tbuckley/cabot-search huggingface dataset:
NCMP-10. EFFECT OF EXTENT OF RESECTION ON GLIOMA SEIZURE OUTCOMES BASED ON MOLECULAR GROUPS
Authors: Emily Xu, Zachary Gersey, Jonathan Sussman, Nduka Amankulor
Journal: Neuro-Oncology (2024)

Abstract INTRODUCTION Increased extent of resection (EOR) is a known predictor of seizure freedom in glioma patients. However, it is unknown how tumor genomic alterations affect EOR-induced seizure control. OBJECTIVE To evaluate the genotype-specific impact of EOR on post-operative seizure control METHODS Records of 553 glioma patients who underwent tumor resection from 2012-2023 were reviewed. All patient tumors were analyzed with next generation sequencing and FISH analysis. The unsupervised machine learning algorithm non-negative matrix factorization (NMF) was used to cluster the genomic data. Clinical variables including extent of resection of contrast enhancing tumor and non-enhancing tumor, temozolomide therapy, and radiation therapy were analyzed using Cox Proportional Hazards models. RESULTS NMF clustering of tumor sequencing data revealed four molecular groups: Group 1 (n=56): CDKN2a loss, EGFR copy number gain or mutation, TERT promoter (TERTp) mutation, and MGMT methylated; Group 2 (n=27): IDH mutation, TP53 mutation, and MGMT methylated; Group 3 (n=60): TP53 mutation, TERTp mutation and MGMT methylated; Group 4 (n=244): MGMT unmethylated. Thresholds in the post-operative residual non-enhancing tumor volume (NETV) were identified which marked the most difference in seizure control. For patients in Group 1, the NETV threshold that led to improved epilepsy outcomes was &amp;lt;94.7 cc (p=0.047), whereas the threshold for Group 4 was &amp;lt;89.1 cc (p=0.016). When analysis was conducted for Group 2, the threshold of 10.2 cc failed to reach significance (p=0.1). Interestingly, the threshold analysis for Group 3 found that having a NETV of &amp;gt; 10.1 cc showed improved seizure outcomes (p=0.016). A multivariable cox proportional hazard analysis found that twelve-month seizure freedom was predictive of better OS in group 1 (HR 0.02, p=0.05) and group 4 (HR 0.21, p=1.63e-9). CONCLUSION Our study reveals clinically distinct molecular groups of glioma that display different seizure responses. This data suggests a tumor-specific approach to aggressiveness of extent of resection in order to achieve optimal seizure control.
CTNI-01. INTERVENTION OUTCOMES OF ENHANCED RECOVERY AFTER SURGERY PROTOCOL VERSUS STANDARD CARE FOR GLIOMA PATIENTS IN SELECTED HOSPITALS IN DEMOCRATIC REPUBLIC OF THE CONGO: RANDOMIZATION AND STRATIFICATION OF PROVIDERS AND HOSPITALS
Authors: Larrey Kasereka Kamabu
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Enhanced Recovery after Surgery (ERAS) protocols have shown promise in improving perioperative care and patient outcomes in various surgical specialties. Aim: This study will aim to assess the efficacy of ERAS compared to the current standard of care (SOC) for glioma patients in DRC hospitals. METHODS A pragmatic, multicenter, randomized controlled trial will be designed to evaluate the outcomes of glioma patients treated with ERAS protocols versus SOC in selected hospitals in DRC. EXPECTED RESULTS A total of 100 glioma patients will be included in this study, with 50 patients in the ERAS group and 50 in the SOC group. The primary analysis will reveal that the ERAS group will have significantly fewer post-operative complications (p &amp;lt; 0.05) and a shorter length of hospital stay (p &amp;lt; 0.05) compare to the SOC