Effect of topical immunotherapy with squaric acid dibutylester for alopecia areata in Japanese patients.

BACKGROUND: The Japanese guidelines for the treatment of alopecia areata list topical immunotherapies as a drug therapy for this condition. However, there is insufficient evidence of its efficacy to support this recommendation. Thus, we sought to clarify the effect of topical immunotherapy on the progression and severity of alopecia areata in Japanese patients. METHODS: To evaluate the effect of topical immunotherapy with squaric acid dibutylester (SADBE) in alopecia areata patients, we performed a retrospective cohort study on 49 alopecia patients who had received topical immunotherapy with SADBE. Patients were evaluated by the change in alopecia severity at 6 and 12 months after the initiation of topical immunotherapy. The improvement rate was calculated by determination of the complete and partial responses rate to treatment with topical immunotherapy by application of SADBE. RESULTS: The improvement rate in all alopecia patients treated with SADBE topical immunotherapy was 57.8% (complete response; 11.1% and partial response; 46.7%). CONCLUSIONS: Topical immunotherapy with SADBE is an effective treatment for alopecia areata. Therefore, the current treatment recommendations for alopecia areata with topical immunotherapies are appropriate.

[Multicentral Questionnaire Results for Consciousness of Medical Personnel on Chemotherapy for Gastric and Colorectal Cancer].

When a medical provider(medical personnel)becomes a medical receiver(patient), does the consciousness about chemotherapy change ? If yes, what is the main reason ? In this study, we conducted a questionnaire on the consciousness of doctors and pharmacologists engaged in chemotherapy for gastric and/or colorectal cancer. The number of questionnaires collected was 83 and 92 for gastric and colorectal cancer, respectively. In adjuvant chemotherapy, 5%and 4%do not want to receive any chemotherapy for gastric and colorectal cancer if they are patients. The main reasons are binding hours, side effects, and no wish for life extension. About 11%and 9%change their consciousness regarding chemotherapy according to whether they are care providers or receivers. The main reasons are medical perspective and their sense of duty. In chemotherapy for advanced cancer, 6% and 5% of gastric and colorectal cancer patients, do not want to receive any chemotherapy. The main reasons are low expectations for being cured, binding hours, and no wish for life extension. Further, 21%and 14%wish to have limited chemotherapy. As regards consciousness on chemotherapy, 26% and 18% reported changes according to whether they are providers or receivers. The main reasons are medical perspective and their sense of duty. As for the purpose of chemotherapy for advanced gastric and colorectal cancer, 96% and 43% answered prolonging life and relief, respectively. The proportion of persons who answered complete cure is statistically higher in colorectal(32%)than in gastric cancer(18%). The most common answer for an adverse event they want to avoid if they are patients is peripheral neuropathy. These results clearly demonstrate that a considerable proportion of medical personnel hold a negative attitude against or are reluctant to receiving chemotherapy, especially for advanced gastric and colorectal cancer. It is of great importance to make use of these results in clinical practice.

The downregulation of microRNA let-7a contributes to the excessive expression of type I collagen in systemic and localized scleroderma.

Systemic and localized scleroderma (SSc and LSc) is characterized by excessive deposition of collagen and tissue fibrosis in the skin. Although they have fundamental common characteristics including autoimmunity, little is known about the exact mechanism that mediates the excessive collagen expression in these disorders. In the current study, we tried to evaluate the possibility that microRNAs (miRNAs) play some roles in the pathogenesis of fibrosis seen in these diseases. miRNA expression patterns were evaluated by miRNA array analysis, real-time PCR, and in situ hybridization. The function of miRNAs in dermal fibroblasts was assessed using miRNA inhibitors, precursors, or protectors. In the mouse model of bleomycin-induced dermal sclerosis, the overexpression of miRNAs was performed by i.p. miRNA injection. We demonstrated let-7a expression was downregulated in SSc and LSc skin both in vivo and in vitro, compared with normal or keloid skin. The inhibition or overexpression of let-7a in human or mouse skin fibroblasts affected the protein expression of type I collagen or luciferase activity of collagen 3'-untranslated region. Also, we found let-7a was detectable and quantitative in the serum and investigated serum let-7a levels in patients with SSc or LSc. let-7a concentration was significantly decreased in these patients, especially in LSc patients. Moreover, we revealed that the intermittent overexpression of let-7a in the skin by i.p. miRNA injection improved the skin fibrosis induced by bleomycin in mice. Investigation of more detailed mechanisms of miRNA-mediated regulation of collagen expression may lead to new therapeutic approaches against SSc and LSc.

