bluuebunny/crossref_metadata_2025_split huggingface dataset:
Stenosis of the glomerulotubular neck in progressive chronic kidney disease
Authors: Cohen Eric P , Denic Aleksandar , Aperna Fnu , Mullan Aidan F , Barisoni Laura , Sharma Vidit , Gibson Ian W , Rule Andrew D 
Published: October 2024

ABSTRACT

Background
Morphology and morphometric evaluation of lesions beyond conventional parameters can inform the pathophysiology of chronic kidney disease (CKD). We sought to determine whether the occurrence of glomerulotubular neck stenoses associates with progressive CKD.

Methods
We evaluated the normal parenchyma from radical nephrectomies removed for tumor between 2000 and 2021 and analyzed cortex for stenoses of the glomerulotubular neck. Stenosis of the glomerulotubular neck is defined a focal narrowing for which the draining tubule has a greater diameter than at the neck. Progressive CKD was defined as dialysis, kidney transplantation, sustained estimated glomerular filtration rate (eGFR) &lt;10 mL/min/1.73 m2 or sustained 40% decline from the post-nephrectomy eGFR. Each case of progressive CKD was age- and sex-matched to two controls without progressive CKD. Logistic regression models assessed the risk of progressive CKD with stenotic necks adjusting for other histological features, kidney function and CKD risk factors.

Results
There were 65 cases with a mean of 255 glomeruli and 130 controls with a mean of 329 glomeruli. Among both cases and controls, 5% of glomeruli showed visible glomerulotubular necks. The proportion of necks that were stenotic was higher in cases than controls (35% vs 11%, P &lt; .0001). Stenotic necks associated with progressive CKD independent of other histologic and clinical characteristics.

Conclusion
Glomerulotubular neck stenosis is associated with development of progressive CKD.
KS01.4.A CHARACTERIZATION AND THERAPEUTIC TARGETING OF ASTROCYTE REACTIVITY STATES DURING PROGRESSION FROM PRIMARY TO POST-RADIOTHERAPY RECURRENT GLIOBLASTOMA
Authors: Jeannot P , Rosberg R , Lindgren D , Smolag K I , Manou D , Berg T J , Dawson J , Elliott R , Ceberg C , Carragher N , Pietras A 
Published: October 2024

Abstract

BACKGROUND
Despite early response to radiotherapy, glioblastomas invariably recur, frequently within the field receiving high-dose irradiation. Stromal radiation responses remain poorly characterized, but recent evidence suggest that cells of the tumor microenvironment generate tumor-supportive conditions in the post-radiotherapy brain. Here, we explored the character of astrocyte reactivity states induced during tumor progression and treatment, identified compounds to target such states, and evaluated their suitability as therapeutic targets for glioblastoma.

MATERIAL AND METHODS
Murine glioblastomas were generated using the RCAS/tv-a system and treated (or not) with 10 Gy radiation upon symptoms. Healthy brain and tumor tissues were subjected to single cell RNA sequencing and spatial transcriptomics, and further analyzed using highly multiplexed immunohistochemistry. An image-based approach was developed and validated to quantify astrocyte reactivity, and this approach was utilized in high-throughput screens to identify compounds able to block astrocyte reactivity.

RESULTS
Single cell RNA sequencing revealed distinct astrocyte states in healthy brains and tumor tissues, and relative changes in state abundance as tumors progressed from primary to recurrent glioblastomas. Astrocyte states were spatially separated, with some enriched in peri-tumoral regions and others within the tumor core. Using an image-based method to quantify astrocyte reactivity in vitro, we screened 1600 compounds and identified 31 drugs able to inhibit astrocyte reactivity induced by radiotherapy. Among them, Flunarizine, a calcium-entry blocker approved to treat migraine, was confirmed to inhibit radiation-induced astrocyte reactivity and reactive astrocytes’ effect on glioblastoma cells in vitro. In a mouse model of glioblastoma, Flunarizine significantly extended the survival of mice in combination with radiotherapy while not affecting the outcome for non-irradiated mice, suggesting that Flunarizine targets a radiation-induced phenotype. Flunarizine treatment had no effect on primary glioblastoma cells, supporting the idea of microenvironmental targeting.