group. Patient satisfaction scores will also higher in the ERAS group. Subgroup analyses by hospital center will indicate consistent trends in favor of the ERAS protocol. Randomization of providers and stratification by hospital will aim to mitigate the influence of individual provider practices and hospital-specific factors on the study outcomes. This approach will be expected to enhance the validity of the results and ensure equitable representation across hospitals. CONCLUSIONS The unique design of randomizing providers and stratifying by hospital will be a critical component of this multicenter trial, which seeks to provide valuable insights into the potential benefits of ERAS protocols for glioma patients in DRC. The findings will guide clinical practice and healthcare policy in resource-constrained settings, ultimately improving the care and outcomes of glioma patients
CTNI-14. RADIOTHERAPY VERSUS TMZ FOR HIGH-RISK LOW-GRADE GLIOMA. FINAL RESULTS AFTER MEDIAN FOLLOW-UP OF 13 YEARS OF PHASE III EORTC/NCIC-CTG/TROG/MRC-CTU (EORTC 22033-26033) STUDY
Authors: Brigitta G Baumert, Monika E Hegi, Martin Van den Bent, Andreas von Deimling, Thierry Gorlia, Khe Hoang-Xuan, Alba A Brandes, Paul Sargos, Martin Taphoorn, Elodie Vauleon, Claire Phillips, Johan M Kros, Pierre Bady, Wolfgang Wick, Roelien Enting, Michele Reni, Brian Thiessen, Frederic Dhermain, Jacoline Bromberg, Julian Jacob, Jaap C Reijneveld, Olivier Chinot, Anja Gijtenbeek, John Rossiter, Marie-Ange Lentz, Carmen Balana, Ana Luisa Silva Azevedo, Paul M Clement, Anna Berghoff, Tzahala Tzuk, Michael Weller, Robert Nordal, Jeremy Rees, Denis Lacombe, Warren P Mason, Roger Stupp
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND We previously reported on progression-free survival of our randomized phase 3 trial [Lancet Oncol. 2016;17:1521-1532]. Here we report results of long-term follow-up (FU) including overall survival (OS) and molecular subgroup analyses. METHODS 487 patients were randomized between 2005-2012 to either standard radiotherapy (RT, 50.4 Gy/ 28 fractions) or primary dose-dense temozolomide [TMZ] chemotherapy (75 mg/m² daily x 21/28 days, up to 12 cycles). Treatment at progression was at investigators discretion and commonly included cross-over to the alternative treatment modality. RESULTS At a median follow-up of 13 years, 68% of patients had died. Median age at inclusion was 45 years (range 18-75), 96% had a performance status of 0-1. There was no significant difference in PFS nor OS: PFS was 3.6 years (95% CI: 3.0-4.1) and 3.1 years (95% CI: 2.7-3.6), HR 1.12 (95% CI: 0.92-1.36); OS 6.6 years (95% CI: 5.8-7.5) and 8.0 years (95% CI: 6.9-9.1), HR 0.87 (95% CI: 0.69-1.09), for RT or TMZ, respectively. Subgroup analyses were performed for patients when available tissue allowed for molecular analyses (n=351/487,73%). In astrocytoma, IDHmt/1p/19q non-codeleted (n = 178), median OS with RT was 6.6 years (95% CI: 5.3-7.6) and with TMZ was 6.7 years (95% CI: 5.7-8.0); HR 0.98 (95% CI: 0.67-1.44). For oligodendroglioma, IDHmt/codeleted (n = 109) median OS with RT was 12.9 years (95% CI: 9.4 - NE) and with TMZ 14.9 years (95% CI: 10.1 - NE); HR 1.01 (95% CI: 0.56-1.81). For a heterogenous group of IDHwt tumors (n = 64), median OS with RT was 2.5 years (95% CI: 1.8-3.3) and with TMZ 4.7 years (95% CI: 2.2-7.2); HR 0.37 (95% CI: 0.18-0.77). CONCLUSIONS Primary treatment with RT or TMZ provided comparable PFS and OS. Choice of primary treatment can be tailored to individual tumor characteristics and patient preference.
