Citations

Abstract Glioblastoma is an aggressive brain cancer with poor prognosis. Recent evidence implicates metabolic reprogramming, including the hexosamine biosynthetic pathway (HBP) and pentose phosphate pathway (PPP), as critical for tumor survival, therapy resistance, and progression. HBP inhibition with a proprietary small molecule (G2Bz) reduced stemness and migration and increased apoptosis of GBM in vitro. HBP inhibition was concomitant with an accumulation of metabolites in the Pentose Phosphate Pathway (PPP). Therefore, we further inhibited HBP with G2Bz and/or PPP with 6-aminonicotinamide (6-AN) in primary patient-derived GBM lines and evaluated additive or synergistic effects. Ultrastructural and functional changes were examined by electron microscopy (EM), high content imaging of endoplasmic reticulum (ER) and lipid droplets (LD), extracellular-flux analysis, and lipid profiling. Synergism was validated in an orthotopic model receiving lipoparticle-encapsulated G2Bz via intranasal delivery and/or intraperitoneal 6-AN; tumor burden was monitored via bioluminescence. Dual inhibition of HBP/PPP revealed additive or synergistic anti-proliferative effect. EM displayed severe ultrastructural cell damage with mitochondrial disorganization, ER dilation, and cytoskeletal remodeling. These changes coincided with increased ROS generation and reduced spare respiratory capacity suggesting higher sensitivity and lower ability to fight stress. Reduced ER–mitochondria contacts accompanied by increased expression of BiP and ER expansion suggest an unfolded protein response. Loss of LDs were associated with downregulation of lipid biosynthesis regulator SREBF1 and an increase in free fatty acids with a rise in lipid peroxidation. Reduced mitochondria–LD contacts correlate with lower endogenous fatty acid oxidation and a shift to exogenous fatty acid utilization. Dual inhibition in-vivo, suppressed tumor growth compared to control. These findings support that dual inhibition of HBP/PPP synergistically disrupts tumor metabolism, promoting organelle disorganization and lipid remodeling and highlight metabolic co-targeting as a strategy to impair GBM metabolism.

Abstract BACKGROUND Understanding long-term sequelae of cancer care is critical. Cognitive impairment is a common and disabling survivorship issue. Because sex influences tumor biology, therapy exposure, and dementia risk, we examined whether cancer care for a prior malignancy alters late-life cognitive outcomes differently in males and females. METHODS We assessed adults ≥50 years, cognitively normal at study entry, from a longitudinal, population-based cohort (Mayo Clinic Study of Aging). Participants were linked to our institutional cancer registry (excluding non-melanoma skin cancers). Mild cognitive impairment (MCI) and dementia were adjudicated by consensus. We fitted multivariable Cox proportional-hazards models to estimate how prevalent cancer diagnosis influenced the risk of developing MCI/dementia. Sex-specific effects were determined by incorporating a cancer×sex interaction term and by generating separate hazard ratios. Analyses were controlled for age, APOE4 status, education, and presence of vascular/metabolic conditions. RESULTS 5793 MCSA participants (female: 49.4%, APOE4 positive: 27.5%) were included in the study, with a mean age of 73 years at study entry. Incident MCI was recorded in 866 participants, and 737 were diagnosed with incident dementia. About 20% (n=1176) of the cohort had a cancer diagnosis, most commonly prostate (n=423) and breast (n=277). There was no independent relationship between history of cancer and risk for MCI or dementia. We found that males with cancer had an increased risk for MCI (HR 1.28, 95% CI 1.04-1.57, p=0.003) and dementia (HR 1.29, 95% CI 1.04-1.6, p=0.053). Conversely, females with cancer had a lower risk for MCI (HR 0.79, 95% CI 0.61-1.01, p=0.063), although this was not statistically significant. CONCLUSIONS Our data suggests male cancer survivors may be more susceptible to cognitive impairment, independent of age, APOE4 status, education, and vascular/metabolic burden. Elucidating the hormonal, treatment-related, and systemic pathways driving this should be a priority for future mechanistic studies.

