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Myelodysplastic neoplasms (MDS) are defined by cytopenia and morphologic dysplasia originating from clonal hematopoiesis. They are also frequently complicated with diseases caused by immune dysfunction, such as Behçet's disease (BD) and secondary pulmonary alveolar proteinosis (sPAP). MDS with both BD and sPAP is extremely rare, and their prognosis is poor. In addition, haploinsufficiency of the hematopoietic transcription factor gene GATA2 is recognized as a cause of familial MDS and is frequently complicated by sPAP. Herein, we report a case of MDS combined with both BD and sPAP in association with GATA2 deficiency in a Japanese woman. Because she developed progressive leukopenia and macrocytic anemia during BD treatment at the age of 61, she underwent a bone-marrow examination and was diagnosed with MDS. She subsequently developed sPAP. At the age of 63, she underwent allogeneic hematopoietic stem cell transplantation (allo-HSCT). Since allo-HSCT, she has maintained complete remission of MDS as well as the symptoms of BD and sPAP. Furthermore, we performed whole exome sequencing and identified the GATA2 Ala164Thr germline mutation. These findings suggest that patients with MDS, BD and sPAP should be considered for early allo-HSCT., (© 2023. Japanese Society of Hematology.)

Background: The safety and efficacy of omalizumab in chronic spontaneous urticaria (CSU) patients has been established, but real-world long-term data remain scarce, especially in Japan., Methods: 52-week, open-label, single-arm, observational study evaluated the safety and effectiveness of first-time omalizumab in Japanese CSU patients responding inadequately to conventional therapies., Results: Overall, 235 of 280 patients completed the study. Most patients were aged ≥ 18 and < 65 years; adolescents (≥ 12 and ≤ 18 years) accounted for 9.6% of the total population. The mean ± standard deviation (SD) duration of CSU at baseline was 1.6 ± 3.1 years; 46.1% of patients had had CSU for < 6 months. At baseline, the mean ± SD of Urticaria Control Test (UCT) score, Weekly Urticaria Activity Score (UAS7), and Dermatology Life Quality Index (DLQI) were 5.1 ± 3.2, 25.2 ± 11.9, and 8.4 ± 5.9, respectively. The mean ± SD duration of the observation period was 330.3 ± 86.2 days. Relapse was reported in 65 patients, 51, 9, and 5 of whom required retreatment with omalizumab 1, 2, and ≥ 3 times, respectively. The incidence of adverse events (AEs), serious AEs, and adverse drug reactions (ADRs) was reported in 11.8%, 1.4%, and 3.9% of patients, respectively. The most common AEs were urticaria (1.8%) and eczema (1.1%). No adolescents experienced ADRs. A cumulative of 92.8% of patients responded in the Physician's Global Impression of Change, with 81.3%, 75.0%, and 95.1% of patients achieving UCT ≥ 12, UAS7 ≤ 6, and DLQI ≤ 5 up to Week 52, respectively., Conclusions: This study supports the safety and effectiveness of omalizumab in CSU patients who responded inadequately to conventional therapies in real-world clinical practice in Japan., (Copyright © 2022 Japanese Society of Allergology. Published by Elsevier B.V. All rights reserved.)

Castleman disease (CD) is a lymphoproliferative disorder that manifests as hypergammaglobulinemia and severe inflammation with multiorgan involvement. However, renal involvement has been infrequently described in CD. We present a case of a 63-year-old Japanese male patient with multicentric CD (MCD) in whom kidney involvement, including impaired renal function and massive proteinuria, is present. He had a 2-year history of inflammatory arthritis and was referred to our clinic with newly developed proteinuria, renal dysfunction, and elevated levels of acute-phase proteins. Abdominal computed tomography scan revealed hepatosplenomegaly, including mesenteric and inguinal lymph node enlargements. The patient underwent inguinal lymph node resection. Excisional biopsy of the inguinal lymph node showed multiple lymphoid follicles and expansion of interfollicular areas by marked plasmacytosis consistent with mixed type CD. The patient was diagnosed with human herpes virus 8-negative MCD according to the international diagnostic criteria for CD. Diagnostic renal biopsy was not performed following the medical viewpoint. Tocilizumab (TCZ) treatment was highly effective in reducing proteinuria and stabilizing renal function, as well as improving other clinical symptoms. The patient responded to TCZ treatment, and the renal involvement was rapidly improved. Our preliminary immunohistochemical analysis indicated AA amyloid deposits in urinary epithelial cells suggesting a possible renal involvement of AA amyloidosis. TCZ could potentially be one of the therapeutic options in patients with MCD with renal involvement.

Background: Comparisons of distal bypass outcomes between hemodialysis-dependent (HD) and renal transplant (RT) patients have been reported, but the influences of immunosuppressive therapy on the outcomes remain unclear because of the limited number of RT patients who underwent distal bypass or cohort heterogenicity. We compared outcomes of distal bypass for chronic limb-threatening ischemia (CLTI) with homogenous ischemic limb pathology., Methods: Between January 2014 and December 2019, we performed 334 infrapopliteal bypass procedures using vein grafts for 275 consecutive CLTI patients with tissue loss. Among them, there were 130 HD patients (47.3%) (163 limbs) and 11 RT patients (4%) (15 limbs), and 30-day mortality, 5-year primary and secondary patency (PP and SP), limb salvage (LS), amputation-free survival rates, and wound healing (WH) status were compared between the HD and RT patient groups., Results: Nine HD patients died within 30 days after surgery (7%), whereas no deaths were observed among the RT patients. Five-year PP and SP rates in the RT group 39% and 41%, which were significantly worse compared to 64% and 82% in the HD group (P < 0.01). Unsuccessful rate of revision surgery including hemodynamically failed grafts after revision reached over 80% in the RT group, which was technically unfeasible pathology for graft salvage (vs. 3% in the HD group), and WH, and LS rates were significantly worse in the RT group., Conclusions: In comparison with HD patients, RT patients showed a lower LS rate for CLTI. The lower LS rate was associated with a lower SP rate, which was caused by disease progression of distal arteries in the foot., (Copyright © 2022. Published by Elsevier Inc.)

