elizabeth Chloe
Published: November 2023

Cryonics, the ‘freezing’ of the human body after death in the hope of reanimation in the future, remains a remote possibility, and yet it is becoming a more popular choice. There has been much academic discussion of the ethics of cryopreservation; however, the legal problems have received little attention. There are, however, several potential current conflicts that might arise, as was illustrated by the case of JS in England, in which a 14-year-old girl who sought cryopreservation against her father’s wishes. In the USA, there have been disputes within families about cryonic preservation, and between cryonics organizations and loved ones of the deceased when there is negligent preservation. Cryopreservation raises questions concerning the law on death and posthumous interests, property in the body, contract law, and (potentially) negligence. We argue that, in the absence of proper regulation, cryonics organizations may be able to exploit the dying and dead. The potential legal problems that we have identified in relation to the law in England and Wales demonstrate that the law is ill-equipped to protect the interests of the dead and their next of kin.
ANGI-04. IKIP SUPPRESSES MIGRATION AND INVASION OF GLIOBLASTOMA BY DOWNREGULATING THBS1/FAK SIGNALING
Authors: Liu Hao , Hu Yanjia , Zhu Zhaoying
Published: November 2023

BACKGROUND

The role of the inhibitor of NF-κB kinase-interacting protein (IKIP) in glioblastoma (GBM) migration and invasion remains poorly understood, despite its known involvement in the negative regulation of NF-κB signaling and inflammation. This study aimed to investigate the impact of IKIP on GBM metastasis and elucidate the underlying molecular mechanisms.

METHODS

Expression levels of IKIP were analyzed in gliomas and normal brain tissues using bioinformatic analysis of public databases and immunohistochemical staining of clinical samples. Transwell and wound healing assays were employed to assess the migration and invasion of GBM cell lines. RNA sequencing was conducted to unravel the molecular pathways involved.

RESULTS

Bioinformatic analysis revealed a significantly higher expression of IKIP in GBM compared to normal brain tissues, and its upregulation was associated with a poor prognosis in glioma patients. However, immunohistochemical and immunofluorescent staining demonstrated the downregulation of IKIP in GBM. Furthermore, functional assays demonstrated that IKIP overexpression suppressed the migratory and invasive capabilities of GBM cell lines, whereas IKIP knockdown enhanced migration and invasion. Mechanistically, IKIP overexpression downregulated THBS1 at the transcriptional level, resulting in the inhibition of THBS1/FAK signaling.

CONCLUSIONS

This study provides evidence for the first time that IKIP exerts inhibitory effects on GBM migration and invasion by downregulating THBS1/FAK signaling. These findings shed light on the complex mechanisms underlying GBM progression and identify IKIP as a potential therapeutic target for GBM invasion.
BIOM-03. LACK OF CORRELATION OF MR-DETERMINED WHITE MATTER INJURY(WMI)WITH NEUROCOGNITIVE FUNCTION (NCF)6 MONTHS FOLLOWING WBRT+/-HIPPOCAMPAL AVOIDANCE(HA)+MEMANTINE:SECONDARY ANALYSIS OF NRG ONCOLOGY NRGCC001
Authors: Bovi Joseph , Pugh Stephanie , Brown Paul , Gondi Vinai , Robinson Clifford , Wefel Jeffrey , Sabsevitz David , Sprenger Markus , Kundapur Vijayananda , Roberge David , Devisetty Kiran , Shah Sunjay , Usuki Kenneth , Stea Baldassarre , Yoon Harold , Donnelly Eric , Laack Nadia , Baschnagel Andrew , Paulus Rebecca , Kachnic Lisa
Published: November 2023

PURPOSE

Previous analysis of NRG-CC001 suggested pre-treatment WMI volume was a significant imaging-biomarker predictor of post-treatment neurocognitive decline at 4-and 12-months following HA-WBRT+Memantine. This suggested patients with greater pre-treatment WMI were more susceptible to neurocognitive decline, specifically when undergoing HA-WBRT, but not standard-WBRT. The current analysis examined the relationship between changes in MR-determined WMI and NCF 6-months following WBRT+memantine+/-HA.

