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Introduction Revascularization surgery for young children with moyamoya disease (MMD) is challenging. Although indirect revascularization is preferred because of the technical difficulty in direct anastomosis, higher risks of postoperative infarction remain a problem. We aimed to investigate the effect of superficial temporal artery to middle cerebral artery (STA-MCA) bypass on postoperative outcomes during the acute postoperative period in young children ≤ 5 years old with MMD. Methods This retrospective study included consecutive young children with MMD who underwent surgical revascularization of the anterior cerebral circulation. Groups were determined according to the procedures performed, namely, the combined (STA-MCA bypass with indirect revascularization) and the indirect revascularization groups. The incidences of radiological or symptomatic infarction, transient neurological events, and new neurological deficits that remained at discharge were compared between groups. Results Of 39 surgical procedures, there were 23 combined and 16 indirect revascularizations. The median age of the patients was 3.0 years, which was significantly different between groups (P P P

Background: Intracranial arterial stenosis (ICAS) is an important cause of ischemic stroke worldwide due to its higher risk of recurrence with medical therapy. Although some large randomized studies failed to show the superiority of surgical treatment compared with medical therapy, the results of medical therapy are not sufficient. There are patients who still benefit from surgical treatment. This retrospective analysis aimed to evaluate the long-term efficacy of surgical therapy with percutaneous transluminal angioplasty and/or stenting (PTA/PTAS) or extracranial-intracranial (EC/IC) bypass surgery for patients with ICAS. Methods: Between October 2005 and December 2016, 55 ICAS patients were treated with PTA/PTAS or EC-IC bypass surgery. Their electronic medical records were retrospectively reviewed and analyzed. The primary outcome was all adverse events beyond 30 days after a revascularization procedure. Results: We performed 21 cases (35%) of PTA, 4 cases (7%) of PTAS, and 34 cases (58%) of EC-IC bypass surgery and the median follow-up duration was 66 months (range 1-144 months). The occurrence rate of the primary outcome was 10.2% and only 1 patient (1.8%) experienced ipsilateral disabling ischemic stroke beyond 30 days. The long-term functional independent survival rate was 83.6%. Conclusions: We demonstrated a long-term favorable outcome of combined surgical intervention for ICAS patients with PTA/PTAS and EC-IC bypass surgery, and the result was better than previously reported outcomes of medical therapy. Additional multicenter studies are required to draw firm conclusions on the efficacy of reduction of recurrent stroke in patients with ICAS.

Trigone meningiomas are considered a surgical challenge, as they tend to be considerably large and hypervascularized at the time of presentation. We experienced a case of a large and very hard trigone meningioma that was effectively treated using initial microsurgical feeder occlusion followed by surgery in stages. A 19-year-old woman who presented with loss of consciousness was referred to our hospital for surgical treatment of a brain tumor. Radiological findings were compatible with a left ventricular trigone meningioma extending laterally in proximity to the Sylvian fissure. At initial surgery using the transsylvian approach, main feeders originating from the anterior and lateral posterior choroidal arteries were occluded at the inferior horn; however, only a small section of the tumor could initially be removed because of its firmness. Over time, feeder occlusion resulted in tumor necrosis and a 20% decrease in its diameter; the mass effect was alleviated within 1 year. The residual meningioma was then totally excised in staged surgical procedures after resection became more feasible owing to ischemia-induced partial softening of the tumor. When a trigone meningioma is large and very hard, initial microsurgical feeder occlusion in the inferior horn can be a safe and effective option, and can lead to necrosis, volume decrease, and partial softening of the residual tumor to allow for its staged surgical excision.

