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Rationale: MultiStem® (HLM051) is one of the promising allogenic cell products for acute ischemic stroke with strong evidence. A previous phase 2 randomized, double-blind, placebo-controlled, multicenter dose-escalation trial showed the safety of MultiStem® for acute ischemic stroke, with a time window beyond that of rt-PA and endovascular thrombectomy. We aim to obtain stronger evidence and to show the efficacy of the MultiStem® for treatment of ischemic stroke. Sample size: Estimated sample size is 220 (110 patients per group), which has 90% power at 5% significance level. Methods and design: TREASURE is a randomized, double-blind, placebo-controlled, multicenter phase 2/3 trial. The trial will be done at 31 medical centers in Japan. Patients with acute ischemic stroke including motor or speech deficit defined by a National Institution of Health Stroke Scale (NIHSS) score of 8-20 at baseline will be randomized 1:1 to receive a single intravenous infusion of MultiStem® or placebo within 18-36 h of stroke onset. Study outcomes: Primary outcome in this study is the proportion of patients with an excellent outcome at day 90 defined by the functional assessment. Trial registration: ClinicalTrials.gov (NCT02961504). Conclusion: The TREASURE trial will provide a novel treatment option and expand the therapeutic window for patients with stroke if the results are positive. [ABSTRACT FROM AUTHOR]

Background: Stroke is a leading cause of death and disability, and despite intensive research, few treatment options exist. However, a recent breakthrough in cell therapy is expected to reverse the neurological sequelae of stroke. Although some pioneer studies on the use of cell therapy for treating stroke have been reported, certain problems remain unsolved. Recent studies have demonstrated that bone marrow stromal cells (BMSCs) have therapeutic potential against stroke. We investigated the use of autologous BMSC transplantation as a next-generation cell therapy for treating stroke. In this article, we introduce the protocol of a new clinical trial, the Research on Advanced Intervention using Novel Bone marrOW stem cell (RAINBOW).Methods/design: RAINBOW is a phase 1, open-label, uncontrolled, dose-response study, with the primary aim to determine the safety of the autologous BMSC product HUNS001-01 when administered to patients with acute ischemic stroke. Estimated enrollment is 6-10 patients suffering from moderate to severe neurological deficits. Approximately 50 mL of the bone marrow is extracted from the iliac bone of each patient 15 days or later from the onset. BMSCs are cultured with allogeneic human platelet lysate (PL) as a substitute for fetal calf serum and are labeled with superparamagnetic iron oxide for cell tracking using magnetic resonance imaging (MRI). HUNS001-01 is stereotactically administered around the area of infarction in the subacute phase. Each patient will be administered a dose of 20 or 50 million cells. Neurological scoring, MRI for cell tracking, 18F-fuorodeoxyglucose positron emission tomography, and 123I-Iomazenil single-photon emission computed tomography will be performed for 1 year after the administration.Discussion: This is a first-in-human trial for HUNS001-01 to the patients with acute ischemic stroke. We expect that intraparenchymal injection can be a more favorable method for cell delivery to the lesion and improvement of the motor function than intravenous infusion. Moreover, it is expected that the bio-imaging techniques can clarify the therapeutic mechanisms.Trial Registration: The trial was registered at The University Hospital Medical Information Network on February 22, 2017 (UNIN ID: UMIN000026130 ). The findings of this trial will be disseminated to patients and through peer-reviewed publications and international presentations. [ABSTRACT FROM AUTHOR]

Background. Brain radiation necrosis (BRN) can be a complication of radiotherapy for primary and secondary brain tumors, as well as head and neck tumors. Since vascular endothelial growth factor (VEGF) is also a vascular permeability factor in the brain, bevacizumab, a humanized antibody that inhibits VEGF, would be expected to reduce perilesional edema that often accompanies BRN. Methods. Patients with surgically untreatable, symptomatic BRN refractory to conventional medical treatments (eg, corticosteroid, anticoagulants, or hyperbaric oxygen therapy) were enrolled. We judged that a major cause of perilesional edema with a lesion-tonormal brain ratio ≤1.8 on 11C-methionine or ≤2.5 on 18F-boronophenylalanine PET was BRN, not tumor recurrence, and 6 cycles of biweekly bevacizumab (5 mg/kg) were administered. The primary endpoint was a ≥30% reduction from the patients' registration for perilesional edema continuing for ≥1 month. Results. Of the 41 patients enrolled, 38were fully eligible for the response assessment. The primary endpoint was achieved in 30 of the 38 (78.9%) patients at 3.0 months (median) after enrollment. Sixteen patients (42.1%) experienced improvement of their Karnofsy Performance Score. Corticosteroid use could be reduced in 29 patients (76.3%). Adverse events at grade≥3 occurred in 10 patients (24.4%). Conclusions. Bevacizumab treatment offers certain clinical benefits for patients with surgically untreatable, symptomatic BRN. The determination of BRN using amino-acid PET, not biopsy, is adequate and less invasive for determining eligibility to receive bevacizumab. [ABSTRACT FROM AUTHOR]

