Citations

Abstract There are no approved treatments for relapsed/refractory (R/R) PCNSL. We show promising efficacy in the salvage setting using emavusertib in combination with ibrutinib, which targets the BCR and TLR pathways. These 2 major pathways are associated with activation of NF-κB. Updated safety and efficacy data of this combination in R/R PCNSL from the ongoing Phase 1/2 TakeAim Lymphoma trial (NCT03328078) will be presented. As of 01 May 2025, 33 patients with R/R PCNSL were treated with emavusertib in combination with ibrutinib. Eligible patients receive emavusertib in combination with ibrutinib until tumor progression or unacceptable toxicity. Median age was 63 years (range 43-81); 16 patients were male. Median prior anti-cancer therapy was 2 (range 1-5); 26 (78.8%) patients had prior BTKi exposure. Median duration of emavusertib/ibrutinib treatment was 51 days (range 5-798). Grade ≥ 3 treatment-related adverse events (TRAEs) were reported in 11 (33.3%) patients; neutropenia in 5 (15.2%) patients, amylase increased, lipase increased, and leukopenia in 2 (6.1%) patients each. The majority of Grade ≥ 3 TRAEs were reversible and manageable. Among the 19 BTKi-experienced patients treated for ≥ 28 days, there were 5 CRs and 2 PRs, with an ORR of 36.8%. Three patients with CR were on treatment for 10+ mos, with 1 CR patient ongoing with DOT of 26.2+ mos. Among the 5 BTKi-naïve patients treated for ≥ 28 days, 1 achieved CR and 3 had PR, with ORR of 80%; the CR patient is ongoing with DOT of 18.1+ mos. The ORR in the combined population was 45.8% (6 CRs; 5 PRs). The combination of emavusertib and ibrutinib demonstrates promising clinical activity and an acceptable safety profile in patients with R/R PCNSL. This regimen appears capable of overcoming resistance to prior BTKi therapy. Patient enrollment in this trial continues.

Abstract PCNSL is a rare and aggressive NHL with no approved treatments for R/R patients, representing a critical unmet need. MyD88 mutations in ~70% of PCNSL patients drive IRAK4 activation, promoting NF-κB signaling, inflammation, and tumor progression. Emavusertib, a potent oral IRAK4 inhibitor, crosses the blood-brain barrier and shows preclinical synergy with BTKis, and has the ability to re-sensitize BTKi-resistant cell lines. This study evaluates the molecular and PK data associated with responses to emavusertib + ibrutinib combination therapy in R/R PCNSL patients. The safety, clinical activity, and potential biomarkers of emavusertib in R/R PCNSL are being investigated in the ongoing TakeAim Lymphoma trial (NCT03328078). Pre-dose and 1.5-hour post-dose plasma samples were collected on Day 1 of Cycles 3, 5, and 7. CSF samples were obtained via a lumbar puncture within 1.5 hrs of collection of the post-dose plasma PK sample on Cycle 3 Day 1. As of 06 December 2024, CSF concentration was available for 7 patients. The mean emavusertib concentration in CSF was 81.3 ng/ml (54.7-104.0) in patients receiving 100 mg emavusertib BID (n=4). In patients receiving 200 mg emavusertib BID (n=3), the mean emavusertib concentration in CSF was higher at 175.7 ng/ml (114.8-209.4), which is 2.2 × the mean value in patients who received 100 mg emavusertib BID (p-value = 0.02). MyD88 mutation status was available for 7 patients of which all had prior BTKi exposure. Among these patients, 6 had MyD88 mutations of which 4 had responded (3 CRs and 1 PR) to the combination with DOR up to 18.9 mos with data collection ongoing. Preliminary CNS PK data demonstrate that emavusertib concentration in CSF increases with increasing emavusertib dose. Patients with MyD88 mutations showed expected promising preliminary efficacy to emavusertib + ibrutinib combination and may overcome BTKi resistance. Enrollment is ongoing.