We report a case of unruptured fungal internal carotid artery (ICA) aneurysm and review the pertinent literature. A 79-year-old man presented with decreased visual acuity on the right side, and he was diagnosed with retrobulbar optic neuritis. Medical treatment with steroids resulted in Aspergillus meningoencephalitis spreading to the bottom of bilateral frontal lobes, caused by an intracranial extension of sphenoid sinusitis. Magnetic resonance imaging (MRI) performed 26 days after the start of antifungal therapy showed a denovo right ICA aneurysm projecting anteriorly into the sphenoid sinus. As the aneurysm grew rapidly, it was trapped surgically after establishing a high-flow bypass from the external carotid artery to the middle cerebral artery. The patient's postoperative course was uneventful. Anti-fungal medication was continued until plasma concentrations of beta-D-glucan decreased to within normal limits. Although fungal ICA aneurysm carries a high mortality rate, early detection and prompt treatment by trapping and high-flow bypass can lead to good clinical outcome.

clinical indications of the EOS device include management of venous (eg, varicocele, ovarian varices, varicose veins) and arterial (eg, emergency arterial embolization in trauma patients) conditions. As no late imaging was obtained in the present case, durable occlusion with the EOS device could be assessed in future studies. To conclude, the EOS may provide a safe and reliable method of immediate vessel occlusion in the peripheral arterial circulation. Its shortand long-term clinical efficacy in patients remains a subject for future research.

Aspiration due to dysphagia is a factor associated with pneumonia during acute stroke. In such cases, it is likely that secretions in the pyriform sinuses enter the laryngeal inlet. The present study was based on the idea that it is possible to reduce aspiration pneumonia by periodically suctioning and removing such secretions (pyriform sinus suctioning), a study was conducted in a single facility. The incidence of pneumonia as a dependent variable was compared between before (control) and after (intervention group) intervention with pyriform sinus suctioning as an independent variable. With a view of unifying the quality and frequency of intervention, two programs to: initially confirm the safety of such suctioning; subsequently enhance/evaluate knowledge and skills related to the procedure (educational); and specify conditions for the implementation and criteria for determining its appropriateness (practical), were developed. The study involved 33 (mean age: 74.6 ± 12.4) and 30 (80.0 ± 8.8) control and intervention group members, respectively, 25 (83.3%) of the latter were treated with pyriform sinus suctioning for 5 days after a stroke. Pneumonia developed in 7 (21.2%) and 2 (6.7%) of the former and latter, respectively. As individuals with a Japan Coma Scale (JCS) score of III or a midline shift on head CT tend to develop pharyngeal dysphagia, the patients were also divided into 2 groups to compare the incidence of pneumonia based on the risk level: low: Japan Coma Scale scores of I-II without a midline shift on head CT; and high: scores of II-III with it. In the latter, the incidence after intervention was markedly lower (p = 0.06, φ = 0.326), while the former did not show changes (p = 0.574, φ = 0.066), supporting the effectiveness of pyriform sinus suctioning to prevent aspiration pneumonia among patients with a low risk level.

X-linked chronic granulomatous disease is a primary immunodeficiency caused by mutations in CYBB. Although large deletions involving CYBB are known to cause contiguous gene syndrome (CGS), only a few patients have been studied precisely at the molecular levels. Our study determined the deletion breakpoints in two patients with CGS involving CYBB by array comparative genomic hybridization and the following PCR and DNA walking studies. The deletion size was 3.5 Mb in Patient 1 and 0.8 Mb in Patient 2. There were no homologous architectural features between the telomeric and centromeric breakpoint junctions in the deletions of either patient. However, the telomeric breakpoint of Patient 2 was embedded in a stretch of low-copy repeats and the centromeric breakpoint was also embedded in a stretch of short segments with significant sequence homology. These findings suggest the potential involvement of genome architecture in stimulating genomic rearrangements in Patient 2.

