A meta-analysis and polygenic score study identifies novel genetic markers for waist-hip ratio in African populations.

OBJECTIVE: Understanding the genetic underpinnings of anthropometric traits in diverse populations is crucial for gaining insights into their biological mechanisms and potential implications for health. METHODS: We conducted a genome-wide association study, meta-analysis, and gene set analysis of waist-hip ratio (WHR), WHR adjusted for BMI (WHRadjBMI), waist circumference, BMI, and height using the African Collaborative Center for Microbiome and Genomics Research (ACCME) cohort (n = ~11,000) for discovery and polygenic score target analyses and the Africa America Diabetes Mellitus (AADM) study (n = ~5200) for replication and polygenic score validation. We generated and compared polygenic scores from European, African, Afro-Caribbean, and multiethnic ancestry populations. RESULTS: The top loci associated with each trait in the meta-analysis were in CD36 (rs3211826 [p = 5.90 × 10-12] for WHR and rs73709003 [p = 1.75 × 10-13] for WHRadjBMI), IFI27L1 (rs59775050 [p = 2.66 × 10-08] for waist circumference), INPP4B (rs2636629 [p = 1.44 × 10-09] for BMI), and HMGA1 (rs6937622 [p = 1.40 × 10-15] for height) gene regions. A novel variant rs7797157, near GNAT3, was also significantly associated with WHR (p = 2.50 × 10-10) and WHRadjBMI (p = 2.66 × 10-11). The ancestry-specific parameters for the best predictive polygenic scores were European ancestry (R2 = 0.68%; p = 1.63 × 10-16) and multiethnic ancestry (R2 = 0.06%; p = 1.29 × 10-02) for WHR; European ancestry (R2 = 1.36%; p = 2.94 × 10-31) and multiethnic ancestry (R2 = 1.12%; p = 3.52 × 10-25) for BMI; and European ancestry (R2 = 3.16%; p = 2.95 × 10-73), African ancestry (R2 = 4.16%; p = 1.75 × 10-96), and African and Afro-Caribbean ancestry (R2 = 2.67%; p = 4.35 × 10-62) for height. CONCLUSIONS: The discovery of a novel locus for WHR and genetic signals for each trait and the assessment of polygenic score performance underscore the importance of conducting well-powered studies in diverse populations.

Reduction in neurons immunoreactive for calcium-binding proteins in the anteroventral thalamic nuclei of individuals with Down syndrome.

The anterior thalamic nuclei are important for cognition, and memory in particular. However, little is known about how the anterior thalamic nuclei are affected in many neurological disorders partly due to difficulties in selective segmentation in in vivo scans, due to their size and location. Post-mortem studies, therefore, remain a valuable source of information about the status of the anterior thalamic nuclei. We used post-mortem tissue to assess the status of the anteroventral thalamic nucleus in Down syndrome using samples from males and females ranging from 22-65 years in age and comparing to tissue from age matched controls. As expected, there was increased beta-amyloid plaque expression in the Down syndrome group. While there was a significant increase in neuronal density in the Down syndrome group, the values showed more variation consistent with a heterogeneous population. The surface area of the anteroventral thalamic nucleus was smaller in the Down syndrome group suggesting the increased neuronal density was due to greater neuronal packing but likely fewer overall neurons. There was a marked reduction in the proportion of neurons immunoreactive for the calcium-binding proteins calbindin, calretinin, and parvalbumin in individuals with Down syndrome. These findings highlight the vulnerability of calcium-binding proteins in the anteroventral nucleus in Down syndrome, which could both be driven by, and exacerbate, Alzheimer-related pathology in this region.

Gadolinium Enhanced T2 FLAIR is an Imaging Biomarker of Radiation Necrosis and Tumor Progression in Patients with Brain Metastases.

