Phase I pharmacokinetic, safety, and preliminary efficacy study of tiragolumab in combination with atezolizumab in Chinese patients with advanced solid tumors.

PURPOSE: Tiragolumab is an immunoglobulin G1 monoclonal antibody targeting the immune checkpoint T cell immunoreceptor with immunoglobulin and immunoreceptor ITIM domains. Targeting multiple immune pathways may improve anti-tumor responses. The phase I YP42514 study assessed the pharmacokinetics (PK), safety, and preliminary efficacy of tiragolumab plus atezolizumab in Chinese patients with advanced solid tumors. METHODS: Adult patients from mainland China with Eastern Cooperative Oncology Group performance score 0/1, life expectancy of ≥ 12 weeks, and adequate hematologic/end organ function were eligible. Patients received tiragolumab 600 mg and atezolizumab 1200 mg intravenous every 3 weeks. Key endpoints were PK (serum concentrations of tiragolumab and atezolizumab) and safety. Results from this study were compared with the global phase I study, GO30103 (NCT02794571). RESULTS: In this study, 20 patients received a median of five doses of tiragolumab plus atezolizumab. Median age was 57.5 years, 85.0% of patients were male and the most common tumor type was non-small cell lung cancer. Exposures in Chinese patients were comparable to the global GO30103 population: geometric mean ratio was 1.07 for Cycle 1 tiragolumab area under the concentration-time curve0-21 and 0.92 and 0.93 for Cycle 1 peak and trough atezolizumab exposure, respectively. Treatment-related adverse events were consistent across the Chinese and global populations. Two patients (10.0%) in this study achieved a partial response. CONCLUSION: In this study, tiragolumab plus atezolizumab was tolerable and demonstrated preliminary anti-tumor activity. There were no meaningful differences in the PK or safety of tiragolumab plus atezolizumab between the Chinese and global populations. CLINICAL TRIAL REGISTRATION NUMBER: China Clinical Trial Registry Identifier CTR20210219/YP42514. Date of registration 16 March 2021.

Effect of Seating Arrangement on Class Engagement in Team-based Learning: a Quasi-Experimental Study.

INTRODUCTION: This study investigated the effects of seating distance and orientation on engagement in novice and experienced learners in a large classroom explicitly designed for team-based learning (TBL). Learning what affects TBL engagement may improve its implementation. METHODS: Participants were novice first-year and experienced second-year undergraduate medical students in Singapore (male = 103, female = 57). Their age ranged from 18 to 23 (M = 19.5, SD = 1.06). This quasi-experimental study considered two factors. Firstly, the distance from the teams' table to the tutor's table. Secondly, students' orientation at each table, with either their front or back facing the tutor. Engagement was measured using two instruments, Situational Cognitive Engagement Measure and Classroom Engagement Survey at two TBL sessions - before and after swapping seating arrangements. RESULTS: For experienced students, seating distance did not significantly affect engagement (p = 0.08-0.89). Novice student's engagement levels decreased significantly for those who moved further; M = 3.30 to 2.98 (p = 0.009-0.023). However, overall engagement also decreased post-swap regardless of direction moved; M = 3.26 to 3.00 (p = 0.004). For both cohorts, seating orientation did not significantly affect engagement (p = 0.07-0.62). Those unaffected by seating arrangement commended the classroom's design, such as screens all around and quality audio-visual system. Novice students exhibited a stronger preference to sit nearer to the tutor than experienced students. Both groups preferred sitting with their front-facing the tutor. DISCUSSION: Within specially designed TBL classrooms, seating distance and orientation did not significantly affect engagement. Technologically enhanced team-centric spaces provide a favourable environment for TBL, though students' preferences for seats may change with more TBL experience. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s40670-021-01469-7.

A new case of a LUMBAR syndrome.

LUMBAR syndrome (lower body congenital infantile hemangiomas and other skin defects; urogenital anomalies and ulceration; myelopathy; bony deformities; anorectal malformations and arterial anomalies; and rectal anomalies) is a rare association between infantile hemangiomas of the lower half of the body and regional congenital anomalies. Since 1986, 53 cases have been reported and no etiology has been identified. We report on the 54th case in a male infant and review the literature concerning the manifestations of the LUMBAR syndrome.

Radial construction of an arterial wall.

Some of the most serious diseases involve altered size and structure of the arterial wall. Elucidating how arterial walls are built could aid understanding of these diseases, but little is known about how concentric layers of muscle cells and the outer adventitial layer are assembled and patterned around endothelial tubes. Using histochemical, clonal, and genetic analysis in mice, here we show that the pulmonary artery wall is constructed radially, from the inside out, by two separate but coordinated processes. One is sequential induction of successive cell layers from surrounding mesenchyme. The other is controlled invasion of outer layers by inner layer cells through developmentally regulated cell reorientation and radial migration. We propose that a radial signal gradient controls these processes and provide evidence that PDGF-B and at least one other signal contribute. Modulation of such radial signaling pathways may underlie vessel-specific differences and pathological changes in arterial wall size and structure.

Therapeutic responses to exogenous VEGF-C administration in experimental lymphedema: immunohistochemical and molecular characterization.

