Statistical analysis plan for the multicenter, open, randomized controlled clinical trial to assess the efficacy and safety of intravenous tirofiban vs aspirin in acute ischemic stroke due to tandem lesion, undergoing recanalization therapy by endovascular treatment (ATILA trial).

RATIONALE: In-stent reocclusion after endovascular therapy has a negative impact on outcomes in acute ischemic stroke (AIS) due to tandem lesions (TL). Optimal antiplatelet therapy approach in these patients to avoid in-stent reocclusion is yet to be elucidated. AIMS: To assess efficacy and safety of intravenous tirofiban versus intravenous aspirin in patients undergoing MT plus carotid stenting in the setting of AIS due to TL. SAMPLE SIZE ESTIMATES: Two hundred forty patients will be enrolled, 120 in every treatment arm. METHODS AND DESIGN: A multicenter, prospective, randomized, controlled (aspirin group), assessor-blinded clinical trial will be conducted. Patients fulfilling the inclusion criteria will be randomized at MT onset to the experimental or control group (1:1). Intravenous aspirin will be administered at a 500-mg single dose and tirofiban at a 500-mcg bolus followed by a 200-mcg/h infusion during the first 24 h. All patients will be followed for up to 3 months. STUDY OUTCOMES: Primary efficacy outcome will be the proportion of patients with carotid in-stent thrombosis within the first 24 h after MT. Primary safety outcome will be the rate of symptomatic intracranial hemorrhage. DISCUSSION: This will be the first clinical trial to assess the best antiplatelet therapy to avoid in-stent thrombosis after MT in patients with TL. TRIAL REGISTRATION: The trial is registered as NCT05225961. February, 7th, 2022.

Spatially patterned 3D model mimics key features of cancer metastasis to bone.

Bone is the most common target of metastasis in breast cancer and prostate cancer, leading to significant mortality due to lack of effective treatments. The discovery of novel therapies has been hampered by a lack of physiologically relevant in vitro models that can mimic key clinical features of bone metastases. To fill this critical gap, here we report spatially patterned, tissue engineered 3D models of breast cancer and prostate cancer bone metastasis which mimic bone-specific invasion, cancer aggressiveness, cancer-induced dysregulation of bone remodeling, and in vivo drug response. We demonstrate the potential of integrating such 3D models with single-cell RNA sequencing to identify key signaling drivers of cancer metastasis to bone. Together, these results validate that spatially patterned 3D bone metastasis models mimic key clinical features of bone metastasis and can serve as a novel research tool to elucidate bone metastasis biology and expedite drug discovery.

Safety and efficacy of tirofiban in acute ischemic stroke due to tandem lesions undergoing mechanical thrombectomy: A multicenter randomized clinical trial (ATILA) protocol.

Background: In-stent thrombosis after mechanical thrombectomy (MT) worsen outcomes in acute ischemic stroke (AIS) due to tandem lesions (TL). Although an optimal antiplatelet therapy is needed, the best approach to avoid in-stent thrombosis is yet to be elucidated. Hypothesis: Low-dose intravenous tirofiban is superior to intravenous aspirin in avoiding in-stent thrombosis in patients undergoing MT plus carotid stenting in the setting of AIS due to TL. Methods: The ATILA-trial is a multicenter, prospective, phase IV, randomized, controlled (aspirin group as control), assessor-blinded clinical trial. Patients fulfilling inclusion criteria (AIS due to TL, ASPECTS ⩾ 6, pre-stroke modified Rankin Scale ⩽2 and onset <24 h) will be randomized (1:1) at MT onset to experimental (intravenous tirofiban) or control group (intravenous aspirin). Intravenous aspirin will be administered at a 500 mg single dose and tirofiban at a 500 µg bolus followed by a 200 µg/h infusion during first 22 h. All patients will be followed up to 3 months. Sample size estimated is 240 patients. Outcomes: The primary efficacy outcome is the proportion of patients with carotid in-stent thrombosis within the first 24 h after MT. The primary safety outcome is the rate of symptomatic intracranial hemorrhage. Secondary outcomes include functional independence defined as modified Rankin Scale 0-2, proportion of patients undergoing rescue therapy due to in-stent aggregation during MT and carotid reocclusion at 30 days. Discussion: ATILA-trial will be the first clinical trial regarding the best antiplatelet therapy to avoid in-stent thrombosis after MT in patients with TL. Trial registration: NCT0522596.

Economic impact of the first pass effect in mechanical thrombectomy for acute ischaemic stroke treatment in Spain: a cost-effectiveness analysis from the national health system perspective.