BACKGROUND AND PURPOSE: Differentiating radiation necrosis (RN) from tumor progression (TP) after radiotherapy for brain metastases is an important clinical problem requiring advanced imaging techniques which may not be widely available and are challenging to perform at multiple time points. The ability to leverage conventional MRI for this problem, could have meaningful clinical impact. The purpose of this study was to explore contrast enhanced T2 FLAIR (T2FLAIRc) as a new imaging biomarker of RN and TP. MATERIALS AND METHODS: This single-institution retrospective study included patients with treated brain metastases undergoing DSC-MRI between January 2021 and June 2023. Reference standard assessment was based on histopathology or serial follow-up including results of DSC-MRI for a minimum of 6 months from the first DSC-MRI. The index test was implemented as part of the institutional brain tumor MRI protocol and preceded the first DSC-MRI. T2FLAIRc and gadolinium enhanced T1 MPRAGE (T1c) signal were normalized against normal brain parenchyma and expressed as z-score. Mean signal intensity of enhancing disease for RN and TP groups were compared using unpaired t-test. Receiver operator characteristic (ROC) curves and area under the ROC curve (AUC) were derived by bootstrapping. DeLong test was used to compare AUC. RESULTS: 56 participants (mean age, 62 years +/-12.7 [SD]; 39 females); 28 RN, 28 TP were evaluated. The index MRI was performed on average 73 days +/-34 [SD] before the first DSC-MRI. Significantly higher z-scores were found for RN using T2FLAIRc (8.3 versus 5.8, p<0.001) and T1c (4.1 versus 3.5, p=0.02). AUC for T2FLAIRc (0.83, 95% CI, 0.72-0.92) was greater than T1c (0.70, 95% CI, 0.560.83) (p = 0.04). The AUC of DSC derived rCBV (0.82, 95% CI, 0.70-0.93) was not significantly different from T2FLAIRc (p = 0.9). CONCLUSIONS: A higher normalized T1c and T2FLAIRc signal intensity was found for RN. In a univariable test, mean T2FLAIRc signal intensity of enhancing voxels showed good discrimination performance for distinguishing RN from TP. The results of this work demonstrate the potential of T2FLAIRc as an imaging biomarker in the work-up of RN in patients with brain metastases. ABBREVIATIONS: AUC = area under the receiver operating characteristic curve; RN = radiation necrosis; ROC = receiver operating characteristic; SRS = stereotactic radiosurgery; T1c = contrast enhanced T1; T2FLAIRc = contrast enhanced T2 FLAIR; TP = tumor progression.

Genetic Variations in TrkB.T1 Isoform and Their Association With Somatic and Psychological Symptoms in Individuals With IBS.

Irritable bowel syndrome (IBS), a disorder of gut-brain interaction, is often comorbid with somatic pain and psychological disorders. Dysregulated signaling of brain-derived neurotrophic factor (BDNF) and its receptor, tropomyosin-related kinase B (TrkB), has been implicated in somatic-psychological symptoms in individuals with IBS. We investigated the association of 10 single-nucleotide polymorphisms (SNPs) in the regulatory 3' untranslated region of neurotrophic receptor tyrosine kinase-2 (NTRK2) kinase domain-deficient truncated isoform (TrkB.T1) and BDNF Val66Met SNP with somatic and psychological symptoms and quality-of-life (QoL) in a cohort from the United States (IBS, n = 464; healthy controls, n = 156). We found that the homozygous recessive genotype (G/G) of rs2013566 in individuals with IBS is associated with worsened somatic symptoms, including headache, back pain, joint pain, muscle pain, and somatization as well as diminished sleep quality, energy level, and overall QoL. Validation using United Kingdom BioBank data confirmed the association of rs2013566 with an increased likelihood of headache. Several SNPs (rs1627784, rs1624327, and rs1147198) showed significant associations with muscle pain in our U.S. cohort. These 4 SNPs are predominantly located in H3K4Me1-enriched regions, suggesting their enhancer and/or transcription regulation potential. Our findings suggest that genetic variation within the 3' untranslated region region of the TrkB.T1 isoform may contribute to comorbid conditions in individuals with IBS, resulting in a spectrum of somatic and psychological symptoms impacting their QoL. These findings advance our understanding of the genetic interaction between BDNF/TrkB pathways and somatic-psychological symptoms in IBS, highlighting the importance of further exploring this interaction for potential clinical applications. PERSPECTIVE: This study aims to understand the genetic effects on IBS-related symptoms across somatic, psychological, and quality-of-life (QoL) domains, validated by United Kingdom BioBank data. The rs2013566 homozygous recessive genotype correlates with worsened somatic symptoms and reduced QoL, emphasizing its clinical significance.

