Citations

Abstract Decision-makers objectively commit to a definitive choice, yet at the subjective level, human decisions appear to be associated with a degree of certainty. Whether decisions are definitive—concluding in all-or-none choices, or whether the underlying representations are graded, has been unclear. To address this issue, we recorded neural signals directly from the brain while naive human subjects made perceptual decisions. The recordings revealed that each individual’s decisions formed within broadband gamma activity. The gamma activity was graded by decision evidence. Crucially, this analog, grading effect prevailed beyond the time of choice, instead of assuming a switch-like command. The effect was strongest in parietal and premotor cortex, brain regions traditionally implicated in decision-making. These data provide neural evidence for a graded nature of the decision process.

Abstract Background Female underrepresentation in oncology clinical trials can result in outcome disparities. We evaluated female participant representation in US oncology trials by intervention type, cancer site, and funding. Materials and Methods Data were extracted from the publicly available Aggregate Analysis of ClinicalTrials.gov database. Initially, 270,172 studies were identified. Following the exclusion of trials using Medical Subject Heading terms, manual review, those with incomplete status, non-US location, sex-specific organ cancers, or lacking participant sex data, 1650 trials consisting of 240,776 participants remained. The primary outcome was participation to prevalence ratio (PPR): percent females among trial participants divided by percent females in the disease population per US Surveillance, Epidemiology, and End Results Program data. PPRs of 0.8-1.2 reflect proportional female representation. Results Females represented 46.9% of participants (95% CI, 45.4-48.4); mean PPR for all trials was 0.912. Females were underrepresented in surgical (PPR 0.74) and other invasive (PPR 0.69) oncology trials. Among cancer sites, females were underrepresented in bladder (odds ratio [OR] 0.48, 95% CI 0.26-0.91, P = .02), head/neck (OR 0.44, 95% CI 0.29-0.68, P < .01), stomach (OR 0.40, 95% CI 0.23-0.70, P < .01), and esophageal (OR 0.40 95% CI 0.22-0.74, P < .01) trials. Hematologic (OR 1.78, 95% CI 1.09-1.82, P < .01) and pancreatic (OR 2.18, 95% CI 1.46-3.26, P < .01) trials had higher odds of proportional female representation. Industry-funded trials had greater odds of proportional female representation (OR 1.41, 95% CI 1.09-1.82, P = .01) than US government and academic-funded trials. Conclusions Stakeholders should look to hematologic, pancreatic, and industry-funded cancer trials as exemplars of female participant representation and consider female representation when interpreting trial results.

340 Background: TIS, an anti-programmed cell death protein 1 (PD-1) antibody, + chemo as 1L therapy demonstrated statistically significant and clinically meaningful improvement in overall survival (OS) vs PBO + chemo in patients with advanced or metastatic ESCC (hazard ratio [HR] 0.66 [95% confidence interval (CI) 0.54, 0.80]; P< 0.0001), with a manageable safety profile, at interim analysis of the phase 3, double-blind RATIONALE-306 study (NCT03783442). Here, we report data from the non-Asia subgroup (Europe, Northern America, and Oceania). Methods: Adults with advanced or metastatic ESCC, with no prior systemic treatment for advanced disease were randomized 1:1, (stratified by region, prior definitive therapy, and investigator [INV]-chosen chemo) to receive TIS 200 mg intravenously (IV) once every 3 weeks (Q3W) (Arm A) or PBO IV Q3W (Arm B), with platinum + fluoropyrimidine, or platinum + paclitaxel until disease progression by INV per RECIST v1.1, intolerable toxicity, or withdrawal. The primary endpoint was OS in the intent-to-treat population. Secondary endpoints included: progression-free survival (PFS), objective response rate (ORR), and duration of response (DoR) by INV per RECIST v1.1; OS in the programmed death-ligand 1 score ≥10%; and safety. Results: Of 649 randomized patients, 163 (25.1%) were from the non-Asia subgroup (Arm A, n = 83; Arm B, n = 80). At data cutoff (Feb 28, 2022), the median study follow-up time in the non-Asia subgroup was 16.0 months (mo) in Arm A vs 8.4 mo in Arm B. OS (median 16.3 vs 9.0 mo; unstratified HR 0.66 [95% CI 0.45, 0.96]) and PFS (median 7.7 vs 5.5 mo; unstratified HR 0.59 [95% CI 0.41, 0.83]) were improved in Arm A vs Arm B, respectively. Arm A had higher ORR (61.4% vs 41.3%, odds ratio 2.27 [95% CI 1.21, 4.25]) and longer median DoR (7.1 mo [95% CI 5.6, 9.6] vs 5.7 mo [95% CI 3.8, 8.3]) than Arm B. More patients in Arm A vs Arm B experienced ≥1 treatment-related adverse event (TRAE; 94.0% vs 88.5%), serious TRAEs (25.3% vs 17.9%), and discontinuation due to treatment-emergent AEs (42.2% vs 35.9%, respectively). Similar proportions of patients in Arm A vs Arm B had ≥grade 3 TRAEs (56.6% vs 52.6%), and TRAEs leading to death (1.2% vs 1.3%), respectively. Conclusions: In the non-Asia subgroup, 1L TIS + chemo showed a clinically meaningful improvement in OS vs PBO + chemo in patients with advanced or metastatic ESCC, with a manageable safety profile, consistent with published results in the overall population. Clinical trial information: NCT03783442 .

