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Background: Immune profiling has become an important tool for identifying predictive, prognostic and response biomarkers for immune checkpoint inhibitors from tumor microenvironment (TME). We aimed to build a multiplex immunofluorescence (mIF) panel to apply to formalin-fixed and paraffin-embedded tissues in mice tumors and to explore the programmed cell death protein 1/ programmed cell death 1 ligand 1 (PD-1/PD-L1) axis. Results: An automated eight-color mIF panel was evaluated to study the TME using seven antibodies, including cytokeratin 19, CD3e, CD8a, CD4, PD-1, PD-L1, F4-80 and DAPI, then was applied in six mice lung adenocarcinoma samples. Cell phenotypes were quantified by software to explore the co-localization and spatial distribution between immune cells within the TME. This mice panel was successfully optimized and applied to a small cohort of mice lung adenocarcinoma cases. Image analysis showed a sparse degree of immune cell expression pattern in this cohort. From the spatial analysis we found that T cells and macrophages expressing PD-L1 were close to the malignant cells and other immune cells. Conclusions: Comprehensive immune profiling using mIF in translational studies improves our ability to correlate the PD-1/PD-L1 axis and spatial distribution of lymphocytes and macrophages in mouse lung cancer cells to provide new cues for immunotherapy, that can be translated to human tumors for cancer intervention.

Triple-negative breast cancer (TNBC) with high tumour-infiltrating lymphocytes (TILs) has been associated with a promising prognosis. To better understand the prognostic value of immune cell subtypes in TNBC, we characterised TILs and the interaction between tumour cells and immune cell subtypes. A total of 145 breast cancer tissues were stained by multiplex immunofluorescence (mIF), including panel 1 (PD-L1, PD-1, CD3, CD8, CD68 and CK) and panel 2 (Foxp3, Granzyme B, CD45RO, CD3, CD8 and CK). Phenotypes were analysed and quantified by pathologists using InForm software. We found that in the ER-negative (ER <1% and HER2-negative) group and the ER/PR-low positive (ER 1–9% and HER2-negative) group, 11.2% and 7.1% of patients were PD-L1+by the tumour cell score, 29.0% and 28.6% were PD-L1+by the modified immune cell score and 30.8% and 32.1% were PD-L1+by the combined positive score. We combined ER-negative and ER/PR-low positive cases for the survival analysis since a 10% cut-off is often used in clinical practice for therapeutic purposes. The densities of PD-L1+tumour cells (HR: 0.366, 95% CI: 0.138–0.970; p= 0.043) within the tumour compartment and CD3+immune cells in the total area (tumour and stromal compartments combined) (HR: 0.213, 95% CI: 0.070–0.642; p= 0.006) were favourable prognostic biomarkers for overall survival (OS) in TNBC. The density of effector/memory cytotoxic T cells (CD3+CD8+CD45RO+) in the tumour compartment was an independent prognostic biomarker for OS (HR: 0.232, 95% CI: 0.086–0.628; p= 0.004) and DFS (HR: 0.183, 95% CI: 0.1301–0.744; p= 0.009) in TNBC. Interestingly, spatial data suggested that patients with a higher density of PD-L1+tumour cells had shorter cell-cell distances from tumour cells to cytotoxic T cells (p< 0.01). In conclusion, we found that phenotyping tumour immune cells by mIF is highly informative in understanding the immune microenvironment in TNBC. PD-L1+tumour cells, total T cells and effector/memory cytotoxic T cells are promising prognostic biomarkers in TNBC.

Triple-negative breast cancer (TNBC) with high tumour-infiltrating lymphocytes (TILs) has been associated with a promising prognosis. To better understand the prognostic value of immune cell subtypes in TNBC, we characterised TILs and the interaction between tumour cells and immune cell subtypes. A total of 145 breast cancer tissues were stained by multiplex immunofluorescence (mIF), including panel 1 (PD-L1, PD-1, CD3, CD8, CD68 and CK) and panel 2 (Foxp3, Granzyme B, CD45RO, CD3, CD8 and CK). Phenotypes were analysed and quantified by pathologists using InForm software. We found that in the ER-negative (ER <1% and HER2-negative) group and the ER/PR-low positive (ER 1–9% and HER2-negative) group, 11.2% and 7.1% of patients were PD-L1+by the tumour cell score, 29.0% and 28.6% were PD-L1+by the modified immune cell score and 30.8% and 32.1% were PD-L1+by the combined positive score. We combined ER-negative and ER/PR-low positive cases for the survival analysis since a 10% cut-off is often used in clinical practice for therapeutic purposes. The densities of PD-L1+tumour cells (HR: 0.366, 95% CI: 0.138–0.970; p= 0.043) within the tumour compartment and CD3+immune cells in the total area (tumour and stromal compartments combined) (HR: 0.213, 95% CI: 0.070–0.642; p= 0.006) were favourable prognostic biomarkers for overall survival (OS) in TNBC. The density of effector/memory cytotoxic T cells (CD3+CD8+CD45RO+) in the tumour compartment was an independent prognostic biomarker for OS (HR: 0.232, 95% CI: 0.086–0.628; p= 0.004) and DFS (HR: 0.183, 95% CI: 0.1301–0.744; p= 0.009) in TNBC. Interestingly, spatial data suggested that patients with a higher density of PD-L1+tumour cells had shorter cell-cell distances from tumour cells to cytotoxic T cells (p< 0.01). In conclusion, we found that phenotyping tumour immune cells by mIF is highly informative in understanding the immune microenvironment in TNBC. PD-L1+tumour cells, total T cells and effector/memory cytotoxic T cells are promising prognostic biomarkers in TNBC.