No benefit from TMZ treatment in glioblastoma with truly unmethylated MGMT promoter: Reanalysis of the CE.6 and the pooled Nordic/NOA-08 trials in elderly glioblastoma patients.

BACKGROUND: The treatment of elderly/ frail patients with glioblastoma is a balance between avoiding undue toxicity, while not withholding effective treatment. It remains debated, whether these patients should receive combined chemo-radiotherapy with temozolomide (RT/TMZ→TMZ) regardless of the O6-methylguanine DNA methyltransferase gene promoter (MGMTp) methylation status. MGMT is a well-known resistance factor blunting the treatment effect of TMZ, by repairing the most genotoxic lesion. Epigenetic silencing of the MGMTp sensitizes glioblastoma to TMZ. For risk-adapted treatment, it is of utmost importance to accurately identify patients, who will not benefit from TMZ treatment. METHODS: Here, we present a reanalysis of the clinical trials CE.6 and the pooled NOA-08 and Nordic trials in elderly glioblastoma patients that compared RT to RT/TMZ→TMZ, or RT to TMZ, respectively. For 687 patients with available MGMTp methylation data, we applied a cutoff discerning truly unmethylated glioblastoma, established in a pooled analysis of 4 clinical trials for glioblastoma, with RT/TMZ→TMZ treatment, using the same quantitative methylation-specific MGMTp PCR assay. RESULTS: When applying this restricted cutoff to the elderly patient population, we confirmed that glioblastoma with truly unmethylated MGMTp derived no benefit from TMZ treatment. In the Nordic/NOA-08 trials, RT was better than TMZ, suggesting little or no benefit from TMZ. CONCLUSIONS: For evidence-based treatment of glioblastoma patients validated MGMTp methylation assays should be used that accurately identify truly unmethylated patients. Respective stratified management of patients will reduce toxicity without compromising outcomes and allow testing of more promising treatment options.

Impact of Implementing Serious Illness Conversations Across a Comprehensive Cancer Center Using an Interdisciplinary Approach.

BACKGROUND: Gaps in communication of end-of-life care preferences increase risk of patient harm. Adoption of oncology practice guidelines advocating serious illness communication for patients with advanced cancer is limited. OBJECTIVES: (1) Increase Serious Illness Conversation (SIC) use across oncology teams via an interdisciplinary quality improvement (QI) approach and (2) assess patient reported shared decision making (SDM) experiences with clinicians engaged in SIC implementation. DESIGN: QI methodology was applied to spread the implementation of SIC across 4 oncology teams. CollaboRATE scores were used to evaluate patient reported outcomes of SDM for patients with advanced cancer. SETTINGS/SUBJECTS: The SIC QI initiative was a component of the Promise Partnership Learning Health System (PPLHS) piloted in the Dartmouth Cancer Center, Lebanon, NH, USA. MEASUREMENTS: (1) The percentage of eligible patients with documented SIC and (2) a comparison of a patient reported measure of SDM (CollaboRATE) among SIC eligible patients in encounters with providers who took part in the implementation versus those who did not. RESULTS: Oncology teams screened a total of 538 patients, identified 278 eligible patients, and completed 144 SIC conversations. The teams improved the proportion of documented SIC among eligible patients from near 0% to a collective frequency of 52%. For clinicians' top-box CollaboRATE scores, a chi-squared test demonstrated a statistically significant association between providers implementing SIC into practice and patient reported shared decision making (.16, p = .031). CONCLUSIONS: This approach allows for tailoring of iterative improvement cycles to mitigate barriers and improve the practice of SIC among oncology teams.

An international multicenter cohort study on implantable cardioverter-defibrillators for the treatment of symptomatic children with catecholaminergic polymorphic ventricular tachycardia.

