the-stroke-preclinical-assessment-network-multi-laboratory-model

The Stroke Preclinical Assessment Network Multi-Laboratory Model of Thromboembolic Stroke with Thrombolysis: TE-MCAo

Current translational rodent stroke models induce middle cerebral artery occlusion (MCAo) using nylon filaments, injected emboli, intraluminal thrombin, ...

Icahn School of Medicine at Mount Sinai

The SPAN trial (Stroke Preclinical Assessment Network) is the largest preclinical study testing acute stroke interventions in experimental focal cerebral ischemia using endovascular filament middle cerebral artery occlusion (MCAo). Besides testing interventions against controls, the prospective design captured numerous biological and procedural variables, highlighting the enormous heterogeneity introduced by the multicenter structure that might influence stroke outcomes. Here, we leveraged the unprecedented sample size achieved by the SPAN trial and the prospective design to identify the biological and procedural variables that affect experimental stroke outcomes in transient endovascular filament MCAo.

Biological and Procedural Predictors of Outcome in the Stroke Preclinical Assessment Network (SPAN) Trial.

Black race is associated with poorer prognosis in hormone receptor (HR)-positive, HER2-negative early breast cancer (EBC). The impact of race/ethnicity on the risk distribution and prognostic information provided by the 70-gene MammaPrint assay was evaluated.

Impact of race/ethnicity on MammaPrint genomic assay risk and prognosis in early breast cancer: A National Cancer Data Base analysis.

Redo surgical aortic valve replacement (rSAVR) has for long been the therapeutic reference standard for degenerated surgical aortic bioprostheses. Valve-in-valve transcatheter aortic valve replacement (ViV-TAVR) has emerged as an alternative for patients at high surgical risk due to its lower invasiveness. The long-term clinical efficacy of ViV-TAVR in patients at low to intermediate surgical risk remains unknown.

Rationale and Design of the REPEAT Trial: A Multicenter Randomized Trial Comparing Redo Surgical Aortic Valve Replacement to Valve-in-Valve Transcatheter Aortic Valve Replacement.

The SPAN (Stroke Preclinical Assessment Network) is a confirmatory multicenter trial network to test cerebroprotective interventions in experimental acute stroke. In a first-of-its-kind trial, SPAN tested 6 interventions in a rodent model of transient focal ischemic stroke. Here, we report the efficacy of fasudil, an isoform-nonselective rho-associated kinase inhibitor, on primary and secondary outcomes in the SPAN trial.

Multicenter SPAN Trial of Fasudil in Ischemic Stroke.

Evidence for sex differences in cognition in childhood is established, but less is known about the underlying neural mechanisms for these differences. Recent findings suggest the existence of brain-behavior relationship heterogeneities during infancy; however, it remains unclear whether sex underlies these heterogeneities during this critical period when sex-related behavioral differences arise. A sample of 316 infants was included with resting-state functional magnetic resonance imaging scans at neonate (3 weeks), 1 year and 2 years of age. We used multiple linear regression to test interactions between sex and resting-state functional connectivity on behavioral scores of working memory, inhibitory self-control, intelligence, and anxiety collected at 4 years of age. We found 6 age-specific, intra-hemispheric connections showing significant and robust sex differences in functional connectivity-behavior relationships. All connections are either with the prefrontal cortex or in regions with direct anatomical pathways to the prefrontal cortex. These sex differences in functional connectivity only emerge when associated with behavior and not in functional connectivity independently. Taken together, we capture robust and conserved brain mechanisms that are distinct to sex and are defined by their relationship to behavioral outcomes. Our results establish brain-behavior mechanisms as an important feature in the search for sex differences during development.

Sex differences in brain-behavior relationships in the first 2 years of life.

