Citations

Background: Acoramidis is a novel, potent, investigational, transthyretin (TTR) stabilizer under development for the treatment of TTR amyloidosis that results in near-complete (≥90%) TTR stabilization. In a phase 3 study, ATTRibute-CM, acoramidis demonstrated improved clinical outcomes in participants with transthyretin amyloid cardiomyopathy (ATTR-CM), including a 50% reduction in the risk of CVH compared to placebo over 30 months. The study also demonstrated that cardiovascular hospitalization (CVH) during the study predicted a higher subsequent mortality in participants with ATTR-CM. Hypothesis: CVH portends a higher risk of mortality in participants with ATTR-CM. Since acoramidis reduces CVH, it can improve the prognosis of participants with ATTR-CM. Aim: To evaluate the relationship between CVH and survival in the acoramidis group within ATTRibute-CM. Methods: In this post-hoc analysis, the relationship between those with or without CVH and survival was analyzed within the acoramidis treatment group using the Kaplan-Meier (KM) estimator method. Results: Demographics and baseline disease characteristics were mostly comparable between acoramidis-treated participants with and without CVH, although participants with CVH had a higher baseline NT-proBNP and lower eGFR. At Month 30, in acoramidis-treated participants, those without any CVH (n=300) had a higher survival [86.8% (95% CI = 82.2, 90.3)] versus 62.4% (95% CI = 52.6, 70.7) in those who had any CVH (n=109); p<0.0001 from log-rank test (Figure). Conclusion: In the ATTRibute-CM study, pts without any CVH receiving acoramidis have a higher survival rate. CVHs remain a powerful predictor of mortality. This reinforces the importance of an effective therapy that reduces CVH and in turn may improve survival in patients with ATTR-CM.

Abstract The DNA damage response (DDR) and the blood tumor barrier (BTB) restrict chemotherapeutic success for primary brain tumors like glioblastoma (GBM). Coherently, GBM almost invariably relapse with fatal outcome. We here show that interaction of GBM and myeloid cells simultaneously induces chemoresistance on the genetic and the vascular level by activating GP130 receptor signaling, which can be addressed therapeutically. We performed transcriptomic and immunohistochemical screens with human brain material, pharmacological experiments with a humanized organotypic GBM model, proteomics and cell-based assays and observed that nanomolar concentrations of the signaling peptide Humanin promoted TMZ resistance through DDR activation. GBM mouse models recapitulating intratumoral Humanin-release showed accelerated BTB formation. Genetic analysis of pericyte to endothelial cell signaling in transgenic mice revealed increased GP130 activation in Humanin releasing tumors as compared to controls. GP130 blockade attenuated both DDR activity and BTB formation resulting in improved preclinical chemotherapeutic efficacy. Altogether, we describe an overarching mechanism for TMZ resistance and outline a translatable strategy with predictive markers to improve chemotherapy for GBM.

Spinal cord stimulation (SCS), first used for pain relief in 1967, serves as an invasive neuromodulation with the targeted delivery of stimulations and the alertness of neural activities. Based on the gate-controlled theory of pain and multiple research studies, the application of SCS to motor recovery, pain relief, and sensory and cognitive restoration has been shown to be significant. Considering that movement disorders and pain are complications of various diseases, the categories, applications, and technical operation of SCS are coming of age. In terms of its impact on the immune system, SCS alters the trajectory of neurological diseases by modulating local immune responses through immunomodulatory mechanisms that vary depending on the different patterns of SCS. In addition to existing targets, the combinations of SCS and emerging techniques deepen the research at the molecular level, contributing to the exploration of potential targets and novel treatments. However, to secure a place in the future trend of non-invasive and precise treatment, it is necessary to improve SCS in terms of mechanism research, cost reduction, and application to more diseases.