Objectives: A post-marketing all-patient surveillance program was conducted to evaluate the safety and effectiveness of canakinumab, a monoclonal anti-interleukin-1β antibody, in patients in Japan with cryopyrin-associated periodic fever syndrome (CAPS), including familial cold auto-inflammatory syndrome, Muckle-Wells syndrome, and neonatal onset multisystem inflammatory disease., Methods: All patients with CAPS who received canakinumab treatment after drug approval in Japan were registered in this non-interventional, observational study. The observation period per patient was two years. Patients newly treated with canakinumab (New patients; NP) and those continuously treated with canakinumab following clinical trials (Roll-over patients; RP) were included. Data collection of clinical symptoms affecting physical function and prognosis was not mandated but assessed where available. Here, the interim results are reported., Results: Of 87 patients in the safety set, the proportion of patients with any adverse drug reactions (ADRs) and any serious ADRs was 31.03% and 3.45%, respectively. The most common ADRs reported under system organ class were infections and infestations (20.69%). Of 84 patients in the effectiveness set, 75.76% and 83.33% of NP and RP, respectively, were responders at Week 24, achieving complete response without relapse. Responder rates were maintained up to Week 104. Clinical symptoms affecting physical function and prognosis remained unchanged in over half of those patients., Conclusions: Interim results provided the safety profile of canakinumab in a real-world setting, and identified no new safety concerns. Treatment with canakinumab has suggested sustained remission in the majority of patients in the real-world setting.

This phase III study assessed the efficacy and safety of sacubitril/valsartan compared with those of olmesartan in Japanese patients with essential hypertension. Patients (n = 1161, aged ≥20 years) with mild to moderate hypertension (mean sitting systolic blood pressure [msSBP] ≥150 to <180 mmHg) were randomized to receive sacubitril/valsartan 200 mg (n = 387), sacubitril/valsartan 400 mg (n = 385), or olmesartan 20 mg (n = 389) once daily for 8 weeks. The primary assessment was a reduction in msSBP from baseline with sacubitril/valsartan 200 mg vs. olmesartan 20 mg at Week 8. Secondary assessments included msSBP reduction with sacubitril/valsartan 400 mg vs. olmesartan at Week 8 and reductions in mean sitting diastolic blood pressure (msDBP), mean sitting pulse pressure (msPP), and overall blood pressure (BP) control rate for all treatment groups at Week 8. Sacubitril/valsartan 200 mg provided a significantly greater reduction in msSBP from baseline than olmesartan at Week 8 (between-treatment difference: -5.01 mmHg [95% confidence interval: -6.95 to -3.06 mmHg, P < 0.001 for noninferiority and superiority]). Greater reductions in msSBP with sacubitril/valsartan 400 mg vs. olmesartan, as well as in msDBP and msPP with both doses of sacubitril/valsartan vs. olmesartan (P < 0.05 for all), were also observed. Patients treated with sacubitril/valsartan achieved an overall higher BP control rate. The safety and tolerability profiles of sacubitril/valsartan were generally comparable to those of olmesartan. The adverse event rate with sacubitril/valsartan was not dose-dependent. Treatment with sacubitril/valsartan was effective and provided superior BP reduction, with a higher proportion of patients achieving target BP goals than treatment with olmesartan in Japanese patients with mild to moderate essential hypertension., (© 2022. The Author(s).)

Objective To evaluate the long-term safety and efficacy of indacaterol/glycopyrronium (IND/GLY) in patients with chronic obstructive pulmorary disease (COPD) in a real-world setting in Japan. Methods This 52-week, multicentre, post-marketing surveillance conducted in Japan between December 2013 and August 2019 included patients using IND/GLY for the first time to relieve airway obstructive disorder-related symptoms. Safety outcomes included the incidence of adverse events (AEs), serious AEs (SAEs), adverse drug reactions (ADRs), and serious ADRs during the 52-week period. The incidence of priority variables, including cardiovascular/cerebrovascular (CCV) AEs, β-adrenergic-related or anticholinergic AEs and cough, was also assessed. Safety outcomes were also evaluated in elderly patients. Efficacy outcomes included a physician's global assessment, COPD assessment test (CAT) and lung function test. Results Of the 1,167 patients registered, 1,108 were included in the safety and efficacy analysis. In the safety analysis population, the incidence of AEs was 13.54%, that of SAEs was 4.69%, that of ADR was 3.61%, and that of serious ADRs was 0.36% over 52 weeks. CCV AEs, β-adrenergic-related and anticholinergic AEs and cough were reported as 2.62%, 1.99% and 0.63%, respectively. The physician's global assessment showed that the overall response rate at the last assessment was 74.19%. The mean (95% confidence interval) CAT scores decreased from the start of treatment to Week 52 with IND/GLY [-6.9 (-7.8 to -6.1)]. The lung function (FEV 1 and FVC) improved over time from the start of IND/GLY to Week 52. Conclusion IND/GLY demonstrated a good long-term safety profile in a real-world setting in Japanese patients with COPD, with beneficial effects in terms of the lung function and symptoms in clinical use.

Objective: To evaluate the long-term safety and efficacy of glycopyrronium (GLY) in patients with COPD in a real-world setting in Japan., Methods: This 52-week, multicentre, post-marketing surveillance conducted in Japan, between February 2013 and August 2019, included patients using GLY for the first time for the relief of airway obstructive disorder-related symptoms. Safety outcomes included incidence of adverse events (AEs), serious AEs (SAEs), adverse drug reactions (ADRs), serious ADRs (SADRs) and priority variables included cardiovascular/cerebrovascular (CCV) AEs and anticholinergic AEs during the 52-week period. Safety outcomes were also assessed in elderly patients. Efficacy outcomes included physician's global assessment, COPD assessment test (CAT) and lung function test., Results and Discussion: Of the 1,331 patients registered for this surveillance, safety and efficacy outcomes were evaluated in 1,277 patients. In the safety analysis population, the incidence of AEs was 15.51%, SAEs 4.70%, ADRs 5.01% and SADRs 0.31%. The CCV AEs and anticholinergic AEs were reported by 0.70% and 2.58% patients, respectively. Physician's global assessment showed that the overall response rate at the last assessment was 70%. The mean (95% CI) CAT scores decreased from the start of treatment to Week 52 with GLY, (-6.2 [-7.0 to -5.4]). Lung function in terms of trough FEV 1 and FVC improved over time from the start of GLY to Week 52., Conclusion: GLY demonstrated an acceptable long-term safety profile with no new safety concerns in a real-life setting. It demonstrated improvement in lung function and symptom control in Japanese COPD patients., Competing Interests: Chihiro Kato, Dong Wang, Noriko Nakamura, Takayoshi Sasajima, and Hajime Yoshisue are the employees of Novartis Pharma K.K., Tokyo, Japan., (© 2022 Kato et al.)

