Efficacy and safety of plasma exchange in interstitial lung diseases with anti-melanoma differentiation-associated 5 gene antibody positive clinically amyopathic dermatomyositis.

OBJECTIVE: Clinically amyopathic dermatomyositis (CADM) patients frequently develop refractory interstitial lung disease (ILD), with a poor prognosis. We aimed to verify the efficacy and safety of plasma exchange (PE) treatment for ILD in CADM. METHOD: A retrospective case-control study was conducted to compare clinical outcomes with and without PE treatment in CADM-ILD patients refractory to combination therapy of high-dose glucocorticoids, calcineurin inhibitors, and cyclophosphamide. Among 19 enrolled patients, 11 were further treated with PE. We compared survival rates and other clinical characteristics. PE consisted of either fresh-frozen plasma or albumin as a replacement solution. RESULTS: Basal clinical characteristics at diagnosis, including age, gender, serum ferritin, Krebs von den Lungen-6 (KL-6), C-reactive protein, and respiratory function tests, did not differ between the two groups. The survival rate for treatment with PE was higher than for treatment without PE (91% and 50%, respectively, p < 0.05). Among PE-treated patients, anti-melanoma differentiation-associated gene-5 (anti-MDA-5) antibody titre, ferritin, and KL-6 as serological activity markers were sustainably reduced only after initiating PE. Therapeutic intervention with PE reduced the frequency of exacerbation of ILD requiring methylprednisolone pulse therapy. The occurrence of bacterial, fungal, and cytomegalovirus infection did not differ between the groups with and without PE, and adverse events associated with PE resolved with appropriate intervention. CONCLUSION: Combination therapy with PE was associated with an improved survival rate, and may be effective for the management of refractory ILD in CADM patients. A personalized therapeutic strategy including PE could be introduced for fatal rapidly progressive ILD.

Downward Terrestrial Gamma-Ray Flash Observed in a Winter Thunderstorm.

During a winter thunderstorm on 24 November 2017, a strong burst of gamma rays with energies up to ∼10 MeV was detected coincident with a lightning discharge, by scintillation detectors installed at the Kashiwazaki-Kariwa Nuclear Power Station at sea level in Japan. The burst had a subsecond duration, which is suggestive of photoneutron production. The leading part of the burst was resolved into four intense gamma-ray bunches, each coincident with a low-frequency radio pulse. These bunches were separated by 0.7-1.5 ms, with a duration of ≪1 ms each. Thus, the present burst may be considered as a "downward" terrestrial gamma-ray flash (TGF), which is analogous to upgoing TGFs observed from space. Although the scintillation detectors were heavily saturated by these bunches, the total dose associated with them was successfully measured by ionization chambers, employed by nine monitoring posts surrounding the power plant. From this information and Monte Carlo simulations, the present downward TGF is suggested to have taken place at an altitude of 2500±500 m, involving 8_{-4}^{+8}×10^{18} avalanche electrons with energies above 1 MeV. This number is comparable to those in upgoing TGFs.

Suppression of Trapped Energetic Ions Driven Resistive Interchange Modes with Electron Cyclotron Heating in a Helical Plasma.

The resistive interchange mode destabilized by the resonant interaction with the trapped energetic ions is fully suppressed when the injected power of electron cyclotron heating exceeds a certain threshold. It is shown for the first time that the complete stabilization of the energetic-particle-driven mode without relaxing the energetic particle (EP) pressure gradient is possible by reducing the radial width of the eigenmodes δ_{w}, especially when δ_{w} narrows to a small enough value relative to the finite orbit width of EP.

Cholestatic Liver Injury After Biliary Reconstruction Impairs Transplanted Islet Viability and Function.

Islet autotransplantation following total pancreatectomy differs from allograft transplantation with respect to the requirement of biliary reconstruction. Although it is known that careful consideration should be given to postoperative cholestatic liver injury after biliary reconstruction, its direct effects on transplanted islets have not been completely elucidated. In this study, we developed a murine model of postoperative cholestatic liver injury after biliary reconstruction with islet autotransplantation that involved syngeneic intraportal islet transplantation into chemically induced diabetic mice and common bile duct ligation. We assessed the viability and function of the transplanted islets. The impaired viability of transplanted islets and increased blood glucose levels indicated restoration of the diabetic state after common bile duct ligation in this murine model. Furthermore, impaired islet viability and function occurred earlier in the transplanted islets than in the surrounding liver tissues, which was consistent with the faster and higher expression of oxidative stress markers in the transplanted islets. Transplanted islets may be more vulnerable to oxidative stress caused by cholestatic liver injury than the surrounding liver tissue. Therefore, patients should be intensively managed after total pancreatectomy with islet autotransplantation to preserve viability and function of the transplanted islets.