METHODS

NCF-testing was performed at baseline, 2, 4, 6, and 12 months post-WBRT, and included Hopkins Verbal Learning Test–Revised (HVLT-R), Trail Making Test (TMT) Parts A and B, and Controlled Oral Word Association (COWA). Pre-treatment WMI was measured by FLAIR-volume corrected for whole brain volume and corrected for the FLAIR volume associated with metastases (met vol) (FLAIR-volume/(whole brain volume–met-vol). Pearson correlation coefficients were used to assess the correlation between pre-treatment WMI and change from baseline to 6-months for each standardized NCF score.

RESULTS

Of the 518 randomized patients, 443 (217 patients WBRT+Memantine and 226 HA-WBRT+Memantine) had WMI data available at baseline, and of those, 162 patients (89 patients WBRT+Memantine and 73 HA-WBRT+Memantine) had both baseline and 6-month imaging available. For these patients, there was only a trend toward significance for change in corrected FLAIR-volume from baseline to 6-months (p = 0.174) but no significant change in met-vol (p = 0.438) or whole brain volume (p = 0.977). The change in standardized TMT Part A and B and the change in composite 6-month change scores were moderately correlated with change in corrected FLAIR volume adjusted for met-vol but only in the WBRT+Memantine arm (rho=-0.35, -0.34, -0.39 and p-value = 0.003, 0.006, 0.001).

CONCLUSIONS

Despite an increase in post-WBRT MR-WMI at 6-months, analysis did not show strong correlation between NCF and MR-WMI as determined by FLAIR-volume change between baseline and 6-months. Similar analyses are underway for the NRG-CC003 imaging data.
BIOM-05. FIRST-IN-HUMAN PROSPECTIVE TRIAL OF SONOBIOPSY IN GLIOBLASTOMA PATIENTS USING NEURONAVIGATION-GUIDED FOCUSED ULTRASOUND
Authors: Yuan Jinyun , Xu Lu , Chien Chih-Yen , Yang Yaoheng , Yue Yimei , Fadera Siaka , Stark Andrew H , Schwetye Katherine , Nazeri Arash , Desai Rupen , Athiraman Umeshkumar , Chaudhuri Aadel , Chen Hong , Leuthardt Eric
Published: November 2023

INTRODUCTION

Blood-based liquid biopsy for brain cancer offers a noninvasive alternative to invasive surgical biopsies. However, the presence of the blood-brain barrier (BBB) limits the release of brain tumor-derived molecular biomarkers into the bloodstream for sensitive diagnosis. Focused ultrasound (FUS)-enabled blood-based liquid biopsy (sonobiopsy) locally disrupts the BBB and releases tumor-derived biomarkers into blood circulation. Our previous studies have demonstrated that sonobiopsy improved the detection sensitivity of glioblastoma (GBM)-specific cirulating tumor DNA (ctDNA) in animal models of GBM. This study aimed to evaluate the feasibility and safety of sonobiopsy in enriching circulating tumor biomarkers in a first-in-human, prospective clinical trial.

METHODS

Five GBM patients (G01-05) were enrolled in the initial study. The sonobiopy procedures were performed prior to tumor resection, using a nimble FUS device integrated with a clinical neuronavigation system. The plasma level of glial fibrillary acidic protein (GFAP) was quantified using ultrasensitive single-molecule array (Simoa), while the cell-free DNA (cfDNA) levels were quantified using Bioanalyzer. Patient-specific tumor variants were comprehensively analyzed using a personalized tumor-informed ctDNA assay (Invitae Personalized Cancer Monitoring assay). Additionally, the two most common GBM-specific tumor variants were analyzed using customized ddPCR assays.

