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Background: Individual symptoms are predictors of mortality in adults with heart failure (HF). However, symptom clusters may be more predictive of future risks than isolated symptoms, yet research on these symptom clusters in older adults with HF is limited. Aims: To explore the extent to which symptom cluster profiles predict all-cause mortality among community-dwelling older adults with HF, while adjusting for known risk factors. Methods: We conducted a secondary analysis of data of the 2008 to 2016 surveys of the U.S. Health and Retirement Study using latent class analysis to identify baseline cluster profiles, and survival analysis for time to death with Cox proportional hazard (Cox PH) models, and Kaplan Meier survival analyses. Results: We included 684 participants [mean age=74.9, (SD=10) years, 56.6% female, 16.2% Black/African American]. Three baseline symptom cluster profiles were identified: high-burden (pain, shortness of breath, fatigue, swelling, depressive symptoms, dizziness), low-burden, and cardiopulmonary-depressive (shortness of breath, pain, and dizziness). The estimated median time-to-death was 71 (95% CI=64, 79) months. Of the 364 participants in the cardiopulmonary-depressive profile, 240 (65.9%) died (median time= 65 months, 95% CI= 55, 73) compared to those in the low-burden profile, of which 49% died. Approximately 61% in the high burden profile died (median time=67 months, 95% CI= 51, 90). A significant difference in survival times between the 3 cluster profiles was found (Log-rank= 9.13, p = 0.01). In the adjusted Cox PH model, participants in the high symptom burden and respiratory-depressive distress profiles had adjusted HR of 1.48 (95% CI=1.15, 1.94) and 1.44 (95% CI=1.14, 1.80) compared to those in the low burden symptom cluster profile, after controlling for age, gender, smoking, and comorbidities. Conclusions: The identified symptom cluster profiles predict 8-year all-cause mortality in older adults with HF, after controlling for known risk factors. An evaluation of symptom clusters, rather than individual symptoms, may provide additive prognostic information.

The NCCN Guidelines for the Management of Immunotherapy-Related Toxicities are intended to provide oncology practitioners with guidance on how to manage the wide-ranging and potentially fatal toxicities that may occur with cancer immunotherapy. The guidelines address immune-related adverse events related to immune checkpoint inhibitors, CAR T-cell therapies, and lymphocyte engagers (which include T-cell–engaging bispecific antibodies). These NCCN Guidelines Insights highlight recent guideline updates pertaining to the management of emerging toxicities related to cancer immunotherapy.

Abstract Targeted gene expression profiling improves risk stratification for meningiomas, but the utility of this approach for low grade meningiomas is incompletely understood. To address this, 466 meningiomas that were initially used to validate a 34-gene expression biomarker were combined with 270 previously unpublished samples for an analysis of biomarker performance in newly diagnosed (n=691) or recurrent (n=45) WHO grade 1 meningiomas treated with gross total (GTR) or subtotal resection (STR), and newly diagnosed WHO grade 2 meningiomas treated with GTR. Prediction of local freedom from recurrence (LFFR) or overall survival (OS) was measured using Cox proportional hazards models and the Kaplan-Meier method. The cohort included 736 patients, 69.4% female, with a median age at diagnosis of 58 years. There were 635 WHO grade 1 meningiomas, 498 with GTR and 133 with STR, and 101 WHO grade 2 meningiomas with GTR. The median follow-up was 4.6 years, the local recurrence rate was 12.0% and the rate of death was 8.4%. The biomarker classified 51.5% of meningiomas as intermediate risk and 9.6% as high risk. Combining the biomarker with extent of resection identified 19.7% as unfavorable (intermediate molecular risk with STR or high molecular risk), including 7.4% of newly diagnosed WHO grade 1 meningiomas with GTR. The risk score was prognostic for LFFR overall (hazard ratio per 0.1 increase in risk score 1.89, 95% confidence interval 1.58-2.25) and across WHO grades, extents of resection, and newly diagnosed or recurrent settings. Gene expression risk groups were prognostic for LFFR, with improved outcomes among low molecular risk compared to intermediate molecular risk (Log-rank, p=0.0002) and high molecular risk meningiomas (Log-rank, p<0.0001). These data suggest that a targeted gene expression biomarker can identify low grade meningiomas that are more likely to recur after surgery, possibly changing management for approximately one-fifth of cases.