Abstract BACKGROUND Mirdametinib, a MEK1/2 inhibitor, is the first FDA-approved medicine for both adults and children (≥2y) with NF1-PN not amenable to complete resection. In the phase 2b ReNeu trial (NCT03962543), confirmed objective response rate (ORR) was 41% in adults and 52% in children. This analysis explored relationships between baseline characteristics and mirdametinib responses in ReNeu. METHODS Confirmed ORR was the proportion of patients with ≥20% reduction from baseline in target PN volume by magnetic resonance imaging on consecutive scans during the 24-cycle treatment phase (“responders”) as assessed by blinded independent central review. Characteristics included age, body surface area (BSA), sex, race, ethnicity, target PN location, PN type (typical, nodular, or solitary nodular), target PN volume, and progression status. Rates of dose reductions and treatment-related adverse events (TRAEs) were evaluated. These factors were descriptively analyzed for potential relationships with confirmed objective response (data cutoff: 20September2023). RESULTS With mirdametinib, there was no clear difference between responders (n=53) and non-responders (n=61) in age (mean, 22.89 and 22.67y), BSA (mean, 1.42 and 1.51 m2), sex (60.4% and 57.4% female), race (83.0% and 68.9% White), or ethnicity (83.0% and 85.2% non-Hispanic/Latino). The majority of responders and non-responders had head/neck for target PN location (50.9% and 47.5%), typical PN type (81.1% and 63.9%), and baseline progression status (60.4% and 55.7%). Mean (95% CI) target PN volume was 283.43 (155.19, 411.66) and 415.74 (211.71, 619.77) mL, respectively. Dose reduction (11.3%; 18.0%) and TRAE rates (96.2%; 96.7%) were comparable. CONCLUSIONS This analysis suggests mirdametinib provides clinical benefit across a broad range of patient and NF1-PN tumor characteristics; a relationship between analyzed baseline characteristics and confirmed objective response was not established. Mean PN volume was higher in non-responders, though CIs overlapped. Dose reductions and emergence of TRAEs did not appear to impact response to mirdametinib. SUPPORT SpringWorks Therapeutics, Inc.

Abstract INTRODUCTION Recurrent IDH-mutant gliomas pose a significant therapeutic challenge, with limited treatment options following progression after standard therapy. Combining PARP inhibitors with immune checkpoint blockade has been proposed as a synergistic strategy in IDH-mutant high-grade gliomas, leveraging vulnerabilities in homologous recombination repair and increased PD-L1 expression following PARP inhibition. OBJECTIVE This phase II trial (NCT03991832) evaluated the combination of the PARP inhibitor olaparib and the PD-L1 inhibitor durvalumab in patients with recurrent IDH-mutant glioma. We also investigated the potential of the plasma tumor methylome as a non-invasive biomarker of treatment response. METHODS Twenty-nine patients (median age 40.5 years; 41% female) were enrolled between January 2020 and February 2023. All patients received olaparib (300 mg twice daily) and durvalumab (1,500 mg IV every four weeks) until radiographic or clinical progression. Plasma samples were collected at baseline and monthly, and cell-free methylated DNA immunoprecipitation sequencing (cfMeDIP-seq) was performed. RESULTS The objective response rate was 10%, and median overall survival was 9.3 months. Longitudinal cfMeDIP-seq profiling enabled development of a circulating methylome classifier that accurately distinguished responders from non-responders. Integration with matched tumor transcriptomic and methylation data revealed enrichment of immune and DNA repair pathways in responders. Whole-exome sequencing identified no consistent mutational correlates. Spatial transcriptomic analysis demonstrated a more interactive, immune-rich tumor microenvironment and reduced malignant cell state diversity in responders. CONCLUSION This study supports the safety of combined PARP and PD-L1 blockade in recurrent IDH-mutant glioma and highlights the plasma methylome as a promising non-invasive biomarker of therapeutic response.

