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.

18F-FDG PET/CT Imaging of G-CSF-Producing Inflammatory Myofibroblastic Tumor of the Pleura.

ABSTRACT: We report a case of granulocyte colony-stimulating factor (G-CSF)-producing inflammatory myofibroblastic tumor of the pleura in a 71-year-old man. Contrast-enhanced CT demonstrated multiple pleural masses with pulmonary hilar lymph nodes swelling. 18F-FDG PET/CT demonstrated marked focal FDG uptake in the thoracic masses with diffuse uptake in the bone marrow. Based on the pathological findings and elevated serum G-CSF level, the patient was diagnosed as G-CSF-producing inflammatory myofibroblastic tumor. Because G-CSF-producing tumors demonstrate aggressive clinical course, early and accurate diagnosis is important.

18F-FDG PET/CT Findings of G-CSF-Producing Gallbladder Cancer.

ABSTRACT: We report a case of granulocyte colony-stimulating factor (G-CSF)-producing gallbladder cancer in a 64-year-old man. Contrast-enhanced CT showed an exophytic hypoattenuation mass with peripheral enhancement in the gallbladder. 18F-FDG PET/CT showed avid FDG uptake in the gallbladder mass and diffuse FDG uptake in the bone marrow. The patient was diagnosed with G-CSF-producing gallbladder cancer based on an elevated serum level of G-CSF and histological findings. G-CSF-producing tumors are associated with a poor prognosis because of rapid progression. Early and accurate diagnosis of G-CSF-producing tumors based on characteristic PET/CT findings is important to determine treatment strategies and improve prognosis of patients.

Mobile endovascular therapy for acute treatment of ruptured vertebral artery dissecting aneurysm in multiple hospitals.

BACKGROUND: The patients with ruptured vertebral artery dissecting aneurysm (rVADA) should be treated as early as possible because VADA carries extremely high risk of rebleeding in the acute phase. We have established a mobile endovascular strategy for the patients with rVADA between our flagship center and its affiliated local hospitals. We introduced and reviewed our mobile endovascular therapy in this study. METHODS: We retrospectively evaluated 98 consecutive patients who underwent endovascular surgery for rVADA from 2000 to 2018 at our institution or five affiliated hospitals. When each patient was initially transported to the local affiliated hospitals, neuroendovascular surgeons traveled directly to the affiliated hospital from the flagship center in order to treat the patient there. Clinical outcomes using modified Rankin Scale at 6 months after treatment, radiological results, and procedure-related complications were reviewed to justify our mobile endovascular strategy. RESULTS: All aneurysms were cured successfully by internal trapping. Favorable outcome was achieved in 61 patients (62.2%) even though 53 patients (54.1%) had presented with severe subarachnoid hemorrhage. Overall mortality rate, treatment-related mortality rate, and treatment related complication rate were 18.4% (18/98), 0%, and 16% (16/98), respectively. There were no differences in clinical and radiological outcomes between the patients treated in the flagship center and those who treated in the affiliated hospitals. Treatment in the affiliated hospital was not a predictive factor of unfavorable outcome in our multivariate analysis, and elderly age (≥ 60) was negatively associated with favorable outcome. CONCLUSIONS: Our results prove the efficacy and safety of mobile endovascular therapy for the treatment of rVADA in the ultra-acute stage. Mobile endovascular therapy may work well in the acute treatment of rVADAs in the certain circumstance.

Imaging findings of granulocyte colony-stimulating factor-producing tumors: a case series and review of the literature.

Granulocyte colony-stimulating factor (G-CSF)-producing tumors have an aggressive clinical course. Here, we report five cases of G-CSF-producing tumors and review the literature, focusing on imaging findings related to tumor-produced G-CSF. In addition to our cases, we identified 30 previous reports of G-CSF-producing tumors on which 18F-fluorodeoxyglucose positron emission tomography (FDG-PET)/CT, bone scintigraphy, or evaluation of bone marrow MR findings was performed. White blood cell count, serum C-reactive protein, and serum interleukin-6 were elevated in all cases for which these parameters were measured. G-CSF-producing tumors presented large necrotic masses (mean diameter 83.2 mm, range 17-195 mm) with marked FDG uptake (mean maximum standardized uptake value: 20.09). Diffuse FDG uptake into the bone marrow was shown in 28 of the 31 cases in which FDG-PET/CT was performed. The signal intensity of bone marrow suggested marrow reconversion in all seven MRI-assessable cases. Bone scintigraphy demonstrated no significant uptake, except in two cases with bone metastases. Splenic FDG uptake was increased in 8 of 10 cases in which it was evaluated. These imaging findings may reflect the effects of tumor-produced G-CSF. The presence of G-CSF-producing tumors should be considered in patients with cancer who show these imaging findings and marked inflammatory features of unknown origin.