BACKGROUND: Catecholaminergic polymorphic ventricular tachycardia (CPVT) may cause sudden cardiac death (SCD) despite medical therapy. Therefore, implantable cardioverter-defibrillators (ICDs) are commonly advised. However, there is limited data on the outcomes of ICD use in children. OBJECTIVE: The purpose of this study was to compare the risk of arrhythmic events in pediatric patients with CPVT with and without an ICD. METHODS: We compared the risk of SCD in patients with RYR2 (ryanodine receptor 2) variants and phenotype-positive symptomatic CPVT patients with and without an ICD who were younger than 19 years and had no history of sudden cardiac arrest at phenotype diagnosis. The primary outcome was SCD; secondary outcomes were composite end points of SCD, sudden cardiac arrest, or appropriate ICD shocks with or without arrhythmic syncope. RESULTS: The study included 235 patients, 73 with an ICD (31.1%) and 162 without an ICD (68.9%). Over a median follow-up of 8.0 years (interquartile range 4.3-13.4 years), SCD occurred in 7 patients (3.0%), of whom 4 (57.1%) were noncompliant with medications and none had an ICD. Patients with ICD had a higher risk of both secondary composite outcomes (without syncope: hazard ratio 5.85; 95% confidence interval 3.40-10.09; P < .0001; with syncope: hazard ratio 2.55; 95% confidence interval 1.50-4.34; P = .0005). Thirty-one patients with ICD (42.5%) experienced appropriate shocks, 18 (24.7%) inappropriate shocks, and 21 (28.8%) device-related complications. CONCLUSION: SCD events occurred only in patients without an ICD and mostly in those not on optimal medical therapy. Patients with an ICD had a high risk of appropriate and inappropriate shocks, which may be reduced with appropriate device programming. Severe ICD complications were common, and risks vs benefits of ICDs need to be considered.

Predictors of Tumor Dynamics Over a 6-Week Course of Concurrent Chemoradiotherapy for Glioblastoma and the Effect on Survival.

PURPOSE: We present the final analyses of tumor dynamics and their prognostic significance during a 6-week course of concurrent chemoradiotherapy for glioblastoma in the Glioblastoma Longitudinal Imaging Observational study. METHODS AND MATERIALS: This is a prospective serial magnetic resonance imaging study in 129 patients with glioblastoma who had magnetic resonance imaging obtained at radiation therapy (RT) planning (F0), fraction 10 (F10), fraction 20 (F20), and 1-month post-RT. Tumor dynamics assessed included gross tumor volume relative to F0 (Vrel) and tumor migration distance (dmigration). Covariables evaluated included: corpus callosum involvement, extent of surgery, O6-methylguanine-DNA-methyltransferase methylation, and isocitrate dehydrogenase mutation status. RESULTS: The median Vrel were 0.85 (range, 0.25-2.29) at F10, 0.79 (range, 0.09-2.22) at F20, and 0.78 (range, 0.13-4.27) at 1 month after completion of RT. The median dmigration were 4.7 mm (range, 1.1-20.4 mm) at F10, 4.7 mm (range, 0.8-20.7 mm) at F20, and 6.1 mm (range, 0.0-45.5 mm) at 1 month after completion of RT. Compared with patients who had corpus callosum involvement (n = 26), those without corpus callosum involvement (n = 103) had significant Vrel reduction at F20 (P = .03) and smaller dmigration at F20 (P = .007). Compared with patients who had biopsy alone (n = 19) and subtotal resection (n = 71), those who had gross total resection (n = 38) had significant Vrel reduction at F10 (P = .001) and F20 (P = .001) and a smaller dmigration at F10 (P = .03) and F20 (P = .002). O6-Methylguanine-DNA-methyltransferase methylation and isocitrate dehydrogenase mutation status were not significantly associated with tumor dynamics. The median progression-free survival and overall survival (OS) were 8.5 months (95% CI, 6.9-9.9) and 20.4 months (95% CI, 17.6-25.2). In multivariable analyses, patients with Vrel ≥ 1.33 at F10 had worse OS (hazard ratio [HR], 4.6; 95% CI, 1.8-11.4; P = .001), and patients with dmigration ≥ 5 mm at 1-month post-RT had worse progression-free survival (HR, 1.76; 95% CI, 1.08-2.87) and OS (HR, 2.2; 95% CI, 1.2-4.0; P = .007). CONCLUSIONS: Corpus callosum involvement and extent of surgery are independent predictors of tumor dynamics during RT and can enable patient selection for adaptive RT strategies. Significant tumor enlargement at F10 and tumor migration 1-month post-RT were associated with poorer OS.