SummaryMitochondria are the controllers of cell metabolism and are recognized as decision makers in cell death pathways, organizers of cytoplasmic signaling networks, managers of cellular stress responses, and regulators of nuclear gene expression. Cells of the immune system are particularly dependent on mitochondrial resources, as they must swiftly respond to danger signals with activation, trafficking, migration, and generation of daughter cells. Analogously, faulty immune responses that lead to autoimmunity and tissue inflammation rely on mitochondria to supply energy, cell building blocks and metabolic intermediates. Emerging data endorse the concept that mitochondrial fitness, and the lack of it, is of particular relevance in the autoimmune disease rheumatoid arthritis (RA) where deviations of bioenergetic and biosynthetic flux affect T cells during early and late stages of disease. During early stages of RA, mitochondrial deficiency allows naïve RA T cells to lose self-tolerance, biasing fundamental choices of the immune system toward immune-mediated tissue damage and away from host protection. During late stages of RA, mitochondrial abnormalities shape the response patterns of RA effector T cells engaged in the inflammatory lesions, enabling chronicity of tissue damage and tissue remodeling. In the inflamed joint, autoreactive T cells partner with metabolically reprogrammed tissue macrophages that specialize in antigen-presentation and survive by adapting to the glucose-deplete tissue microenvironment. Here, we summarize recent data on dysfunctional mitochondria and mitochondria-derived signals relevant in the RA disease process that offer novel opportunities to deter autoimmune tissue inflammation by metabolic interference.

Abstract INTRODUCTION Immunotherapies targeting PD-1 in recurrent glioblastoma (rGBM) have shown limited activity. We hypothesize combining therapies targeting immunosuppressive pathways with cytotoxic and antiangiogenic therapies will improve survival. This nonrandomized, noncomparative Phase II study examines safety and efficacy of an anti-PD-1 monoclonal antibody (retifanlimab), hypofractionated radiotherapy (HFRT), and bevacizumab, with or without an IDO1 inhibitor (epacadostat), in patients with rGBM. METHODS This is an open-label Phase II study of two regimens. Regimen A examines retifanlimab (500mg IV Q4W) + bevacizumab (10mg/kg IV Q2W) + HFRT (3.5Gy/day x 10) in patients with IDH1/2-WT rGBM. Regimen B adds epacadostat. Key inclusions include dexamethasone ≤ 4 mg/day and reirradiation candidacy. The primary endpoint is overall survival (OS) probability at 9 months (OS-9). An increase of OS-9 from 38% (bevacizumab alone) to 60% was considered clinically relevant and required 24 efficacy evaluable patients. RESULTS Regimen A accrual is complete; interim results are as follows: 26 rGBM enrolled, with 24 evaluable [median age 64.2 years (42.1-81.8); 29% female; 29% MGMT promotor methylated; 33.3% with multi-focal disease; median KPS 90 (70-100); median baseline dexamethasone 0 mg (0-4) and ALC 1,000 cells/µl (300-3,700)]. Patients received a median of 6 cycles as of May 2022 (2-24). Median follow-up is 16.0 months. Interim median PFS is 7.0 months (95%CI: 4.5~11.1) and median OS is 12.2 months (95%CI 7.1~18.0). Regimen A met primary endpoint with OS-9 of 67% (95%CI: 44~82%). Overall response rate is currently 58% (95%CI: 36.94~77.2%). There were five possible immune-related grade 3+ toxicities to date (n = 1 each colitis, vomiting, and seizure; n = 2 diarrhea). Regimen B is enrolling. CONCLUSIONS Interim analysis suggests combination retifanlimab, HFRT, and bevacizumab in rGBM is generally well-tolerated, with encouraging OS and PFS at the time of submission. Correlative analysis is ongoing and will be presented at the meeting.

3D time-of-flight (TOF) MR angiography (MRA) benefits from ultra-high-field MRI (≥7 T) due to improved contrast and increased signal-to-noise ratio. However, high-resolution TOF MRA at 7T usually requires longer acquisition times. In addition, relatively higher specific absorption rate (SAR) at 7T limits the choice of optimal pulse sequence parameters, especially if venous saturation is employed. Here, we illustrate the clinical application of ultra-high resolution cerebral 7T TOF MRA using compressed sensing in cases of artery of Percheron and lacunar infarcts, which showed superior resolution and exquisite details pertinent to the clinical diagnosis. The technical challenges associated with high-resolution 7T imaging were alleviated by optimization of sequence parameters and utilization of compressed sensing acceleration.