Utility of real-time image fusion technology in ultrasonography-guided fiducial marker implantation for stereotactic body radiation therapy for liver tumors.

BACKGROUND: Ultrasonography (US) is useful when implanting fiducial markers in the liver. However, the implant position is sometimes lost. Recently, real-time image fusion technology (Volume Navigation [V-navi]; GE Healthcare, Milwaukee, WI, USA) has been introduced as a technique for using images from different modalities, and its utility for fiducial marker implantation has been hypothesized. PURPOSE: To evaluate the utility of US-guided fiducial marker implantation in the liver using V-navi compared to conventional US. MATERIAL AND METHODS: We retrospectively reviewed 35 patients who underwent fiducial marker implantation for stereotactic body radiation therapy of liver tumors in 2013-2018. To avoid artifacts obscuring the tumor, the target point of implantation was set 10 mm cranial or caudal to the tumor. Marker implantation was then performed using US alone (US group, n = 24) or V-navi with computed tomography (CT) or magnetic resonance imaging (V-navi group, n = 11). Postprocedural CT was evaluated to determine technical success, distances between marker and either tumor surface or target point, and whether marker-induced artifacts obscured the tumor. Complications were also evaluated. Results were compared between groups. RESULTS: Technical success was obtained in 33 patients. Distance between the tumor and marker showed no significant difference between groups. Distance between target point and marker was shorter in the V-navi group (P = 0.0093). Tumor-obscuring artifacts were seen in 12 patients (V-navi group, n = 1; US group, n = 11; P = 0.055). The only complication was minor bleeding in the US group (n = 1). CONCLUSION: V-navi appears useful for US-guided fiducial marker implantation in the liver compared with conventional US.

Optimizing b-values for accurate depiction of pancreatic cancer with tumor-associated pancreatitis on computed diffusion-weighted imaging.

PURPOSE: To determine the optimal b-value for accurate depiction of pancreatic cancer (PC) in patients with active tumor-associated pancreatitis (TAP), using computed diffusion-weighted imaging (cDWI) with a range of b-values up to 3000 s/mm2. METHODS: The study protocol was approved by the institutional review board. We retrospectively analyzed 34 consecutive PC cases with active TAP who underwent pancreatectomy without preoperative therapy. Four cDWI datasets with b-values of 1500-3000 s/mm2 (cDWI1500-cDWI3000) were generated from the original DWI datasets with b-values of 0 and 1000 s/mm2 obtained using a 3-T scanner. Two board-certified radiologists evaluated images qualitatively (tumor conspicuity and total image quality), and another two board-certified radiologists placed regions of interest for quantitative evaluations (apparent diffusion coefficient [ADC] values of both lesions, contrast ratio [CR] of PC to active TAP, and volume ratio [VR] of PC to surgical specimen). RESULTS: As the b-value increased, tumor conspicuity improved significantly in cDWI2000 and cDWI2500 (P = 0.0121 and 0.0015, respectively), although total image quality decreased in all cDWIs compared with DWI1000 (P < 0.0001). Significantly lower ADC values were seen in PC (P < 0.0001). All cDWI groups showed positive correlation between the tumor conspicuity and ADC difference between PC and TAP. CR increased with the b-value, while VR decreased. Significant equivalence of VR to the surgical specimen was seen on cDWI2000 (P = 0.0031). CONCLUSION: Accurate depiction of PC was optimal with cDWI2000 in the presence of active TAP.

Duodenal obstruction induced by retroperitoneal progression of bladder cancer: a report of two cases.