Type B insulin resistance syndrome (TBIR) is a rare autoimmune disease characterised by autoantibodies targeting insulin receptors. TBIR is often complicated by systemic lupus erythematosus (SLE). We describe the case of a 59-year-old Japanese man with TBIR complicated with lupus nephritis (LN), who presented with nephrotic syndrome and severe hypoglycaemia. Treatment with prednisolone (PSL), mycophenolate mofetil (MMF), and tacrolimus (TAC) resulted in improved SLE activity and glucose intolerance with the reduction of anti-insulin receptor autoantibodies. To the best of our knowledge, this is the first reported case of TBIR complicated with LN that was successfully treated using multitarget therapy with PSL, MMF, and TAC., (© Japan College of Rheumatology 2021. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Gastrointestinal lesions, which sometimes develop in Behçet's disease (BD), are referred to as intestinal BD. Although rare, intestinal BD can be accompanied by myelodysplastic syndrome (MDS) with abnormal karyotype trisomy 8, which is refractory to immunosuppressive therapy. Pulmonary alveolar proteinosis is a rare lung complication of BD and MDS. Herein, we present an extremely rare case of intestinal BD presenting with MDS and several chromosomal abnormalities, followed by secondary pulmonary proteinosis., Case Presentation: A 58-year-old Japanese woman with a 3-year history of genital ulcers and oral aphthae was admitted to our hospital. The patient developed abdominal pain and persistent diarrhea. Colonoscopy revealed multiple, round, punched-out ulcers from the terminal ileum to the descending colon. Intestinal BD was diagnosed and the patient was treated with colchicine, prednisolone, and adalimumab. However, her symptoms were unstable. Bone marrow examination to investigate the persistent macrocytic anemia revealed the presence of trisomy 8, trisomy 9, and X chromosome abnormalities (48, + 8, + 9, X, i(X) (q10) in 12 out of the examined 20 cells). Based on her hypoplastic bone marrow, the patient was diagnosed with low-risk MDS (refractory anemia). At the age of 61, the patient developed pneumonia with fever and diffuse ground-glass opacities on the lung computed tomography (CT). Chest high-resolution CT and histopathology via transbronchial lung biopsy revealed the presence of pulmonary alveolar proteinosis (PAP). These findings combined with the underlying disease led to the diagnosis of secondary PAP., Conclusions: Secondary pulmonary proteinosis may accompany intestinal BD with MDS and several chromosomal abnormalities. Physicians should pay attention to lung complications, such as PAP, in patients with intestinal BD complicated by MDS. Genetic abnormalities may be associated with the development of such diseases., (© 2021. The Author(s).)

Immunoglobulin A (IgA) vasculitis is a systemic small-vessel vasculitis involving the skin, kidney, joints, and gastrointestinal tract. Familial Mediterranean fever (FMF) is the most common autoinflammatory disease characterized by periodic fever, peritonitis, pleuritis, or arthritis. It is well known that FMF may coexist with vasculitis, especially small and medium vessel vasculitis. Here we present a Japanese male patient with FMF who later developed IgA vasculitis and a relapsing disease course. A 51-year-old Japanese male was referred because of upper abdominal pain, arthralgia, and bilateral purpura of the lower limbs. He fulfilled the criteria for IgA vasculitis, which was successfully treated by corticosteroid and immunosuppressive therapy. He had a medical history of periodic fever since the age of 10 years old. The Mediterranean fever (MEFV) gene analysis revealed that he was heterozygous for M694I and E148Q mutations. Colchicine therapy resolved his periodic febrile attacks. To our knowledge, coexistence of FMF with IgA vasculitis has not been reported in East Asia, including Japan. Our case suggests that MEFV gene exon 10 mutations could be related to the development of IgA vasculitis and affects its clinical course.

Objective Evidence concerning the safety and efficacy of indacaterol maleate in a real-life setting is limited. The objective of this post-marketing surveillance was to evaluate the real-life safety and efficacy of indacaterol maleate in Japanese patients with chronic obstructive pulmonary disease (COPD). Methods This was a 52-week post-marketing surveillance conducted between April 2012 and December 2018. The safety endpoints included the incidence of adverse events (AEs), serious adverse events (SAEs), and adverse drug reactions (ADRs). The efficacy endpoints included the physician-reported global evaluation of treatment effectiveness (GETE), change from baseline in the COPD assessment test (CAT) results, forced vital capacity (FVC), forced expiratory volume in 1 second (FEV 1 ), and %FEV 1 following 4, 12, 26, and 52 weeks of indacaterol administration. Results Of the 1,846 enrolled patients, 1,726 were included in the safety and efficacy analyses. The mean age of the patients was 72.5 years old. Cough, pneumonia and COPD worsening were the most common AEs reported, while pneumonia (1.04%) was the most common SAE, and cough (1.68%) was the most common ADR. GETE showed that 69.70% of patients achieved an excellent/good/moderate response following indacaterol treatment. The CAT score decreased, and lung function parameters (FVC, FEV 1 and %FEV 1 ) improved across all the COPD stages following treatment with indacaterol. Conclusion Indacaterol showed a favorable safety and tolerability profile in Japanese patients with COPD without new safety signals observed in real-life settings. These findings demonstrated that indacaterol is an effective maintenance treatment in real-life practice for Japanese patients with COPD.