Abstract Acquired tumor alterations are part of the WHO diagnosis of glioma. However, germline predisposition to these alterations is unknown. GWAS in European and Asian populations identified germline variants in 30 regions, many in or near genes that also acquire alterations, suggesting that interactions between inherited and acquired genetics are involved in glioma development. To evaluate such interactions, we used 3686 glioma cases and 1889 controls. A case-control design and multinomial logistic regression were used to identify germline variants associated with development of TERT-promoter mutant gliomas, generating two interesting observations. First, TERT germline variants were associated with predisposition to IDHwt glioma that have a TERT promoter mutation, but not with IDH-mutant codeleted gliomas that have a TERT promoter mutation. Second, two novel regions were observed in this more homogeneous subgroup of TERT mutated tumors: variants in TXNDC11 (OR=2.66, p=5.7x10-8) and RUVBL2 (OR=3.1, p=5.8x10-8). High tumor expression of TXNDC11 is associated with poor prognosis in glioma and RUVBL2 interacts with TERT to affect telomerase activity. Similar analyses are being performed on additional clinically relevant acquired alterations. In parallel, case-case GWAS analyses were performed to evaluate germline variants associated with other tumor alterations. Comparing IDH-mutant versus IDHwt stratified by rs55705857 genotype, the most significant variants were PHLDB1 (p=1.2x10-13) and D2HGDH (p=2.1x10-10), highlighting the importance of these two variants independent of CCDC26 for the development of IDH-mutant glioma. As a parallel approach, we utilized recursive partitioning and regression trees (rpart) to classify IDH mutation status using the 30 known variants. The top four branches of the regression tree included CCDC26, D2HGDH, PHLDB1, and MAML2, as well as two Asian variants (RAB27A, CYP4F12). This highlights the importance of utilizing variants discovered in non-European populations in analyses. Overall, understanding these interactions are necessary to develop therapeutics, stratify clinical trials, and to develop relevant tumor models.

Abstract Accurate response assessment in patients with high-grade gliomas (HGGs) is complicated by post-treatment radiographic changes that are equivocal for treatment effect versus progression. Plasma-based liquid biopsy assays for circulating tumor DNA (ctDNA) have had limited sensitivity to date, due in part to the presence of the blood-brain barrier that limits the diffusion of tumor-derived analytes out of the central nervous system. To address this challenge, we developed a ctDNA plasma-based assay to detect individualized tumor-derived amplified junctions in patients with HGGs. These junctions occur due to large-scale chromosomal rearrangements, such as those associated with epidermal growth factor receptor (EGFR) or cyclin-dependent kinase 4 (CDK4) amplification. To identify these amplified junctions, whole genome sequencing was performed on resected tissue. Primers were designed to flank junction breakpoints and were then utilized on each patient’s plasma samples to detect the amplified junction via qPCR. Tumor-specific amplified junctions were robustly detected in plasma from 14/14 (100%) patients with IDH-mutant or wild-type grade 4 astrocytomas whose tumor genomes demonstrated amplification-related junctions, located at chromosomes 7, 11, or 12. In comparison, ctDNA could not be detected in three control cases that did not have an amplification or did not have high copy number junctions. Importantly, serial plasma samples obtained prior to and at disease recurrence in 4 patients demonstrated an increasing abundance of amplified junctions that accurately correlated with disease progression in 4/4 patients (100%). In two of these patients, increasing abundance of amplified junctions preceded radiographic changes compatible with disease progression by approximately 2 or 4 months, respectively. In conclusion, tumor-specific amplified junctions could reliably be detected in plasma from patients with IDH-mutant or wild-type grade 4 astrocytomas and correlated with changes in disease burden. Further work is currently ongoing to evaluate these promising results in a larger cohort of patients with serial plasma samples.