Scleroderma dermal fibroblasts overexpress vascular endothelial growth factor due to autocrine transforming growth factor ß signaling.

OBJECTIVES: Overexpression of vascular endothelial growth factor (VEGF) in scleroderma (SSc) skin may play a role in the pathogenesis of the disease. Our study was undertaken to evaluate whether dermal fibroblasts function as one of the sources of the increased VEGF in SSc, and to clarify its mechanism. METHODS: Protein and mRNA levels of VEGF were analyzed using immunoblotting, enzyme-linked immunosorbent assay, and real-time PCR. The DNA-binding ability of Smad3 was evaluated by DNA affinity precipitation. RESULTS: VEGF mRNA expression in vivo was increased in SSc skin compared to skin with other collagen diseases. Expression of VEGF protein and mRNA in cultured SSc dermal fibroblasts was constitutively and significantly upregulated. Ectopic TGF-ß stimulation induced VEGF synthesis in normal fibroblasts, and TGF-ß knockdown normalized the upregulated VEGF levels in SSc fibroblasts. Furthermore, Smad3 overexpression induced VEGF levels. We found that bp -532 to -521 on the VEGF promoter is a putative binding site for Smads, and that the binding activity of Smad3 to VEGF promoter was constitutively increased in SSc fibroblasts as well as in normal fibroblasts treated with exogenous TGF-ß1. CONCLUSIONS: We demonstrated that VEGF were overexpressed due to autocrine TGF-ß/Smad signaling in SSc. TGF-ß signaling may contribute to the pathogenesis of angiopathy as well as tissue fibrosis.

microRNA-92a expression in the sera and dermal fibroblasts increases in patients with scleroderma.

OBJECTIVES: microRNAs (miRNAs) play a part in various cellular activities. However, the role of miRNA in SSc is not fully understood. This study investigated the expression and role of miR-92a in SSc patients and evaluated the possibility that miR-92a is involved in the pathogenesis of this disease. METHODS: Serum samples were obtained from 61 SSc patients. mRNAs were purified from serum and levels of miR-92a and miR-135 were measured with quantitative real-time PCR. miR-92a expression in dermal fibroblasts was also determined by quantitative real-time PCR. Immunoblotting was performed to detect MMP-1 protein. RESULTS: The median serum levels of miR-92a, not miR-135, were significantly higher in SSc patients than normal subjects. The constitutive up-regulated miR-92a expression was also found in cultured dermal fibroblasts from SSc skin, which was decreased by the transfection with siRNA of TGF-ß. Furthermore, the forced overexpression of miR-92a in normal dermal fibroblasts using miR-92a mimic resulted in the down-regulation of MMP-1 expression. CONCLUSION: The increase of miR-92a in SSc may be due to the stimulation of intrinsic TGF-ß activation seen in this disease. There is also a possibility that MMP-1 is the target of miR-92a and that increased miR-92a expression therefore plays a role in excessive collagen accumulation in SSc via the down-regulation of MMP-1. Clarifying the role of miRNAs in SSc may result in a better understanding of this disease and the development of new therapeutic approaches.

Kinesin family member 20A is a novel melanoma-associated antigen.