RESULTS

Analysis of plasmas collected before and after FUS sonication showed sonobiopsy enhanced plasma circulating tumor biomarker levels, including a maximum increase of 1.3-fold for GFAP, 1.6-fold for the concentration of mono-nucleosomal cfDNA fragment (120–280 bp), 1.9-fold increase in patient-specific tumor variant levels, and 5.6-fold increase in the TERT mutation level. Histological analysis of surgically resected tumors confirmed the safety of the procedure. Transcriptome analysis of sonicated and nonsonicated tumor tissues found that FUS sonication mainly modulated cell physical structure-related genes.

CONCLUSIONS

These feasibility and safety data support the continued investigation of sonobiopsy for noninvasive molecular diagnosis of brain diseases.
BIOM-06. LONGITUDINAL CEREBROSPINAL FLUID LIQUID BIOPSY IN PHASE 0/2 TRIAL OF NIRAPARIB FOR NEWLY-DIAGNOSED GLIOBLASTOMA
Authors: Furey Charuta , DeSantis Anita , White Connor , Tien An-Chi , Mehta Shwetal , Sanai Nader
Published: November 2023

INTRODUCTION

Effective drug development in glioblastoma (GBM) requires visualization of tumor evolution in response to experimental therapy. Today, genetic and epigenetic mechanisms of tumor resistance are undetected in clinical trials. Here, we establish the feasibility of a liquid biopsy paradigm in tracking tumor evolution in response to a novel therapeutic using an intra-cavitary reservoir for serial cerebrospinal fluid (CSF) collection.

METHODS

We conducted a Phase 0/2 clinical trial of niraparib, a potent PARP1/2 inhibitor, in newly-diagnosed GBM patients (NCT05076513). Intra-cavitary reservoirs were placed in select patients following tumor resection. Monthly outpatient CSF samples were collected to longitudinally examine cell-free tumor DNA (cfDNA) using a 293-gene amplicon-based next-generation sequencing (NGS) panel and circulating tumor cells using single cell RNA-sequencing (scRNA-seq). Concordance analysis was performed using paired tumor tissue samples against multiple liquid biopsies.

RESULTS

Tumor-derived cfDNA and circulating tumor cells were successfully isolated from intra-cavitary reservoirs at regular intervals for the duration of the clinical trial. Twelve patients so far have been implanted with the reservoirs for CSF collection. Among 55 CSF samples, 53 (94%) has detectable cfDNA. Radiographic tumor burden is associated with concentration of cfDNA (ng/ml, p< 0.01). No adverse events were observed during liquid biopsy acquisition. CSF sequencing data was highly concordant with NGS analyses of tumor tissue. cfDNA and single-cell analyses from serial CSF samples reflected the disparate evolution of GBM patient tumors in the face of PARP1/2 inhibition.

CONCLUSION

This is the first reported experience of serial CSF liquid biopsy to monitor DNA- and RNA-based tumor evolution in the context of an experimental therapy. Our data demonstrate the feasibility of cfDNA NGS and scRNA-seq using longitudinal CSF sampling of clinical trial patients. This new strategy for serial tumor profiling will be an important component of future drug development efforts targeting the moving biology of glioblastoma.
BIOM-07. NON-TUMOR PLASMA EXTRACELLULAR VESICLES PREDICT THE OCCURRENCE OF GBM: A MACHINE LEARNING ANALYSIS
Authors: Aibaidula Abudumijiti (Zack) , Ghaith Abdul Karim , Bydon Mohamad , Parney Ian
Published: November 2023

INTRODUCTION

Glioblastoma (GBM) is the most common primary malignant brain tumor and has a poor clinical outcome. Extracellular vesicles (EVs) are promising biomarkers to assist the differential diagnosis between pseudoprogression and true tumor progression. We aimed to identify non-tumor plasma EV markers that predicted GBM occurrence using trained multiple tree-based machine learning algorithms.

METHODS

We included plasma samples of 40 GBM and 40 non-GBM (20 brain metastasis, 20 normal donors). Spectral flow cytometry was performed to determine plasma EV subpopulation frequency based on CD9,CD81,CD63,CD11b,CD45,CD31, and CD41a expression. Multiparametric t-SNE and FlowSOM analysis clustered plasma EVs based on these markers. Decision trees and random forest classifiers were trained and tested to predict the disease status (GBM vs non-GBM) based on plasma EV subpopulations.