Abstract Brain metastases significantly impact neurocognitive function and overall survival. Stereotactic radiosurgery (SRS) is a cornerstone of treatment for patients with limited metastases and expected survival beyond three months. Despite current guidelines, up to 20% of patients with brain metastases undergoing SRS have been reported to die within 90 days. This study retrospectively evaluates prognostic factors associated with 90-day survival after SRS, aiming to improve patient selection. We retrospectively analyzed a cohort of 1,546 patients who underwent Gamma Knife SRS for brain metastases at our institution between 2015 and 2023. One hundred seventy patients who survived fewer than 90 days post-SRS were identified and case-matched to 170 patients who survived over 90 days. Measured variables included patient demographics, tumor characteristics, treatment history, functional status, and control of the primary cancer. We modeled post-SRS 90-day survival using binomial and multivariate logistic regression. Multivariate analysis highlighted Karnofsky Performance Status (KPS) < 70 (OR: 17.4, p < 0.001), prior whole brain radiation (OR: 6, p = 0.004), and focal neurological deficits (OR: 3.02, p = 0.003) as significant predictors of early deaths, while CNS progression before SRS (OR: 0.22, p < 0.001) and control of systemic cancer (OR: 0.556, p = 0.002) were associated with a less than 90-day survival. The predictive model demonstrated acceptable performance with an area under the curve (AUC) of 0.85, accuracy of 80%, sensitivity of 87%, and specificity of 71%. Key predictors of 90-day survival following SRS for brain metastases include functional status (KPS), control of systemic cancer, CNS progression status, and focal neurologic deficits. These findings are complementary factors that can assist in making decisions and SRS patient selection.

BACKGROUND: Transthyretin amyloidosis with cardiomyopathy is a progressive disease caused by the deposition of transthyretin (TTR) as amyloid in the myocardium. Current therapies may slow disease progression but do not clear existing deposits. Coramitug is a humanized monoclonal antibody that targets misfolded transthyretin, designed to promote clearance of transthyretin amyloid through antibody-mediated phagocytosis. METHODS: This phase 2, double-blind, placebo-controlled trial randomized participants with transthyretin amyloidosis with cardiomyopathy to receive infusions every 4 weeks of either coramitug at 2 dosages (10 mg/kg or 60 mg/kg) or placebo in a 1:1:1 ratio for 52 weeks. The primary end points were the change from baseline to week 52 in the 6-minute walk test and NT-proBNP (N-terminal pro-B-type natriuretic peptide) levels. Safety was assessed for up to 64 weeks by assessing treatment-emergent adverse events, all-cause mortality, and number of cardiovascular events (comprising hospitalization caused by cardiovascular events or urgent heart failure visits). RESULTS: In total, 104 participants (median age, 77 years; 93% men; 84% New York Heart Association class II; 13% with variant transthyretin amyloidosis with cardiomyopathy) were randomized and dosed: 34 to 10 mg/kg of coramitug, 35 to 60 mg/kg of coramitug, and 35 to placebo. Median NT-proBNP was 1985 pg/mL (interquartile range, 1224, 3406). In total, 90% of participants were receiving disease-modifying therapy; 84% were treated with tafamidis and 7 (6.7%) with transthyretin silencers (patisiran, n=4; vutrisiran, n=3). From baseline to week 52, 60 mg/kg of coramitug significantly reduced NT-proBNP levels compared with placebo (–48% [95% CI, –65% to –22%]; P =0.0017). The change in 6-minute walk test from baseline to week 52 was not statistically different from placebo with either dose. Coramitug (60 mg/kg) was associated with improved functional echocardiographic parameters and was well tolerated. CONCLUSIONS: This phase 2 trial showed that coramitug, an antibody targeting misfolded transthyretin in transthyretin amyloidosis with cardiomyopathy, was well tolerated and, at a dose of 60 mg/kg, resulted in a statistically significant reduction in NT-proBNP, a validated marker of disease progression, with no statistically significant effect on 6-minute walk test within 52 weeks. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT05442047.