Enhanced ultrasonography using a nano/microbubble contrast agent for islet transplantation.

Recent basic and clinical studies have assessed the use of highly sensitive imaging modalities for visualizing transplanted islets. We investigated the utility of enhanced ultrasonography, combined with fluorescent acoustic liposome nano/microbubbles (FALs), for evaluating angiogenesis and the endocrine function of transplanted islets. BALB/c mice were classified into three groups: Diabetic mice that underwent syngeneic islet transplantation into the subrenal capsule and achieved normoglycemia (Tx group); those that failed to achieve normoglycemia (Tx-DM group); and those not receiving any treatment (DM group). Mice were examined by FAL-enhanced high frequency ultrasonography. The echogenicity of the islets increased rapidly within the first minute after injection of FALs and remained at a higher level in the Tx group, while small increases were observed in the other two groups. In histological assessments, fluorescently stained erythrocytes could be seen in and around the transplanted islets, indicating that the transplanted islets were enhanced by infusion of FALs via vessel networks between the engrafted islets and tissue. Furthermore, the echogenicity correlated significantly with endocrine parameters, including blood glucose (BG), serum insulin, and the BG change in the glucose tolerance test. In conclusion, the echogenicity of the islets under FAS-enhanced ultrasonosonography correlated with the endocrine status of transplanted islets.

Objective tumor response to denosumab in patients with giant cell tumor of bone: a multicenter phase II trial.

BACKGROUND: Giant cell tumor of bone (GCTB) is a rare primary bone tumor, characterized by osteoclast-like giant cells that express receptor activator of nuclear factor-kappa B (RANK), and stromal cells that express RANK ligand (RANKL), a key mediator of osteoclast activation. A RANKL-specific inhibitor, denosumab, was predicted to reduce osteolysis and control disease progression in patients with GCTB. PATIENTS AND METHODS: Seventeen patients with GCTB were enrolled. Patients were treated with denosumab at 120 mg every 4 weeks, with a loading dose of 120 mg on days 8 and 15. To evaluate efficacy, objective tumor response was evaluated prospectively by an independent imaging facility on the basis of prespecified criteria. RESULTS: The proportion of patients with an objective tumor response was 88% based on best response using any tumor response criteria. The proportion of patients with an objective tumor response using individual response criteria was 35% based on the modified Response Evaluation Criteria in Solid Tumors (RECIST) criteria, 82% based on the modified European Organization for Research and Treatment of Cancer (EORTC) criteria, and 71% based on inverse Choi criteria. The median time of study treatment was 13.1 months. CONCLUSION: The findings demonstrate that denosumab has robust clinical efficacy in the treatment of GCTB.

Resistive interchange modes destabilized by helically trapped energetic ions in a helical plasma.

A new bursting m=1/n=1 instability (m,n: poloidal and toroidal mode numbers) with rapid frequency chirping down has been observed for the first time in a helical plasma with intense perpendicular neutral beam injection. This is destabilized in the plasma peripheral region by resonant interaction between helically trapped energetic ions and the resistive interchange mode. A large radial electric field is induced near the edge due to enhanced radial transport of the trapped energetic ions by the mode, and leads to clear change in toroidal plasma flow, suppression of microturbulence, and triggering an improvement of bulk plasma confinement.

Surgical treatment for pyogenic vertebral osteomyelitis using iodine-supported spinal instruments: initial case series of 14 patients.

Reports have detailed the increasing use of spinal instrumentation in the treatment of pyogenic vertebral osteomyelitis, with the aims of achieving a lower pseudoarthrosis rate and restoring spinal alignment. However, controversy remains over the use of instrumentation in the presence of active infection because of concerns about increased bacterial adherence and biofilm formation on the metallic implant surface. Fourteen consecutive patients were followed who were diagnosed as having pyogenic vertebral osteomyelitis and underwent surgery with spinal instrumentation with iodine-containing surfaces that could be directly supported to existing titanium implants. Bone-cage interfaces and implant-related complications after surgery were evaluated. The white blood cell (WBC) count and C-reactive protein (CRP) level were analyzed during the follow-up period. To confirm the influence of iodine release from the implant, thyroid-stimulating hormone (TSH), free triiodothyronine (FT3), and free thyroxine (FT4) were also examined. The infection subsided in all 14 patients. Both WBC counts and CRP levels returned to normal ranges by the final follow-up. One patient showed a lucent area around the screw and two patients showed lucencies inside the cage. However, no cage dislocations, cage migrations, or screw pull-outs were noted, and all patients' FT3, FT4, and TSH levels were within normal ranges during the follow-up period. We demonstrated the efficacy of iodine-supported titanium implants in the management of pyogenic vertebral osteomyelitis. No cytotoxicity or adverse effects were noted in this series.