RESULTS

Compared to non-GBM, GBM had increased frequency of CD9+ EVs (64.52% vs 40.69%, p< 0.0001), CD9+CD63-CD81- EVs (54.45% vs 37.26%, p< 0.0001) and myeloid-derived EVs (CD9+CD11b+ EVs, 20.77% vs 12.48%, p = 0.0241). In the decision tree analysis, low frequency of CD9+ EVs was found in 44% of all cases and represented a chance of 75% to be classified as non-GBM cases. An algorithm based on random forest analysis (n = 500 trees) using these markers had a sensitivity of 85.71% and specificity of 77.8% with an overall accuracy of 81.25% for identifying GBM. The frequencies of CD9+, CD9+CD63-CD81-, and CD9+CD63+CD81+ were the most critical factors in predicting GBM diagnosis. FlowSOM analysis identified 20 plasma EV subpopulations but had a lower accuracy (62.5%) when combined with our machine learning algorithm.

CONCLUSIONS

Non-tumor plasma EV expression profile combined with tree-based machine learning demonstrated high accuracy in predicting patient disease status. CD9+ EV frequency was one of the most promising biomarkers to assist in this diagnosis. We will continue to test our established algorithm and further validate our findings in a larger cohort.
BIOM-08. SINGLE-MOLECULE SYSTEMS FOR DETECTION OF PLASMA CIRCULATING ONCOPROTEINS IN DIFFUSE MIDLINE GLIOMA
Authors: Erez Nir , Furth Noa , Fedyuk Vadim , Wadden Jack , Aittaleb Rayan , Schwark Kallen , Miclea Madeline , Venneti Sriram , Koschmann Carl , Shema Efrat
Published: November 2023

Diffuse midline glioma (DMG) is a high-risk pediatric brain tumor that has primarily been diagnosed and monitored via medical imaging (MRI) due to risks associated with re-biopsying midline brain structures. Recent advances in molecular diagnostics have improved classification and molecular characterization of DMG; these tumors are in dire need of non-invasive, molecular-based diagnostic tools to supplement serial assessments of radiographic response. Our group recently developed a single-molecule imaging platform, Epigenetics of Plasma Isolated Nucleosomes (EPINUC), to profile histone modification patterns in cell-free tumor DNA (ctDNA) from plasma of cancer patients. We developed a novel strategy for single-molecule detection of the histone mutation H3K27M, a key DMG genetic driver, by capturing mutant nucleosomes on a PEG-streptavidin coated surface and detecting them with fluorescently labeled antibodies targeting histone modifications enriched on these mutant nucleosomes. We applied this method to 46 H3K27M and 10 H3 wildtype DMG samples and found significantly higher signal in K27M samples. Using this data, we generated a predictive model of H3 status with an AUC of 0.81, sensitivity 90%, specificity 71%, and precision 73%. This test was found to be highly reproducible and rapid (60 minutes) and required less than 100 uL of plasma. We also analyzed mutant p53 protein in plasma samples from 11 p53-mutant and 4 p53-wildtype DMG patients, seeing significant separation between the two groups. We overlayed H3K27M and p53 cell-free protein results with H3.3K27M and TP53 ctDNA variant allele fraction (VAF) by digital droplet PCR (ddPCR) in serial plasma samples from n = 3 DMG patients undergoing experimental therapy. These data highlighted unique patterns of disease response by (1) MRI, (2) plasma tumor protein, and (3) plasma ctDNA. Overall, these results demonstrate the clinical potential of our platform for non-invasive and accurate detection and monitoring of levels of key oncoproteins in plasma of DMG patients.
BIOM-09. OPPOSING EFFECTS OF LINKED CX3CR1 GERMLINE VARIANTS ON SURVIVAL AND IMMUNE ACTIVATION IN GLIOMA
Authors: Khan Abdul Basit , McDonald Malcolm , Curry Rachel , Yang Yuhui , Khatri Latha , Deneen Benjamin , Serin-Harmanci Akdes , Rao Ganesh
Published: November 2023