Bladder cancer usually forms a papillary structure. Progression along the cavity or membranous structures surrounding the bladder, rectum, or retroperitoneum without formation of a discrete mass is rare. We here present two patients with duodenal obstruction caused by retroperitoneal progression of bladder cancer, in both of whom computed tomography revealed bladder and rectal wall thickening with a malignant target sign, thickened mesorectal fascia with abnormal tissue stranding, and increased perirectal fat density. Both cancers progressed despite treatment, as indicated by faint abnormal tissue stranding and increased retroperitoneal fat density along the retromesenteric plane from the pelvis to the duodenum. Subsequently, both patients developed obstruction in the horizontal portion of the duodenum, still without formation of a mass lesion. These two patients highlight the challenges associated with retroperitoneal invasion by bladder cancer in the absence of a mass lesion and underscore the importance of considering cancer progression in patients with bowel obstruction, even when there is no obvious mass lesion and/or only minor retroperitoneal findings. Progression along the retromesenteric plane may be the key pathway via which progressive bladder cancer results in duodenal obstruction without or with a minor mass lesion.

Combined gene therapy with vascular endothelial growth factor plus apelin in a chronic cerebral hypoperfusion model in rats.

OBJECTIVE The aim of this study was to evaluate whether combined gene therapy with vascular endothelial growth factor (VEGF) plus apelin during indirect vasoreconstructive surgery enhances brain angiogenesis in a chronic cerebral hypoperfusion model in rats. METHODS A chronic cerebral hypoperfusion model induced by the permanent ligation of bilateral common carotid arteries (CCAs; a procedure herein referred to as "CCA occlusion" [CCAO]) in rats was employed in this study. Seven days after the CCAO procedure, the authors performed encephalo-myo-synangiosis (EMS) and injected plasmid(s) into each rat's temporal muscle. Rats were divided into 4 groups based on which plasmid was received (i.e., LacZ group, VEGF group, apelin group, and VEGF+apelin group). Protein levels in the cortex and attached muscle were assessed with enzyme-linked immunosorbent assay (ELISA) on Day 7 after EMS, while immunofluorescent analysis of cortical vessels was performed on Day 14 after EMS. RESULTS The total number of blood vessels in the cortex on Day 14 after EMS was significantly larger in the VEGF group and the VEGF+apelin group than in the LacZ group (p < 0.05, respectively). Larger vessels appeared in the VEGF+apelin group than in the other groups (p < 0.05, respectively). Apelin protein on Day 7 after EMS was not detected in the cortex for any of the groups. In the attached muscle, apelin protein was detected only in the apelin group and the VEGF+apelin group. Immunofluorescent analysis revealed that apelin and its receptor, APJ, were expressed on endothelial cells (ECs) 7 days after the CCAO. CONCLUSIONS Combined gene therapy (VEGF plus apelin) during EMS in a chronic cerebral hypoperfusion model can enhance angiogenesis in rats. This treatment has the potential to be a feasible option in a clinical setting for patients with moyamoya disease.

[Multiple brain abscesses in the territory of the vertebral-basilar artery resulting from an infected aortic arch graft].

A 62-year-old man with high fever and in a state of disorientation was transferred to our hospital. One year before this transfer, he had undergone total arch replacement surgery for thoracic aortic dissection. On admission to our hospital, head MRI revealed multiple brain abscesses in the territory of the vertebral-basilar artery, and chest CT showed gas around the aortic graft, in particular, at the origin of the left subclavian artery. We diagnosed him with brain abscesses in the left vertebral-basilar artery resulting from an infected aortic graft. We immediately began administration of intravenous antibiotics. Although his blood, urine, and cerebrospinal fluid cultures were negative, fortunately, the brain abscesses and ectopic gas disappeared. Since reports of only antibiotic use for treating brain abscesses due to aortic graft infection are rare, the appropriate duration of antibiotic administration has not been established yet. Therefore, careful observation is required in this case.

Nationwide survey of the nature and risk factors of complications in embolization of meningiomas and other intracranial tumors: Japanese Registry of NeuroEndovascular Therapy 2 (JR-NET2).

INTRODUCTION: Embolization of intracranial tumor is widely performed in Japan, mainly before neurosurgical resection. A retrospective, multicenter, observational study in Japan was conducted to clarify the nature, frequency, and risk factors of complications in intracranial tumor embolization. METHODS: Patients were derived from the Japanese Registry of NeuroEndovascular Therapy 2 (JR-NET2). A total of 20,854 patients were enrolled in JR-NET2, of which 1,018 patients (4.88 %) with intracranial tumors underwent embolization. The primary end point was the proportion of patients with a modified Rankin scale (mRS) score of 0-2 (independency) at 30 days. The secondary end point was the occurrence of complications related to the procedures. The risk factors of the occurrence of complications were studied. RESULTS: The proportion of patients with mRS scores ≤2 at 30 days after procedure was 91.3 %. Complications occurred in 15 of the 1,012 patients (1.48 %). Multivariate analysis showed that embolization for tumors other than meningioma (OR, 4.626; 95 % CI, 1.347-14.59; p = 0.0105) was significantly associated with the development of complications. CONCLUSION: The frequency of complications after intracranial tumor embolization was relatively low in this large Japanese cohort. Embolization for tumors other than meningioma was the only significant risk factor for the occurrence of complications.