RADT-19. PILOT STUDY OF VELOCITY-SELECTIVE ARTERIAL SPIN LABEL MRI (VSASL-MRI) DERIVED RELATIVE CEREBRAL BLOOD FLOW TO DISTINGUISH IMAGING CHANGES AFTER RADIOSURGERY (SRS) FROM PROGRESSIVE BRAIN METASTASIS (BM)
Authors: Dan Zhu, Feng Xu, Dapeng Liu, Lisa Katulis, Doris Lin, Lawrence Kleinberg
Journal: Neuro-Oncology (2024)

Abstract Management of imaging progression on standard contrast enhanced MRI (cMRI) after SRS for brain metastasis is challenging as treatment effect/necrosis appears similar to progressive tumor. VSASL-MRI uses water labeled based on velocity, rather than spatial location, as an endogenous contrast agent and is therefore insensitive to transit delay impacting other ASL-MRI techniques. Other advantages include no IV contrast, limited susceptibility artifact, and absence of confounding leakage of gadolinium contrast into tissues. VSASL-MRI was performed (median 15 (4-123) months after SRS) to evaluate SRS treated solid tumor BM with clinician determined imaging progression on cMRI to evaluate the hypothesis that VSASL-MRI may distinguish biologic tumor (hyperperfused compared with normal brain) from treatment effect/necrosis (hypoperfused). 17 patients (19 progressing lesions) were enrolled. 13/19 index lesions had hypoperfusion. Of these, 3/13 had resection with no tumor present, 8/13 were conservatively managed and appeared to be treatment effect/necrosis as they stabilized or improved on follow-up cMRI without further BM directed intervention, and 2/13 had resection for further progression with active tumor present. For 6 index lesions that were hyperperfused: 3/6 had pathology were confirmed to be tumor, whereas the other 3/6 continued to progress (one got additional RT, two expired with progression). In addition, two pts had concurrent identification of new non-index previously untreated lesions on cMRI that were hyperperfused on VSASL-MRI and were treated. One of these patients had subsequent VSASL-MRI demonstrating post-SRS resolution of perfusion 2 months after treatment. This pilot data supports the hypothesis that VSASL-MRI may be useful in distinguishing tumor progression from radiation related imaging changes and/or be an early biomarker of radiosurgery response. We are initiating further study (1R01CA282928-01, PI; Qin) to refine the technique and prospectively assess the value of this approach in a larger number of patients.
CTNI-18. RESULTS FROM A PHASE 1 STUDY OF SONODYNAMIC THERAPY WITH WHOLE HEMISPHERIC LOW INTENSITY NON-ABLATIVE ULTRASOUND IN PATIENTS WITH RECURRENT HIGH GRADE GLIOMA
Authors: Michael Schulder, Tanner Johans, Laszlo Mechtler, Vijay Agarwal
Journal: Neuro-Oncology (2024)

Abstract We report the first use of a novel device that delivers non-ablative low intensity diffuse ultrasound (LIDU) across the entire hemisphere in combination with the oral sonosensitizing agent 5-ALA for the treatment of recurrent high grade glioma. LIDU in combination with 5-ALA focally targets tumor cells with sonodynamic therapy (SDT), causing selective tumor cell death across the entire hemisphere via 1) direct tumor targeting and 2) stimulation of immunogenic cell death. In this 3x3 clinical trial designed for safety (n=12, NCT05362409), two patients were enrolled after multiple recurrences and seven patients had multifocal or multicentric disease. Treatments were delivered monthly for a minimum of four sessions. A treatment duration of 120 minutes was established after dose escalation and expansion. SDT delivered via a novel device and in conjunction with 5-ALA was well tolerated, with no duration-limiting toxicities or serious related adverse events. Compared to historical data, we observed a significant increase in overall survival (mOS of 14.0+ months, with 7 of 12 patients still alive at the time of this submission and final median OS not yet achieved). A Phase 2b randomized, multicenter, double-blind, placebo-controlled study has been planned to commence in 2025 to assess the safety and efficacy of LIDU with sonosensitization in patients with newly diagnosed GBM.