The efficacy of stereotactic radiotherapy (SRT) has been well established for postoperative residual and recurrent nonfunctioning pituitary adenomas (NFPAs). However, the risk of visual impairment due to SRT for lesions adjacent to the optic pathways remains a topic of debate. Herein, we evaluated the long-term clinical outcomes of hypofractionated stereotactic radiotherapy (HFSRT) for perioptic NFPAs. From December 2002 to November 2015, 32 patients (18 males and 14 females; median age 63 years; range, 36-83 years) with residual or recurrent NFPAs abutting or displacing the optic nerve and/or chiasm (ONC) were treated with HFSRT. The median marginal dose was 31.3 Gy (range, 17.2-39.6) in 8 fractions (range, 6-15). Magnetic resonance imaging (MRI) and visual and hormonal examinations were performed before and after HFSRT. The median follow-up period was 99.5 months (range, 9-191). According to MRI findings at the last follow-up, the tumor size had decreased in 28 (88%) of 32 patients, was unchanged in 3 (9%), and had increased in 1 (3%). The successful tumor size control rate was 97%. Visual functions remained unchanged in 19 (60%) out of 32 patients, improved in 11 (34%), and deteriorated in 2 (6%). Two patients had deteriorated visual functions; no complications occurred because of the HFSRT. One patient developed hypopituitarism that required hormone replacement therapy. The result of this long-term follow-up study suggests that HFSRT is safe and effective for the treatment of NFPAs occurring adjacent to the ONC.

Background: Omalizumab is approved as add-on therapy for pediatric asthma since 2013 in Japan, however, its data in clinical practice is limited. This post-marketing surveillance aimed to evaluate long-term safety and effectiveness of omalizumab in Japanese pediatric patients with severe allergic asthma in real-life setting., Methods: This 104-week, multicenter surveillance was conducted from September 2013 to May 2019 by central registration method. Patients with severe allergic asthma aged ≥6 and < 15 years at initiation of treatment who were first-time omalizumab users were included. The primary endpoints included incidence of adverse drug reactions and physician's Global Evaluation of Treatment Effectiveness (GETE). The secondary endpoints included incidence of serious adverse events, adverse events and adverse drug reactions of special interest and asthma exacerbation-related events., Results: Of the 128 patients enrolled, 127 completed the surveillance and were included for safety and effectiveness analysis. Thirteen patients experienced 20 adverse drug reactions with an incidence rate of 10.2%. The most frequent adverse drug reactions were pyrexia (2.4%) and urticaria (1.6%). In total, adverse events and serious adverse events occurred in 60 (47.2%) and 30 patients (23.6%) respectively. Two patients experienced anaphylactic reaction and 1 patient experienced type 1 hypersensitivity. 77.2% had an effective response to omalizumab according to GETE at final assessment, and frequency of all asthma exacerbation-related events decreased in post-treatment versus pre-treatment., Conclusions: Long-term omalizumab treatment showed no new safety signals in pediatric patients with severe allergic asthma. The observed safety and effectiveness profile was consistent with previous studies., (Copyright © 2021 Japanese Society of Allergology. Production and hosting by Elsevier B.V. All rights reserved.)

Rationale: Anti-myelin oligodendrocyte protein antibody-associated disease (MOGAD) is a new disease entity with various clinical phenotypes. MOGAD often present with recurrent optic neuritis (ON), and it can also develop as a compartment of neuromyelitis optica spectrum disorder (NMOSD). Moreover, multiple autoantibodies such as an anti-myeloperoxidase antineutrophil cytoplasmic antibody (MPO-ANCA) had been reported in the serum of patients with NMOSD., Patient Concerns: We report an 86-year-old woman with a 2-year history of microscopic polyangiitis (MPA). The patient had a rapid loss of vision in her left eye. No abnormal findings were observed on her left fundus, and she tested negative for MPO-ANCA upon admission. However, anti-MOG antibodies were observed in the patient's serum and cerebrospinal fluid., Diagnosis: A diagnosis of MOGAD complicated with MPA was made., Interventions: The patient received twice steroid pulse therapy and oral azathioprine as maintenance therapy., Outcomes: Her vision rapidly recovered, and no subsequent relapse was observed during the 8-month observation period., Conclusion: To the best of our knowledge, this is the first case of MOGAD complicated with MPA, and steroid pulse therapy and azathioprine therapy were effective for ON caused by MOGAD., Competing Interests: The authors have no conflicts of interests to disclose., (Copyright © 2021 the Author(s). Published by Wolters Kluwer Health, Inc.)

Pleomorphic xanthoastrocytoma (PXA) is a rare glial tumor, however, its histological differentiation from high-grade gliomas is often difficult. Molecular characteristics may contribute to a better diagnostic discrimination. Prognostic factors of PXA are also important but few relevant reports have been published. This study investigated the molecular features and prognostic factors of PXAs. Seven university hospitals participated in this study by providing retrospective clinical data and tumor samples of PXA cases between 1993 and 2014. Tumor samples were analyzed for immunohistochemical (IHC) neuronal and glial markers along with Ki67. The status of the BRAF and TERT promoter (TERTp) mutation was also evaluated using the same samples, followed by feature extraction of PXA and survival analyses. In all, 19 primary cases (17 PXA and 2 anaplastic PXA) were included. IHC examination revealed the stable staining of nestin and the close association of synaptophysin to NFP. Of the PXA cases, 57% had the BRAF mutation and only 7% had the TERTp mutation. On univariate analysis, age (≥60 years), preoperative Karnofsky performance status (KPS) (≤80%), and marked peritumoral edema were significantly associated with progression-free survival (PFS). No independent factor was indicated by the multivariate analysis. In conclusion, PXA was characterized by positive nestin staining and a few TERTp mutations. The neuronal differential marker and BRAF status may help in diagnosis. Patient age, preoperative KPS, and marked perifocal edema were associated with PFS. The present study is limited because of small number of cases and its retrospective nature. Further clinical study is needed.