Marizomib for patients with newly diagnosed glioblastoma: A randomized phase 3 trial.

BACKGROUND: Standard treatment for patients with newly diagnosed glioblastoma includes surgery, radiotherapy (RT), and temozolomide (TMZ) chemotherapy (TMZ/RT→TMZ). The proteasome has long been considered a promising therapeutic target because of its role as a central biological hub in tumor cells. Marizomib is a novel pan-proteasome inhibitor that crosses the blood-brain barrier. METHODS: European Organisation for Research and Treatment of Cancer 1709/Canadian Cancer Trials Group CE.8 was a multicenter, randomized, controlled, open-label phase 3 superiority trial. Key eligibility criteria included newly diagnosed glioblastoma, age > 18 years and Karnofsky performance status > 70. Patients were randomized in a 1:1 ratio. The primary objective was to compare overall survival (OS) in patients receiving marizomib in addition to TMZ/RT→TMZ with patients receiving the only standard treatment in the whole population and in the subgroup of patients with MGMT promoter-unmethylated tumors. RESULTS: The trial was opened at 82 institutions in Europe, Canada, and the U.S. A total of 749 patients (99.9% of the planned 750) were randomized. OS was not different between the standard and the marizomib arm (median 17 vs. 16.5 months; HR = 1.04; P = .64). PFS was not statistically different either (median 6.0 vs. 6.3 months; HR = 0.97; P = .67). In patients with MGMT promoter-unmethylated tumors, OS was also not different between standard therapy and marizomib (median 14.5 vs. 15.1 months, HR = 1.13; P = .27). More CTCAE grade 3/4 treatment-emergent adverse events were observed in the marizomib arm than in the standard arm. CONCLUSIONS: Adding marizomib to standard temozolomide-based radiochemotherapy resulted in more toxicity, but did not improve OS or PFS in patients with newly diagnosed glioblastoma.

Impairments in the early consolidation of spatial memories via group II mGluR agonism in the mammillary bodies.

mGluR2 receptors are widely expressed in limbic brain regions associated with memory, including the hippocampal formation, retrosplenial and frontal cortices, as well as subcortical regions including the mammillary bodies. mGluR2/3 agonists have been proposed as potential therapeutics for neurological and psychiatric disorders, however, there is still little known about the role of these receptors in cognitive processes, including memory consolidation. To address this, we assessed the effect of the mGluR2/3 agonist, eglumetad, on spatial memory consolidation in both mice and rats. Using the novel place preference paradigm, we found that post-sample injections of eglumetad impaired subsequent spatial discrimination when tested 6 h later. Using the immediate early gene c-fos as a marker of neural activity, we showed that eglumetad injections reduced activity in a network of limbic brain regions including the hippocampus and mammillary bodies. To determine whether the systemic effects could be replicated with more targeted manipulations, we performed post-sample infusions of the mGluR2/3 agonist 2R,4R-APDC into the mammillary bodies. This impaired novelty discrimination on a place preference task and an object-in-place task, again highlighting the role of mGluR2/3 transmission in memory consolidation and demonstrating the crucial involvement of the mammillary bodies in post-encoding processing of spatial information.

Quantification of CD3, FoxP3, and granzyme B immunostaining in canine renal cell carcinoma.

Tumor-infiltrating lymphocyte (TIL) density plays an important role in anti-tumor immunity and is associated with patient outcome in various human and canine malignancies. As a first assessment of the immune landscape of the tumor microenvironment in canine renal cell carcinoma (RCC), we retrospectively analyzed clinical data and quantified CD3, FoxP3, and granzyme B immunostaining in formalin-fixed paraffin-embedded tumor samples from 16 dogs diagnosed with renal cell carcinoma treated with ureteronephrectomy. Cell density was low for all markers evaluated. Increased numbers of intratumoral FoxP3 labelled (+) cells, as well as decreased granzyme B+: FoxP3+ TIL ratio, were associated with poor patient outcomes. Our initial study of canine RCC reveals that these tumors are immunologically cold and Tregs may play an important role in immune evasion.

A universal biventricular coordinate system incorporating valve annuli: Validation in congenital heart disease.