Linkage-disequilibrium connects CX3CR1 V249I and T280M single-nucleotide polymorphisms; V249I occurs as a single-variant (SV) and T280M exclusively as a double-variant (DV) concurrent with V249I. In low-grade gliomas (LGG), we found improved median overall-survival (mOS) in SV (n = 14, mOS 21.03yrs), compared to WT (n = 45, mOS 9.41yrs) and DV (n = 31, mOS 10.49yrs; p = 0.037 Log-rank). In TCGA glioblastoma (GBM), SV (n = 69, mOS 15.65mo) improved survival over DV (n = 106, mOS 11.74mo; p = 0.044 Log-rank). In a separate GBM cohort, bulk RNA-sequencing revealed MMP9 over-expression in DV (n = 15) compared to SV (n = 10; log2FC 2.87, p-adj 0.079). On a single-gene basis, MMP9 expression was decreased in SV compared to DV and WT (n = 33; p = 0.044, Kruskal-Wallis). MMP9 promotes tumor angiogenesis and invasion. SV showed SPP1 over-expression compared to DV (log2FC -1.75, p-adj 0.026), with decreased SPP1 expression in both WT and DV compared to SV (p = 0.004, Kruskal-Wallis). SPP1 is a pro-inflammatory cytokine enriched in glioma-associated macrophages. Gene Ontology revealed enrichment of biological processes: neutrophil migration, granulocyte chemotaxis, and neutrophil chemotaxis in SV (p< 0.05). We single-cell RNA-sequenced IDH mutant gliomas (51777 cells). We subset and re-clustered myeloid-derived cells (microglia/macrophages, 8944 cells), identifying thirteen clusters. Myeloid-derived cells clustered by CX3CR1 status, with 50.8% of SV cells in cluster five and 85.3% of DV cells in clusters six or seven. Cluster five over-expressed IL1B (average-log2FC 3.23), a tumor-suppressive M1 macrophage marker. Clusters six and seven were characterized by IFIT genes – immunomodulatory in myeloid-derived cells (IFIT3 average-log2FC 2.65 and 2.06). Assessing CX3CR1 status in normal population – 74.2% are WT, 10.0% SV, and 15.7% DV. In glioma patients, we identify 59.9% WT, 14.9% SV, and 25.2% DV – an increase of 49% in SV and 61% in DV (p = 1.95e-6, Chi-square). Our findings demonstrate opposing effects of linked CX3CR1 germline variants on glioma survival and indicate enhanced immune activation in SV.
BIOM-10. KI-67 IS ASSOCIATED WITH PROGRESSION-FREE SURVIVAL IN PATIENTS WITH GLIOBLASTOMA
Authors: Bergman Drew , Anand Sumyuktha , Gill Gobind , Harris Brent , Fadul Camilo , Havrda Matthew , Pointer Kelli
Published: November 2023