Glioblastoma-initiating cells (GIC) are a tumorigenic cell subpopulation resistant to radiotherapy and chemotherapy, and are a likely source of recurrence. However, the basis through which GICs are maintained has yet to be elucidated in detail. We herein demonstrated that the carcinoembryonic antigen-related cell adhesion molecule Ceacam1L acts as a crucial factor in GIC maintenance and tumorigenesis by activating c-Src/STAT3 signaling. Furthermore, we showed that monomers of the cytoplasmic domain of Ceacam1L bound to c-Src and STAT3 and induced their phosphorylation, whereas oligomerization of this domain ablated this function. Our results suggest that Ceacam1L-dependent adhesion between GIC and surrounding cells play an essential role in GIC maintenance and proliferation, as mediated by signals transmitted by monomeric forms of the Ceacam1L cytoplasmic domain. [ABSTRACT FROM AUTHOR]

Background: Olfactory neuroblastoma (ONB) is a rare tumor originating from olfactory epithelium. Here we retrospectively analyzed the long-term treatment outcomes and toxicity of radiotherapy for ONB patients for whom computed tomography (CT) and three-dimensional treatment planning was conducted to reappraise the role of radiotherapy in the light of recent advanced technology and chemotherapy. Methods: Seventeen patients with ONB treated between July 1992 and June 2013 were included. Three patients were Kadish stage B and 14 were stage C. All patients were treated with radiotherapy with or without surgery or chemotherapy. The radiation dose was distributed from 50 Gy to 66 Gy except for one patient who received 40 Gy preoperatively. Results: The median follow-up time was 95 months (range 8'173 months). The 5-year overall survival (OS) and relapse-free survival (RFS) rates were estimated at 88% and 74%, respectively. Five patients with stage C disease had recurrence with the median time to recurrence of 59 months (range 7'115 months). Late adverse events equal to or above Grade 2 in CTCAE v4.03 were observed in three patients. Conclusion: Multimodal therapy including radiotherapy with precise treatment planning based on CT simulation achieved an excellent local control rate with acceptable toxicity and reasonable overall survival for patients with ONB. [ABSTRACT FROM AUTHOR]

Abstract Purpose  To report a patient with agenesis of both internal carotid canals who presented with incomplete oculomotor palsy with pupil sparing. Methods  The incomplete oculomotor palsy was followed clinically, and the precise anatomical relation of the aneurysm to the subarachnoid oculomotor nerve was investigated during clipping surgery for the aneurysm. Results  A 39-year-old woman with agenesis of both internal carotid arteries was admitted because of diplopia and left blepharoptosis. The left superior palpebral and the superior rectus muscles were severely palsied. The paralysis of the medial rectus muscle was milder than that of the former two muscles, and the inferior rectus was the least affected muscle. The papillary reflexes were normal. Examination during clipping surgery showed that the aneurysm was located below the oculomotor nerve in the subarachnoid space about 6.5 mm from its exit from the midbrain. The differences in severity and resolution time of the palsies of the extraocular muscles suggested that the fibers destined for the superior levator and the superior rectus were concentrated on the caudomedial portion of the subarachnoid oculomotor nerve. The fibers innervating the medial rectus muscle were located within the core of the nerve, and the fibers innervating the pupils and the inferior rectus muscle occupied a more rostral part. Conclusions  The functional distribution of fibers within the subarachnoid oculomotor nerve about 6.5 mm from its exit from the midbrain succeeds to that of the intraparenchymal oculomotor nerve. Jpn J Ophthalmol 2007;51:470–473 © Japanese Ophthalmological Society 2007 [ABSTRACT FROM AUTHOR]