Importance Treatment for cognitive dysfunction due to postacute sequelae of long COVID (ie, symptoms of fatigue, malaise, weakness, confusion that persist beyond 12 weeks after an initial COVID infection) remains a significant unmet need. Objective To test evidence-based rehabilitation strategies for improving cognitive symptoms in persons with long COVID. Design, Setting, and Participants This was a 5-arm, multicenter, randomized clinical trial of 3 remotely delivered interventions conducted between August 17, 2023, and June 10, 2024. The study took place at 22 trial sites and included the screening of individuals with cognitive long COVID. Interventions Participants were randomized to 1 of 5 arms: adaptive computerized cognitive training (BrainHQ [Posit Science]), cognitive-behavioral rehabilitation involving both group and individual counseling sessions (PASC-Cognitive Recovery [PASC-CoRE]) paired with BrainHQ, and transcranial direct current stimulation (tDCS) paired with BrainHQ. Two comparator arms were included as follows: unstructured computer puzzles and games (active comparator) and sham tDCS paired with BrainHQ. The interventions occurred 5 times per week over 10 weeks. Main Outcomes and Measures Cognitive and behavioral in-person assessments were performed at baseline, midintervention, at the end of intervention, and 3 months after the end of the intervention. The primary outcome measure was the modified Everyday Cognition Scale 2 (ECog2) completed at the end of the intervention compared to the baseline visit based on participant self-report looking back over the prior 7 days. Results A total of 378 individuals were screened, from which there were 328 participants (median [IQR] age, 48.0 [37.0-58.0] years; 241 female [73.5%]; race: 15 Asian [4.6%], 47 Black [14.3%], and 235 White [71.6%]; ethnicity: 52 Hispanic [15.9%]). None of the 3 active interventions demonstrated benefits on the modified ECog2 in the intention-to-treat population by the end of the intervention period. The adjusted differences in mean change were 0.0 (95% CI, −0.2 to 0.2) for BrainHQ vs active comparator, 0.1 (95% CI, −0.1 to 0.3) for PASC-CoRE + BrainHQ vs active comparator, 0.0 (95% CI, −0.2 to 0.2) for tDCS-active + BrainHQ vs tDCS-sham + BrainHQ, and 0.1 (95% CI, −0.1 to 0.3) for PASC-CoRE + BrainHQ vs BrainHQ alone. Secondary participant-reported outcomes and neuropsychological tests showed no differential benefits for any treatment arm. All 5 arms demonstrated some improvements over time on the modified ECog2 and on secondary outcomes. There were no serious adverse events attributable to the interventions. Conclusions and Relevance This phase 2 randomized clinical trial failed to demonstrate differential benefits for online cognitive training, a structured cognitive rehabilitation program, and tDCS for cognitive long COVID. Trial Registration ClinicalTrials.gov Identifier: NCT05965739 .

