Citations

Abstract BACKGROUND Craniopharyngiomas are a rare tumor along the pituitary-hypothalamic axis. Genetic analysis revealed that 95% of papillary craniopharyngiomas (PCP) have BRAF V600E mutations (Brastianos et al. Nature Genetics 2014). We previously reported that BRAF/MEK inhibition was associated with significant anti-tumor activity in newly-diagnosed PCP patients (Brastianos et al. NEJM 2023). We have now evaluated the efficacy of vemurafenib/cobimetinib in a separate cohort of patients with recurrent PCP whose tumors progressed after prior radiation. METHODS In this multicenter, NCI-sponsored cooperative group trial, patients with histologically confirmed BRAF-positive PCP who progressed after radiation were treated with vemurafenib/cobimetinib. The primary endpoint of response rate (RR) based on centrally determined imaging data was to be evaluated in 16 patients, where a partial response was defined as ≥20% decrease in volume. This single arm, Simon two-stage phase 2 trial had 89% power to detect a true RR ≥ 30% (vs. null 5%; α=0.04). In this design, 3 or more observed responses in 16 evaluable patients would be considered evidence of promising activity. RESULTS Of the planned 16 patients, a total of 5 patients enrolled before the study was closed due to slow accrual. Median follow-up was 50 months (95% CI: 32 to not yet reached). Based on volumetric response criteria, all 5 patients had a response to treatment (100%; 95% CI: 47.8% to 100%). To date, 2 patients progressed, one of whom died 22 months after study entry. This cohort met the criteria for efficacy under the original design with >3 responders. No grade 4 or 5 toxicities were observed. CONCLUSIONS Vemurafenib/cobimetinib resulted in an objective response in all patients with previously treated PCP. The study met primary endpoint, similar to that reported for previously untreated PCP. Thus, BRAF/MEK inhibitors could be an effective tool for previously treated PCP and warrants further evaluation. SUPPORT U10CA180821; U10CA180882; Genentech, https://acknowledgments.alliancefound.org;ClinicalTrials.gov: NCT03224767

Abstract BACKGROUND Most meningiomas are considered benign tumors, however, a subset of meningiomas are characterized by a more aggressive clinical course and require multimodal treatment. Beyond surgery and radiation, there are no effective medical treatments available. Somatostatin receptor 2 (SSTR2) is expressed by the majority of meningiomas. [177Lu]Lu-DOTA-TATE (177Lu-Dotatate) is a SSTR2-targeting radioligand therapeutic agent that has been successful in other oncological entities, including neuroendocrine tumors. Here we report the results of a phase 2 clinical trial (NCT03971461) evaluating 177Lu-Dotatate in patients with advanced and treatment-refractory intracranial meningiomas. METHODS In this multicenter, open-label, phase 2 study, adults with advanced intracranial meningiomas received 177Lu-Dotatate at 7.4 GBq (200 mCi) every eight weeks for four doses. [68Ga]Ga-DOTA-TATE (68Ga-Dotatate) PET was performed before and at the end of treatment. The primary endpoint was progression-free survival at 6 months (PFS-6). Correlative studies evaluated the association of PFS-6, objective response rate, progression-free survival, overall survival with radiographic tumor measurements, and 68Ga-Dotatate uptake on PET. RESULTS Thirty-two patients (F=21, M=11) with progressive meningiomas (WHO 1=7, WHO 2=24, WHO 3=1) were enrolled. Median age was 65.5 (range 41-78) years. All patients previously underwent tumor resection and at least one course of radiation. Three patients (9%) had received medical therapy. Treatment with 177Lu-Dotatate was well tolerated, no treatment-limiting toxicities were observed. Of 29 evaluable patients at the data cutoff, 19 patients (66%) had achieved PFS-6 (WHO 1=4, WHO 2=15). Radiographically, the best response was partial response (PR) in 2 patients (6%) and stable disease (SD) in 20 patients (63%). CONCLUSIONS Treatment with SSTR2-targeting 177Lu-Dotatate is well tolerated and 66% of patients achieved PFS-6, comparing favorably to historical benchmarks, 177Lu-Dotatate therefore may be a useful new therapeutic modality for patients with advanced meningiomas and will be further explored in MOMENTUM-1 (NCT#06955169), an open-label, randomized, phase 2 trial.