Abstract The prevalence of asymptomatic, incidental meningiomas is increasing due to greater frequency of brain imaging. This retrospective cohort study of adult patients presenting at a single institution from 1996-2020 integrated clinical data, serial magnetic resonance imaging (MRI) volumetrics, DNA methylation profiling, and targeted gene expression profiling to define the natural history and molecular architecture of incidental meningiomas. Volumetrics were calculated from contrast-enhanced brain MRIs at time of diagnosis compared to serial surveillance MRIs (average 3 MRIs per patient pre-intervention, range: 1-12) DNA methylation groups and gene expression risk scores were defined for 123 samples that underwent resection. Time-to-event analyses were performed for progression-free survival (PFS), symptom-free survival (SFS), and treatment-free survival (TFS). The cohort included 238 meningiomas from 207 patients. Median age at diagnosis was 59 years and 81.5% of patients were female. Median clinical and imaging follow-up were 9.1 and 6.7 years, respectively, during which time 50.8% progressed. Median maximum diameter and volume at diagnosis were 2.20 cm and 4.25 cm3, respectively, and median pre-treatment volumetric growth rate was 19.2% per year. Median pre-treatment PFS and TFS were 3.10 and 1.27 years, respectively, and median SFS and post-treatment PFS were not reached. Cox proportional hazards regression identified maximum diameter at diagnosis as a significant predictor of worse pre-treatment PFS (multivariate HR 1.65 per 1 cm [95% CI 1.19–2.28], p=0.0027) and worse TFS (multivariate HR 1.44 per 1 cm [95% CI 1.17–1.76], p<0.001). Skull base tumors had with worse SFS (multivariate HR 2.48 [95% CI 1.02–6.00], p=0.045). Molecular and histological features among incidental meningiomas that ultimately underwent resection (n=176, 74.0%) were reassuring (89.2% WHO grade 1, 10.2% WHO grade 2). These findings suggest maximum diameter at diagnosis of incidental meningiomas is significantly associated with earlier progression and eventual treatment, and skull base tumors have earlier symptom development.

Abstract BACKGROUND Standard of care treatment for recurrent malignant glioma after prior radiotherapy (RT) is not well established. Proton therapy (PT) is increasingly used for reirradiation (ReRT) at the time of recurrence; however, treatment outcomes, toxicity, and prognostic factors for patients treated with PT-ReRT remain poorly defined. METHODS The prospective, multi-institutional Proton Collaborative Group (PCG) registry was queried for patients with malignant glioma who previously received RT and underwent PT-ReRT between 7/2011-12/2023. Overall survival (OS) and progression-free survival (PFS) were assessed using the Kaplan-Meier method, and Cox proportional hazards regression was used for uni- and multivariate analysis (UVA and MVA). Dose was calculated using equivalent dose in 2-Gy fractions (EQD2). RESULTS 143 consecutive patients were identified. Median follow-up was 11.2 months and median time interval (TI) from prior RT (median 58.5 Gy) to PT-ReRT (median 44.6 Gy) was 42.4 months. Primary histology was glioblastoma (n=74), astrocytoma (n=35), and oligodendroglioma (n=34). Median PFS and OS were 8.1 and 11.2 months, respectively. On UVA, improved OS was associated with oligodendroglioma (HR 0.37) and astrocytoma histology (HR 0.53) compared to glioblastoma, TI >60 months (HR 0.2), CNS WHO Grade 2 compared to 4 (HR 0.42), and ECOG performance status 0 (HR 0.47). On MVA, improved OS remained associated only with oligodendroglioma (HR 0.42) and TI >60 months (HR 0.49). Acute and Late Grade 3 toxicity occurred in 7% and 4% of patients. Acute Grade 3 toxicity was associated with poor performance status (HR 16.15). CONCLUSIONS In the largest series of glioma PT-ReRT reported to date, retreatment appears well tolerated with variable outcomes based on clinical prognostic factors. Toxicity rates were acceptable compared to historical photon-based literature despite a high median prescription dose.