Mannitol enhances therapeutic effects of intra-arterial transplantation of mesenchymal stem cells into the brain after traumatic brain injury.

Traumatic brain injury (TBI) sustained in a traffic accident or a fall is a major cause of death that affects a broad range of ages. The aim of this study was to investigate the therapeutic effects of intra-arterial transplantation of mesenchymal stem cells (MSCs) combined with hypertonic glycerol (25%) or mannitol (25%) in a TBI model of rats. TBI models were produced with a fluid percussion device. At 24h after TBI, MSCs (1×10(6)cells/100µl) with glycerol or mannitol were administered via the right internal carotid artery. Rats were evaluated behaviorally and immunohistochemically, and hyperpermeability of the blood-brain barrier (BBB) induced by hypertonic solutions was explored. Compared to PBS or glycerol, the administration of mannitol resulted in increased BBB disruption. The mannitol-treated rats showed significant improvement in motor function. Intra-arterial transplantation of MSCs caused no thromboembolic ischemia. Immunohistochemically, more MSCs were observed in the injured brain tissues of mannitol-treated rats than in glycerol or PBS-treated rats at 24h after transplantation. Intra-arterial transplantation of MSCs combined with mannitol is an effective treatment in a TBI model of rats. This technique might be used for patients with diseases of the central nervous system including TBI.

[Endovascular treatment of basilar artery aneurysms associated with fenestration].

Aneurysms at the vertebrobasilar junction are often found with basilar artery(BA)fenestration. We encountered 10 consecutive cases of aneurysms associated with BA fenestration. The purpose of this study is to describe the frequency, clinical features, and outcome of these aneurysms treated by endovascular procedure. The incidence of these aneurysms in our series was 1.9%. All aneurysms were successfully treated by coil embolization. Half of them were treated by using simple technique, and the other half were treated by using adjunctive techniques such as balloon remodeling technique. 70% of these cases were ruptured, and all except one case showed good recovery at the time of discharge. We found 63 reported cases of this aneurysm in the literature between 2000 and 2012. 57 out of 63 aneurysms were treated by endovascular means with good clinical results. The usefulness of endovascular procedure is reported to be superior to surgical clipping because of their anatomical complexity and the difficulty of surgical exposure for clipping. We conclude that outcome of these aneurysms is favorable and endovascular procedure has become their standard treatment for these aneurysms.

[Endovascular treatment for cervical carotid artery aneurysm: a case report].

We report here a case of cervical carotid artery aneurysm. This 37-year-old male suffered from acute neck swelling when he was taking lunch after physical work. Ultrasonography demonstrated a cervical pseudoaneurysm and a jet flow, which was blowing into the dome from the carotid artery. Angiogram revealed an aneurysm with a diameter of 3 cm at the bifurcation of the common carotid artery. Coil embolization using double-catheter technique was performed and complete occlusion of the aneurysm was obtained without any complications. The patient returned to his normal life. Cervical carotid artery aneurysms are rare and they induce pain by swelling in the neck, hoarseness, swallowing disturbance, hemorrhage, and cerebral ischemia due to embolism. In case of a cervical carotid artery aneurysm, safe and effective treatments are required and endovascular treatment should be considered. Although stent-assisted coil embolization or covered-stent placement were reported as an effective treatment for cervical aneurysms, coil embolization without using a stent was performed in this particular patient who is a young, blue-collar worker because the avoidance of long-term anti-platelet therapy was desirable. Preoperative evaluation is important to select adequate treatment.

[A case of a paraspinal arteriovenous fistula presenting with retroperitoneal hemorrhage treated by staged transarterial and transvenous embolization].

