Efficacy and safety of inebilizumab in Asian participants with neuromyelitis optica spectrum disorder: Subgroup analyses of the N-MOmentum study.

BACKGROUND: Inebilizumab, an anti-CD19 B cell-depleting antibody, reduced the risk of a neuromyelitis optica spectrum disorder (NMOSD) attack, disability worsening, magnetic resonance imaging (MRI) lesion activity, and disease-related hospitalizations in participants with NMOSD in the N-MOmentum study (NCT02200770). However, the efficacy and safety outcomes of inebilizumab specific to an Asian population were not fully reported. Therefore, subgroup analyses of the N-MOmentum study were conducted post hoc to evaluate the efficacy and safety of inebilizumab in Asian participants with NMOSD. METHODS: The N-MOmentum study was a multicenter, double-blind, randomized, placebo-controlled phase 2/3 trial with an open-label extension period (OLP). In the subgroup analyses, data from Asian participants from the N-MOmentum study were compared with those of non-Asian participants. Eligible participants were randomly allocated (3:1) to receive 300 mg intravenous (IV) inebilizumab or placebo on Days 1 and 15. Participants who had an NMOSD attack or completed the randomized controlled period (RCP) could enter the OLP, where they received inebilizumab for ≥2 years. All participants who entered the OLP received inebilizumab 300 mg IV every 6 months. RESULTS: Overall, 230 participants received treatment (174 received inebilizumab and 56 received placebo), of whom 47 were Asian (39 received inebilizumab and 8 received placebo). Baseline characteristics were similar between the Asian and non-Asian subgroups, except for disease duration, annualized relapse rate prior to randomization in this study, and previous maintenance therapy. In the Asian subgroup, the risk of NMOSD attacks was reduced with inebilizumab versus placebo (hazard ratio, 0.202) and the attack-free rate at 28 weeks was 82.1% with inebilizumab versus 37.5% with placebo, in the 6-month RCP. NMOSD attack rates were comparable between the Asian and non-Asian subgroups. In the Asian subgroup, the rates of Expanded Disability Status Scale worsening from baseline, active MRI lesions, and disease-related hospitalizations tended to be lower in the inebilizumab group than in the placebo group; similar results were shown in the non-Asian subgroup. For long-term efficacy and safety (RCP and OLP), the annualized adjudicated NMOSD attack rate in Asian participants treated with inebilizumab was reduced (0.096) compared with that at baseline (1.04), with a mean follow-up period of inebilizumab treatment of 3.38 years, which was consistent with the results in the non-Asian subgroup. The risk of NMOSD attack decreased with prolonged duration of treatment in both the inebilizumab/inebilizumab and placebo/inebilizumab groups in the Asian and non-Asian subgroups. The incidence of treatment-emergent adverse events (TEAEs) was similar between the Asian and non-Asian subgroups. In the Asian and non-Asian subgroups, 15.2% and 35.2% of participants, respectively, had at least one serious TEAE and/or Grade ≥3 TEAE during long-term therapy. No deaths occurred in the Asian subgroup whereas three deaths occurred in the non-Asian subgroup. CONCLUSION: Inebilizumab reduced the risk of an NMOSD attack, progression of disability, MRI lesion activity, and disease-related hospitalizations in Asian participants with NMOSD. The efficacy of inebilizumab in reducing NMOSD attacks continued without any unexpected safety signals or concerns during long-term use in Asian participants.

Fish Bone Descending in the Mediastinum.

Ingested sharp foreign bodies rarely migrate extraluminally into adjacent organs such as the pharynx, lungs, and liver. Herein, we report a case of fish bone ingestion where the foreign body followed a unique migration trajectory. Computed tomography revealed a fish bone extraluminally located in the aortopulmonary space in the left mediastinum and peri-esophageal pneumomediastinum. Endoscopic examination indicated no injury to the esophageal mucosa but showed mucosal lacerations in the left hypopharynx. Accordingly, we reasoned that the fish bone penetrated the laryngopharynx and then descended in the mediastinum.

Single-Direction Approach for Thoracoscopic Segmentectomy of the Left Upper Lobe Anterior Segment With Mediastinal Lingular Artery.

Thoracoscopic resection of the anterior segment of the left upper lobe (S3) is technically challenging because of the intricate hilar structure and multiple intersegmental planes to be dissected. A single-direction approach for S3 segmentectomy is a technique in which surgeons dissect the hilum structures exclusively from the ventral side without dividing the interlobar fissure. Our consecutive case series and a representative surgical video demonstrated the feasibility of this approach in cases where the lingular artery arises from the first branch of the left pulmonary artery (mediastinal lingular artery).

The treatment and survival of patients with postoperative recurrent thymic carcinoma and neuroendocrine carcinoma: a multicenter retrospective study.

PURPOSE: There are few data available on the outcomes of postoperative recurrent thymic carcinoma (TC) and thymic neuroendocrine carcinoma (TNEC). The aim of this study is to evaluate the treatment and survival in patients with recurrent TC and TNEC after undergoing surgical resection. METHODS: A retrospective chart review was performed using our multicenter database to identify patients with a postoperative recurrence of TC and TNEC from 1995 to 2018. The clinicopathological factors were reviewed and the survival outcomes were analyzed. RESULTS: Sixty patients were identified among 152 patients who underwent resection of TC and TNEC. The median follow-up period from the first recurrence was 14.8 months (range 0-144). The 5-year post-recurrence survival was 23% for the whole cohort. According to a univariable analysis, advanced stage [hazard ratio (HR) 2.81, 95% confidence interval (CI) 1.09-9.54], interval between primary surgery and recurrence (HR 0.97, 95% CI 0.95-0.99), any treatment for recurrence (HR: 0.27, 95% CI 0.13-0.58) and chemotherapy for recurrence (HR: 0.46, 95% CI 0.22-0.95) were significant factors related to post-recurrence survival. CONCLUSIONS: Chemotherapy rather than surgery appears to be the mainstay treatment for managing patients with postoperative recurrent TC and TNEC and it may also be considered in multidisciplinary management. Further studies with a larger sample size are required to confirm our findings.