Cerebral ischemia during clamping of the carotid artery is a procedure-related complication in carotid endarterectomy (CEA). A correlation between the status of the circle of Willis, especially A1-A2 morphology, and the alteration of intraoperative somatosensory evoked potentials (SEP) was evaluated in 68 patients. All carotid endarterectomies were performed under general anesthesia without shunting. Patients were classified into 3 groups based on A1-A2 morphology in preoperative cerebral angiography. The amplitude of intraoperative SEP was decreased in 57.1% of patients with hypoplasia or absence of contralateral A1. On the other hand, amplitude was decreased in 26.7% of patients with hypoplasia or absence of ipsilateral A1 and in 11.4% of patients with patent bilateral A1. Incompleteness of the anterior part of the circle of Willis, especially hypoplasia or absence of contralateral A1, is a significant risk factor for developing of ischemia during clamping of the carotid artery.

Background: Primary immunodeficiency diseases (PID) are rare but have a high associated risk of death from overwhelming infection in early childhood. Stem cell transplantation (SCT) can be curative for PID, but standardized protocols for each disease have not yet been established. Methods: Between May 1995 and May 2005, nine patients diagnosed with a PID received SCT at the Department of Pediatrics, Hokkaido University Hospital. The median age of the patients (eight boys and one girl) was 1.0 year (range: 6 months–4 years). Five patients had Wiskott–Aldrich syndrome (WAS), three had severe combined immunodeficiency (SCID), and one had X-linked hyper-IgM syndrome (X-HIGM). Four patients received bone marrow transplantation (BMT), and five received cord blood stem cell transplantation (CBSCT). All patients, including those with SCID, received a conditioning regimen: six (WAS and X-HIGM) received a myeloablative conditioning regimen, and three (SCID) received a reduced-intensity conditioning regimen. Results: All the patients are alive and have stable, complete chimerism, based on a median follow-up period of 4 years. Moreover, all patients have good immune reconstitution, and none required immunoglobulin replacement therapy. Two patients had significant acute graft-versus-host disease (GVHD), and three patients had chronic GVHD. Four of the nine patients developed cytomegalovirus (CMV) infection after SCT. Conclusion: The transplantation procedures appear to have provided a permanent cure in nine PID patients. Early diagnosis and prompt performance of SCT with an optimal donor and conditioning regimen contributed to the favorable outcomes.

A 14-year-old Japanese girl with a progressing combined immunodeficiency had developed non-Hodgkin's diffuse large B cell lymphoma. Her molecular analysis showed a compound heterozygote of novel mutations in the LIG4 gene, M249V substitution and a five nucleotides deletion from nucleotide position 1,270-1,274. She had also a set of characteristic clinical features of LIG4 syndrome. Mutations in the LIG4 gene, which plays a critical role in the repair of DNA double-strand breaks, imply a correlation with malignancies and several cases with leukemia or lymphoma have already been reported. We report here on a case of LIG4 syndrome complicated with distinct EBV-associated B-cell lymphoma.

Objective We here describe treatment outcomes in two adenosine deaminase (ADA)-deficiency patients (pt) who received stem cell gene therapy (SCGT) with no cytoreductive conditioning. As this protocol has features distinct from those of other clinical trials, its results provide insights into SCGT for ADA deficiency. Patients and Methods Pt 1 was treated at age 4.7 years, whereas pt 2, who had previously received T-cell gene therapy, was treated at age 13 years. Bone marrow CD34(+) cells were harvested after enzyme replacement therapy (ERT) was withdrawn; following transduction of ADA cDNA by the gamma-retroviral vector GCsapM-ADA, they were administered intravenously. No cytoreductive conditioning, at present considered critical for therapeutic benefit, was given before cell infusion. Hematological/immunological reconstitution kinetics, levels of systemic detoxification, gene-marking levels, and proviral insertion sites in hematopoietic cells were assessed. Results Treatment was well tolerated, and no serious adverse events were observed. Engraftment of gene-modified repopulating cells was evidenced by the appearance and maintenance of peripheral lymphocytes expressing functional ADA. Systemic detoxification was moderately achieved, allowing temporary discontinuation of ERT for 6 and 10 years in pt 1 and pt 2, respectively. Recovery of immunity remained partial, with lymphocyte counts in pts 1 and 2, peaked at 408/mm(3) and 1248/mm(3), approximately 2 and 5 years after SCGT. Vector integration site analyses confirmed that hematopoiesis was reconstituted with a limited number of clones, some of which were shown to have myelo-lymphoid potential. Conclusions Outcomes in SCGT for ADA-SCID are described in the context of a unique protocol, which used neither ERT nor cytoreductive conditioning. Although proven safe, immune reconstitution was partial and temporary. Our results reiterate the importance of cytoreductive conditioning to ensure greater benefits from SCGT.

