Citations

Abstract GBM AGILE(NCT03970447) is a phase 2/3 Bayesian adaptive registration platform trial testing multiple therapies against a common control. Paxalisib, a PI3K/mTOR inhibitor, is the 3rd arm in the trial to conclude evaluation. METHODS Paxalisib was open to patients with newly diagnosed unmethylated (NDU) and recurrent (RD) glioblastoma, with three possible signatures: NDU, RD, and All(NDU+RD). Arm enrollment occurred Dec2020 through May2022. Control patients were enrolled from study initiation (July2019) and were treated with temozolomide(NDU) or lomustine(RD). GBM AGILE investigational arms have 1 or 2 stages, with adaptive randomization in stage 1 and fixed randomization if arms continue to stage 2. Efficacy is based on OS hazard ratio(HR) of Arm/Control. Efficacy goal is final Bayesian probability ≥ 98% for HR<1.00 in combined Stages. An Arm continues to Stage 2 if Bayesian predictive power (PP) ≥ 0.8. An Arm stops accruing in Stage 1 if it reaches maximal sample size(N) or does not meet a minimum efficacy threshold (PP<0.25 for all signatures when N>50). Clinical cut-off is 12 months after accrual stops. The maximum N for paxalisib was approximately 150(Stage 1) and 50(Stage 2). RESULTS After paxalisib reached >150 patients in Stage 1, accrual stopped [Paxalisib/control N 54/75(NDU), 100/188(RD)]. Neither PP thresholds for moving to Stage 2 nor stopping for minimum efficacy were met. Following an unplanned public disclosure that the arm did not continue to stage 2, clinical cut-off for final analysis (planned May2023) was updated to public disclosure date (August2022). At final analysis mean HRs were 0.89(NDU), 1.25(RD), 1.05(All), probabilities of HR<1.00 of 0.72(NDU), 0.076(RD), 0.398(All). Model estimated median OS paxalisib/control (months) were 14.77/13.84(NDU) and 8.58/10.06(RD). CONCLUSION Paxalisib did not show survival benefit over cumulative control in final primary analysis; additional secondary analyses are being considered. GBM AGILE continues to rapidly and efficiently assess therapies in ND and RD glioblastoma.

AbstractBackground and ObjectivesIn the setting of tissue hypoxia, S‐nitrosylated haemoglobin (SNO‐Hb) plays crucial roles in the control of blood flow. This is associated with decreased oxygen affinity to haemoglobin and increase in tissue oxygenation. Red blood cell (RBC) transfusion is primarily performed to improve tissue oxygenation in anaemic patients. RBCs after storage undergo a variety of biochemical and functional alterations, including deficiency of nitric oxide (NO) bioactivity. However, how donor characteristics affect NO levels during RBC storage is unclear. We sought to investigate the association of blood donor age, gender and storage duration with NO and SNO‐Hb levels in blood units.Materials and MethodsBlood samples from 42 healthy younger (≤30 years) and older (≥45 years) donors were collected and stored for up to 42 days. Total NO kits were used to detect total nitrite and nitrate levels in blood storage solution. SNO‐Hb levels in RBCs were detected and analysed by quantitative mass spectrometry.ResultsTotal NO levels in the blood storage solution significantly increased with donor age and storage duration. Proteomic analysis revealed that RBCs from older donors, particularly older females, significantly lost SNO‐Hb during storage. Our findings indicate that RBCs from older donors are associated with reduced SNO‐Hb levels and increased NO metabolites in storage solution after ≥35 days storage.ConclusionThe findings suggest stored RBCs from older donors may have reduced capacity to deliver oxygen to tissues under hypoxia. A shorter shelf life may be required for storing RBCs from older donors, particularly older females.

Arteriovenous malformations (AVMs) are abnormal connections of arteries and veins without intermediate capillary components. As such, AVMs can remain asymptomatic or have a variety of clinical presentations ranging from mild headaches to severe symptoms like seizures, hemorrhage, and subsequent coma. Papilledema and increased intracranial pressure without hydrocephalus or hemorrhage are rare forms of presentations of cerebral AVM. The mechanism of intracranial hypertension accompanying brain AVMs is not entirely understood, and the right treatment strategy is controversial. Here, we present the treatment and outcomes of four patients with unruptured AVMs who presented with intracranial hypertension accompanied by visual symptoms, papilledema, and without evidence of hydrocephalus. In cases of AVMs accompanied by intracranial hypertension, AVM treatment should be considered the main target of management.