Background: Omalizumab is an anti-immunoglobulin E monoclonal antibody approved for patients with severe allergic asthma in Japan. With regard to omalizumab dosage in Japanese adults with severe allergic asthma in clinical practice settings, this post-marketing surveillance evaluated safety and efficacy of the dosing table revision (DTR) based on a dosing regimen of omalizumab administration every 4 weeks dosing regimen and dosing table expansion (DTE) for patients with baseline IgE levels >700 IU/mL., Methods: This 52-week, multicenter study, conducted from September 2013 to November 2018, evaluated omalizumab safety outcomes including adverse events (AEs), serious AEs (SAEs), adverse drug reactions (ADRs), efficacy outcomes including Global Evaluation of Treatment Effectiveness (GETE), change in oral corticosteroid dose, and asthma exacerbation-related events such as hospitalization, emergency room visits, and worsening of symptoms., Results: Of the 405 patients registered in the study, safety was evaluated in 392 and efficacy in 390. The mean age of patients was 58.5 years and 58.7% were women. In total, 41.3% of the patients were subjected to DTE and 58.7% to DTR. In the safety dataset, 6.6% experienced an ADR, 32.9% experienced an AE, and 16.1% experienced an SAE. In the efficacy dataset, 63.3% of patients at Week 16 and 63.5% at Week 52 had an 'effective' or 'good' GETE score. Omalizumab was associated with a reduction in worsening of asthma symptoms requiring systemic corticosteroids and frequency of hospitalization. All outcomes were comparable among the DTE and DTR subgroups., Conclusion: The findings from this study support the safety and efficacy of omalizumab administered based on the revised and expanded dosing table in Japanese patients with severe allergic asthma., (Copyright © 2020 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Objective: In the past five decades, many small caliber vascular grafts have been developed as bypasses for infrapopliteal or coronary arteries. However, reliable grafts have not been obtained owing to poor patency, mainly caused by early thrombosis or neointimal hyperplasia in the intermediate period after implantation. We developed a novel small caliber heparin-loaded polyethylene terephthalate ultrafine microfiber (HL-PET) graft and evaluated the feasibility to overcome those main causes of graft failure in canine carotid artery implantation., Methods: The HL-PET graft with a diameter of 3 mm and length of 30 mm was made with combination of three key technologies: (1) weaving with PET ultrafine microfiber with a high biological porosity allowing for cell ingrowth, (2) heparin loading on microfiber surfaces, and (3) an outer coating with a flexible bioabsorbable polymer for prevention of blood leakage and graft kinking. Kink resistance, water permeability, and loaded heparin were assessed. One HL-PET graft each was implanted into a carotid artery of six animals. Graft patency rate and healing were assessed 24 weeks after implantation., Results: Among the six grafts, five were deemed patent (patency rate of >83%), with one occluded 20 weeks after implantation. Histopathology of the patent grafts showed neointima formation with confluent endothelial cell lining (estimated mean endothelial cell coverage area, 89 ± 18%). Intimal hyperplasia at the anastomotic sites and severe chronic inflammatory responses were not observed. Immunohistochemistry with antibodies to endothelial nitric oxide synthase, alpha 2 smooth muscle actin and calponin 1 revealed luminal surface endothelial cell layer with expression of endothelial nitric oxide synthase and vascular smooth muscle cells with contractile phenotype in the subintimal layer., Conclusions: The HL-PET graft showed no early postoperative thrombosis and was able to demonstrate a high patency rate with no severe biological response observed after 24 weeks. These results strongly suggest the potential of the HL-PET graft to be used for distal bypasses., (© 2020 by the Society for Vascular Surgery. Published by Elsevier Inc.)

Background: Growing teratoma syndrome(GTS)is the progression of a mature teratoma during or following radiochemotherapy for germ cell tumors. We report two surgical cases of GTS. CASE 1: A 24-day-old new-born presented with vomiting and head enlargement. Blood alfa-feto protein(AFP)and beta-human chorionic gonadotropin(β-hCG)were within or at the upper limits of the normal ranges. Magnetic Resonance Imaging(MRI)demonstrated a large mass in the posterior fossa causing the severe hydrocephalus. Tumor removal was immediately performed. Histological diagnosis given was immature teratoma. While chemotherapy effectively reduced the level of tumor makers, multiple recurrence was noticed on MRI 70 days after the surgery. GTS was suspected and total removal was performed. Histological examination revealed a mature teratoma. The patient is growing normally thereafter, 2.5 years after the onset. CASE 2: A 16-year-old male presented with binasal hemianopsia. Blood AFP and β-hCG were within or at the upper limits of the normal ranges. MRI demonstrated an intrasellar mass protruding upward. Tumor removal was performed and histological diagnosis given was mixed germ cell tumor. While radiochemotherapy effectively normalized the tumor makers, recurrence was noticed on MRI 190 days after the surgery. Total removal was performed with the diagnosis of GTS. Histological examination revealed a mature teratoma. The patient lives a normal school life thereafter as followed up after a year after the onset., Conclusion: It is important to diagnose and perform the surgery early enough to enable total removal of the mass presenting as GTS because total surgical removal is the only treatment for GTS.