CONCLUSION
Astrocytes react to the tumor microenvironment by adopting cell states distinct from those present in healthy brain, and further adapt their phenotypes as tumors undergo radiotherapy. Screening for compounds able to inhibit astrocyte reactivity revealed Flunarizine as a promising candidate for glioblastoma treatment.
KS02.6.A SINGLE-CELL MULTIMODAL ANALYSIS OF IDH-MUTANT GLIOMAS UNCOVERS SHIFT FROM EPIGENETIC TO GENETIC DRIVERS WITH TUMOR PROGRESSION
Authors: Gonzalez Castro L , Wu J , Battaglia S , El Farran C , D’Antonio J , Miller T , Suva M , Bernstein B 
Published: October 2024

Abstract

BACKGROUND
Isocitrate dehydrogenase (IDH) mutant gliomas are progressive, invariably fatal brain tumors affecting young and middle-age adult patients. Previous single-cell transcriptomic characterization of IDH-mutant gliomas has uncovered a heterogeneity of cell states, with a developmental hierarchy that starts with neural progenitor-like stem cells that transition to more differentiated malignant cell states. Despite this understanding, the dynamics of these cell state transitions as tumors undergo grade progression, and the factors that facilitate or restrict cell state transitions remain poorly understood.

MATERIAL AND METHODS
Here, we characterize the cell states of IDH-mutant gliomas via single-cell gene expression (scRNA-seq) and single-cell analyses of accessible chromatin (scATAC-seq) in tumors spanning all grades using fresh patient samples and compare them with transcriptional programs and chromatin accessibility profiles of normal brain cells. We perform mechanism validation experiments using IDH-mutant glioma organoids.

RESULTS
We find that tumor transcriptional cell states experience a marked shift as tumors undergo progression. In low-grade tumors, predominant cell states mimic slow-cycling oligodendrocyte progenitor-like cells (OPCs). With grade progression, predominant cell states transition to resemble highly proliferative neural progenitor-like cells (NPCs). Additionally, scATAC-seq analyses revealed novel permissive chromatin states, which could facilitate this transition. Genetic analyses identified several molecular alterations in high-grade tumors, including loss of DNA methylation, oncogene amplification, and the deletion of genes associated with the interferon (IFN) response. Those IFN genes, as well as tumor suppressors, are initially repressed by DNA hypermethylation in low-grade tumors. Lastly, we validate the role of DNA hypomethylation in favoring immune evasion with grade progression using an IDH-mutant glioma organoid model.

CONCLUSION
Overall, our findings provide evidence that tumor progression in IDH-mutant gliomas is driven by an interplay of epigenetic and genetic mechanisms, with the former being determinant in low-grade tumors and the latter in high-grade tumors. The emergence of genetically-driven mechanisms promotes more mitotically active cell states as well as decreased anti-tumoral immune activation.
JS06.4.A RADIOTHERAPY QUALITY ASSURANCE IN THE ROAM/EORTC1308 ATYPICAL MENINGIOMA RANDOMISED CONTROLLED TRIAL: PROSPECTIVE REVIEW IMPROVES RADIOTHERAPY QUALITY AND CONSISTENCY
Authors: Jenkinson M D , Mayles H , Weber D C , Haylock B J ,   ROAM/EORTC1308 Trial Management Group
Published: October 2024

Abstract

BACKGROUND
ROAM/1308 is an international randomised controlled phase III trial comparing radiotherapy (60Gy in 30 fractions) to observation following complete surgical resection of atypical meningioma. We embedded prospective radiotherapy quality assurance (RTQA) within the trial with the aim of ensuring consistent radiotherapy planning and delivery.

MATERIAL AND METHODS
The radiotherapy protocol described the consensus contouring/planning guidelines. Pre-trial assessment included benchmark cases (outlining/planning) and a technology ‘Dummy Run’. Individual case reviews were undertaken. Non-conformities were classed as ‘major’ (undertreatment of dural margins/over treatment of brain or organs at risk) or ‘minor’ (for education). Resubmissions were mandated for all major non-conformities. All plans were approved before radiotherapy delivery.