It has been shown recently that immunotherapy for advanced melanoma is effective. However, in order to improve the efficacy of immunotherapy, the identification of more specific melanoma-associated antigens is urgently needed. Kinesin family member 20A (KIF20A) has been reported to be a promising immunotherapeutic target for pancreatic cancer. To investigate the expression of KIF20A in melanoma, we performed quantitative reverse transcript (RT)-PCR and western blotting analyses of melanoma cell lines. We also investigated primary melanomas and naevus tissues with immunohistochemistry and real-time RT-PCR. KIF20A expression was detected in 59% of melanomas and 12% of naevi by immunohisto-chemistry, and 64% of melanomas and 60% of naevi by real-time RT-PCR. The primary melanomas that were positive for KIF20A showed a significantly greater thickness than those that were negative, and patients with KIF20A+ melanoma tended to develop recurrence earlier. These results suggest that immunotherapy with KIF20A may be a novel treatment option for advanced melanoma.

Increased serum levels of miR-1266 in patients with psoriasis vulgaris.

MicroRNAs (miRNAs) are post-transcriptional regulators that bind to complementary sequences in the 3' UTRs of mRNAs, leading to gene silencing, and their serum levels can be useful biomarkers for diagnosis, prognosis and therapeutic value in various diseases. Although miRNAs are thought to be involved in the pathogenesis of human diseases, little is known about miRNAs in psoriasis. Recently, psoriasis has attracted attention for its characteristics as a Th17 disease; the expression of IL-17 is increased in lesional skin and serum. We hypothesized that miRNAs contribute to the mechanism underlying the overexpression of IL-17. Therefore, serum levels of miR-1266, a putative regulator of IL-17A, in psoriasis patients were determined with the expectation that miR-1266 levels may be decreased in these patients, which may result in induction of IL-17. However, real-time PCR demonstrated that serum miR-1266 levels were considerably higher in psoriasis patients than in healthy control subjects. Furthermore, miR-1266 levels showed weak inverse correlations with Psoriasis Area Severity Index scores and body surface areas of involved skin. Taken together, serum miR-1266 may have potential for a new disease marker. miR-1266 is not likely to regulate IL-17A expression directly, but may be involved in the pathogenesis of psoriasis by regulating other target molecules.

[Ascending aorta cannulation in stanford type a acute aortic dissection].

Establishment of cardiopulmonary bypass for Stanford type A acute aortic dissection( type A AAD) should be quick and safe. The femoral artery, axillary artery, ascending aorta, and left ventricular apex are potential access points for cannulation. The most important reason for establishing cardiopulmonary bypass for type A AAD is to allow antegrade blood flow through the true lumen. Starting in 2007, Jakob et al, and Inoue et al. applied the technique of ascending aortic cannulation for type A AAD. From 2008, we applied this method of ascending aorta cannulation in 8 patients and compared preoperative, operative, and postoperative data with a control group, or the femoral artery cannulation group. Ascending aorta cannulation was done safely and easily with the use of the Seldinger technique under epiaortic color Doppler echography and transesophageal echography. No cerebral events or hypoperfusion-based complications occurred in the group of ascending aorta cannulation. Given that no cases of complication occurred using this method, it could be considered as an effective choice of cannulation for cardiopulmonary bypass.

Rapidly Growing Locally Advanced Non-Small Cell Lung Cancer Treated with Definitive Chemoradiotherapy Using Adaptive Volumetric Modulated Arc Therapy Followed by Durvalumab Maintenance: A Case Report.