Overall response (OR) that combines complete (CR) and partial responses (PR) is the conventional end point for acute graft-versus-host disease (GVHD) trials. Because PR includes heterogeneous clinical presentations, reclassifying PR could produce a better end point. Patients in the primary treatment cohort from the Japanese Society for Transplantation and Cellular Therapy (JSTCT) were randomly divided into training and validation sets. In the training set, a classification and regression tree algorithm generated day 28 refined response (RR) criteria based on symptoms at treatment and day 28. We then evaluated RR for primary and second-line treatments, using the area under the receiver operating characteristic curve (AUC) and negative predictive value (NPV) for 6-month nonrelapse mortality as performance measures. RR considered patients with grade 0/1 at day 28 without additional treatment as responders. RR for primary treatment produced higher AUCs than OR with small improvement of NPVs in both validation sets: JSTCT (AUC, 0.73 vs 0.69 [P < .001]; NPV, 92.0% vs 89.6% [P < .001]) and the Mount Sinai Acute GVHD International Consortium (MAGIC; AUC, 0.71 vs 0.68 [P = .032]; NPV, 90.9% vs 89.8% [P = .009]). RR for second-line treatment produced similar AUCs but much higher NPVs than OR in both validation sets of JSTCT (AUC, 0.64 vs 0.63 [P = .775]; NPV, 74.5% vs 66.0% [P < .001]) and MAGIC (AUC, 0.67 vs 0.64 [P = .105]; NPV, 86.8% vs 76.1% [P = .004]). Classifying persistent but mild skin symptoms as responses and residual lower gastrointestinal GVHD as nonresponses were major drivers in improving the prognostic performance of RR. Our externally validated day 28 RR would serve as a better end point than conventional criteria in future first- and second-line treatment trials.

Refinement of day 28 treatment response criteria for acute GVHD: a collaboration study of the JSTCT and MAGIC.

Randomized controlled trial participants are expected to embrace assignment to any of the study arms, yet individuals' relative preference for the study arms invariably affects who participates in trials and for how long.

Preference for behavior change strategies in randomized controlled trials: Evidence from weight management.

Fingolimod is an immunomodulatory drug that has shown promising effects in stroke treatment, including improvements in neurofunctional recovery and a reduction in infarct size. Fingolimod modulates the sphingosine-1-phosphate receptors, which leads to the internalization of sphingosine-1-phosphate receptors on T and B lymphocytes, thereby preventing their egress from secondary lymphoid organs. Here, we report a secondary analysis from the Stroke Preclinical Assessment Network trial. We assessed the effects of fingolimod versus vehicle on stroke outcomes to better evaluate its therapeutic potential.

Fingolimod as a Potential Cerebroprotectant Results From the Stroke Preclinical Assessment Network.

Preclinical stroke research faces a critical translational gap, with animal studies failing to reliably predict clinical efficacy. To address this, the field is moving toward rigorous, multicenter preclinical randomized controlled trials (mpRCTs) that mimic phase 3 clinical trials in several key components. This collective statement, derived from experts involved in mpRCTs, outlines considerations for designing and executing such trials. mpRCTs offer advantages such as increased sample sizes, robust statistical design, incorporation of heterogeneity, and standardized protocols, but they face challenges in finding the right balance between standardization and heterogeneity, appropriate stroke model selection, and outcome measures, as well as the implementation of complex network infrastructure. We discuss the importance of rigorous study design, including appropriate stroke models, representation of biological variables and comorbidities, functional outcome readouts, and handling of attrition and mortality. Statistical considerations such as adaptive sequential designs, covariate adjustments, and appropriate handling of missing data are also addressed. The integration of machine learning, the implementation of common data elements, and the selection of appropriate therapeutic candidates are crucial for maximizing the efficiency and utility of mpRCTs. Furthermore, the transition toward mpRCT platforms, akin to clinical trial platforms, holds promise for facilitating continuous evaluation of therapies. Finally, we discuss data-sharing practices and the collateral benefits of mpRCTs, emphasizing their potential to improve preclinical stroke research and bridge the translational gap. Altogether, we hope that this article will serve as a starting point for a lasting debate on the future of stroke mpRCTs and their evolution toward a universally accepted set of principles.

Preclinical Ischemic Stroke Multicenter (PRISM) Trials Collective Statement: Opportunities, Challenges, and Recommendations for a New Era.

The Stroke Preclinical Assessment Network tested 6 therapeutic interventions initiated at the time of reperfusion after focal ischemic stroke in young mice, aging mice, obese mice, and spontaneously hypertensive rats. This randomized, controlled trial was conducted across 6 sites with concealed treatment and blinded neurobehavior assessments. The trial had an adaptive design with preset levels of efficacy and futility interrogated after each of 4 stages. The primary outcome was turning preference on the corner test at 1 month. The PARP (poly(ADP-ribose) polymerase) inhibitor, veliparib, was considered futile after the second stage when pooling all animal models (=231 veliparib; =344 placebo).