Chronic active Epstein-Barr virus infection mimicking autoimmune hepatitis exacerbation in a patient with systemic lupus erythematosus.

Chronic active Epstein-Barr virus infection (CAEBV) is characterized by chronic infectious mononucleosis-like symptoms. We report a very rare case with autoimmune hepatitis (AIH) complicated by CAEBV. A 50-year-old woman with systemic lupus erythematosus (SLE) complicated by AIH began to suffer from acute respiratory failure and her clinical symptoms improved rapidly in response to steroid treatment. However, during the gradual tapering of the steroid dose, a steady increase of the serum hepatobiliary enzyme levels subsequently was observed and the patient began to have continuous fever. Moreover, upper gastrointestinal endoscopy revealed multiple intractable gastric ulcers. When EBER-ISH was performed on liver biopsy and gastric mucosal biopsy specimens, EBER-positive lymphocytes were observed. When peripheral blood was examined, 2.1 × 10(6) copies/µg of EBV-DNA were observed in the CD4-positive T cells, confirming the diagnosis of CAEBV. A cooling therapy was started by steroid and cyclosporine. Thereafter, despite the start of CHOP therapy, she developed a malignant lymphoma (PTCL-NOS) and died of hepatic failure. When treatment-resistant AIH patients are encountered, not only AIH exacerbation but also CAEBV should be considered in the differential diagnosis.

Hardening and termination of long-duration γ rays detected prior to lightning.

We report the first observation of 3-30 MeV prolonged gamma-ray emission that was abruptly terminated by lightning. The gamma-ray detection was made during winter thunderstorms on December 30, 2010, by the Gamma-Ray Observation of Winter Thunderclouds experiment carried out in a coastal area along the Sea of Japan. The gamma-ray flux lasted for less than 3 min, continuously hardening closer to the lightning occurrence. The hardening at energies of 3-10 MeV energies was most prominent. The gamma-ray flux abruptly ceased less than 800 ms before the lightning flash that occurred over 5 km away from the experimental site. In addition, we observed a clear difference in the duration of the 3-10 MeV gamma rays and those >10 MeV, suggesting that the area of >10 MeV gamma-ray emission is considerably smaller than that of the lower-energy gamma rays. This work may give a manifestation that a local region emitting prolonged gamma rays connects with a distant region to initiate lightning.

W-band millimeter-wave back-scattering system for high wavenumber turbulence measurements in LHD.

A 90 GHz W-band millimeter-wave back-scattering system is designed and installed for measuring electron scale turbulence (k⊥ρs ∼ 40). A metal lens relay antenna is used for in-vessel beam focusing, and a beam diameter of less than 40 mm is achieved in the plasma core region. This antenna can be steered at an angle of 159° ± 6°, which almost covers the plasma radius. The estimated size of the scattering volume is ∼105 mm at the edge and 135 mm at the core, respectively. A 60 m corrugated waveguide is used to achieve a low transmission loss of ∼8 dB. A heterodyne detection system for millimeter-wave circuits with probing power modulation can distinguish the scattered signal from background noise.

Associations of PD-L1, PD-L2, and HLA class I expression with responses to immunotherapy in patients with advanced sarcoma: post hoc analysis of a phase 1/2 trial.

BACKGROUND: Although immunotherapy is thought to be a promising cancer treatment, most patients do not respond to immunotherapy. In this post hoc analysis of a phase 1/2 study, associations of programmed death ligand 1 (PD-L1), PD-L2, and HLA class I expressions with responses to dendritic cells (DCs)-based immunotherapy were investigated in patients with advanced sarcoma. METHODS: This study enrolled 35 patients with metastatic and/or recurrent sarcomas who underwent DC-based immunotherapy. The associations of PD-L1, PD-L2, and HLA class I expressions in tumor specimens, which were resected before immunotherapy, with immune responses (increases of IFN-γ and IL-12) and oncological outcomes were evaluated. RESULTS: Patients who were PD-L2 (+) showed lower increases of IFN-γ and IL-12 after DC-based immunotherapy than patients who were PD-L2 (-). The disease control (partial response or stable disease) rates of patients who were PD-L1 (+) and PD-L1 (-) were 0% and 22%, respectively. Disease control rates of patients who were PD-L2 (+) and PD-L2 (-) were 13% and 22%, respectively. Patients who were PD-L1 (+) tumors had significantly poorer overall survival compared with patients who were PD-L1 (-). No associations of HLA class I expression with the immune response or oncological outcomes were observed. CONCLUSIONS: This study suggests that PD-L1 and PD-L2 are promising biomarkers of DC-based immunotherapy, and that addition of immune checkpoint inhibitors to DC-based immunotherapy may improve the outcomes of DC-based immunotherapy.