OBJECTIVE: The mechanical thrombectomy (MT) benefit is related to the degree of reperfusion achieved. First pass effect (FPE) is defined as complete/near revascularisation of the large-vessel occlusion (modified Thrombolysis in Cerebral Infarction (mTICI) 2c-3) after a single device pass. This study assessed the health benefit and economic impact of achieving FPE for acute ischaemic stroke (AIS) patients from the Spanish National Health System (NHS) perspective. DESIGN: A lifetime Markov model was used to estimate incremental costs and health outcomes (measured in quality-adjusted life-years (QALYs)) of patients that achieve FPE. A subanalysis of the Systematic Evaluation of Patients Treated With Neurothrombectomy Devices for Acute Ischaemic Stroke (STRATIS) registry was performed to obtain clinical outcomes. The base case included all patients that achieved at least a final mTICI ≥2 b, while the alternative scenario included all patients regardless of their final mTICI (0-3). Treatment costs were updated to reflect current practice based on expert panel consensus, while other acute and long-term costs were obtained from a previous cost-effectiveness analysis of MT performed in Spain. Sensitivity analyses were performed to assess the model's robustness. SETTING: Spanish healthcare perspective. PARTICIPANTS: AIS patients in Spain. INTERVENTIONS: FPE following MT. OUTCOME MEASURES: The model estimated QALYs, lifetime costs and net monetary benefit for the FPE and non-FPE group, depending on the inclusion of reperfusion groups and formal care costs. RESULTS: STRATIS subanalysis estimated significantly better clinical outcomes at 90 days for the FPE group in all scenarios. In the base case, the model estimated lifetime cost saving per patient of €16 583 and an incremental QALY gain of 1.2 years of perfect health for the FPE group. Cost savings and QALY gains were greater in the alternative scenario (-€44 289; 1.75). In all scenarios, cost savings were driven by the long-term cost reduction. CONCLUSION: Achieving FPE after MT can lead to better health outcomes per AIS patient and important cost savings for the Spanish NHS.

A 3D Osteosarcoma Model with Bone-Mimicking Cues Reveals a Critical Role of Bone Mineral and Informs Drug Discovery.

Osteosarcoma (OS) is an aggressive bone cancer for which survival has not improved over three decades. While biomaterials have been widely used to engineer 3D soft-tissue tumor models, the potential of engineering 3D biomaterials-based OS models for comprehensive interrogation of OS pathology and drug discovery remains untapped. Bone is characterized by high mineral content, yet the role of bone mineral in OS progression and drug response remains unknown. Here, a microribbon-based OS model with bone-mimicking compositions is developed to elucidate the role of 3D culture and hydroxyapatite in OS signaling and drug response. The results reveal that hydroxyapatite in 3D is critical to support retention of OS signaling and drug resistance similar to patient tissues and mouse orthotopic tumors. The physiological relevance of this 3D model is validated using four established OS cell lines, seven patient-derived xenograft (PDX) cell lines and two animal models. Integrating 3D OS PDX models with RNA-sequencing identified 3D-specific druggable target, which predicts drug response in mouse orthotopic model. These results establish microribbon-based 3D OS models as a novel experimental tool to enable discovery of novel therapeutics that would be otherwise missed with 2D model and may serve as platforms to study patient-specific OS heterogeneity and drug resistance mechanisms.

Treatment of Intracranial Aneurysms Using the New Silk Vista Flow Diverter: Safety Outcomes at Short-Term Follow-Up.

Background: Flow diverters are widely used as the first endovascular treatment option for complex brain aneurysms due to their high percentage of occlusion and low morbi-mortality. The Silk Vista device is a new generation of flow diverters designed to facilitate full visibility, improve apposition to the vessel wall, and enhance navigability. Indeed, its greatest advantage is that it enables the easier navigation of stents between 3.5 and 4.75 mm through a 0.021 microcatheter. The objective of this study was to evaluate the safety and effectiveness of Silk Vista systems for treating cerebral aneurysms. Methods: This prospective observational study included 25 consecutive patients with 27 wide-necked unruptured aneurysms treated with SILK Vista who were retrospectively analyzed for safety and efficacy. Results: Endovascular treatment was successfully performed in all patients. The final morbidity and mortality rates were both 0.0%. Short-term (3-5 months) angiographic follow-up revealed 21 complete occlusions and 6 near-complete occlusions. No significant parent artery stenosis was observed. Conclusions: This report demonstrates the efficacy of Silk Vista in treating brain aneurysms, although longer experiences should be carried out to confirm our results.

Gradient Hydrogels for Optimizing Niche Cues to Enhance Cell-Based Cartilage Regeneration.