Neuropilin-1 modulates TGFß signaling to drive glioblastoma growth and recurrence after anti-angiogenic therapy.

Glioblastoma (GBM) is a rapidly progressive brain cancer that exploits the neural microenvironment, and particularly blood vessels, for selective growth and survival. Anti-angiogenic agents such as the vascular endothelial growth factor-A (VEGF-A) blocking antibody bevacizumab yield short-term benefits to patients due to blood vessel regression and stabilization of vascular permeability. However, tumor recurrence is common, and this is associated with acquired resistance to bevacizumab. The mechanisms that drive acquired resistance and tumor recurrence in response to anti-angiogenic therapy remain largely unknown. Here, we report that Neuropilin-1 (Nrp1) regulates GBM growth and invasion by balancing tumor cell responses to VEGF-A and transforming growth factor ßs (TGFßs). Nrp1 is expressed in GBM cells where it promotes TGFß receptor internalization and signaling via Smad transcription factors. GBM that recur after bevacizumab treatment show down-regulation of Nrp1 expression, indicating that altering the balance between VEGF-A and TGFß signaling is one mechanism that promotes resistance to anti-angiogenic agents. Collectively, these data reveal that Nrp1 plays a critical role in balancing responsiveness to VEGF-A versus TGFß to regulate GBM growth, progression, and recurrence after anti-vascular therapy.

Neuropilin 1 balances ß8 integrin-activated TGFß signaling to control sprouting angiogenesis in the brain.

Angiogenesis in the developing central nervous system (CNS) is regulated by neuroepithelial cells, although the genes and pathways that couple these cells to blood vessels remain largely uncharacterized. Here, we have used biochemical, cell biological and molecular genetic approaches to demonstrate that ß8 integrin (Itgb8) and neuropilin 1 (Nrp1) cooperatively promote CNS angiogenesis by mediating adhesion and signaling events between neuroepithelial cells and vascular endothelial cells. ß8 integrin in the neuroepithelium promotes the activation of extracellular matrix (ECM)-bound latent transforming growth factor ß (TGFß) ligands and stimulates TGFß receptor signaling in endothelial cells. Nrp1 in endothelial cells suppresses TGFß activation and signaling by forming intercellular protein complexes with ß8 integrin. Cell type-specific ablation of ß8 integrin, Nrp1, or canonical TGFß receptors results in pathological angiogenesis caused by defective neuroepithelial cell-endothelial cell adhesion and imbalances in canonical TGFß signaling. Collectively, these data identify a paracrine signaling pathway that links the neuroepithelium to blood vessels and precisely balances TGFß signaling during cerebral angiogenesis.

In vitro reconstruction and functional development of the superior colliculus in the retinotectal pathway.

In order to examine the formation of a neural network and the functional development of a visual pathway, we performed in vitro reconstruction of the retinotectal pathway using organotypic explants and co-culture methods. Retinas and superior colliculus (SC) slices obtained from embryonic rats were co-cultured on microelectrode array (MEA) substrates for four weeks. We observed retinal ganglion cell neurites innervating SC slices that evoked responses in retinas or SC slices after applying electrical stimulation. Functional connections between retinas and SC slices were formed in the cultures. At the same time, spontaneous electrical activities were recorded from both the retinas and SC slices over the four weeks. In the co-cultured SC slices, sporadic firings were initially observed at 3-4 days in vitro (DIV), and thereafter the frequency of spontaneous firing increased and synchronized activities occurred after two weeks in vitro (WIV). In most of the single-cultured SC slices, however, only sporadic firings were observed over four weeks. In addition, the retinas and SC slices were co-cultured to enable the exchange of soluble factors with each other via culture medium but not via direct neural connections. The activity patterns resembled ones of single-cultured SC slices. These results suggest that signal inputs from retinas through direct neural connections affect the development of SCs in the retinotectal pathway.

The astrocyte-expressed integrin αvß8 governs blood vessel sprouting in the developing retina.

The mouse retina is vascularized after birth when angiogenic blood vessels grow and sprout along a pre-formed latticework of astrocytes. How astrocyte-derived cues control patterns of blood vessel growth and sprouting, however, remains enigmatic. Here, we have used molecular genetic strategies in mice to demonstrate that αvß8 integrin expressed in astrocytes is essential for neovascularization of the developing retina. Selective ablation of αv or ß8 integrin gene expression in astrocytes leads to impaired blood vessel sprouting and intraretinal hemorrhage, particularly during formation of the secondary vascular plexus. These pathologies correlate, in part, with diminished αvß8 integrin-mediated activation of extracellular matrix-bound latent transforming growth factor ßs (TGFßs) and defective TGFß signaling in vascular endothelial cells, but not astrocytes. Collectively, our data demonstrate that αvß8 integrin is a component of a paracrine signaling axis that links astrocytes to blood vessels and is essential for proper regulation of retinal angiogenesis.