Identifying predictive and prognostic markers for glioblastoma (GBM) is an area of intense investigation. The objective of this study was to evaluate OLIG2 and Ki-67 as prognostic biomarkers. A tissue microarray with clinical data was created for 70 patients diagnosed with GBM between 2002-2007 at a single institution. Immunohistochemistry was performed to evaluate expression of OLIG2 and Ki-67. Overall survival and progression free survival (PFS) were calculated using the Kaplan-Meier method. Univariable (UVA) and multivariable (MVA) analysis was performed using Cox proportional hazards modeling. The median age of diagnosis was 63, 66% of patients were male, 80% had a KPS ≥70, 64% had a subtotal resection or biopsy, and 36% had a gross total resection. Median OS and PFS were 13.3 months and 9.5 months respectively. For patients who received resection plus chemoradiation, median OS and PFS were 16.7 months and 9.5 months respectively. 36.4% of patient samples had Ki-67 expression fraction > 20%. 18.0% had heavy OLIG2 staining. On MVA, lower KPS was associated with shorter OS and radiation therapy was associated with longer OS. OLIG2 was not associated with OS or PFS. Patients who had a Ki-67 < 20% had a shorter PFS, but not OS on MVA. Our data demonstrate higher Ki-67 levels correlate with improved PFS without an OS benefit. This association persisted for patients receiving standard of care treatment. OLIG2 levels did not correlate with PFS or OS in either cohort. Our study indicates that further investigation is needed to determine whether Ki-67 is useful in predicting recurrence risk and potentially changing treatment strategies for these patients, as well as the mechanism behind the associated improvement seen with higher Ki-67 levels. These data are currently limited by lack of IDH and MGMT status but suggest Ki-67 should be further investigated as a biomarker for progression.
BIOM-12. ULTRA-DEEP WHOLE GENOME SEQUENCING UNCOVERS A HIGH PREVALENCE OF GLIOBLASTOMA-DERIVED CELL-FREE DNA IN PLASMA
Authors: Underhill Hunter , Farrell Andrew , Dean Charlie , Harrison Brion , Bronner Mary , Colman Howard , Jensen Randy
Published: November 2023

The detection of glioblastoma-derived circulating cell-free DNA (ccfDNA) has proven formidable because tumor-specific mutations are hidden among the abundance of ccfDNA from healthy cells. While capture-enrichment panels provide the necessary read depth to detect low-frequency variants, searches are constrained to a narrow range of targets and largely limited to single nucleotide variants (SNVs). Here, we use ultra-deep whole genome sequencing (WGS) to broaden the search for somatic mutations across the entire genome. In addition, a kmer-based reference-free variant caller, which mitigates the bias and errors that accrue during alignment, is used to extend the mutation search beyond SNVs to include insertions/deletions (INDELS) and structural variants (SVs) such as large INDELS ( >20 bp) and tandem duplications. In tumor DNA and ccfDNA, we achieve a WGS (GRCh38) mean read depth of 263X and 225X, respectively. WGS of matched buffy coat DNA and sequencing reads from the 1000 Genome Database were used to eliminate germline polymorphisms, sequencing artifacts, and common variants. We detected 20,488 somatic mutations in tumor DNA of which 17.3% affected a coding sequence, 31.9% were INDELS, 91 were large INDELs, and 18 were tandem duplications. A tumor-informed search identified 489 of these somatic mutations in ccfDNA which included a large INDEL and a similar portion of mutations affecting a coding sequence. Using an unguided search for glioblastoma-derived ccfDNA uncovered an additional 8,794 somatic mutations of which 16.6% involved a coding sequence, 60.7% were INDELS, 30 were large INDELS, and 3 were tandem duplications. The high prevalence of somatic mutations discovered in ccfDNA using an unbiased approach highlights the low yield of tumor-informed searches in spatially genetically heterogeneous cancers like glioblastoma. Our findings demonstrate that ultra-deep WGS detects glioblastoma-derived ccfDNA by broadening the search for variants across the entire genome and through the inclusion of INDELS and SVs.
BIOM-13. ASSOCIATION OF HAND-FOOT SKIN REACTIONS WITH SURVIVAL IN RECURRENT GLIOBLASTOMA PATIENTS TREATED WITH REGORAFENIB
Authors: Werner Jan-Michael , Hau Peter , Kowalski Thomas , Treiber Hannes , Roth Patrick , Wollring Michael , Stetter Isabelle , Tscherpel Caroline , Rosen Elena , Ceccon Garry , Chapuy Claudia , Schlegel Uwe , Weller Michael , Fink Gereon , Galldiks Norbert
Published: November 2023

INTRODUCTION

The phase 2 REGOMA trial suggested a survival benefit of the multikinase inhibitor regorafenib for treating patients with glioblastoma at first recurrence. Hand-foot skin reactions (HFSR) following multikinase inhibitor therapy have been reported to predict prolonged overall survival (OS) in patients with solid tumors. The predictive value of HFSR in patients with recurrent glioblastoma undergoing regorafenib therapy remains to be investigated.