Background: Arterial reconstruction (AR) for limb ischemia may improve ambulatory function (AF) and health-related quality of life (HR-QoL). However, the efficacy of AR in terms of HR-QoL varies in studies, probably because of cohort differences in disease severity, hemodynamic outcomes, and observation duration. We assessed HR-QoL for patients with various severities of ischemia in a 3-year observational study., Methods: We conducted a single-center 3-year observational study using Short Form 36 in patients with chronic limb ischemia. Between 2001 and 2009, 515 consecutive patients had AR, and 330 who underwent elective AR consented to the study. Of the 330 patients (claudicants 49%, critical limb ischemia [CLI] 51%), 307 underwent bypass and 23 endovascular therapy. Postal questionnaires were sent after AR, and 8 domains, the physical and mental component summary (PCS and MCS) scores, and the patient-reported AF were compared, and negative predictors were identified., Results: Overall, the MCS was minimally affected, but AF and the PCS were impaired. After AR, these measures were significantly improved, and maximum recovery was attained at 6 months. In subgroup analysis, significant predictors of a negative impact on postoperative PCS included age ≥80, CLI, physical aftereffects of stroke (PAS), and previous major amputation (PMA). Of these, PMA was associated with the lowest PCS score, followed by PAS; for these patients, AR contributed minimally to HR-QoL recovery. PCS scores of claudicants attained a maximum value at 6 months; however, PCS scores of CLI patients were significantly lower than intermittent claudication patients (P < 0.0001), and patients with major tissue loss required 2 years to attain maximum PCS recovery., Conclusions: This 3-year observational study verified the efficacy of AR in improving AF and HR-QoL. Age ≥80, CLI, PAS, and PMA were definitive predictors, and for patients with the latter 2, AR contributed minimally to improving HR-QoL., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Objectives : The dipeptidyl peptidase-4 (DPP-4) inhibitor vildagliptin is indicated for type 2 diabetes mellitus (T2DM). However, the long-term safety, effectiveness, and clinical relationship with cardiovascular events of vildagliptin have not been evaluated in Japan. Methods : The authors conducted post-marketing surveillance (PMS) to evaluate the safety and effectiveness of vildagliptin in more than 3000 Japanese T2DM patients for up to 3 years. Main assessments included demographics, major adverse cardiovascular events (MACE), adverse events (AEs), adverse drug reactions (ADRs), and glycated hemoglobin (HbA1c). Results : In this PMS, 3831 patients (775 sites) were registered in April 2010 - April 2012. The safety analysis population comprised 3769 patients; 2085 patients were aged ≥65 years, and 240, 411, and 114 had renal impairment, hepatic impairment, and heart failure, respectively. The median treatment duration was 2.7 years. The incidence of MACE was 6.04 cases/1000 person-years, mostly attributable to cerebrovascular events (4.27 cases/1000 person-years). The AE and ADR incidences were 26.0% and 5.3%, respectively. The incidence of hypoglycemia was 0.6%. No significant changes in body weight occurred and mean change in HbA1c from baseline at final assessment was -0.74 ± 1.41% ( p < 0.0001). Conclusions : In real-world clinical settings, vildagliptin was well tolerated, with similar profiles as previously reported.

Introduction: To facilitate safe anastomosis of a vascular prosthesis onto the proximal ascending aorta without side clamping, a clampless anastomotic device with large diameter aortic puncher was developed., Report: First, a vascular prosthesis is anastomosed onto the aorta without making a hole, then the aortic wall within the prosthesis is punched out using the device., Discussion: After further refinement of the present device, endovascular surgery with debranching could be performed more safely and quickly., (© 2020 The Author(s).)

We report a patient with dermatomyositis (DM) complicated with progressive pleural effusion and ascites. A 40-year-old woman was hospitalized in our department because of severe myalgia and dysphagia, complicated with pleural effusion and massive ascites. Elevated muscle enzymes, Gottron's papules, and electromyography (EMG) confirmed the diagnosis of DM. Combined immunosuppressive treatment consisting of intravenous immunoglobulin (IV-IG), intravenous-cyclophosphamide (IV-CY) and tacrolimus resolved her myopathy and dysphagia as well as pleural effusion and massive ascites. Her clinical course and the absence of other factors that cause pleural effusion and ascites suggest that these symptoms were related to the pathophysiology of DM.

Objective: Intimal hyperplasia (IH) is the main cause of therapeutic failure after vascular and endovascular surgery. However, there is currently no targeted therapy for the treatment of IH. We recently reported that the inhibition of cyclic adenosine monophosphate response element (CRE) binding protein (CREB) activation is important in vein graft IH. We focused on a decoy oligodeoxynucleotide (ODN) therapeutic strategy for suppressing IH as a clinical application. The objective of this study was to confirm the therapeutic effect of a CRE decoy ODN in an animal model as a novel therapy for preventing intimal hyperplasia as the first step of the preclinical study of our strategy., Methods: We designed two phosphorothioate CREs and two scramble decoy ODNs and screened them using a CREB transcription assay to check their ability to bind to a CRE sequence. We chose a CRE decoy ODN with high first-binding ability and transfected it into vascular smooth muscle cells (VSMCs) in vitro. Proliferation and migration were assessed using MTS (3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium) assays and modified Boyden chamber assays. We examined CRE activity using a luciferase reporter gene assay. We assessed the expression of messenger RNAs by quantitative real-time polymerase chain reaction. In a wire-injury mouse model (C57BL6, n = 6), CRE decoy ODN was transfected into the injured vessel wall using an ultrasound-sonoporation method in vivo. Mitogen-activated protein kinase-activated protein kinase 3 (MAPKAPK3) and four and a half LIM domains 5 (FHL5) expression of pregrafting vein remnants were assessed by immunohistologic analyses., Results: Compared with scramble decoy ODN, the selected CRE decoy ODN could significantly decrease CRE activity (mean ± standard error of the mean: 0.20 ± 0.03 vs 1.00 ± 0.16, n = 6; P < .05) as shown by a luciferase reporter gene assay, VSMC proliferation (0.73 ± 0.04 vs 0.89 ± 0.02, n = 6; P < .05) and migration (96.4 ± 6.1 vs 311.4 ± 19.1 migrated VSMCs/well, n = 6; P < .05) after 24-hour transfection. The CRE decoy ODN significantly suppressed the formation of IH at injured vessel walls in an animal model, as analyzed by pathologic staining (0.20 ± 0.02 vs 0.56 ± 0.08, area of the intima/area of the artery vs the control after 21 days' transfection, n = 6; P < .05). Furthermore, MAPKAPK3 and FHL5, which are CREB activators, were significantly expressed in pregrafting vein remnants in diabetes mellitus patients., Conclusions: CREB-CRE signaling is an important mechanism of IH formation, and CRE decoy therapy can help preventing IH. This study is the first part of the preclinical study of our strategy., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