RESULTS
The UK RTQA group coordinated European sites. The Australian RTQA group (TROG) reviewed their sites and provided all data to the UK for review. Four radiation oncologists reviewed contours and physicists/dosimetrists reviewed plans. All sites (20 UK, 25 EORTC, 11 TROG) undertook the benchmark/’Dummy Run’ cases prior to opening. Resubmissions were: UK (1 contour, 0 plans), EORTC (2 contours, 6 plans) and TROG (1 contour, 3 plans). Trial communications and outlining workshops were used to provide feedback. Radiotherapy was delivered to 30, 26 and 7 patients at 11 UK, 12 EORTC and 5 TROG sites, respectively. Overall, 25 (40%) patient cases needed resubmitting: 23 (37%) sets of outlines (2 cases twice) and 9 (14%) treatment plans (1 plan twice).

CONCLUSION
Prospective quality assurance and case review are essential to ensure consistent high-quality radiotherapy and benchmark/’Dummy Run’ alone is not sufficient. RTQA should be used for future trials in rare tumours where centres may only treat a few patients. The consistent high-quality radiotherapy in ROAM/EORTC1308 ensures the primary outcome (progression free survival: to report 2026) will be a robust assessment and any difference between treatment arms cannot be attributed to variation in radiotherapy planning or delivery.
OS03.5.A A PHASE I CLINICAL TRIAL ON THE INTRACRANIAL ADMINISTRATION OF AUTOLOGOUS CD1C(BDCA-1)+ /CD141(BDCA-3)+ MYELOID DENDRITIC CELLS IN COMBINATION WITH IPILIMUMAB AND NIVOLUMAB IN PATIENTS WITH RECURRENT HIGH-GRADE GLIOMA
Authors: Duerinck J , Lescrauwaet L , Dirven I , Del’haye J , Cammaert M , Geens W , Geeraerts X , Stevens L , Brock S , Kockx M , Everaert H , Vanbinst a , Tuyaerts S , Neyns B 
Published: October 2024

Abstract

BACKGROUND
Intracranial (iCran) administration of the PD-1 and CTLA-4 blocking monoclonal antibodies nivolumab (NIVO) and ipilimumab (IPI) at the time of resection of recurrent high-grade glioma (rHGG) is safe and resulted in encouraging survival (NCT03233152). CD1c(BDCA-1)+ /CD141(BDCA-3)+ myeloid dendritic cells (myDC) play a pivotal role in initiating an adaptive anti-tumor immune response and licensing immune anti-tumor effector cells within the tumor microenvironment. iCran injection of autologous myDC in pts with rHGG was found to be safe but the potential added benefit for survival has not been established.

MATERIAL AND METHODS
rHGG pts (after prior RT and TMZ, not in need of supraphysiological doses of corticotherapy), underwent leukapheresis followed by isolation/cryopreservation of myDC. NIVO (10 mg IV) was administered preoperatively. Autologous myDC (5-, 10-, or 20.106 cells) were injected into the brain tissue lining the resection cavity (iCer) following a maximal safe resection (MSR) or intratumorally (iTum) following a stereotactic core needle biopsy (SCNB). IPI (5 mg) plus NIVO (10 mg) were co-injected iCer or iTum with the myDC. Postoperative NIVO was administrated intracavitary via an Ommaya reservoir (iCav, 10 mg) and intravenously (IV, 10 mg) Q2w (max 11x).

RESULTS
21 pts (13 M; med 49 y [range 20 -78]; IDHwt 17 pts, ECOG PS 0 or 1: 18-, 3 pts) underwent procurement of myDC; intraoperative administration of myDC was preceded by MSR in 19 pts, and SCNB in 2 pts. Respectively 6-, 3-, and 12 pts were treated at the 3 myDC dose levels. All pts received the peri-op iTum/iCer/IV-administration of IPI and NIVO as planned. The median postoperative iCav and IV NIVO-administration was 7 (range 0-11) and 8 (0-11). Study treatment was discontinued early at first progression in 9- and AE in 3 pts. Most important TRAEs: bacterial colonization of the Ommaya reservoir (n=4), craniotomy wound dehiscence (n=2), and bacterial meningitis (n=1). At DBL (01MAY2024), 6 pts (29%) remain progression-free (incl. 3 pts with &gt;2y PFS). PFS (med. 24w [95% CI 8- 39]) is superior when compared to the pts (n=70) with resectable rHGG treated in 4 other cohorts of the GlITIpNi trial (p=.003). When including a durable benefit from bevacizumab at first PD in 3 pts (out of 10 pts who were treated with a low-dose bevacizumab regimen at first progression), PFS compared favorably to a historical pooled cohort (n: 469) of rHGG treated with VEGF(R)-inhibitors (p=.007). The 1-year OS-rate was 50% [95% CI 24-76].

