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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.

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.

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.

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.