Objective : This multicenter observational study was conducted in order to investigate the incidence of cancer in patients with critical limb ischemia. Materials and Methods : We prospectively investigated the incidence of cancer in 68 patients with critical limb ischemia over a two-year period. Patients underwent an intensive examination at enrollment, which included tumor marker levels and chest and abdominal computed tomography, as well as one- and two-year follow-up examinations. We compared the observed incidence of cancer with the expected incidence calculated from national cancer rates by the standardized incidence ratio (SIR). Results : The majority (83.6%) of the patients were men, and 92.5% of the patients had a peripheral arterial disease that was classified as Fontaine stage III or IV. During enrollment, newly diagnosed cancers were detected in seven patients. Four additional cancers were detected during the follow-up period. All of the detected cancers were asymptomatic. We observed an increased risk of cancer (SIR, 4.04; 95% confidence interval, 1.31-9.42) in patients with critical limb ischemia. Conclusion : This study suggests that critical limb ischemia is associated with an increased risk of cancer. Our findings should be taken into serious consideration by future investigators considering the use of therapeutic angiogenesis., Competing Interests: Disclosure StatementMaeda received lecture fees from Bayer Yakuhin, Ltd. Nishibe received honoraria from Daiichi Sankyo, Ltd. Tanemoto received a donation from Senko Medical Instrument Mfg. Co., Ltd. The remaining authors disclose no conflicts of interest.

Background: Omalizumab (anti-IgE monoclonal antibody) is an approved add-on therapy for Japanese patients with severe allergic asthma. As directed by the Ministry of Health, Labor and Welfare Japan, a post-marketing surveillance (PMS) study on omalizumab was conducted between 2009 and 2017., Methods: The PMS observed safety and efficacy of omalizumab in patients treated with open-label omalizumab for 52 weeks (with optional 2-year extension period). Primary safety outcomes included incidence and severity of adverse events (AEs) and adverse drug reactions (ADRs). Primary efficacy outcomes included physician-assessed global evaluation of treatment effectiveness (GETE). Asthma-exacerbation-related events including requirement for additional systemic steroid therapy, hospitalization, emergency room visits, unscheduled doctor visits, and absenteeism were also evaluated., Results: Of 3893 patients registered, 3620 (age [mean ± SD] 59.3 ± 16.11 years) were evaluated for 52 weeks; 44.12% were aged ≥65 years and 64.45% were women. Overall, 32.24% reported AEs and 15.30% reported serious AEs. ADRs were seen in 292 (8.07%) patients. GETE results showed that the majority of patients experienced clinical improvements (58.29% at 16 weeks and 62.40% at 52 weeks). Nearly half of all patients (47.96%) were free from asthma exacerbations after therapy. Omalizumab also reduced all events related to asthma exacerbations. No specific ADRs were observed in the elderly population., Conclusions: This post-marketing study confirmed the clinically meaningful benefits of omalizumab in a majority of patients from Japan, and showed safety and efficacy in a real-life clinical setting to be consistent with previous reports., (Copyright © 2018. Published by Elsevier Ltd.)

We have used scanning tunneling microscopy (STM) to elucidate the nanoscale electronic structures of graphene oxide (GO). The unreduced GO layer was imaged using STM without reduction processes when deposited on a Au(111) surface covered with an octanethiolate self-assembled monolayer (C8S-SAM). The STM image of the GO sheet exhibits a grainy structure having a thickness of about 1 nm, which is in good agreement with the previous results obtained using atomic force microscopy (AFM). We found that the C8S-SAM suppresses the adsorption of water remaining on the substrate, which would be important to accomplish the nanoscale imaging of the unreduced GO by STM. Furthermore, we successfully detected the π and π* states localized in the GO sheet using scanning tunneling spectroscopy (STS). The π-π* gap energy and the gap center are not uniform within the GO sheet, indicating the existence of various sizes of the sp2 domain and evidence for the local electronic doping by the substituents.

Objective: The aim of this study was to elucidate the efficacy of paramalleolar or inframalleolar bypass (PIMB) in hemodialysis-dependent (HD) patients with critical limb ischemia (CLI) and nonhemodialysis-dependent (NHD) patients in terms of clinical outcomes., Methods: Between January 2000 and December 2013, there were 333 consecutive arteriosclerosis obliterans patients with CLI who underwent 401 PIMB procedures for limb salvage (LS). Of the 333 patients, 188 (56.5%) were HD patients. Vein grafts were exclusively used, and 172 paramalleolar and 229 inframalleolar bypasses were performed. Five-year primary and secondary cumulative graft patency, LS, and amputation-free survival (AFS) rates were compared between the two groups, and the independent determinants of these outcomes were identified in each group., Results: The 5-year primary and secondary cumulative graft patency rates were 53% and 82% in HD patients and 69% and 92% in NHD patients (primary cumulative graft patency, P < .05; secondary cumulative graft patency, nonsignificant), respectively. The LS rates were 87% and 99% (P < .01) in HD patients and NHD patients, respectively. Overall, 48% and 70% of HD and NHD patients were ambulatory before PIMB (P < .01), and 73% and 85% of HD and NHD patients were ambulatory 12 months after PIMB (including 1-year survivors; nonsignificant), respectively, demonstrating drastic post-PIMB improvement in HD patients. The 5-year AFS rates in the HD and NHD groups were 27% and 69% (P < .01), respectively, demonstrating very poor AFS rates in HD patients. In HD patients, factors negatively associated with AFS were female gender (hazard ratio [HR], 2.102; 95% confidence interval [CI], 1.254-3.524), history of congestive heart failure (HR, 2.075; 95% CI, 1.395-3.085), and preoperative nonambulatory status (HR, 1.974; 95% CI, 1.305-2.986), whereas older age (HR, 2.601; 95% CI, 1.372-4.931) and history of congestive heart failure (HR, 2.928; 95% CI, 1.496-5.731) were identified as independent factors negatively associated with AFS in NHD patients., Conclusions: The use of PIMB for CLI was associated with excellent LS rates in both HD and NHD patients with low operative mortality and complications. However, the AFS rate observed in HD patients was significantly lower than that observed in NHD patients, indicating the necessity of a specific management program to improve AFS after LS in HD patients., (Copyright © 2017 Society for Vascular Surgery. Published by Elsevier Inc. All rights reserved.)

