Allogeneic Stem Cell Therapy for Acute Ischemic Stroke: The Phase 2/3 TREASURE Randomized Clinical Trial.

Importance: Cell therapy is a promising treatment approach for stroke and other diseases. However, it is unknown whether MultiStem (HLCM051), a bone marrow-derived, allogeneic, multipotent adult progenitor cell product, has the potential to treat ischemic stroke. Objective: To assess the efficacy and safety of MultiStem when administered within 18 to 36 hours of ischemic stroke onset. Design, Setting, and Participants: The Treatment Evaluation of Acute Stroke Using Regenerative Cells (TREASURE) multicenter, double-blind, parallel-group, placebo-controlled phase 2/3 randomized clinical trial was conducted at 44 academic and clinical centers in Japan between November 15, 2017, and March 29, 2022. Inclusion criteria were age 20 years or older, presence of acute ischemic stroke (National Institutes of Health Stroke Scale [NIHSS] score of 8-20 at baseline), confirmed acute infarction involving the cerebral cortex and measuring more than 2 cm on the major axis (determined with diffusion-weighted magnetic resonance imaging), and a modified Rankin Scale (mRS) score of 0 or 1 before stroke onset. Data analysis was performed between May 9 and August 15, 2022. Exposure: Patients were randomly assigned to either intravenous MultiStem in 1 single unit of 1.2 billion cells or intravenous placebo within 18 to 36 hours of ischemic stroke onset. Main Outcomes and Measures: The primary end points were safety and excellent outcome at day 90, measured as a composite of a modified Rankin Scale (mRS) score of 1 or less, a NIHSS score of 1 or less, and a Barthel index score of 95 or greater. The secondary end points were excellent outcome at day 365, mRS score distribution at days 90 and 365, and mRS score of 0 to 1 and 0 to 2 at day 90. Statistical analysis of efficacy was performed using the Cochran-Mantel-Haenszel test. Results: This study included 206 patients (104 received MultiStem and 102 received placebo). Their mean age was 76.5 (range, 35-95) years, and more than half of patients were men (112 [54.4%]). There were no between-group differences in primary and secondary end points. The proportion of excellent outcomes at day 90 did not differ significantly between the MultiStem and placebo groups (12 [11.5%] vs 10 [9.8%], P = .90; adjusted risk difference, 0.5% [95% CI, -7.3% to 8.3%]). The frequency of adverse events was similar between treatment groups. Conclusions and Relevance: In this randomized clinical trial, intravenous administration of allogeneic cell therapy within 18 to 36 hours of ischemic stroke onset was safe but did not improve short-term outcomes. Further research is needed to determine whether MultiStem therapy for ischemic stroke has a beneficial effect in patients who meet specific criteria, as indicated by the exploratory analyses in this study. Trial Registration: ClinicalTrials.gov Identifier: NCT02961504.

Bilateral Magnetic Resonance Imaging-Guided Focused Ultrasound Thalamotomy for Essential Tremor.

INTRODUCTION: Essential tremor is the most common movement disorder in adults. Bilateral symptoms are typical; however, bilateral thalamotomy for essential tremor is associated with a high probability of adverse events. We retrospectively investigated the efficacy and safety of staged bilateral ventral intermediate nucleus thalamotomy for refractory essential tremor using magnetic resonance imaging-guided focused ultrasound. METHODS: We enrolled 5 consecutive patients with refractory essential tremor between September 2016 and March 2020. Patients underwent a second operation at least 1 year after the first operation. The second lesion was created asymmetrically to the first lesion. RESULTS: Mean patient age was 57.6 years, and the mean interval between the 2 operations was 27.8 months. The second lesion center was superior to the first lesion in all patients. The mean baseline, second preoperative, and second postoperative Clinical Rating Scale for Tremor total scores were 63.6, 49.2, and 21.8, respectively. The mean baseline, second preoperative, and second postoperative Clinical Rating Scale for Tremor part C scores were 18.4, 8.2, and 2.6, respectively. One patient had permanent adverse events of slight dysarthria and discomfort in the tongue. No patient experienced dysphagia or cognitive dysfunction after the second operation. Four of the 5 patients were satisfied with the results of the bilateral treatment, including the patient who had permanent adverse events. CONCLUSIONS: Magnetic resonance imaging-guided focused ultrasound is an effective method for bilateral thalamotomy when adhering to the following considerations: (1) asymmetrical lesions are created and (2) sufficient interval (>1 year) between operations.

Cerebral and spinal cord tanycytic ependymomas in a young adult with a mutation in the NF2 gene.

We studied one frontal lobe tumor and multiple spinal cord tumors (one in an extramedullary location) that had been resected from a 24-year-old man. The frontal lobe tumor was well demarcated and non-infiltrating, and consisted of eosinophilic, elongated fibrillary cells arranged in a fascicular pattern. A similar histology was reproduced in the spinal cord tumors, with additional areas showing standard features of ependymoma. Immunohistochemical and ultrastructural observations revealed that all the tumors were ependymal in nature with positivity for GFAP and epithelial membrane antigen and negativity for oligodendrocyte transcription factor 2, showing intra- and intercellular microrosettes, leading us to a diagnosis of tanycytic ependymoma for the frontal lobe tumor and tanycytic ependymoma with ordinary ependymomatous component for the spinal cord tumors. The spinal extramedullary tumor was a schwannoma. Importantly, a heterozygous truncating mutation in the NF2 gene was identified in the blood lymphocytes from the patient. It is known that multiple nervous system tumors can occur in neurofibromatosis type 2 (NF2), which is caused by mutation in the NF2 gene, and that occurrence of ependymoma, including the tanycytic variant, can be associated with this genetic condition. The present case provides further information about the clinicopathology of tanycytic ependymoma with details of the immunohistochemical, ultrastructural and genetic features.