METHODS

Fifty-seven patients (age range, 35-77 years) with recurrent IDH-wildtype glioblastomas were retrospectively identified from five centers in Germany and Switzerland. Regorafenib was administered at 160 mg/d for the first three weeks of each 4-week cycle, with individual dose adjustments according to toxicity. Patients were stratified into two groups based on the occurrence of HFSR following regorafenib. Group differences were investigated using the Mann-Whitney rank-sum and Fisher's exact tests. Kaplan-Meier analysis was used for univariate analyses, and the Cox proportional hazards regression model for multivariate analyses.

RESULTS

Patients received a median of two regorafenib cycles (range, 1-14 cycles). Median follow-up after recurrence was 7.0 months (range, 0.6-35.9 months). The median number of previous treatment lines was 2 (range, 1-6 lines). At the time of data analysis, 47 patients (82%) had died. HFSR were observed in 14 out of 57 patients (25%) and associated with a significantly longer OS (10.6 vs. 6.0 months; P = 0.040). No significant group differences (HFSR compared to no HFSR) were observed regarding age, the extent of resection, MGMT promoter methylation, Karnofsky performance status, or the number of completed regorafenib cycles (all P > 0.05). Cox proportional hazards regression analysis confirmed that HFSR were associated with longer OS (P = 0.039; HR, 0.438), independent of age, Karnofsky performance status, and the number of previous treatment lines (all P > 0.05).

CONCLUSION

Our data suggest that the occurrence of HFSR following regorafenib is associated with longer OS in recurrent glioblastoma patients.
BIOM-16. LONGITUDINAL GLIOMA CEREBROSPINAL FLUID CELL-FREE DNA FOR MONITORING AND TREATMENT RESPONSE ASSESSMENT
Authors: Riviere-Cazaux Cecile , Dong Xiaoxi , Mo Wei , Luo Shujun , Wang Amy , Du Pan , Ghadimi Keyvan , Warrington Arthur , Burns Terry
Published: November 2023

Few methods exist via which to assess treatment response with high fidelity in gliomas. While CSF has previously been used as a source of cfDNA, it remains unknown how cfDNA abundance and sequencing changes throughout treatment and inevitable recurrence in gliomas. We utilized our biobank of longitudinal intracranial CSF specimens to determine the potential utility of CSF cfDNA as a monitoring tool for treatment response in patients with gliomas. Longitudinal CSF specimens were acquired via Ommaya reservoirs (NCT04692337) or ventriculoperitoneal shunts (NCT04692324) in patients with gliomas. cfDNA was extracted from 1-5 mL of CSF, and next-Generation sequencing or low-pass whole genome sequencing (LPWGS) was performed by Predicine, Inc. CSF acquired prior to versus after resection demonstrated an increase in quantified cfDNA (2.97x, range: 1.58-5.26x), consistent with the impact of increased parenchymal disruption and closer contact with CSF. Thereafter, CSF cfDNA continued to decrease throughout chemoradiation and adjuvant treatment and increased at recurrence, including in patients co-enrolled in immunotherapy trials for IL-7 agonists and pembrolizumab. Copy number burden (CNB) increased by the time of recurrence in three patients with known disease progression, and continued to decrease throughout immunotherapy treatment in one patient despite concerns of pseudoprogression. In one patient with a hypermutated glioblastoma, CSF cfDNA revealed over 59 genomic alterations, including MAP2K1, KIT, and PDGFRA, excluding even more variants of unknown significance, each of which had been detected in sequencing of the tissue acquired at resection and subsequently decreased with chemoradiation. In another patient with a known progressing EGFR-amplified GBM, over 200 new variants were identified by the patient’s final sample and EGFR copy number increased from 2 to over 30. In conclusion, cfDNA analysis over a patient’s disease course, including resection and treatment with standard-of-care and experimental therapies, may be of use for disease monitoring and treatment response.