To describe the characteristics of patients with ankylosing spondylitis (AS) and patients with nonradiographic axial spondyloarthritis (SpA) in the US. Demographics, clinical characteristics, patient‐reported outcomes, and treatment characteristics of patients with ASand those with nonradiographic axial SpA were assessed at the time of enrollment in the Corrona Psoriatic Arthritis/Spondyloarthritis Registry. Patients with ASwere defined as those who fulfilled the 1984 modified New York criteria for AS; patients with nonradiographic axial SpA were defined as all other patients with axial SpA who did not fulfill the radiology criterion. Of the 407 patients with a diagnosis of axial SpA who were included in this study, 310 had AS, and 97 had nonradiographic axial SpA. Although patients with nonradiographic axial SpA were younger and showed a trend toward a shorter symptom duration, the nonradiographic axial SpA and ASgroups shared a similar disease burden, as reflected by comparisons of disease activity and function, quality of life, pain, fatigue, job absenteeism, and loss of work productivity (all P> 0.05). The proportions of patients with nonradiographic axial SpA and patients with ASwho received prior biologic disease‐modifying drugs (DMARDs) (74.2% and 64.8%, respectively) or were currently receiving biologic DMARDs (63.9% and 61.3%, respectively) were also similar (P> 0.05). This was the first nationwide study to characterize patients with ASand nonradiographic axial SpA in the US. Consistent with studies published outside of the US, this study showed that patients with nonradiographic axial SpA and patients with ASshared a comparable degree of disease burden and had similar treatment patterns in clinical practice.

Objective.We analyzed the characteristics of patients with psoriatic arthritis (PsA) with and without axial involvement in the US-based Corrona Psoriatic Arthritis/Spondyloarthritis Registry.Methods.All patients were included who had PsA and data on axial involvement, defined as physician-reported presence of spinal involvement at enrollment, and/or radiograph or magnetic resonance imaging showing sacroiliitis. Demographics, clinical measures, patient-reported outcomes, and treatment characteristics were assessed at enrollment.Results.Of 1530 patients with PsA, 192 (12.5%) had axial involvement and 1338 (87.5%) did not. Subgroups were similar in sex, race, body mass index, disease duration, presence of dactylitis, and prevalence of most comorbidities. However, patients with axial involvement were younger and more likely to have enthesitis, a history of depression, and more frequently used biologics at enrollment. They were also more likely to have moderate/severe psoriasis (body surface area ≥ 3%, 42.5% vs 31.5%) and significantly worse disease as measured by a lower prevalence of minimal disease activity (30.1% vs 46.2%) and higher nail psoriasis scores [visual analog scale (VAS) 11.4 vs 6.5], enthesitis counts (5.1 vs 3.4), Bath Ankylosing Spondylitis Disease Activity Index (4.7 vs 3.5) scores, Bath Ankylosing Spondylitis Functional Index (3.8 vs 2.5) scores, C-reactive protein levels (4.1 vs 2.4 mg/l), and scores for physical function (Health Assessment Questionnaire, 0.9 vs 0.6), pain (VAS, 47.7 vs 36.2), and fatigue (VAS, 50.2 vs 38.6).Conclusion.Presence of axial involvement was associated with a higher likelihood of moderate/severe psoriasis, with higher disease activity and greater effect on quality of life. These findings highlight the importance of monitoring patients with PsA for signs of axial symptoms or spinal involvement.

The purpose of this study was to assess the incidence of deterioration, fluctuation, and associated risk of poor outcome in patients with subcortical stroke (SCS).

The Combined Lysis of Thrombus in Brain Ischemia With Transcranial Ultrasound and Systemic T-PA-Hands-Free (CLOTBUST-HF) study is a first-in-human, National Institutes of Health–sponsored, multicenter, open-label, pilot safety trial of tissue-type plasminogen activator (tPA) plus a novel operator-independent ultrasound device in patients with ischemic stroke caused by proximal intracranial occlusion.

Argatroban is a direct thrombin inhibitor that safely augments recanalization achieved by tissue-type plasminogen activator (tPA) in animal stroke models. The Argatroban tPA Stroke Study was an open-label, pilot safety study of tPA plus Argatroban in patients with ischemic stroke due to proximal intracranial occlusion.

The beneficial effect of intravenous thrombolytic therapy in patients with acute ischemic stroke attributable to internal carotid artery (ICA) occlusion remains unclear. The aim of this study was to evaluate the efficacy and safety of intravenous recombinant tissue-type plasminogen activator in these patients.