Abstract PURPOSE Age over 40 years is commonly regarded as a “high risk” feature and potential indication for adjuvant chemoradiotherapy for patients with lower grade glioma in most clinical practice guidelines. However, these recommendations are based on retrospective observations and their subsequent incorporation into legacy clinical trials. It is unclear whether age remains a relevant prognostic factor in the molecular era. METHODS The Prospective Gliomas Research [PROGRES] Database contains individual patient-level data from 11 prospective clinical trials or observational registries, including seven international trials from the RTOG, EORTC, or Alliance cooperative groups. We determined the association of age with progression-free survival (PFS) in low grade or anaplastic glioma, stratified by isocitrate dehydrogenase (IDH1/2) status. We validated our findings in a separate multi-institutional retrospective cohort (Retrospective Glioma Research [REGRES] Database). RESULTS We identified 1,619 and 1,271 eligible patients in the PROGRES and REGRES cohorts, respectively. IDH-wildtype tumors were more common in patients >40 years (38% vs, 5%, odds ratio: 11.3 [95%CI 6.5 – 19.7]). Age was associated with PFS in IDH-wildtype (5-year PFS: 6% vs, 24%, P =.003) but not in IDH-mutant glioma (60% vs, 59%, P = 0.22, P value of interaction <.001). In IDH-wildtype tumors, older age predicted aggressive molecular features, including TERT promoter mutation (65% vs, 28%), EGFR amplification (41% vs, 15%), and chromosome +7/-10 alteration (57% vs, 25%). Age was not predictive of a benefit from chemoradiotherapy versus radiotherapy alone in IDH-mutant glioma. CONCLUSION Older age is a putative surrogate for IDH-wildtype status, but was not an independent predictor of progression in IDH-mutant lower grade glioma and did not predict benefit from chemoradiotherapy. In the absence of additional clinical or molecular risk factors, age alone should not be considered an indication for administration or deferral adjuvant treatment. Practice guidelines should be revised to reflect contemporary prognostic factors in the molecular era.

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 .

Abstract Background The associations between different types of diabetes, characterized by distinct pathophysiology and genetic architecture, and pancreatic ductal adenocarcinoma (PDAC) risk are not understood. Methods We investigated associations of genetic susceptibility to type 2 diabetes (T2D), 8 T2D mechanistic clusters, type 1 diabetes (T1D), and maturity-onset diabetes of the young (MODY) with PDAC risk. We used genome-wide association study (GWAS) summary-level statistics for T2D (242 283 cases, 1 569 734 controls), T1D (18 942 cases, 501 638 controls), and PDAC (10 244 cases and 360 535 controls) in individuals of European ancestry. Results Two-sample Mendelian randomization (MR) using the Robust Adjusted Profile Score (MR-RAPS) method indicated that genetically predicted T2D was associated with PDAC risk (OR = 1.10; 95% CI = 1.05 to 1.15), particularly the T2D obesity (OR = 1.28; 95% CI = 1.15 to 1.42) and lipodystrophy (OR = 1.25; 95% CI = 1.03 to 1.51) clusters. No association was observed for T1D with PDAC risk (OR = 1.01; 95% CI = 0.99 to 1.02). Pathway/gene-set analysis using the summary-based Adaptive Rank Truncated Product (sARTP) method revealed a significant association between the MODY gene-sets and PDAC risk (P = 1.5 × 10−8), which remained after excluding 20 known PDAC GWAS loci (P = 7.6 × 10−4). HNF1A, FOXA3, and HNF4A were the top contributing genes after excluding the previously identified GWAS loci regions. Conclusions Our results from this genetic association study support that T2D, particularly the obesity and lipodystrophy mechanistic clusters, and MODY genomic susceptibility regions play a role in the etiology of PDAC.

Background. Delayed graft function (DGF) in deceased-donor kidney transplantation increases morbidity, prolongs hospitalization, and increases healthcare costs. Hypothermic machine perfusion (HMP) has emerged as a promising strategy to reduce DGF; however, large-scale real-world data remain limited. Methods. We performed a retrospective cohort analysis using the Scientific Registry of Transplant Recipients (2014–2024), including adult dialysis-dependent recipients of deceased-donor kidneys preserved using either static cold storage (SCS) or HMP. The primary outcome was DGF, defined as dialysis requirement within 7 d posttransplant. A matched-pairs analysis was conducted using kidneys from the same donor. Results. The overall cohort included 59 859 recipients (46.8% SCS, 53.2% HMP), with 2208 matched pairs identified. In the overall cohort, HMP grafts had longer cold ischemia times and a higher kidney donor risk index. They were more frequently obtained from older and donation after circulatory death donors. Although the overall DGF incidence was higher with HMP (34.4% versus 30.9%, P < 0.001), matched-pairs analysis revealed significantly lower DGF rates with HMP (29.8% versus 36.1%, P < 0.001). Adjusted analyses identified HMP as protective against DGF (overall cohort odds ratio, 0.71; 95% confidence interval, 0.66-0.78; paired cohort OR, 0.68; 95% CI, 0.50-0.93). Additional modifiable risk factors include prolonged cold ischemia time, higher recipient body mass index, and longer dialysis duration. Conclusions. This real-world study demonstrates that HMP is associated with a significant reduction in DGF risk in kidney transplantation compared with SCS, supporting its broader implementation and targeted management of modifiable risk factors.