BACKGROUND: In a widely employed murine tail model of human acquired lymphedema, we have previously observed that, distal to the site of experimental lymphatic ablation, there is immunohistochemical evidence of a profound increase in cutaneous lymphatic vessel number and size that normalizes after VEGF-C administration. OBJECTIVE: In order to investigate the mechanistic basis of the lymphatic microvascular remodeling, we have studied the lymphedematous responses to VEGF-C after co-administration of systemic VEGFR-3 neutralizing antibody. We have also undertaken genome-wide whole-tissue transcriptional profiling of lymphedematous tissues before and after exogenous VEGF-C administration. STUDY DESIGN: We provoked postsurgical lymphedema in the mouse tail model and assessed the effects of exogenously administered human recombinant VEGF-C in the presence of a monoclonal anti-VEGFR-3 antibody. Polyclonal IgG was administered to a series of control subjects. Microvascular lymphatic remodeling was assessed through quantitative and qualitative anti-LYVE1 immunohistochemistry. Genome-wide transcriptional profiling was performed in whole skin derived from lymphedema with and without exogenous VEGF-C administration. Normal mice and surgical shams served as controls. RESULTS: In the presence of the monoclonal anti-VEGFR-3 neutralizing antibody, positive lymphatic microvascular remodeling in lymphedematous skin is nearly completely abrogated. Furthermore, the therapeutic impact of added VEGF-C is markedly attenuated, as is the ability of the growth factor to ameliorate tissue edema. Transcriptional profiling of the VEGF-C responses in treated lymphedema reveals a very restricted list of genes whose expression is upregulated in lymphedema and re-normalized following VEGF-C treatment. CONCLUSION: The postsurgical murine tail model of lymphedema closely simulates attributes of human lymphedema. The current series of investigations underscores the utility of the murine tail model to the preclinical and translational investigation of lymphedema. The derived insights continue to focus favorably upon the central role of the VEGFR-3 receptor and its ligands in the development and therapeutic resolution of lymphedema. Whole tissue transcriptional profiling continues to shed light on disease mechanisms and potential future targets for therapeutic intervention.

An experimental model for the study of lymphedema and its response to therapeutic lymphangiogenesis.

BACKGROUND: Evaluation of the efficacy of molecular treatment strategies for lymphatic vascular insufficiency requires a suitable preclinical animal model. Ideally, the model should closely replicate the untreated human disease in its pathogenesis and pathological expression. OBJECTIVE: We have undertaken a study of the time course of the development and resolution of acquired, experimental lymphedema and of its responses to vascular endothelial growth factor (VEGF)-C lymphangiogenesis in the mouse tail model. STUDY DESIGN: We provoked post-surgical lymphedema in the mouse tail model and assessed the effects of exogenously administered human recombinant VEGF-C. Quantitative assessment of immune traffic function was performed through sequential in vivo bioluminescent imaging. RESULTS: In untreated lymphedema, tail edema was sustained until day 21. Exogenous administration of human recombinant VEGF-C produced a significant decrease in volume. Untreated lymphedema in the mouse tail model was characterized by the presence of dilated cutaneous lymphatics, marked acute inflammatory changes, and hypercellularity; VEGF-C produced a substantial reversion to the normal pattern, with notable regression in the size and number of cutaneous lymphatic vessels that express lymphatic vessel endothelial hyaluronan receptor-1 (LYVE-1). In vivo imaging confirmed the presence of an impairment of immune traffic in lymphedema that was ameliorated after VEGF-C administration. CONCLUSION: The post-surgical murine tail model of lymphedema closely simulates attributes of human lymphedema and provides the requisite sensitivity to detect therapeutically induced functional and structural alterations. It can, therefore, be used as an investigative platform to assess mechanisms of disease and its responses to candidate therapies, such as therapeutic lymphangiogenesis.

Inflammatory manifestations of experimental lymphatic insufficiency.

BACKGROUND: Sustained lymph stagnation engenders a pathological response that is complex and not well characterized. Tissue inflammation in lymphedema may reflect either an active or passive consequence of impaired immune traffic. METHODS AND FINDINGS: We studied an experimental model of acute post-surgical lymphedema in the tails of female hairless, immunocompetent SKH-1 mice. We performed in vivo imaging of impaired immune traffic in experimental, murine acquired lymphatic insufficiency. We demonstrated impaired mobilization of immunocompetent cells from the lymphedematous region. These findings correlated with histopathological alterations and large-scale transcriptional profiling results. We found intense inflammatory changes in the dermis and the subdermis. The molecular pattern in the RNA extracted from the whole tissue was dominated by the upregulation of genes related to acute inflammation, immune response, complement activation, wound healing, fibrosis, and oxidative stress response. CONCLUSIONS: We have characterized a mouse model of acute, acquired lymphedema using in vivo functional imaging and histopathological correlation. The model closely simulates the volume response, histopathology, and lymphoscintigraphic characteristics of human acquired lymphedema, and the response is accompanied by an increase in the number and size of microlymphatic structures in the lymphedematous cutaneous tissues. Molecular characterization through clustering of genes with known functions provides insights into processes and signaling pathways that compose the acute tissue response to lymph stagnation. Further study of genes identified through this effort will continue to elucidate the molecular mechanisms and lead to potential therapeutic strategies for lymphatic vascular insufficiency.