TMOD-28. MODELING MICROENVIRONMENTAL DYNAMICS: A NOVEL 3D GLIOMA-NEURON FUSION MODEL
Authors: Sena Oten, Saritha Krishna, Thiebaud Picart, Andy Daniel, Cesar Nava Gonzales, Katie Lu
Journal: Neuro-Oncology (2024)

Abstract Gliomas engage in bidirectional interactions with their microenvironment, wherein neuronal activity influences glioma proliferation and gliomas induce neuronal hyperexcitability. Although various models elucidate this complex interplay, a preference for a three-dimensional (3D) cell culture model has emerged to mimic intra-tumoral heterogeneity and microenvironmental interactions influencing glioma invasion, resistance, and recurrence. This study introduces an in vitro, self-assembled, scaffold-free, neuron-glioma spheroid fusion model to investigate the electrophysiological and functional interplay between glioma and its microenvironment. Primary mouse cortical neurons (MCN) were isolated from prenatal brain tissues and were cultured at 500,000 cells/spheroid on ultra-low attachment plates. Glioma organoids (WHO Grade 2-4) were developed from primary patient-derived tissue samples and were allowed to self-assemble for at least two weeks. After spontaneous spiking activity was detected in MCN spheroids, they were combined with glioma organoids in culture and allowed to fuse. A multielectrode array (MEA) was used to characterize the electrophysiological properties of the fusion model. Structural and functional characterizations were performed using immunofluorescence staining of proliferation, microglial, astrocytic, synaptic, and tumor markers. Additionally, the electrophysiological effects of the dual-IDH-mutant inhibitor, Vorasidenib, were assessed in WHO grade 2-4 IDH-mutant gliomas. Electrophysiological analysis of glioma-neuron co-cultures using MEA demonstrated a significantly increased network synchrony and firing rate in the fusion model when compared with the neuron-only condition, consistent with 2D models in the past. In correlation, the fusion model also demonstrated a significant increase in the Ki67 proliferation index across WHO grade 2-4 gliomas when compared to the glioma organoid-only condition. Vorasidenib treatment decreased neuronal firing rate and synchrony. Together, these results offer a high-throughput 3D model for recapitulating the tumor-brain microenvironment for both low and high-grade gliomas. Future studies will focus on the use of this model for drug screening and the exploration of malignant transformation in gliomas.
CTNI-73. ASSESSMENT OF MOLECULAR ALTERATIONS IN NEWLY DIAGNOSED GBM MGMT-UNMETHYLATED PATIENTS TREATED WITH VAL-083
Authors: Carlos Kamiya-Matsuoka, Shaio-Pei Weathers, Alfred Yung, Monica Login, Nazanin Majd, Dennis Brown, John Langlands, Richard Schwartz, Stephanie Knight, Vinay Puduvalli, John de Groot, Barbara O’Brien
Journal: Neuro-Oncology (2024)

Abstract Glioblastoma (GBM) commonly features molecular alterations in the TERT, EGFR, PTEN, and TP53 genes, which contributes to uncontrolled cell growth, evasion of apoptosis, and enhanced tumor cell survival. VAL-083 is a bi-functional DNA-targeting agent which rapidly induces inter-strand DNA cross-links at N7 and O6-guanine inducing double-strand breaks causing cell death independently of MGMT DNA repair and DNA mismatch repair deficiency. VAL-083 was evaluated in an open-label, biomarker-driven, phase 2 trial in MGMT-unmethylated, bevacizumab-naïve GBM patients. The molecular profile of tumors from a newly diagnosed GBM patient subgroup who received VAL-083 alone after chemo-radiation with concurrent TMZ, was determined in order to correlate with clinical outcomes. Thirty-four (34/36, 94.4%) patients who received 30 mg/m2 VAL-083 (days 1-3 of 21-day cycle) had available next-generation sequencing data on their primary tissue. Patient median age was 54.8 years (5-95pth: 29.8-66.0), median KPS was 90 (5-95pth: 80-100) and 58.8% were males. The median number of cycles of VAL-083 was 7.5 (5-95pth: 1-12). There were 5 dose reductions due to toxicity. The median time to progression (PFS) and overall survival (OS) were 9.2 mo (95%CI: 7.6-10.2) and 16.5 mo (95%CI: 13.3-19.0), respectively. The mean number of molecular alterations was 3.9 (5-95pth 1-8). Six (17.6%) patients had gene fusions. The most common molecular alterations were TERT promoter (91.2%), EGFR amplification (amp) (52.9%), PTEN (50.0%), EGFR (20.6%), and TP53 (20.6%). Additional alterations (in ≥2 patients; 6%) included EGFR-EGFR (EGFRvIII), BRCA2, CDKN2A/B, CDK4/6 amp, MDM2/4 amp, NF1, NOTCH1, PIK3R1 and RB1. While TP53 mutations showed a trend as predictors for time to progression (P 0.027), this was not observed with OS. None of the molecular alterations were predictors of number of treatment cycles or dose reductions. No specific molecular alterations were identified that predicted either improved or poorer patient outcome, during treatment with VAL-083. Clinicaltrials.gov identifier: NCT02717962.