We report a rare case of a paraspinal arteriovenous fistula(AVF)treated by combined transarterial and transvenous embolization(TAE/TVE). A 72-year-old woman was admitted after a traffic accident. Abdominal enhanced CT disclosed pre-existing large varices at the L3-L4 level in the right retroperitoneum with multiple feeding arteries and veins draining into the extradural venous plexus in the spinal canal. The lesion was diagnosed as a paraspinal AVF. Four days later, the patient went into a state of shock. Emergency abdominal CT showed retroperitoneal hemorrhage due to rupture of the varix. TAE of the feeders from the right L1-L4 arteries was performed, and rebleeding from the varix was prevented. Three months later, follow-up CTA showed regrowth of the AVF, and TVE was performed. Two microcatheters were navigated transvenously into the varix, and detachable coils were delivered into the small compartment just downstream to the shunts, leading to complete obliteration. We conclude that transarterial flow reduction followed by occlusion of the venous side of the shunts is effective to achieve cure of a complex and high-flow paraspinal AVF.

[Surgical and endovascular treatment for superior cerebellar artery aneurysms: report of two cases].

Aneurysms located on the superior cerebellar artery (SCA) are uncommon and their presentation, natural history, and clinical management are poorly understood. Reports related to the endovascular or surgical management of SCA aneurysms are rare. Herein, we report two cases of SCA aneurysm. The first is that of a 70-year-old woman who presented with subarachnoid hemorrhage (SAH). Surgical treatment (neck clipping) of the ruptured SCA aneurysm was performed, and the flow of the parent artery disappeared. The second is that of a 69-year-old woman with an unruptured SCA aneurysm who underwent endovascular surgery to occlude the parent artery. Neither patients exhibited any additional neurological deficits. SCA aneurysms often have either relatively wide or undefinable necks, so it is difficult to preserve the parent artery. According to several surgical reports, occlusion of the SCA appears well tolerated for a variety of reasons.

Improvement of depression after treatment of dural arteriovenous fistula: a case report and a review.

Patients with dural arteriovenous fistulas (DAVFs) in the transverse-sigmoid sinus suffer from several symptoms: bruit, headache, visual impairment, and so on. But depression is rare in patients with DAVF. The authors reported a rare case presenting the improvement of depression after the treatment of a dural arteriovenous fistula in the left transverse-sigmoid sinus. A 46-year-old male had suffered from depression and was treated with antidepressants at a local hospital for four years. The patient was temporarily laid off due to his depression. Afterwards, he had Gerstmann's syndrome and came to our hospital. A DAVF in the left transverse-sigmoid sinus was demonstrated on the angiogram. The DAVF was successfully treated with endovascular surgery, coil embolization of the isolated diseased sinus through the mastoid emissary vein which was a draining vein from the fistula. After this treatment, his depression as well as Gerstmann's syndrome was improved and the quantity of the antidepressants decreased. The patient returned to work without any antidepressant two years after the treatment. DAVFs might be one of the causes of depression. It may be necessary to evaluate cerebral vessels in patients suffering from depression by using MRA or 3D-CTA even if there are not any abnormal findings on plain CT scans.

[Endovascular coiling of thrombosed basilar tip aneurysm using double stents in a y-configuration].

Recent advances in endovascular techniques greatly improved the ability to treat complex cerebral aneurysms. However, patients with wide-necked cerebral aneurysms have posed a special challenge to conventional endovascular therapy. We report a novel method of embolizing wide-necked basilar apex aneurysms by employing a Y-configuration, double stent technique. A 40-year-old woman with a partially thrombosed basilar apex aneurysm transferred to our hospital after diagnosis of subarachnoid hemorrhage. Cerebral angiography revealed a wide-necked aneurysm which neck was incorporating the origins of both the posterior cerebral arteries. In treatment procedure, a microcatheter was inserted into the aneurysm followed by coiling of the upper half of the dome. Next, the first stent was deployed in the right P2 segment extending down to the mid basilar artery and the second stent was then deployed with half of the stent in the left P2 and the other half within the lumen of the previously placed stent. Finally, the microcatheter was withdrawn near the neck, and the rest of the aneurysmal dome was packed by additional coils. The result was favorable. Successful coil embolization of a wide-necked bifurcation aneurysm can be achieved by using the double stenting Y-configuration in this case. This result continues to provide highly encouraging support of this novel technique to treat a subset of complex, wide-necked aneurysms that until recently were considered poor candidates for endovascular therapies.