Universal coordinate systems have been proposed to facilitate anatomic registration between three-dimensional images, data and models of the ventricles of the heart. However, current universal ventricular coordinate systems do not account for the outflow tracts and valve annuli where the anatomy is complex. Here we propose an extension to the 'Cobiveco' biventricular coordinate system that also accounts for the intervalvular bridges of the base and provides a tool for anatomically consistent registration between widely varying biventricular shapes. CobivecoX uses a novel algorithm to separate intervalvular bridges and assign new coordinates, including an inflow-outflow coordinate, to describe local positions in these regions uniquely and consistently. Anatomic consistency of registration was validated using curated three-dimensional biventricular shape models derived from cardiac MRI measurements in normal hearts and hearts from patients with congenital heart diseases. This new method allows the advantages of universal cardiac coordinates to be used for three-dimensional ventricular imaging data and models that include the left and right ventricular outflow tracts and valve annuli.

Lymph-node-targeted, mKRAS-specific amphiphile vaccine in pancreatic and colorectal cancer: the phase 1 AMPLIFY-201 trial.

Pancreatic and colorectal cancers are often KRAS mutated and are incurable when tumor DNA or protein persists or recurs after curative intent therapy. Cancer vaccine ELI-002 2P enhances lymph node delivery and immune response using amphiphile (Amph) modification of G12D and G12R mutant KRAS (mKRAS) peptides (Amph-Peptides-2P) together with CpG oligonucleotide adjuvant (Amph-CpG-7909). We treated 25 patients (20 pancreatic and five colorectal) who were positive for minimal residual mKRAS disease (ctDNA and/or serum tumor antigen) after locoregional treatment in a phase 1 study of fixed-dose Amph-Peptides-2P and ascending-dose Amph-CpG-7909; study enrollment is complete with patient follow-up ongoing. Primary endpoints included safety and recommended phase 2 dose (RP2D). The secondary endpoint was tumor biomarker response (longitudinal ctDNA or tumor antigen), with exploratory endpoints including immunogenicity and relapse-free survival (RFS). No dose-limiting toxicities were observed, and the RP2D was 10.0 mg of Amph-CpG-7909. Direct ex vivo mKRAS-specific T cell responses were observed in 21 of 25 patients (84%; 59% both CD4+ and CD8+); tumor biomarker responses were observed in 21 of 25 patients (84%); biomarker clearance was observed in six of 25 patients (24%; three pancreatic and three colorectal); and the median RFS was 16.33 months. Efficacy correlated with T cell responses above or below the median fold increase over baseline (12.75-fold): median tumor biomarker reduction was -76.0% versus -10.2% (P < 0.0014), and the median RFS was not reached versus 4.01 months (hazard ratio = 0.14; P = 0.0167). ELI-002 2P was safe and induced considerable T cell responses in patients with immunotherapy-recalcitrant KRAS-mutated tumors. ClinicalTrials.gov identifier: NCT04853017 .

Genome wide association joint analysis reveals 99 risk loci for pain susceptibility and pleiotropic relationships with psychiatric, metabolic, and immunological traits.

Chronic pain is at epidemic proportions in the United States, represents a significant burden on our public health system, and is coincident with a growing opioid crisis. While numerous genome-wide association studies have been reported for specific pain-related traits, many of these studies were underpowered, and the genetic relationship among these traits remains poorly understood. Here, we conducted a joint analysis of genome-wide association study summary statistics from seventeen pain susceptibility traits in the UK Biobank. This analysis revealed 99 genome-wide significant risk loci, 65 of which overlap loci identified in earlier studies. The remaining 34 loci are novel. We applied leave-one-trait-out meta-analyses to evaluate the influence of each trait on the joint analysis, which suggested that loci fall into four categories: loci associated with nearly all pain-related traits; loci primarily associated with a single trait; loci associated with multiple forms of skeletomuscular pain; and loci associated with headache-related pain. Overall, 664 genes were mapped to the 99 loci by genomic proximity, eQTLs, and chromatin interaction and ~15% of these genes showed differential expression in individuals with acute or chronic pain compared to healthy controls. Risk loci were enriched for genes involved in neurological and inflammatory pathways. Genetic correlation and two-sample Mendelian randomization indicated that psychiatric, metabolic, and immunological traits mediate some of these effects.