CTNI-70. RESULTS FROM THE PHASE 1 AND PHASE 1 EXPANSION COHORTS OF SJ901: A PHASE 1/2 TRIAL OF SINGLE-AGENT MIRDAMETINIB (PD-0325901) IN CHILDREN, ADOLESCENTS, AND YOUNG ADULTS WITH LOW-GRADE GLIOMA
Authors: Giles Robinson, Anna Vinitsky, Asim Bag, Jason Chiang, Qian Li, Tong Lin, Mary Ellen Hoehn, Angela Edwards, Diana Storment, Anjali Singh, Jennifer Larkin, Jana Freeman, Johanna Pranica, Kelsey Bertrand, Aditi Bagchi, Ibrahim Qaddoumi, Daniel Moreira, Todd Baughman, Thuy Hoang, Todd Shearer
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Mirdametinib is an investigational, oral, selective MEK1/2 inhibitor (MEKi) with high blood-brain-barrier penetration. We hypothesized that mirdametinib would benefit patients with pediatric low-grade gliomas (pLGG) and launched SJ901 (NCT04923126) to determine the recommended Phase 2 dose (RP2D), safety, and efficacy. METHODS For Phase 1 and Phase 1 expansion patients were required to be ≥2 and &amp;lt;25 years-old, MEKi-naive, and have recurrent/progressive pLGG with biopsy-proven MAPK pathway activation (except BRAF V600). Three dose levels (DL1: 2 mg/m2/dose BID, DL2: 2.5mg/m2/dose BID, DL3: 3mg/m2/dose BID administered continuously in 28-day cycles) were evaluated with an expansion cohort to assess the highest tolerated dose level in a total of 12 patients. RP2D was defined as the dose causing ≤3 dose-limiting toxicities (DLTs) in 12 patients within the first cycle of therapy. RESULTS Between June 2021 and December 2023, 23 patients enrolled (DL1=5, DL2=6, and DL3=12). Median age was 8.4 years (2.5-21.9); 52% female. Alterations were seen in BRAF (n=12;52%), FGFR1 (n=5;22%), NF1 (n=3;13%), RAF1 (n=2;9%), and MYB (n=1;4%). The median follow-up time was 14.6 months (3.2-27.8). One DLT was observed (grade-3 thrombocytopenia). Seventeen (74%) patients completed or remain on-therapy; 4(17%) stopped for progression (2 FGFR1; 1 MYB; 1 BRAF); 2 discontinued for toxicities [1 grade-2 rash; 1 grade-4 creatine phosphokinase (CPK) elevation]. Dose modifying adverse events included weight gain, CPK elevations, and rash. No significant cardiac or retinal toxicity was observed. Twelve (63%) of 19 patients with measurable tumors achieved an objective response (1 major, 6 partial, 5 minor). The median time to ≥ minor response was 5.4 months (1.7-7.3). DL3 (3 mg/m2/dose BID) was declared the RP2D. CONCLUSIONS Mirdametinib is well-tolerated and has promising clinical activity in patients with recurrent/progressive pLGG. Phase 2 is ongoing to establish safety and efficacy in newly diagnosed, recurrent/refractory tumors, and in patients with prior MEKi exposure.