CONCLUSION
Intracranial administration of autologous myDC combined with IPI/NIVO is feasible, safe and associated with encouraging survival, deserving further investigation.
OS05.6.A RADIOLOGICAL TREATMENT-ASSOCIATED CHANGES IN GLIOBLASTOMAS WITH OR WITHOUT AN MGMT PROMOTER-METHYLATION TREATED WITH CILENGITIDE: REVIEW OF THE EORTC CENTRIC AND CORE STUDIES
Authors: Flies C M , Friedrich M , Lohmann P , van Garderen K , Smits M , Tonn J C , Weller M , Galldiks N , Snijders T J 
Published: October 2024

Abstract

BACKGROUND
Radiological progression during follow-up of patients with glioblastoma after treatment can result from progressive disease (PD) or treatment-associated changes such as pseudoprogression. Previous studies reported higher rates of treatment-associated changes in patients with an O6-methylguanine DNA methyltransferase (MGMT) promoter-methylated glioblastoma. We reviewed patients from two prospective, randomised EORTC studies with an MGMT promoter-methylated (CENTRIC) or -unmethylated (CORE) glioblastoma who were treated with standard temozolomide chemoradiation with or without the integrin inhibitor cilengitide. The addition of cilengitide did not improve survival. We previously reported on treatment-associated changes in the CENTRIC study. We now assessed the rate of treatment-associated changes for all patients in relation to the MGMT status, cilengitide exposure, and timing after radiotherapy.

MATERIAL AND METHODS
Patients with three or more MRI follow-up scans were included. We applied the modified RANO criteria of 2017. Preliminary PD (PPD) was defined as a 25% or more increase of the sum of perpendicular diameter (SPD) or a new or increasing contrast-enhancing lesion compared to baseline or nadir. Confirmed PD was defined as a further 25%- or more increase of the SPD or as a new lesion outside the radiation field. According to the RANO criteria 2.0 of 2023, we classified patients with PPD and no further follow-up due to clinical progression as PD. Treatment-associated changes were defined as stabilisation or partial/complete regression after PPD. Survival of patients with treatment-associated changes was compared to those with PD.

RESULTS
Follow-up was available for 424 patients from the CENTRIC and for 181 patients from the CORE study. PPD rates were 65% (274 of 424) in methylated tumours, and 86% (155 of 181) in unmethylated tumours. This resulted in treatment-associated changes in 32% (88 of 274) and 17% (27 of 155). Treatment-associated changes were more common in the first three months after radiotherapy (28% (CORE) and 54% (CENTRIC) of all PPD), in patients with tumours with MGMT promoter methylation (relative risk (RR), 1.8; 95%-confidence interval, 1.3-2.7; P=0.002), and after cilengitide (RR, 1.4; 95%-CI, 1.02-1.8; P=0.038). In addition, late treatment-associated changes after six months after radiotherapy were also observed (9% (CORE) and 13% (CENTRIC)). In both studies, patients with treatment-associated changes lived significantly longer than patients with PD (P=0.044 (CORE); P=0.003 (CENTRIC)).

CONCLUSION
The rate of treatment-associated changes varied with timing after radiotherapy, MGMT status and the addition of cilengitide. The role of integrins in the pathophysiology of treatment-associated changes needs to be elucidated further.
OS06.3.A EFFECT OF EARLY INTEGRATION OF PALLIATIVE CARE ON THE QUALITY OF LIFE IN GLIOBLASTOMA PATIENTS
Authors: Golla H , Nettekoven C , Hellmich M , Bausewein C , Thon N , Becker G , Schnell O , Rolke R , Clusmann H , Radbruch L , Herrlinger U , Vatter H , Neukirchen M , Sabel M , Civello D , Müller D , Brumbarova T , Voltz R , Goldbrunner R ,   EPCOG study group
Published: October 2024

Abstract

BACKGROUND
The disease course of glioblastoma (GB) patients is usually characterized by high symptom burden and short median survival (approx. 14 months). Nevertheless, they rarely receive specialized palliative care, especially in the early stage of the disease (early integration of palliative care, EIPC). The “Early Palliative Care for Patients with Glioblastoma” (EPCOG) study therefore aimed at investigating the impact of EIPC on quality of life (QoL) in this cohort of patients.