Carmustine wafers (CW) were approved in Japan for newly diagnosed and recurrent malignant gliomas during 2013. The ventricle is often opened during surgery to achieve maximum resection. While not generally recommended in such situations, CW might be safely achieved by occluding an opened ventricle using gelform or collagen sheets. However, whether CW implantation actually confers a survival benefit for patients who undergo surgery with an open ventricle to treat glioblastoma remains unclear. Clinical, imaging, and survival data were collected in this multicenter retrospective study of 122 consecutive patients with newly diagnosed glioblastoma to determine adverse events and efficacy. Overall, 54 adverse events of all grades developed in 35 (28.6%) patients, with the most common being new seizures (16%). Adverse events did not significantly differ between patients with opened and closed ventricles during surgery. The 10- and 21.7-month, median, progression-free (PFS) and overall survival (OS), respectively did not significantly differ according to resection rates. However, median PFS and OS were significantly longer among patients with closed, than open ventricles (12.8 vs. 7.4 months; p = 0.0039 and 26.9 vs. 18.6 months; p = 0.011, respectively). Implanting CW into the resection cavity during concomitant radiochemotherapy with temozolomide seems to yield better survival rates without increased adverse events. Occlusion of the ventricular opening during surgery might be safe for CW implantation, but less so for treating patients with newly diagnosed glioblastoma.

The authors describe a case of a basilar trunk aneurysm with long-term follow-up after successful bypass and proximal occlusion. A 64-year-old woman had a giant aneurysm of the basilar trunk and underwent external carotid artery-to-posterior cerebral artery vein graft bypass surgery and proximal clipping of the basilar artery, which was followed by low-dose aspirin (100 mg/d) treatment. No ischemic symptoms and lesions developed and the thrombosed aneurysm was stable during 11 years of follow-up. An extracranial-intracranial high flow bypass combined with immediate proximal occlusion and aspirin administration may be an acceptable treatment option for patients with giant posterior circulation aneurysms., (Copyright © 2016 National Stroke Association. Published by Elsevier Inc. All rights reserved.)

Introduction: We examined whether the amino acid PET tracers, trans-1-amino-3-(18)F-fluorocyclobutanecarboxylic acid (anti-(18)F-FACBC) and (11)C-methyl-l-methionine ((11)C-Met), are suitable for detecting early responses to combination therapies including temozolomide (TMZ), interferon-β (IFN), and bevacizumab (Bev) in glioblastoma., Methods: Human glioblastoma U87MG (U87) cells were incubated with low dose TMZ to induce chemoresistance. Both trans-1-amino-3-fluoro-1-(14)C-cyclobutanecarboxylic acid (anti-(14)C-FACBC) and (3)H-methyl-l-methionine ((3)H-Met) uptake were quantified using triple-label accumulation assays to examine the relationship between tracer uptake and proliferation ((3)H-thymidine (TdR) accumulation) in vitro. U87 and U87R (TMZ-resistant subculture) cells were inoculated into the right and left basal ganglia, respectively, of F344/N-rnu rats. The efficacy of single-agent (TMZ, Bev) and combination therapy (TMZ/IFN, TMZ/Bev, TMZ/IFN/Bev) was examined in orthotopic gliomas using MRI, Evans blue extravasation, anti-(14)C-FACBC, and (3)H-Met autoradiography, and MIB-1 immunostaining., Results: TMZ treatment decreased (3)H-TdR accumulation and the volume distribution of anti-(14)C-FACBC and (3)H-Met in U87 but not U87R cells. TMZ/IFN combination therapy significantly decreased these parameters in U87R cells; however, Bev had no additional effect in vitro. In vivo, U87R-derived gliomas were observed as equivocal tumors on MRI and T2-high intensity lesions. Bev treatment, either alone or in combination, markedly decreased U87 enhancing lesions. By contrast, autoradiographic images using anti-(14)C-FACBC and (3)H-Met clearly delineated tumor extent, which spread widely beyond T2-high intensity lesions and enhancing lesions. TMZ therapy significantly decreased tracer accumulation and proliferation of U87- but not U87R-derived tumors. TMZ/IFN combination treatment significantly decreased these parameters in U87R tumors, which were further reduced (in both tumor types) by Bev addition. Tracer uptake correlated with the MIB-1 proliferation index. However, MRI was unsuitable for tumor delineation and assessment of Bev treatment response., Conclusions: Triple-agent therapy (TMZ/IFN/Bev) was effective against even TMZ-resistant glioblastomas. PET with amino acid tracers provides useful information on the early response of glioblastomas to single-agent and combination therapy., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Rapid immunohistochemistry (R-IHC) can contribute to the intraoperative diagnosis of central nervous system (CNS) tumors. We have recently developed a new IHC method based on an alternating current electric field to facilitate the antigen-antibody reaction. To ensure the requirement of R-IHC for intraoperative diagnosis, 183 cases of CNS tumors were reviewed regarding the accuracy rate of diagnosis without R-IHC. The diagnostic accuracy was 90.7 % (166/183 cases) [corrected] in which definitive diagnoses were not provided in 17 cases because of the failure of glioma grading and differential diagnosis of lymphoma and glioma. To establish the clinicopathological application, R-IHC for frozen specimens was compared with standard IHC for permanent specimens. 33 gliomas were analyzed, and the Ki-67/MIB-1 indices of frozen specimens by R-IHC were consistent with the grade and statistically correlated with those of permanent specimens. Thus, R-IHC provided supportive information to determine the grade of glioma. For discrimination between glioma and lymphoma, R-IHC was able to provide clear results of CD20 and Ki-67/MIB-1 in four frozen specimens of CNS lymphoma as well as standard IHC. We conclude that the R-IHC for frozen specimens can provide important information for intraoperative diagnosis of CNS tumors.