BACKGROUND It is difficult to reduce lung toxicity in chemoradiotherapy for locally advanced lung cancer. Volume-modulated arc therapy (VMAT) is a useful lung dose-lowering radiation technique, but it is time-consuming because of its complexity. We present a case of a rapidly growing bulky lung cancer treated with VMAT and intensive adaptation to volume change. CASE REPORT A 43-year-old man with chest pain was diagnosed with non-small cell lung cancer, cT4N3M0 stage IIIC (UICC 8th edition). Concurrent chemoradiotherapy with a VMAT of 60 Gy in 30 fractions and carboplatin/paclitaxel was performed. Despite initiating chemoradiation, monitoring with cone-beam computed tomography (CT) revealed tumor progression. The peak tumor volume was 1.5 times larger than that on CT simulation. The VMAT plan was recreated to cover the increased tumor size. After the irradiation field was enlarged, the tumor, on the contrary, shrank rapidly. Therefore, VMAT planning was performed again to further shrink the irradiation field. CT at the end of the treatment showed a good volume reduction response. Durvalumab therapy was continued for 1 year. After that, the patient was alive and showed no sign of progression. Only asymptomatic radiation pneumonitis was observed as a sub-acute adverse event. CONCLUSIONS We present a case in which proper adaptive VMAT and durvalumab for dramatically progressive non-small cell lung cancer were effective, resulting in 1-year progression-free survival. Even when rapid progression of bulky lung cancer is suggested, the combination of VMAT and adaptive radiotherapy with improved target coverage and reduced lung dose can be a treatment option.

DEAD/H BOX 3 (DDX3) helicase binds the RIG-I adaptor IPS-1 to up-regulate IFN-beta-inducing potential.

Retinoic acid-inducible gene-I (RIG-I)-like receptors (RLR) are members of the DEAD box helicases, and recognize viral RNA in the cytoplasm, leading to IFN-beta induction through the adaptor IFN-beta promoter stimulator-1 (IPS-1) (also known as Cardif, mitochondrial antiviral signaling protein or virus-induced signaling adaptor). Since uninfected cells usually harbor a trace of RIG-I, other RNA-binding proteins may participate in assembling viral RNA into the IPS-1 pathway during the initial response to infection. We searched for proteins coupling with human IPS-1 by yeast two-hybrid and identified another DEAD (Asp-Glu-Ala-Asp) box helicase, DDX3 (DEAD/H BOX 3). DDX3 can bind viral RNA to join it in the IPS-1 complex. Unlike RIG-I, DDX3 was constitutively expressed in cells, and some fraction of DDX3 is colocalized with IPS-1 around mitochondria. The 622-662 a.a DDX3 C-terminal region (DDX3-C) directly bound to the IPS-1 CARD-like domain, and the whole DDX3 protein also associated with RLR. By reporter assay, DDX3 helped IPS-1 up-regulate IFN-beta promoter activation and knockdown of DDX3 by siRNA resulted in reduced IFN-beta induction. This activity was conserved on the DDX3-C fragment. DDX3 only marginally enhanced IFN-beta promoter activation induced by transfected TANK-binding kinase 1 (TBK1) or I-kappa-B kinase-epsilon (IKKepsilon). Forced expression of DDX3 augmented virus-mediated IFN-beta induction and host cell protection against virus infection. Hence, DDX3 is an antiviral IPS-1 enhancer.

Adiponectin expression is decreased in the involved skin and sera of diffuse cutaneous scleroderma patients.

In this study, we determined the adiponectin expression in the serum and lesional skin of patients with scleroderma (SSc). Serum adiponectin concentrations were measured in 32 patients with SSc, 10 patients with SLE, 12 patients with dermatomyositis patients and 13 healthy subjects with specific enzyme-linked immunosorbent assays. Adiponectin mRNA was determined in skin tissues of five patients with diffuse cutaneous SSc (dcSSc), seven patients with limited cutaneous SSc (lcSSc) and seven healthy subjects with real-time polymerase chain reaction. There was a significant reduction in serum adiponectin levels in patients with dcSSc. SSc patients with decreased serum adiponectin levels had higher total skin thickness score and higher incidence of pulmonary fibrosis. Adiponectin mRNA levels in skin tissues from patients with dcSSc were also reduced. Serum adiponectin levels may be a useful biomarker for fibrotic condition in patients with SSc. Clarifying the role of adiponectin in collagen diseases may lead to further understanding of the pathogenesis and new therapeutic approach.

Wound, pressure ulcer and burn guidelines - 6: Guidelines for the management of burns, second edition.