MATERIAL AND METHODS
Confirmatory, multicenter, single blinded, randomized, controlled clinical study. Patients with newly diagnosed/recurrent GB were randomly assigned to the control or interventional group. Patients in the interventional arm received proactive specialized palliative care (PC physician and PC social worker) on a monthly basis for 12 months. The control group received standard care. Data were collected by a blinded researcher every three months for 24 months. The primary outcome was QoL assessed by the sum of three subscales (trial outcome index, TOI) of the Functional Assessment of Cancer Therapy for brain tumor (FACT-Br) from baseline to six months of treatment.

RESULTS
556 patients were screened for eligibility, 231 patients were included in the study. 109 patients were treated in the intervention and 108 patients in the control group. Groups did not differ significantly in terms of age, gender or first/recurrent diagnosis. 34 patients were still alive after 24 months (intervention group: n=15, control group: n=19). 131 patients died during the study (intervention group: n=71, control group: n=60); without a statistically significant difference between groups. Within the intervention period, the TOI relative to the baseline tended to be better in the intervention group than in the control group, especially after three months. However, the difference was not statistically significant.

CONCLUSION
This is the first multicenter, randomized, confirmatory clinical trial to investigate the impact of EIPC on GB patients with an observation period long enough to realistically reflect the course of the disease. Despite the very vulnerable patient group, the study was even feasible with a higher number of patients than originally planned. The selected primary outcome parameter (TOI) included physical and functional, but not emotional and social factors, which may play a more important role in assessing QoL of GB patients.
OS06.9.A A PHASE 0/1 ‘TRIGGER’ TRIAL OF BDTX-1535 IN RECURRENT HIGH-GRADE GLIOMA (HGG) PATIENTS WITH EGFR ALTERATIONS OR FUSIONS
Authors: Sanai N , Umemura Y , Karapetyan V , Margaryan T , Huttenlocher D , Harmon J , Hong A , Yoo W , Tien A , Tovmasyan A , Mehta S 
Published: October 2024

Abstract

BACKGROUND
Alterations to epidermal growth factor receptor (EGFR) occur frequently in high-grade gliomas (HGG) and are critical to its pathogenesis. This Phase 0/1 study evaluates pharmacokinetic (PK), pharmacodynamic (PD), and clinical response to an ATP-competitive, irreversible EGFR inhibitor, BDTX-1535, in recurrent HGG patients with EGFR alterations and/or fusions.

MATERIALS/METHODS
Recurrent HGG patients with EGFR alterations (Arm A) or EGFR fusions (Arm B) received 5 days of BDTX-1535 at 200 mg/daily (cohort 1) or 400 mg/every other day (cohort 2) prior to planned resection at 2-4 hours following the final dose. In the Phase 0 component of the study, total and unbound drug concentrations were measured in tumor tissue (gadolinium (Gd) enhancing and non-enhancing regions), cerebrospinal fluid (CSF), and plasma using validated LC-MS/MS methods. A PK ‘trigger’, defined as unbound drug concentration above 1 nM and 4.1 nM in Gd non-enhancing tumor in patients with EGFR mutations and amplification, respectively, determined eligibility for Phase 1 therapeutic dosing. PD response was assessed by quantification of percentage of positive pEGFR, pERK and MIB-1 cells in the surgical tumor tissue compared to baseline pre-treatment tissue.

RESULTS
Eleven recurrent glioblastoma (GBM) patients were enrolled (Arm A, n=11; Arm B, n=0) and two were excluded from PK/PD analysis due to pseudoprogression. The mean unbound concentrations of BDTX-1535 in Gd non-enhancing tumor regions were 11.9 nM and 18.8 nM in cohorts 1 and 2, respectively. Eight of nine (88.9%) evaluable patients exceeded the PK threshold and qualified for Phase 1. Suppression of pEGFR and MIB1 was observed in 55% and 67% of patients, respectively. No serious adverse events related to BDTX-1535 were observed. Median progression-free and overall survival have not yet been reached.

CONCLUSIONS
BDTX-1535 is well-tolerated in recurrent GBM patients, achieves pharmacologically relevant concentrations in Gd non-enhancing tumor tissue and is associated with suppression of EGFR signaling. Clinical efficacy data accompanying this PK/PD response is maturing.