In order to develop ultimate adjuvant therapy for malignant gliomas, we analysed 77 patients with malignant gliomas (29 anaplastic astrocytomas (AAs) and 48 glioblastoma multiformes (GMs)) treated by three protocols of IMR therapy (human interferon-beta (HuIFN-beta), MCNU and radiation). In protocol 1 (n = 45: AA = 13, GM = 32), 1 x 10(6) IU of HuIFN-beta was administrated intravenously once a day for 7 days. On day 2, MCNU was administrated at a dose of 2 mg/kg b.w. intravenously and from day 3, radiation was started in five weekly fractions of 2 Gy for 6 weeks. Total dose was 60 Gy. Protocol 2 (n = 19: AA = 11, GM = 8) was comparable with protocol 1 except HuIFN-beta was administrated twice a day at a dose of 1 x 10(6) IU each. Protocol 3 (n = 13: AA = 5, GM = 8) differed from protocol 2 only in a high dose-hyperfractionated radiation which was given twice a day at a dose of 1.5 Gy each and for a total dose of 66 Gy. Antitumor effects were evaluated by survival and response rate determined by decrease of tumor size. Significant improvement was obtained in patients with AAs by protocol 2 and 3. Response rates of patients with AAs and GMs were 46.2% and 50% in protocol 1, 63.6% and 50% in protocol 2, and 80% and 50% in protocol 3, respectively. One and two year survival rates in AAs were 46.4% and 34.8% in protocol 1, both 75% in protocol 2, and both 100% in protocol 3. Survival rates in GMs were not different among them. Except of radiation necrosis, which was observed in 38.5% of the patients under protocol 3, there was no significant difference in the adverse effects among the three protocols. In the present study, the efficacy of IMR therapy for patients with malignant gliomas, especially for AAs, was cofirmed. We conclude that twice a day administrations of HuIFN-beta in combination with a high dose-hyperfractionated radiation provide increased efficacy in IMR therapy.

The retrospective clinicopathological characteristics of oligodendroglial tumors were investigated in patients who underwent surgery, radiotherapy, and/or chemotherapy. Regarding oligodendroglioma and oligoastrocytoma without malignancy, patients who had undergone radiation therapy at a total dose of 40-50Gy had relatively long postoperative survival. Of these 15 patients, 6 showed signs of recurrence, and after additional treatment, 5 patients are still alive. On the other hand, regarding anaplastic oligodendroglial tumors, patients with anaplastic oligoastrocytoma responded well to combination chemotherapy with interferon beta, nitrosourea derivatives (ACNU/ MCNU), and radiation therapy (referred to as IAR/IMR) and survived longer than patients with anaplastic oligodendroglioma. In conclusion, patients with oligodendroglial tumors could survive longer by treatment involving surgery and radiotherapy. As for malignancy, cases of anaplastic oligoastrocytoma could be effectively treated by adjuvant therapy using IAR/IMR after surgery, but in cases of anaplastic oligodendroglioma, the response to IAR/IMR was not good, and another strategy of treatment should be recommended.

Castleman disease (CD) is a rare lymphoproliferative disorder of unknown etiology. It is quite difficult to diagnose CD without typical localized signs or symptoms. We present a 5-year-old boy with unicentric plasma cell CD in the mesentery, which was too small to be detected by any conventional imaging. (18)F-fluorodeoxyglucose positron emission tomography image and a serum cytokine profile prompted us to perform a curative surgical excision, confirming his diagnosis. Our case also supported an important role of interleukin-6 in the pathophysiology of plasma cell CD.