Objective: An endoscopically placed duodenal-jejunal bypass liner (DJBL) may provide a safe adjunctive therapy for those with poorly controlled type 2 diabetes mellitus (T2DM) and obesity. Background: Although some endoscopic therapies have been shown to improve glycemic indices secondary to weight loss, small bowel interventions may have direct metabolic effects. A meta-analysis of observational studies demonstrated reduction in HbA1c by 1.3% at 1 year after DJBL in patients with T2DM and obesity. Methods: This was a multicenter, double-blind, randomized, sham-controlled trial comparing DJBL to sham procedure with medical management and lifestyle modification. Primary endpoints included mean difference in changes in HbA1c at 12 months between arms, and device-related serious adverse events (SAEs). Secondary endpoints included percent total weight loss (%TWL) and subjects achieving HbA1c≤7% and TWL≥5% at 12 months. Results: Three hundred twenty subjects were randomized to DJBL (n=212) and sham (n=108). Baseline HbA1c and BMI were 8.79±0.92% and 38.45±5.75 kg/m 2 . On modified intent-to-treat analysis, change in HbA1c at 12 months was −1.10±1.45% and −0.28±1.54% for DJBL and sham groups, respectively ( P =0.0004). Rate of device-related SAEs was 9.4% including intolerance (3.7%), hemorrhage (2.8%), and hepatic abscess (2.3% stopping study early). At 12 months, DJBL group experienced greater weight loss compared with sham (7.7±9.6% TWL and 2.1±5.4% TWL, respectively; P <0.0001), with significantly more patients achieving HbA1c ≤ 7% (28.3% vs. 9.4%; P <0.0003) and TWL ≥ 5% (60.4% vs. 21.3%; P <0.0001). Conclusions: DJBL met primary glycemic control efficacy and primary safety endpoints, while providing clinically significant weight loss, and comorbidity improvement.

Abstract Introduction: While evaluation approaches for community-academic research groups are established, few tools exist for academic institutional advisory groups across multi-core centers and research, education, and clinical care missions. Institutional advisory group evaluation should consider group processes and their impact on community-centered outcomes. This study describes the community-engaged development of a mixed-method evaluation approach to address this gap and presents pilot outcomes across an NIH-funded center. Methods: We utilized a Community of Practice model to co-develop a survey with 14 community and academic representatives of four advisory groups. The final survey included five categories of group process and four categories of outcomes. Storytelling sessions with community partners explored areas where the survey identified discrepancies in perspectives between community and academic team members, as well as areas with lower scores. Results: Nine community and 14 academic (staff and faculty) partners completed the survey. Respondents positively assessed group process outcomes (shared values, leadership, community-centeredness, and decision-making), and slightly less positive assessments of institutional outcomes. Storytelling sessions confirmed the overall satisfaction of community partners but highlighted actionable concerns within power-sharing, decision-making, funding equity, and trust-building. Conclusions: The results of this equity-centered evaluation suggest the utility and importance of participatory, mixed-methods approaches to evaluating community-academic institutional advisory groups.

Anthracyclines are potent chemotherapeutic agents, yet their clinical use is hampered by their cardiotoxicity. Anthracyclines achieve potent anti- cancer effects primarily via TOP2A, but at the same time they induce a dose limiting cardiotoxicity through TOP2B. The use of a catalytic TOP2 inhibitors such as dexrazoxane (ICRF 187) significantly reduces the incidence of anthracycline-induced cardiotoxicity. However, dexrazoxane targets the highly conserved TOP2 dimer interface that is identical between TOP2A and TOP2B, fostering persisting concerns that its inhibition of TOP2A isoenzyme may interfere with anthracycline anticancer effects and augment anthracycline-induced myelosuppression. Thus, isoform- selective TOP2 inhibitors that can control the DNA damage caused by TOP2A vs TOP2B are a significant unmet clinical need. We have developed a new class of highly potent and TOP2B-selective catalytic inhibitors through rational design by building upon the general pharmacophore present in isolates from Calophyllum Brasiliense. Using X-ray crystallography, we demonstrate that our newly developed compounds occupy a previously unidentified druggable binding-site in the TOP2 ATPase domain and function as a physical barrier to block the conformational change triggered by ATP hydrolysis. We have named the class of inhibitors that target this site “obex”, the Latin word for obstacle. The obex binding site contains residues that differ between the TOP2A and TOP2B isoenzymes, based on which we rationally designed, prepared, and systematically evaluated a targeted panel of obex inhibitors. We have identified the lead molecule, namely, topobexin, as the first- in-class TOP2B-specific obex inhibitor that can prevent anthracycline-induced DNA damage. This first TOP2 isoform-specific inhibition underscores the broader potential to improve drug specificity and minimize adverse effects in various medical treatments.