Classification of the superior petrosal veins and sinus based on drainage pattern.

BACKGROUND: The increasing number of reports of complications after sacrificing the superior petrosal veins, the largest veins in the posterior fossa, has led to a need for an increased understanding of the anatomy of these veins and the superior petrosal sinus into which they empty. OBJECTIVE: To examine the anatomy of the superior petrosal veins and their size, draining area, and tributaries, as well as the anatomic variations of the superior petrosal sinus. METHOD: Injected cadaveric cerebellopontine angles and 3-dimensional multifusion angiography images were examined. RESULTS: The 4 groups of the superior petrosal veins based on their tributaries, course, and draining areas are the petrosal, posterior mesencephalic, anterior pontomesencephalic, and tentorial groups. The largest group was the petrosal group. Its largest tributary, the vein of the cerebellopontine fissure, was usually identifiable in the suprafloccular cistern located above the flocculus on the lateral surface of the middle cerebellar peduncle. The medial or lateral segment of the superior petrosal sinus was absent in 40% of cerebellopontine angles studied with venography. CONCLUSION: The superior petrosal veins and their largest tributaries, especially the vein of the cerebellopontine fissure, should be preserved if possible. Obliteration of superior petrosal sinuses in which either the lateral or medial portion is absent may result in loss of the drainage pathway of the superior petrosal veins. Preoperative assessment of the superior petrosal sinus should be considered before transpetrosal surgery in which the superior petrosal sinus may be obliterated.

Cytologic feature by squash preparation of pineal parenchyma tumor of intermediate differentiation.

Pineal parenchyma tumor of intermediate differentiation (PPTID) is a very rare intracranial tumor, and pathological investigation limited to immunohistological and ultrastructural analyses have been published to date. Although intraoperative cytology is one of the important approaches for initial diagnosis in brain tumors, no or little studies on cellular morphology of PPTID have been demonstrated due to its rarity. We report here cytological features of PPTID obtained from stereotactic surgical specimens in a case of 27-year-old female manifested by dizziness and diplopia. Brain MRI revealed an unhomogeneously enhanced, large-sized tumor (56 x 52 x 60 mm) mainly located in the pineal region expanding from the midbrain to superior portion of the cerebellum and the fourth ventricle. Squash cytology showed increased nucleocytoplasmic ratio, hyperchromatic nuclei, and small rosette-like cell cluster but cellular pleomorphism was mild to moderate and necrotic background was not observed. Histology showed high cellularity, moderate nuclear atypia, and small rosette formation but neither bizarre tumor cells nor necrosis was present. Mitotic counts were very low (less than 1 per 10 high-power fields) and the MIB-1 labeling index was relatively high (10.1%). Tumor cells were immunohistochemically positive for neural markers such as synaptophysin, neurospecific enolase but not for glial fibrillary acidic protein or S-100. In some parts, cells were strongly reactive for neurofilament protein. Taken together, we made a final diagnosis of PPTID. This is the first presentation of cytological analysis by squash preparation that gives an important clue to accurate diagnosis of pineal parenchymal tumor and to understand its malignant potential.

A rare case of malignant glioma suspected to have arisen from a cavernous sinus.

A 55-year-old woman presented with a right trigeminal dysfunction (dysesthesia) initially, followed by right oculomotor and abducens paresis lasting 1 month. Neuroimaging studies showed an enhanced mass in the right cavernous sinus extending to the trigeminal ganglion. The extraparenchymal tumor located around the right trigeminal ganglion was totally removed, except for an intracavernous lesion, by the orbitozygomatic approach. The solid tumor was completely separated from the brainstem and seemed to be a trigeminal schwannoma arising from the trigeminal ganglion or cavernous sinus at surgery. A histological examination, however, found a typical malignant glioma that consisted primarily of astrocytic tumor cells. Immunohistochemical staining showed the tumor cells stained intensely for GFAP, S-100 protein, and vimentin, but not for NFP, Schwann/2E, CD34, and CD68. The mean MIB-1 index was 12.4%. The tumor recurred after a short time, and then it rapidly disseminated into the subarachnoid space and left the cerebral hemisphere. The patient died 1 year after the initial symptoms in spite of aggressive surgery, radiation, and chemotherapy with temozolomide. There are no previous reports of a malignant glioma arising from either the cavernous sinus or the trigeminal ganglion. From the pathogenetic point of view, this malignant glioma is an extremely rare case that developed clinically and neuroradiologically from the cavernous sinus and was suspected be being derived from ectopic glial tissue.

[Cranioplasty using autogenous bone cryopreserved with dimethylsulfoxide (DMSO)].

It is generally agreed that the autogenous bone flap which has been removed at the time of external decompression would be superior to any artificial material if it can be used in cranioplasty. Cranioplasty using autogenous frozen bone graft has been reported and showed good results except for infection and severe bone absorption. We conducted 39 cases of cranioplasty with cryopreserved autogenous bone in the presence of 10% of Dimethylsulfoxide (DMSO), which has been reported as a cryoprotective agent. Although no remarkable histological effects have been recognized in frozen bone with or without DMSO, we have obtained excellent clinical results without bone absorption in 24 of the cases. These results suggest that DMSO is helpful for frozen bone preservation.