Objective Idiopathic hypertrophic cranial pachymeningitis is a rare disease, of undetermined pathogenesis, that is characterized by inflammation and fibrosis of the dura mater. Methods We encountered six patients with idiopathic hypertrophic cranial pachymeningitis and analyzed their clinical presentations, radiological findings, and treatment. Results In the six patients, the main manifestations were cranial nerve palsies and headache. Three associations were present, namely optic neuropathy, Tolosa-Hunt syndrome, and diabetes insipidus. Gadolinium-enhanced magnetic resonance imaging was diagnostic, showing intense dural enhancement in a linear or nodular pattern. The responses to corticosteroid therapy were better for patients who exhibited linear, rather than nodular, dural enhancement. For one patient, surgical decompression of the superior orbital fissure provided lasting relief. The course of the disease followed one of three patterns, i.e., sustained remission, relapse with corticosteroid independence, or relapse with corticosteroid dependence. Pulse corticosteroid therapy provided significant relief, while reducing the daily corticosteroid requirement and avoiding side effects, for a corticosteroid-dependent relapsing patient. Conclusion Idiopathic hypertrophic cranial pachymeningitis exhibits varied clinical courses. It is important to prevent irreversible cranial neuropathy during the active phase of the disease, using daily administration of corticosteroids, pulse corticosteroid therapy, or surgical decompression.

Moyamoya disease is a unique disease of unknown etiology characterized by progressive occlusion of the supraclinoid portion of bilateral internal carotid arteries (IC), and the proximal portions of anterior (ACA) and middle cerebral arteries (MCA). Occlusion of the posterior circulation is also involved in 30–40% of patients. In most of the recommended procedures till date, either direct and/or indirect bypass surgery has been advocated to improve cerebral perfusion. In the present study, we performed combined surgery that included both the direct bypass procedures as well as the indirect ones [1,2]. The combination of procedures ensured perfusion of a wider ischemic zone and salvaging of the penumbric area. Indirect procedures like encephalo-duro-arterio-synangiosis (EDAS), encephalo-myo-synangiosis (EMS) or galeal flaps are safe and easy. Direct bypass surgery, however, is more reliable in providing adequate cerebral blood flow but is technically difficult as the recipient artery running on the cortical surface is usually fine and fragile in moyamoya disease.

Juvenile Sjögren's syndrome (SS) is an early-onset type of SS. Autoantibody against the N-terminal 120 kDa form of a-fodrin is a specific and sensitive disease marker for both juvenile and adult SS. We investigated the initial and major determinants of a-fodrin in SS.Sera were obtained from patients with juvenile SS, 10 with primary SS and 10 with secondary SS. Epitope specificities of IgG antibodies were examined by dot-blot analyses using overlapping fusion proteins of the N-terminal part (561 amino acid residues) of a-fodrin as antigens.All sera from patients with primary SS reacted with amino acid residues 1 to 98 and 36 to 150, but not with 91 to 199. Epitope mapping using fusion proteins with subfragments, each consisting of about 50 amino acid residues, showed reactivity with amino acid residues 27-80 and 79-132, suggesting that at least 2 epitopes are contained in the first 150 amino acid residues. All 3 cases with neurological complications had additional epitope specificities. Sera from patients with secondary SS showed more diversified specificities and strongly reacted with amino acid residues 1-98 and 334-432, whereas the reactivities to 36-150, a major epitope in primary SS, were minimal.Major and initial B cell epitopes specifically reside in N-terminal amino acids 36-132 and could be used as a diagnostic tool for primary SS. The epitope subsequently expands to other regions of a-fodrin in association with the development of neurological complications or disease progression. Secondary SS has distinct epitope specificities.