B7-DC, a new dendritic cell molecule with potent costimulatory properties for T cells.

Dendritic cells (DCs), unique antigen-presenting cells (APCs) with potent T cell stimulatory capacity, direct the activation and differentiation of T cells by providing costimulatory signals. As such, they are critical regulators of both natural and vaccine-induced immune responses. A new B7 family member, B7-DC, whose expression is highly restricted to DCs, was identified among a library of genes differentially expressed between DCs and activated macrophages. B7-DC fails to bind the B7.1/2 receptors CD28 and cytotoxic T lymphocyte-associated antigen (CTLA)-4, but does bind PD-1, a receptor for B7-H1/PD-L1. B7-DC costimulates T cell proliferation more efficiently than B7.1 and induces a distinct pattern of lymphokine secretion. In particular, B7-DC strongly costimulates interferon gamma but not interleukin (IL)-4 or IL-10 production from isolated naive T cells. These properties of B7-DC may account for some of the unique activity of DCs, such as their ability to initiate potent T helper cell type 1 responses.

Clinicopathological features of solitary fibrous tumours in the extremities: four case reports and a literature review.

This paper reports on the clinicopathological features of four patients with solitary fibrous tumours arising from the extremities and presents a review of the relevant literature. The patients consisted of three women and one man, with a mean age of 47.8 years. Standard pre-operative work-up data were examined, including: history, clinical examination, plain radiography, computed tomography scans of the lesion and chest, magnetic resonance imaging, angiography, technetium-99m bone scan, thallium-201 scintigraphy and routine laboratory tests. Immunohistochemical staining was performed for CD34, Bcl-2 protein, vimentin, S-100 protein, desmin and smooth muscle actin, and pathological material was reviewed for the presence of histologically malignant components. Immunohistochemically, all of the tumours were diffusely positive for CD34. Clinical and radiological findings of solitary fibrous tumours affecting the extremities are reminiscent of those of aggressive or malignant soft tissue tumours. Pathological and immunohistochemical studies are important in making the correct diagnosis.

Influence of freezing with liquid nitrogen on whole-knee joint grafts and protection of cartilage from cryoinjury in rabbits.

Improving survival rates for sarcoma patients are necessitating more functional and durable methods of reconstruction after tumor resection. Frozen osteoarticular grafts are utilized for joint reconstruction, but the joint may develop osteoarthritic change. We used a frozen autologous whole-rabbit knee joint graft model to investigate the influence of freezing on joint components. Thirty rabbit knee joints that had been directly immersed into liquid nitrogen (L) or saline (C) without use of cryoprotectants were re-implanted. Histological observations were made after 4, 8, and 12 weeks. Both groups had bone healing. In group L, despite restoration of cellularity to the menisci and ligaments, no live chondrocytes were observed and cartilage deterioration progressed over time. It was concluded that cryoinjury of chondrocytes caused osteoarthritic change. Then we tested whether a vitrification method could protect cartilage from cryoinjury. Full-thickness articular cartilage of rabbit knee was immersed into liquid nitrogen with and without vitrification. Histology, ultrastructure, and chondrocyte viability were examined before and after 24h of culture. Vitrified cartilage cell viability was >85% compared with that of fresh cartilage. Transmission electron microscopy revealed preservation of original chondrocyte structure. Our vitrification method was effective for protecting chondrocytes from cryoinjury. Since reconstructing joints with osteoarticular grafts containing living cartilage avert osteoarthritic changes, vitrification method may be useful for storage of living cartilage for allografts or, in Asian countries, for reconstruction with frozen autografts containing tumors.

[Tricuspid annuloplasty, pulmonary valve replacement, ventricular septal defect (VSD) patch closure, and right-sided maze procedure 23-years after corrective repair of tetralogy of Fallot].

Postoperative pulmonary valve regurgitation, stenosis of the right ventricular outflow tract, conduit failure, ventricular septal patch leak, secondary tricuspid valve regurgitation, and various arrhythmias are the major complications that develop after surgical repair of tetralogy of Fallot in adults. A 27-year-old male with pulmonary regurgitation, tricuspid regurgitation, residual ventricular septal defect (VSD), low left ventricular function, and chronic atrial fibrillation underwent tricuspid annuloplasty, pulmonary valve replacement with a stentless aortic valve, VSD patch closure, and right-sided maze procedure, and the postoperative course was uneventful. The cardiothoracic ratio decreased, sinus rhythm was restored, and the patient's complaints were relieved. Reoperation at the optimal time after corrective repair of tetralogy of Fallot in adults may improve the outcome.