"Wound, pressure ulcer and burn guidelines - 6: Guidelines for the management of burns, second edition" is revised from the first edition which was published in the Japanese Journal of Dermatology in 2016. The guidelines were drafted by the Wound, Pressure Ulcer and Burn Guidelines Drafting Committee delegated by the Japanese Dermatological Association, and intend to facilitate physicians' clinical decisions in preventing, diagnosing and treating burn injury. All sections are updated by collecting documents published since the publication of the first edition. Especially, the recommendation levels of dressing materials newly covered by the Japanese national health insurance are mentioned. In addition, the clinical questions (CQ) regarding the initial treatment of electrical (CQ15) and chemical burns (CQ16), and also the use of escharotomy (CQ22), are newly created.

Wound, pressure ulcer and burn guidelines - 1: Guidelines for wounds in general, second edition.

The Japanese Dermatological Association prepared the clinical guidelines for the "Wound, pressure ulcer and burn guidelines", second edition, focusing on treatments. Among them, "Guidelines for wounds in general" is intended to provide the knowledge necessary to heal wounds, without focusing on particular disorders. It informs the basic principles of wound treatment, before explanations are provided in individual chapters of the guidelines. We updated all sections by collecting references published since the publication of the first edition. In particular, we included new wound dressings and topical medications. Additionally, we added "Question 6: How should wound-related pain be considered, and what should be done to control it?" as a new section addressing wound pain, which was not included in the first edition.

Wound, pressure ulcer and burn guidelines - 4: Guidelines for the management of connective tissue disease/vasculitis-associated skin ulcers.

The Japanese Dermatological Association prepared guidelines focused on the treatment of skin ulcers associated with connective tissue disease/vasculitis practical in clinical settings of dermatological care. Skin ulcers associated with connective tissue diseases or vasculitis occur on the background of a wide variety of diseases including, typically, systemic sclerosis but also systemic lupus erythematosus (SLE), dermatomyositis, rheumatoid arthritis (RA), various vasculitides and antiphospholipid antibody syndrome (APS). Therefore, in preparing the present guidelines, we considered diagnostic/therapeutic approaches appropriate for each of these disorders to be necessary and developed algorithms and clinical questions for systemic sclerosis, SLE, dermatomyositis, RA, vasculitis and APS.

Submental perforator flap: location and number of submental perforating vessels.

The sites and numbers of submental perforator vessels were examined using a Doppler probe in 21 volunteers. The subcutaneous vascular network from each perforator was studied in three cases of dissection of upper-neck lymph nodes among the volunteers. A perforator from the submental vessels was noted in all 21 volunteers: a single perforator in 13 cases, and double perforators in eight. The main perforator, which had some subdermal branches, was located 31.8 (8.3) mm in front of the facial artery that was palpated at the mandible. Five patients who presented with skin defects on the cheek and the chin had the submental perforator flap reconstructed, excluding the platysma muscle. All flaps covered the wounds. The submental perforator flap was useful for reconstructing skin defects on the cheek and the chin, because the site of the submental perforator was stable and raising the flap was easy, and the colour and texture matches were acceptable.

Structural relaxation in amorphous 1,2-dichloroethane studied by transformation between conformation isomers.

Structural relaxation in amorphous 1,2-dichloroethane (DCE) samples prepared by vapor deposition on cold substrates were studied by Raman scattering. The gauche and trans molecules of DCE were found to coexist in amorphous states immediately after the deposition, and structural relaxation occurred with temperature elevation before crystallization. Mole fraction of the gauche isomer increased during this relaxation process, although trans is the stable isomer in gaseous and crystalline states. At the final amorphous stage immediately before crystallization, the gauche mole fraction was close to the mole fraction of the supercooled liquid state. It was also found that trans molecules located at positions with lower density were more easily transformed into the gauche conformation, while the distribution of the local structure around the resultant gauche molecules remained almost unchanged during the structural relaxation. Such behaviors of amorphous DCE are discussed from the viewpoint of the characteristic molecular structure of DCE.

microRNA level is raised in the hair shafts of patients with dematomyositis in comparison with normal subjects and patients with scleroderma.