DDDR-39. PI3 KINASE AND CHECKPOINT INHIBITION: A POTENTIALLY NOVEL THERAPEUTIC STRATEGY FOR GLIOBLASTOMA (GBM)
Authors: Ali Jalali, Abu Bakar Siddik, Kwanhu Yu, Richard P Tobin, Charles E Hay, Folefac Aminkeng, Ekokobe Fonkem, M Karen Newell-Rogers
Journal: Neuro-Oncology (2024)

Abstract Glioblastoma is the most common and aggressive malignant brain tumor with a median survival of less than 2 years, highlighting the need for more effective therapeutics. Dual pathway synergism between PI3K inhibitors and check-point inhibitors is a promising therapeutic avenue that has not been explored. Based on this possibility, we hypothesized that the combination of PI3K and checkpoint inhibitors will improve survival in our native glioblastoma mouse model. Treatment with GCT-007, a small molecule PI3K inhibitor, induces growth arrest of GBM cells that is accompanied by increases in the cell surface expression of molecules targeted by the immune system and immunotherapy drugs, including MHC Class II and PD-L1. Treatment of mouse GL261 and human U251 GBM cell lines with GCT-007 caused growth arrest, increased the cell surface expression of PD-L1 and MHC class II, and synergized with radiation to cause growth arrest and cell death. We compared GCT-007 to Paxalisib in our in vitro studies and observed that GCT-007 outperformed Paxalisib at increasing MHC class II and PD-L1 expression on the tumor cells at equivalent doses. We then performed in vivo animal studies using our native mouse GBM model. We treated mice orally with GCT-007 and observed a significantly prolonged survival compared to placebo. Mice treated with anti-PD1 resulted in a sexually dimorphic response consisting of prolonged remission of all female mice, now surviving beyond 1 year, but no improvement in the survival of male mice compared to placebo. Adding GCT-007 to anti-PD1 did not alter the prolonged remission outcome in female mice, it did result in prolonged remission of 25% of the male mice, now beyond 1 year. In conclusion, these results indicate that GCT-007 treatment alone improves survival in our native GBM mouse model and it may also improve the response to immune checkpoint inhibitor therapy in at least a fraction of GBM tumors. These data warrant further investigation as a potentially novel therapeutic approach to GBM.
INNV-15. A PIVOTAL, MULTICENTER TRIAL OF FOCUSED ULTRASOUND FOR BLOOD-BRAIN BARRIER DISRUPTION FOR PLASMA-BASED LIQUID BIOPSY IN PATIENTS WITH GLIOBLASTOMA (LIBERATE)
Authors: Manmeet Ahluwalia, Ahmad Ozair, Terence Burns, Michael McDermott, Arjun Sahgal, John DeGroot, Alon Mogilner, Matthew Hibert, Julia Zhu, Bhavya Shah, Toral Patel, Jordina Rincon-Torroella, Mark Mishra, Richard Everson, Justin Sporrer, Justin Hilliard, Yarema Bezchlibnyk, Jeffrey Weinberg, Christopher Cifarelli, Ali Rezai, Nir Lipsman, Graeme Woodworth
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Liquid biopsy in glioblastoma (GBM) is hindered by insufficient requisite circulating-tumor (ct) and cell-free (cf) DNA in blood due to blood-brain barrier (BBB). This limits the identification of blood-based tumor biomarkers along with biomarker-driven systemic therapies. Real-time image-guided low-intensity focused ultrasound (LIFU) plus IV microbubble oscillators, leads to non-invasive BBB disruption. METHODS LIBERATE is an ongoing, prospective, multi-center, self-controlled, pivotal trial investigating safety and technical efficacy of LIFU-based BBB disruption for increasing blood ctDNA and cfDNA levels in adult GBM patients (aged 18-80 years). Patients with suspected GBM planned for biopsy/resection at ten US centers are being enrolled. Patients with multifocal tumors or tumors arising from deep midline, thalamus, cerebellum, or brainstem are excluded. Patients are administered IV microbubbles for enhanced sonication effects, after which MR-guided BBB disruption using 220kHz LIFU device is performed with real-time acoustic-feedback-control for effective microbubble activation. Pre- and post-LIFU, phlebotomy and MRI brain are performed. Primary study endpoint is defined, per subject, as ratio between their blood cfDNA level 1-hour post-LIFU procedure compared to blood cfDNA pre-procedure. Primary study hypothesis is that BBB disruption leads to ≥2-fold rise in blood cfDNA. Secondary hypothesis is that there exists ≥75% agreement between biomarker pattern in blood cfDNA sample obtained 1-hour post-LIFU and biomarker pattern in tumor tissue obtained later. Trial is powered to evaluate both primary and secondary hypotheses. Based on assumed true agreement rate of 91% and one-sided alpha=0.025, an exact test for binomial proportions provides N=50 with 84% power for secondary hypothesis. Exploratory endpoints include (1) sensitivity of detection of specific somatic mutations in ctDNA from blood collected pre- and post-LIFU, (2) ctDNA estimation in samples collected at 30-minutes, 1-hour, 2-hour, and 3-hour post-LIFU to determine time of greatest yield, (3) correlation of MRI parameters related to grading of BBB disruption and ctDNA-based biomarkers from post-LIFU blood samples. Patient enrollment commenced in 2022 and remains ongoing (NCT05383872).