Abstract BACKGROUND Glioblastoma (GBM) is highly aggressive with poor prognosis, especially in recurrent cases where treatments are limited. Intra-arterial (IA) Yttrium-90 (Y90) microsphere therapy, FDA-approved for hepatocellular carcinoma, offers the potential for targeted radiotherapy in recurrent GBM (rGBM). The FRONTIER trial evaluated the safety and feasibility of IA Y90-glass microsphere treatment for rGBM under an FDA Investigational Device Exemption. Materials and METHODS This prospective, single-arm, multi-center study included patients with rGBM in non-dominant, non-eloquent regions. The primary endpoint was 30-day incidence of treatment-related limiting toxicities (primarily ≥grade 3 non-hematologic, with exclusions). Secondary endpoints included adverse event (AE) rate, neurological changes, technical success (PET absorbed dose within ±20% of target), and efficacy. Treatment regions, defined via cerebral angiography-MRI fusion to cover the recurrent lesion, were targeted with 40±4Gy. Post-treatment evaluations included MRI, Y90-PET, and neurological assessments. RESULTS The procedure was well-tolerated by all twelve subjects and discharge occurred the following day with no decline in neurologic status. No limiting toxicities or device-related AEs were reported. Five patients experienced 8 procedure-related AEs (6 Grade 1, 2 Grade 3). Technical success was 100%, with post-treatment Y90-PET derived median absorbed dose of 41.5 Gy to the treatment region (median volume 80.3 cc). The median tumor absorbed dose was considerably higher at 124.2 Gy (median tumor volume 5.8 cc), indicating preferential tumor perfusion. At 2 months, 67% had stable disease, and 33% showed reduced T1-contrast enhancing volume within the treated area. Median progression-free survival was 3.1 (95% CI 0.92-NE) and overall survival (OS) was 9.3 months (95% CI 5.0-NE) from Y90 treatment. Exploratory analysis revealed a significant OS benefit for patients receiving a tumor absorbed dose above the median (11.9 vs 5.7 months, p=0.0073). CONCLUSION Results from this initial cohort suggest IA Y90-microsphere therapy is technically feasible and well-tolerated in rGBM. Further investigation is warranted.

Abstract While immunotherapy has transformed treatment in multiple solid tumors, its efficacy in high-grade glioma (HGG) remains limited. Understanding the molecular and clinical factors that influence HGG’s response to immunotherapy is essential to improving outcomes. We identified patients with grade 4 gliomas who had been treated with checkpoint inhibitor (CPI), virus therapy, or CMV-specific T- cell therapy and determined the association between their molecular, clinical, and demographic characteristics and survival outcomes. We identified 66 patients, 57 glioblastoma and 9 astrocytoma, IDH-mutant grade 4; 38 were treated with CPI, 22 with virus therapy, and 6 with CMV-specific T- cell therapy. PIK3CA mutation was associated with shorter PFS and OS (p=0.022, 0.073, respectively) among all patients and a shorter OS among CPI-treated patients (p=0.004). PIK3CA wild-type tumors had less PD-1 expression in CD3+/CD8+ T cells. In CPI-treated patients, IDH1/2 mutation was associated with a shorter OS (p=0.002), and mutations in RB1 and TERT promoter were associated with a shorter PFS (p-value=0.00056, 0.022, respectively). Length of CPI therapy of more than 6 months was associated with increased PFS and OS (p=0.048, 0.062, respectively), while steroid use at baseline was associated with a shorter OS (p=0.00023). Multifocal disease was associated with shorter PFS and OS durations (p=0.0017, 0.0013, respectively) among all patients. In HGG, PIK3CA, IDH1/2, RB1, and TERT promoter mutations may be associated with a poor response to immunotherapy. These results need to be validated in larger studies. Our results may provide the rationale for clinical trials combining PI3K and IDH inhibitors with CPI in HGG.

Background/Objectives: Immortality and anti-aging research is accelerating, with implications across medicine. This narrative review explores the biological principles, translational innovations, and ethical considerations at the intersection of aging and plastic surgery, reframed for a broad clinical audience. Methods: A narrative review of the literature from PubMed, clinical trials, and translational studies was conducted, with emphasis on regenerative medicine, stem cells, tissue engineering, gene editing, and longevity pharmacologics within the field of plastic and reconstructive surgery. Results: Key themes include (1) the biology of aging and epigenetic reprogramming, (2) esthetic and regenerative innovations with broader clinical significance, (3) emerging genetic and pharmacologic longevity strategies, (4) ethical and regulatory challenges, and (5) future directions such as nanotechnology, artificial intelligence, and digital immortality. Conclusions: Immortality remains an aspirational frontier, but innovations in regenerative science and longevity research offer opportunities for improving healthspans. Medicine as a whole must balance innovation with ethics, equity, and safety in translating these discoveries to patient care.

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 INTRODUCTION The Consortium for Clarity in Alzheimer's disease related dementias (ADRD) Research Through Imaging (CLARiTI) is a study that aims to collect standardized imaging and plasma biomarkers on 2000 Clinical Core participants enrolled across all Alzheimer's Disease Research Centers (ADRC) sites. We sought to summarize the known heterogeneity across centers regarding scientific focus and initial enrollment plans for CLARiTI. METHODS We developed and distributed a survey capturing information on the 36 CLARiTI site's theme/expertise, recruitment plans, and the intersection of CLARiTI with other ADRC imaging efforts. RESULTS Anticipated CLARiTI enrollees spanned 11 different categories of suspected etiologies underlying impairment. A wide range of risk factors were endorsed across sites regarding the enrollment of unimpaired individuals. Variability also existed regarding site‐level strategies in enrollment into CLARiTI versus other imaging efforts. DISCUSSION We anticipate that the 2000 individuals that will enroll into CLARiTI will reflect the clinical heterogeneity already in place across the ADRC network. Highlights The ADRC Consortium for Clarity in ADRD Research Through Imaging (CLARiTI) will leverage and contribute to the existing Alzheimer's Disease Research Centers (ADRC) program by supporting standardized imaging and plasma collection across all centers. We summarize the variation in scientific focus and enrollment plans across ADRC sites participating in CLARiTI. The anticipated CLARiTI cohort will reflect the clinical heterogeneity that already exists across the ADRC network. CLARiTI will contribute to scientific goals related to the detection of multi‐etiological signatures relevant for Alzheimer's disease and related disorders (ADRDs).