Multicenter Stroke Preclinical Assessment Network Analysis of Cardiovascular Risk Factor Subgroups Treated With the Poly(ADP-Ribose) Polymerase Inhibitor Veliparib.

Advancements in cancer therapies and improvements in survival have led to an increasing need to understand the impact of treatment on both severe and low-grade persisting symptoms and treatment-related toxicities. The National Cancer Institute launched the Cancer Moonshot Tolerability Consortium in 2018 to develop methods to analyze clinical and patient-reported tolerability data.

Analyses of adverse events and patient-reported outcomes with the toxicity index in cancer clinical trials.

CD16a triggers antibody-dependent cellular cytotoxicity (ADCC) and phagocytosis by natural killer (NK) cells and macrophages in anti-tumor immunity. However, CD16a undergoes cleavage by ADAM17 that dampens its anti-tumor immunity. We here develop a monoclonal antibody (F9H4) that binds to CD16a and inhibits its cleavage. F9H4 retains CD16a on the surface of NK cells and macrophages, without triggering or blocking CD16a. F9H4 also binds to and inhibits shedding of CD16b by neutrophils, and inhibits CD16a/b shedding by leukocytes in tumor samples from lung cancer patients. F9H4 promotes ADCC against lung cancer cells that are opsonized by cetuximab, an epidermal growth factor receptor antibody that engages CD16a. F9H4 synergizes with cetuximab to inhibit human lung adenocarcinoma development in immunodeficient mice reconstituted with human NK cells. F9H4 combining with cetuximab also inhibits murine lung carcinoma growth in Fc gamma receptor-humanized mice, and such effect is mediated by NK cells and macrophages. The efficacy of F9H4+cetuximab in lung cancer models is the proof-of-concept for this new approach that promotes anti-tumor functions of Fc-enabled antibodies.

Article	Year
Biological and Procedural Predictors of Outcome in the Stroke Preclinical Assessment Network (SPAN) Trial. Circulation research\| PubMed ID: 39034919	2024
Impact of race/ethnicity on MammaPrint genomic assay risk and prognosis in early breast cancer: A National Cancer Data Base analysis. Cancer\| PubMed ID: 40014375	2025
Rationale and Design of the REPEAT Trial: A Multicenter Randomized Trial Comparing Redo Surgical Aortic Valve Replacement to Valve-in-Valve Transcatheter Aortic Valve Replacement. Journal of the American Heart Association\| PubMed ID: 40371620	2025
Multicenter SPAN Trial of Fasudil in Ischemic Stroke. Stroke\| PubMed ID: 40421536	2025
Sex differences in brain-behavior relationships in the first 2 years of life. Cerebral cortex (New York, N.Y. : 1991)\| PubMed ID: 40485343	2025
Refinement of day 28 treatment response criteria for acute GVHD: a collaboration study of the JSTCT and MAGIC. Blood advances\| PubMed ID: 40590886	2025
Preference for behavior change strategies in randomized controlled trials: Evidence from weight management. Contemporary clinical trials\| PubMed ID: 40738220	2025
Fingolimod as a Potential Cerebroprotectant Results From the Stroke Preclinical Assessment Network. Stroke\| PubMed ID: 40899256	2025
Preclinical Ischemic Stroke Multicenter (PRISM) Trials Collective Statement: Opportunities, Challenges, and Recommendations for a New Era. Stroke\| PubMed ID: 40931817	2025
Multicenter Stroke Preclinical Assessment Network Analysis of Cardiovascular Risk Factor Subgroups Treated With the Poly(ADP-Ribose) Polymerase Inhibitor Veliparib. Journal of the American Heart Association\| PubMed ID: 40996065	2025
Analyses of adverse events and patient-reported outcomes with the toxicity index in cancer clinical trials. Cancer\| PubMed ID: 41123586	2025
A monoclonal antibody that inhibits the shedding of CD16a and CD16b and promotes antibody-dependent cellular cytotoxicity against tumors. Nature communications\| PubMed ID: 41219228	2025

Marcio A. Diniz

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