Hydrogels have been widely used for cell delivery to enhance cell-based therapies for cartilage tissue regeneration. To better support cartilage deposition, it is imperative to determine hydrogel formulation with physical and biochemical cues that are optimized for different cell populations. Previous attempts to identify optimized hydrogels rely mostly on testing hydrogel formulations with discrete properties, which are time-consuming and require large amounts of cells and materials. Gradient hydrogels encompass a range of continuous changes in niche properties, therefore offering a promising solution for screening a wide range of cell-niche interactions using less materials and time. However, harnessing gradient hydrogels to assess how matrix stiffness modulates cartilage formation by different cell types in vivo have never been investigated before. The goal of this study is to fabricate gradient hydrogels for screening the effects of varying hydrogel stiffness on cartilage formation by mesenchymal stem cells (MSCs) and chondrocytes, respectively, the two most commonly used cell populations for cartilage regeneration. We fabricated stiffness gradient hydrogels with tunable dimensions that support homogeneous cell encapsulation. Using gradient hydrogels with tunable stiffness range, we found MSCs and chondrocytes exhibit opposite trend in cartilage deposition in response to stiffness changes in vitro. Specifically, MSCs require soft hydrogels with Young's modulus less than 5 kPa to support faster cartilage deposition, as shown by type II collagen and sulfated glycosaminoglycan staining. In contrast, chondrocytes produce cartilage more effectively in stiffer matrix (>20 kPa). We chose optimal ranges of stiffness for each cell population for further testing in vivo using a mouse subcutaneous model. Our results further validated that soft matrix (Young's modulus <5 kPa) is better in supporting MSC-based cartilage deposition in three-dimensional, whereas stiffer matrix (Young's modulus >20 kPa) is more desirable for supporting chondrocyte-based cartilage deposition. Our results show the importance of optimizing niche cues in a cell-type-specific manner and validate the potential of using gradient hydrogels for optimizing niche cues to support cartilage regeneration in vitro and in vivo. Impact statement The present study validates the utility of gradient hydrogels for determining optimal hydrogel stiffness for supporting cartilage regeneration using both chondrocytes and stem cells. We demonstrate that such gradient hydrogels can be used for fast optimizing matrix stiffness for specific cell type to support optimal cartilage regeneration. To our knowledge, this is the first demonstration of applying gradient hydrogels for assessing optimal niche cues that support tissue regeneration in vivo and may be used for assessing optimal niche cues for different cell types to regeneration of different tissues.

Symptomatic intracranial embolic foreign-body reactions after endovascular neurointerventional procedures: A retrospective study in a tertiary hospital.

INTRODUCTION: Polymer-coats may peel-off the surface of catheters and devices during endovascular procedures and might lead to brain inflammatory foreign-body reactions. METHODS: We conducted a retrospective, descriptive, single-centre study including all patients with symptomatic intracranial oedematous and contrast-enhancing lesions after any neurointerventional procedure performed in our hospital between 2013 and 2019. RESULTS: From a total of 7446 neurointerventional procedures, 11 cases were identified (9 female, 2 male, median age 47 year-old), with an incidence of 0.14 %. The procedures were therapeutic in all: ten aneurysm embolization/isolation, one acute ischaemic stroke recanalization. Intracranial coils, stent or both were placed in all. Symptoms appeared during the following one day to fourteen months (median of 4.2 weeks). Brain MRI showed oedematous, contrast-enhancing lesions scattered through the vascular territory of the canalized vessel. Brain biopsy confirmed the diagnosis in one case and was supportive in another one. Eight patients received immunosuppression. No treatment was started in two. After a median time of follow-up of 3.5 years, five patients are totally asymptomatic. One patient presents slight weakness. Four patients have remote symptomatic seizures, but they have comorbid lesions (previous stroke, intracranial haemorrhage, biopsy needle-track's gliosis). Follow-up MRI showed significant improvement in all the cases, with complete resolution in five. Non-symptomatic lesion fluctuation was observed in three cases. Two patients experienced symptomatic rebounds. CONCLUSION: Intracranial embolic foreign-body symptomatic reactions are uncommon complications of neurointerventional procedures. Diagnostic angiographies might have lower risk of polymer-embolization than therapeutic procedures. This entity's early recognition enables making proper diagnosis and treatment decisions.

Tissue-engineered 3D models for elucidating primary and metastatic bone cancer progression.