BACKGROUND AND OBJECTIVE: This investigation evaluates the safety and efficacy of stereotactic radiosurgery (SRS) vs observation for Koos grade I vestibular schwannomas (VS). METHODS: In a multicenter study, we retrospectively analyzed data of patients with Koos grade I VS who underwent SRS (SRS group) or were observed (observation group). Propensity score matching was used to equilibrate demographics, tumor size, and audiometric data across groups. The outcome analyzed included tumor control, preservation of serviceable hearing, and neurological function. RESULTS: The study matched 142 patients, providing a median follow-up period of 36 months. SRS significantly enhanced tumor control compared with observation, with a 100% control rate at both 5- and 8-year marks in the SRS group vs 48.6% and 29.5% in the observation group at the same time intervals, respectively ( P < .001). Preservation of serviceable hearing outcomes between groups showed no significant difference at 5 and 8 years, ensuring a comparable quality of auditory function (SRS 70.1% vs observation 53.4% at 5 years; P = .33). Furthermore, SRS was associated with a reduced likelihood of tinnitus (odds ratio [OR] = 0.46, P = .04), vestibular dysfunction (OR = 0.17, P = .002), and overall cranial nerve dysfunction (OR = 0.49, P = .03) at last follow-up. CONCLUSION: SRS management of patients with Koos grade I VS was associated with superior tumor control and reduced odds for cranial nerve dysfunction, while not compromising hearing preservation compared with observation. These findings support the safety and efficacy of SRS as a primary care approach for this patient population.

BACKGROUND AND OBJECTIVES: This study assessed the efficacy and safety of stereotactic radiosurgery (SRS) in comparison with watchful waiting for managing Koos grade II vestibular schwannomas (VS). METHODS: A retrospective, multicentric analysis was conducted, focusing on patients with Koos grade II VS who either received SRS (SRS group) or were observed (observation group). To ensure comparability between groups, propensity score matching was used, including factors such as demographic characteristics, tumor dimensions, and hearing assessments. The primary end points examined were tumor control, maintenance of serviceable hearing, and neurological outcomes. RESULTS: A total of 92 patients were equally matched across both cohorts, with a median follow-up of 37 months for the SRS group and 27.5 months for those observed. The SRS cohort exhibited superior tumor control over observation across 3, 5, and 8 years, achieving a 100% control rate vs 47.9%, 40.1%, and 34.3% for the observation group at these time intervals, respectively ( P < .001). Serviceable hearing preservation rates were comparable between the 2 groups throughout 3, 5, and 7 years (72.9% for SRS vs 65.4% for observation at 3 years; P = .86). Moreover, SRS management correlated with a lower incidence of vestibular symptoms (odds ratio = 0.11, P = .002), with no significant disparity in the deterioration of cranial nerve (CN) V or CN VII functions. Notably, the likelihood of experiencing any CN impairment was significantly diminished in the SRS cohort (odds ratio = 0.47, P = .04). CONCLUSION: For patients with Koos grade II VS, SRS offers superior tumor control rate and a lower risk of CN dysfunction without sacrificing hearing preservation.

Abstract Purpose: The three-arm, phase III KEYNOTE-361 study did not meet its dual primary endpoints of progression-free survival (PFS) or overall survival (OS) with first-line pembrolizumab plus chemotherapy versus chemotherapy in advanced urothelial carcinoma. This prespecified exploratory analysis assessed the association of tumor mutational burden (TMB) and PD-L1 combined positive score (CPS) with clinical outcomes. Patients and Methods: TMB and PD-L1 CPS were determined via whole-exome sequencing and PD-L1 IHC 22C3 pharmDx, respectively. The association was evaluated in each treatment arm using logistic regression [objective response rate (ORR)] and Cox proportional hazards regression models (PFS and OS); one-sided (pembrolizumab monotherapy; pembrolizumab plus chemotherapy) and two-sided (chemotherapy) nominal P values were calculated. Significance was prespecified at α = 0.05 without multiplicity adjustment. Efficacy was evaluated by prespecified cutoffs of 175 mutations/exome (TMB) and CPS 10 (PD-L1). Results: Of the 993 treated patients, 820 (82.6%) and 993 (100%) had evaluable TMB and CPS data, respectively. Continuous TMB was positively associated with ORR, PFS, and OS for pembrolizumab monotherapy (one-sided P &lt; 0.001, P &lt; 0.001, and P = 0.007, respectively); PFS and OS for pembrolizumab plus chemotherapy (one-sided P = 0.007 and P = 0.010, respectively); and OS for chemotherapy alone (two-sided P = 0.040). Continuous PD-L1 CPS showed evidence of anticipated association with ORR and PFS for pembrolizumab monotherapy. The subgroup with TMB ≥175 mutations/exome and PD-L1 CPS ≥10 had the highest PFS and OS improvements with pembrolizumab alone or with chemotherapy versus chemotherapy alone. Conclusions: These data suggest that TMB may be predictive of the response to pembrolizumab alone or with chemotherapy in advanced urothelial carcinoma.