Abstract Gliomas are heterogeneous brain tumors with prognostically-significant subtypes and few risk factors. IDH-wildtype glioblastoma, the most common subtype, carries a dismal prognosis. Using the largest GWAS dataset with histological (11,304 cases, 304,523 controls) and molecular (3,418 cases, 8,156 controls) subtypes, we analyzed the plasma and brain proteome to uncover proteins associated with glioma susceptibility. Using protein quantitative trait loci (pQTL) for 1,776 proteins in brain tissue, we identified 21 candidate proteins, including 9 associations with high probability (>70%) of colocalization (shared causal genetic variants for glioma risk and protein abundance). We confirmed known risk genes such as EGFR (p=1.9×10-35) and D2HGDH (p=1.1×10-5). We also identified novel risk proteins, including ENPP6, a choline phosphodiesterase overexpressed in glioma, for IDH-wildtype glioblastoma (OR=0.62, p=7.6×10-5), and galectin-3, a lectin encoded by a tumor fitness gene in CRISPR screens of glioma proliferation and a clinical drug target, for glioma overall (OR=1.37, p=1.3×10-5). Analyses of the plasma proteome using pQTLs for 1,362 proteins from 3 cohorts (N=88,838) identified 9 colocalized associations in whole blood. Most risk signals were subtype-specific, such as CRELD1 (p=2.5×10-5) for triple-negative glioblastoma. We found three candidate risk proteins for IDH-mutant 1p19q-intact glioma: immunoglobulin glycoprotein BCAM (p=9.6×10-8), neurotrophin receptor SorCS2 (p=3.6×10-5) and immune checkpoint PD-1 (p=1.1×10-5). Interestingly, genetically-predicted PD-1 levels had a larger effect on IDH-mutant 1p19q-intact (OR=2.75, 95% CI=1.61-4.69) than IDH-wildtype (OR=0.73, 95% CI=0.51-1.05) tumors, suggesting germline differences in immune checkpoint mechanisms among subtypes. For all colocalized candidates, genetically-predicted protein abundance was correlated with cis-regulated transcriptional activity in brain tissue. For example, genetically-predicted SORCS2 gene expression in brain tissue was associated with plasma SorCS2 levels (Z=16.1, p=1.1×10-68). Our analysis identified candidate proteins involved in immune response and neuronal proliferation, which may enable prioritization of drug targets and provide insight into disease mechanisms for glioma.

Abstract Racial inequities in postpartum weight have been documented with limited studies on the influences of racism and other forms of discrimination. In a prospective longitudinal study applying ecological momentary assessment (EMA) and ambulatory assessment of weight, we measured the association between discrimination, stress, and postpartum weight change. The Postpartum Mothers Mobile Study is a cohort of 313 pregnant and birthing individuals who were followed during their second and third trimesters through 1 year postpartum. They were recruited in clinical settings between 2017 and 2020 in a major city center in Pennsylvania. Measures of racism and gender-based discrimination were collected via random EMA surveys throughout pregnancy and postpartum, and weight was collected via Bluetooth-enabled scales at least weekly. Among Black participants, a 10% increase in the number of days a participant experienced racial discrimination in the past month was associated with retaining 0.3 more pounds, a 10% increase in EMA gender discrimination was associated with retaining 0.4 more pounds, and EMA stress reported in the past month was associated with decreased weight retention. Chronic experiences of racial and gender discrimination may contribute to weight retention immediately after pregnancy and beyond.