Malignant bone tumors are aggressive neoplasms which arise from bone tissue or as a result of metastasis. The most prevalent types of cancer, such as breast, prostate, and lung cancer, all preferentially metastasize to bone, yet the role of the bone niche in promoting cancer progression remains poorly understood. Tissue engineering has the potential to bridge this knowledge gap by providing 3D in vitro systems that can be specifically designed to mimic key properties of the bone niche in a more physiologically relevant context than standard 2D culture. Elucidating the crucial components of the bone niche that recruit metastatic cells, support tumor growth, and promote cancer-induced destruction of bone tissue would support efforts for preventing and treating these devastating malignancies. In this review, we summarize recent efforts focused on developing in vitro 3D models of primary bone cancer and bone metastasis using tissue engineering approaches. Such 3D in vitro models can enable the identification of effective therapeutic targets and facilitate high-throughput drug screening to effectively treat bone cancers. STATEMENT OF SIGNIFICANCE: Biomaterials-based 3D culture have been traditionally used for tissue regeneration. Recent research harnessed biomaterials to create 3D in vitro cancer models, with demonstrated advantages over conventional 2D culture in recapitulating tumor progression and drug response in vivo. However, previous work has been largely limited to modeling soft tissue cancer, such as breast cancer and brain cancer. Unlike soft tissues, bone is characterized with high stiffness and mineral content. Primary bone cancer affects mostly children with poor treatment outcomes, and bone is the most common site of cancer metastasis. Here we summarize emerging efforts on engineering 3D bone cancer models using tissue engineering approaches, and future directions needed to further advance this relatively new research area.

Mineralized Biomaterials Mediated Repair of Bone Defects Through Endogenous Cells.

Synthetic biomaterials that create a dynamic calcium (Ca2+)-, phosphate (PO43-) ion-, and calcium phosphate (CaP)-rich microenvironment, similar to that found in native bone tissue, have been shown to promote osteogenic commitment of stem cells in vitro and in vivo. The intrinsic osteoconductivity and osteoinductivity of such biomaterials make them promising bone grafts for the treatment of bone defects. We thus aimed to evaluate the potential of mineralized biomaterials to induce bone repair of a critical-sized cranial defect in the absence of exogenous cells and growth factors. Our results demonstrate that the mineralized biomaterial alone can support complete bone formation within critical-sized bone defects through recruitment of endogenous cells and neo-bone tissue formation in mice. The newly formed bone tissue recapitulated many key characteristics of native bone such as formation of bone minerals reaching similar bone mineral density, presence of bone-forming osteoblasts and tartrate-resistant acid phosphatase-expressing osteoclasts, as well as vascular networks. Biomaterials that recruit endogenous cells and provide a tissue-specific microenvironment to modulate cellular behavior and support generation of functional tissues are a key step forward in moving bench-side tissue engineering approaches to the bedside. Such tissue engineering strategies could eventually pave the path toward readily available therapies that significantly reduce patient cost of care and improve overall clinical outcomes.

Clinical Outcome of Mechanical Thrombectomy for Stroke in the Elderly.

BACKGROUND: Endovascular revascularization with mechanical devices has proven an effective treatment for proximal occlusions of the major intracranial arteries in stroke patients, but there is only limited information as to whether there should be an age limit for its use. We aimed to evaluate the safety and effectiveness of endovascular revascularization in stroke patients aged 80 years and older, and compare the results with younger patients. METHODS: We prospectively collected 81 consecutive patients subjected to mechanical thrombectomy for proximal occlusion of the anterior circulation during a period of 27 months. According to age, patients were divided into those aged less than 80 years (younger group) and those aged 80 years and older (elderly group). We analyzed favorable outcome, successful and futile recanalization, neurological improvement, in-hospital complications, and mortality in both groups. RESULTS: A favorable outcome (modified Rankin Scale score ≤2 at 3 months) was reached by 51.6% in the elderly group and 64% of younger patients, and neurological improvement (improvement of ≥4 points on National Institutes of Health Stroke Scale) was present in 77.4% of the elderly group. Overall, successful recanalization rates were 95.1% and futile recanalization reached 39% without statistically significant differences between both groups. Elderly patients presented more in-hospital complications (61.3% versus 38%) and higher mortality rates (16.1% versus 8%). CONCLUSIONS: Clinical independence was reached in over half of elderly stroke patients treated with mechanical thrombectomy, supporting the use of this treatment without age restriction.

Hydrogels as Extracellular Matrix Analogs.

The extracellular matrix (ECM) is the non-cellular component of tissue that provides physical scaffolding to cells. Emerging studies have shown that beyond structural support, the ECM provides tissue-specific biochemical and biophysical cues that are required for tissue morphogenesis and homeostasis. Hydrogel-based platforms have played a key role in advancing our knowledge of the role of ECM in regulating various cellular functions. Synthetic hydrogels allow for tunable biofunctionality, as their material properties can be tailored to mimic those of native tissues. This review discusses current advances in the design of hydrogels with defined physical and chemical properties. We also highlight research findings that demonstrate the impact of matrix properties on directing stem cell fate, such as self-renewal and differentiation. Recent and future efforts towards understanding cell-material interactions will not only advance our basic understanding, but will also help design tissue-specific matrices and delivery systems to transplant stem cells and control their response in vivo.