Vorasidenib in IDH1- or IDH2-Mutant Low-Grade Glioma.

BACKGROUND: Isocitrate dehydrogenase (IDH)-mutant grade 2 gliomas are malignant brain tumors that cause considerable disability and premature death. Vorasidenib, an oral brain-penetrant inhibitor of mutant IDH1 and IDH2 enzymes, showed preliminary activity in IDH-mutant gliomas. METHODS: In a double-blind, phase 3 trial, we randomly assigned patients with residual or recurrent grade 2 IDH-mutant glioma who had undergone no previous treatment other than surgery to receive either oral vorasidenib (40 mg once daily) or matched placebo in 28-day cycles. The primary end point was imaging-based progression-free survival according to blinded assessment by an independent review committee. The key secondary end point was the time to the next anticancer intervention. Crossover to vorasidenib from placebo was permitted on confirmation of imaging-based disease progression. Safety was also assessed. RESULTS: A total of 331 patients were assigned to receive vorasidenib (168 patients) or placebo (163 patients). At a median follow-up of 14.2 months, 226 patients (68.3%) were continuing to receive vorasidenib or placebo. Progression-free survival was significantly improved in the vorasidenib group as compared with the placebo group (median progression-free survival, 27.7 months vs. 11.1 months; hazard ratio for disease progression or death, 0.39; 95% confidence interval [CI], 0.27 to 0.56; P<0.001). The time to the next intervention was significantly improved in the vorasidenib group as compared with the placebo group (hazard ratio, 0.26; 95% CI, 0.15 to 0.43; P<0.001). Adverse events of grade 3 or higher occurred in 22.8% of the patients who received vorasidenib and in 13.5% of those who received placebo. An increased alanine aminotransferase level of grade 3 or higher occurred in 9.6% of the patients who received vorasidenib and in no patients who received placebo. CONCLUSIONS: In patients with grade 2 IDH-mutant glioma, vorasidenib significantly improved progression-free survival and delayed the time to the next intervention. (Funded by Servier; INDIGO ClinicalTrials.gov number, NCT04164901.).

Re-irradiation for recurrent high-grade glioma: an analysis of prognostic factors for survival and predictors of radiation necrosis.

PURPOSE: Recurrent high-grade glioma (rHGG) is a heterogeneous population, and the ideal patient selection for re-irradiation (re-RT) has yet to be established. This study aims to identify prognostic factors for rHGG patients treated with re-RT. METHODS: We retrospectively reviewed consecutive adults with rHGG who underwent re-RT from 2009 to 2020 from our institutional database. The primary objective was overall survival (OS). Secondary endpoints included prognostic factors for early death (< 6 months after re-RT) and predictors of radiation necrosis (RN). RESULTS: For the 79 patients identified, the median OS after re-RT was 9.9 months (95% CI 8.3-11.6). On multivariate analyses, re-resection at progression (HR 0.56, p = 0.027), interval from primary treatment to first progression ≥ 16.3 months (HR 0.61, p = 0.034), interval from primary treatment to re-RT ≥ 23.9 months (HR 0.35, p < 0.001), and re-RT PTV volume < 112 cc (HR 0.27, p < 0.001) were prognostic for improved OS. Patients who had unmethylated-MGMT tumours (OR 12.4, p = 0.034), ≥ 3 prior systemic treatment lines (OR 29.1, p = 0.022), interval to re-RT < 23.9 months (OR 9.0, p = 0.039), and re-RT PTV volume ≥ 112 cc (OR 17.8, p = 0.003) were more likely to die within 6 months of re-RT. The cumulative incidence of RN was 11.4% (95% CI 4.3-18.5) at 12 months. Concurrent bevacizumab use (HR < 0.001, p < 0.001) and cumulative equivalent dose in 2 Gy fractions (EQD2, α/ß = 2) < 99 Gy2 (HR < 0.001, p < 0.001) were independent protective factors against RN. Re-RT allowed for less corticosteroid dependency. Sixty-six percent of failures after re-RT were in-field. CONCLUSION: We observe favorable OS rates following re-RT and identified prognostic factors, including methylation status, that can assist in patient selection and clinical trial design. Concurrent use of bevacizumab mitigated the risk of RN.