Importance Transthyretin amyloid cardiomyopathy (ATTR-CM), a progressive disease caused by misfolded transthyretin (TTR), occurs as wild-type (ATTRwt-CM) or variant (ATTRv-CM) forms. p.Val142Ile is the most common variant in the US, linked to rapid progression and increased mortality. Acoramidis achieves near-complete (≥90%) TTR stabilization and showed clinical benefit in the 30-month ATTRibute-CM trial and through month 42 in the ongoing open-label extension (OLE). Objective To evaluate the efficacy of acoramidis in ATTRwt-CM, ATTRv-CM, and variant subgroups (p.Val142Ile and non-p.Val142Ile). Design, Setting, and Participants This international, multicenter, phase 3, randomized placebo-controlled study took place from April 2019 to May 2023 with ongoing OLE (month 42). ATTRibute-CM enrolled 632 participants with ATTR-CM; 611 of 632 were included in the modified intention-to-treat (mITT) population. There were 380 participants who continued into the OLE. These data were analyzed from January 2025 to July 2025. Interventions Oral acoramidis, 712 mg, or placebo twice daily for 30 months, followed by 12 months of open-label treatment. Main Outcomes and Measures All-cause mortality (ACM), cardiovascular-related hospitalizations (CVH), serum TTR, 6-minute walk distance, Kansas City Cardiomyopathy Questionnaire Overall Summary score, and N-terminal pro B-type natriuretic peptide in participants with ATTRwt-CM and ATTRv-CM. Post-hoc analyses were conducted in variant subgroups, including p.Val142Ile. Results Overall, 552 participants with wild-type ATTR-CM (mean [SD] age, 78 [6.3] years; 92.0% male and 8.0% female) and 59 participants with variant ATTR-CM (mean [SD] age, 73 [7.7] years; 77.3% male and 22.7% female) were randomized (mITT population), including 35 with p.Val142Ile. Consistent efficacy was observed in wild-type and variant subgroups for ACM/CVH through month 30 and ACM through month 42. At month 30, acoramidis reduced the risk of ACM/first CVH vs placebo by 31% in ATTRwt-CM (hazard ratio [HR], 0.69; 95% CI, 0.52-0.90; P = .007) and by 59% in ATTRv-CM (HR, 0.41; 95% CI, 0.21-0.81; P = .01). ACM was reduced through month 42 with HRs of 0.70 (95% CI, 0.50-0.98; P = .04) and 0.41 (95% CI, 0.19-0.93; P = .03) in the ATTRwt-CM and ATTRv-CM groups, respectively. Consistent treatment benefit was observed in participants with ATTRwt-CM and ATTRv-CM for secondary end points. Within variant subgroups (p.Val142Ile vs non-p.Val142Ile), consistent treatment benefits were observed for ACM/CVH through month 30 and ACM through month 42. Conclusions and Relevance The beneficial effect of acoramidis was observed consistently in ATTRwt-CM and ATTRv-CM groups. These hypothesis-generating results indicate that further studies are warranted to better characterize the therapeutic benefit of acoramidis in variant subgroups. Trial Registration ClinicalTrials.gov Identifiers: NCT03860935 ; NCT04988386

Abstract Background and Objectives To assess the efficacy of a local volunteer program, delirium optimization with volunteer engagement (DOVE), in preventing in-hospital delirium. Research Design and Methods Between February 2023 and June 2024, volunteers provided structured interventions to patients at risk for delirium, as identified by the Delirium Risk Assessment (DRA) score. Interventions are humanities-based and included sensory aide assistance, completion of “get to know me” forms, and conversation. Data were retrospectively acquired from electronic health records and compared to a control cohort from another medical unit. Delirium occurrence was captured when the nursing confusion assessment method (CAM) documentation was positive, or a clinician documented delirium diagnoses. Cohorts were matched 1:2 (DOVE vs Control) by age, gender, DRA score, month/year of admission, and length of hospital stay. Results A total of 168 patients received interventions by DOVE volunteers, of which 139 were matched with 261 controls. In-hospital delirium occurrence was lower in the DOVE cohort compared to the control cohort (46.8% vs 56.7%; p = .015). Conditional logistic regressions demonstrated a lower odds ratio (OR) for delirium occurrence, 0.55 (95% confidence interval [CI]; 0.34–0.89; p = .015) associated with DOVE intervention. Subgroup analyses of delirium occurrence among patients with DRA score of 3–4 demonstrated an OR of 0.56 (95% CI; 0.31–1.01; p = .053) between the DOVE and control cohorts. Discussion and Implications In-hospital delirium occurrence was ∼10% lower among DOVE cohort patients. This humanities-based intervention offers a feasible strategy, particularly during times of staffing shortages, and should be considered for broader implementation across healthcare institutions.