Severe combined immunodeficiency due to genetic defects of adenosine deaminase (ADA-SCID) has been a target disease of retroviral-mediated gene therapy. Recently, great success was reported in one of such clinical trials conducted in Italy aiming for the correction of patients' hematopoietic stem cells (HSC). In contrast, the US trial which is similar to, but differs significantly from that of Italy has not lead to visible clinical improvement. Considering the differences in protocol between two, absence of concomitant enzyme replacement therapy (PEG-ADA) and/or mild pre-conditioning seem to be critical for the efficacy of stem cell gene therapy (SCGT) for ADA-SCID. However, since immune reconstitution has been achievable by SCGT for untreated XSCID patients, it is still unknown whether pre-conditioning is absolutely necessary for ADA-SCID.

In the previous meeting, we reported the initial follow-up of the two patients with adenosine deaminase (ADA)-deficiency whom we had treated in a clinical trial of retroviral-mediated stem cell gene therapy (SCGT). Our protocol is unique in that patients do not receive any kinds of marrow-preparative conditioning prior to infusion of gene-corrected autologous bone marrow (BM) cells. Since the successful cases of ADA gene therapy reported from Italy used low-dose busulfan to enhance the engraftment of gene-transduced BM cells, it is intriguing to see how the lack of conditioning affects the hematological and immunological reconstitution in our patients.

For ADA-deficiency, a form of severe combined immunodeficiency, retroviral-mediated gene correction of peripheral T cells or hematopoietic stem/progenitor cells (HSCs) is a treatment of choice alternative to bone marrow (BM) transplantation. Recently, two new such clinical trials aiming for the correction of patients' HSCs were conducted in US and Italy, resulting in remarkably different outcomes: Italian patients showed immune reconstitution whereas the US trial led to no clinical improvement. There are two major differences between their protocols, either or both of which may explain these consequences. 1) In Italy, patients were mildly myeloablated, while not in the US trial. 2) US patients were on the concomitant enzyme replacement therapy (PEG-ADA) that may lessen in vivo selective advantages for gene-corrected cells and thus the efficacy of gene therapy. Italian group has not given the enzyme throughout the studies. We thus have proposed a trial that differs from these two to see If only the absence of PEG-ADA is enough to benefit patients, or if any kind of myeloablation is absolutely necessary. Two ADA-deficiency patients (#1, a 4 yr-old girl; #2, a 13 yr-old boy) were treated under the approval by the Japanese authorities. First, PEG-ADA was discontinued prior to the treatment. Rapid decrease in peripheral counts of lymphocytes and of neutrophils, liver enzyme abnormalities, and mild anorexia became evident, suggesting that the generalized toxicity due to ADA-deficiency had deteriorated. Nevertheless, both patients well tolerated the first several weeks with no serious problems. Good purity CD34+ BM cells (>80%) were transduced with the retroviral vector GCsapM-ADA/PG13. The use of serum-free medium, a cocktail of cytokines (SCF, TPO, flt3-L, IL-6, and soluble IL-6 receptor) and the fibronectin fragments resulted in ~50–70% transduction efficiencies and normal levels of ADA activities in the infused cell populations. No immediate adverse reactions were noted upon cell infusion (1.3 and 0.9 × 106 CD34+ cells/kg for #1 and #2, respectively). Patients did not receive any myeloablative conditionings. Although still preliminary in the limited time frames after treatment (6 weeks for #1 and several days for #2), we have observed normalization of liver enzyme abnormalities in #1 with gradual recovering from anorexia. Moreover, her neutrophil counts, not lymphocytes' though, have also returned to normal by week 6, suggesting that gene-corrected HSCs have engrafted and started expanding at least towards the myeloid lineage, while providing the patient with significant amount of ADA enough to detoxify the affected organs. In light of the serious adverse events in the French gene therapy trial for XSCID, careful follow-up of the patients is mandatory and thus underway, including monitoring a clonal expansion of any type of hematopoietic cells. More detailed outcomes will be presented.