BACKGROUND: The diagnosis of dermatomyositis is sometimes difficult. We tried to evaluate the possibility that levels of Homo sapiens microRNA-214 (hsa-miR-214) in hair roots or hair shafts can be a useful marker of the disease. METHODS: A single hair root and five pieces of hair shafts were obtained from nine patients with dermatomyositis, 15 normal subjects, and 18 patients with scleroderma before treatment. RNAs were purified from the hair roots and hair shafts using commercially available kits. cDNA was synthesized from the RNA, and miR-214 levels were measured with quantitative real-time polymerase chain reaction. Receiver operating characteristic curve analysis was performed to evaluate the diagnostic performance of hair microRNA levels. RESULTS: The levels of miR-214 in hair shafts of patients with dermatomyositis were significantly higher than those of normal subjects and patients with scleroderma. By receiver operator curve analysis of hair shaft miR-214 levels to distinguish patients with dermatomyositis from normal subjects, the area under the curve was 0.90. The duration between symptom onset and the first visit to the hospital was significantly shorter in patients with elevated hair shafts miR-214 levels, suggesting that they have more severe subjective symptoms. On the other hand, we could not find significant differences in hair root miR-214 levels among normal subjects and patients with dermatomyositis and scleroderma. CONCLUSIONS: Hair shaft miR-214 levels are useful for diagnosis and evaluating the disease severity of dermatomyositis. Hair microRNA levels may have potential to be a novel and less invasive biomarker.

The wound/burn guidelines - 6: Guidelines for the management of burns.

Burns are a common type of skin injury encountered at all levels of medical facilities from private clinics to core hospitals. Minor burns heal by topical treatment alone, but moderate to severe burns require systemic management, and skin grafting is often necessary also for topical treatment. Inappropriate initial treatment or delay of initial treatment may exert adverse effects on the subsequent treatment and course. Therefore, accurate evaluation of the severity and initiation of appropriate treatment are necessary. The Guidelines for the Management of Burn Injuries were issued in March 2009 from the Japanese Society for Burn Injuries as guidelines concerning burns, but they were focused on the treatment for extensive and severe burns in the acute period. Therefore, we prepared guidelines intended to support the appropriate diagnosis and initial treatment for patients with burns that are commonly encountered including minor as well as moderate and severe cases. Because of this intention of the present guidelines, there is no recommendation of individual surgical procedures.

The wound/burn guidelines - 2: Guidelines for the diagnosis and treatment for pressure ulcers.

The Wound/Burn Guidelines Committee consists of members commissioned by the Board of Directors of the Japanese Dermatological Association (JDA). It held several meetings and evaluations in writing since October 2008, and drafted five guidelines for the diagnosis and treatment including commentaries on wounds in general and the Guidelines for the Diagnosis and Treatment for Pressure Ulcers by taking opinions of the Scientific Committee and Board of Directors of JDA into consideration.

The wound/burn guidelines - 4: Guidelines for the management of skin ulcers associated with connective tissue disease/vasculitis.

The Japanese Dermatological Association prepared guidelines focused on the treatment of skin ulcers associated with connective tissue disease/vasculitis practical in clinical settings of dermatological care. Skin ulcers associated with connective tissue diseases or vasculitis occur on the background of a wide variety of diseases including, typically, systemic sclerosis but also systemic lupus erythematosus (SLE), dermatomyositis, rheumatoid arthritis (RA), various vasculitides and antiphospholipid antibody syndrome (APS). Therefore, in preparing the present guidelines, we considered diagnostic/therapeutic approaches appropriate for each of these disorders to be necessary and developed algorithms and clinical questions for systemic sclerosis, SLE, dermatomyositis, RA, vasculitis and APS.