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This multi-institutional clinical trial evaluated the feasibility of intensity-modulated radiotherapy (IMRT) for patients with locally advanced non-small cell lung cancer (NSCLC).The major inclusion criteria were clinical stage III NSCLC, age 20-74 years, and Eastern Cooperative Oncology Group performance status 0-1. Patients were treated with either cisplatin + S-1 (CS; four cycles every 4 weeks) or carboplatin + paclitaxel (CP; administered weekly with thoracic radiotherapy [RT], plus two consolidation cycles) concurrently with IMRT (60 Gy in 30 fractions). The primary endpoint was a treatment completion rate, defined as at least two cycles of CS or five cycles of CP during IMRT and completing 60 Gy IMRT within 56 days after the start of treatment, assumed its 90% confidence interval exceeds 60%. RT quality assurance was mandatory for all the patients.Twenty-two patients were registered. One patient withdrew due to pulmonary infection before starting treatment. RT plans were reviewed and none was judged as a protocol violation. Grade 2 and 3 pneumonitis occurred in four (19%) and one (5%) patients, respectively. Seventeen patients met the primary endpoint, with a treatment completion rate of 77.3% (90% confidence interval [CI] 58.0%-90.6%). Four patients failed to complete chemotherapy due to chemotherapy-related adverse events, but 20 patients completed IMRT. There were no treatment-related deaths. The 2-year progression-free and overall survival rates were 31.8% (95% CI 17.3%-58.7%) and 77.3% (95% CI 61.6%-96.9%), respectively.The treatment completion rate did not meet the primary endpoint, but 20 of 22 patients completed IMRT.

Generalized pustular psoriasis (GPP) is a severe rare skin disease characterized by widespread eruption of sterile superficial macroscopic pustules with or without systemic inflammation. Generalized pustular psoriasis flares may lead to life-threatening multiorgan complications, which highlights the need for rapid and accurate diagnosis. However, the rarity of the disease and its heterogeneous cutaneous and extracutaneous symptoms, and the resemblance of symptoms to other skin conditions, pose considerable challenges to the timely diagnosis and treatment of patients with GPP. Current laboratory tests used for GPP diagnosis are generally not GPP specific, and are mainly focused on the assessment of inflammatory markers and clinical and histopathologic features of GPP, and emerging genetic screening approaches. A differential diagnosis to distinguish GPP from other similar conditions requires careful assessment of the patient's skin symptoms, potential disease triggers, medical history, histopathologic features, laboratory tests, and clinical disease course. The comprehensive interpretation of these assessments can be challenging owing to the lack of standardized global guidelines. While there is currently a lack of standardized international guidelines for the diagnosis of GPP, recent advances in our understanding of the genetics and pathogenesis of the disease have provided new opportunities to enhance diagnosis. In the future, defining specific GPP subtypes using genetic and histopathologic strategies will guide therapeutic decisions, allowing patients to achieve their treatment goals without delay. In this article, we provide an overview of the current diagnostic methods, differential diagnostic strategies, and future advances in the diagnosis of GPP, as well as features of GPP variants.

A 50-year-old Japanese woman presented with a 4-day history of multiple purpura on her extremities and myalgia. She had been receiving nivolumab therapy for stage IV renal cell carcinoma for 18 months. Nivolumab was temporarily discontinued due to liver dysfunction and resumed 3 months before. Biopsy specimen revealed leukocytoclastic vasculitis, and direct immunofluorescence showed deposition of IgA and C3 in the vessel walls of the upper dermis. Based on these findings, a diagnosis of IgA vasculitis was made. She was treated with 20 mg/day of oral prednisolone, which resulted in the complete disappearance of purpura and myalgia. Although the patient needed temporary cessation of nivolumab therapy, she experienced no recurrence of purpura or myalgia, and the dose of prednisolone was gradually tapered to 5 mg/day. Although nivolumab can lead to various immune-related adverse events, vasculitis is rare. To the best of our knowledge, this is the second case of IgA vasculitis during nivolumab therapy.

In this paper, we propose a novel radiochromic film (RCF)-based computed tomography (CT) dosimetry method, which is different from the method based on CT dose index. RCF dosimetry using Gafchromic QA2 films was performed using two lengths of film-folding phantoms. The phantom was exposed to X-ray CT through a single scan, while the RCF was sandwiched between the phantoms. We analysed the dose profile curve in two directions to investigate the dose distribution. We observed a difference in the dose distribution as the phantom size changed. Our results contradict with the results of previous studies such as Monte Carlo simulation or direct measurement. The ability to visually evaluate 2D dose distributions is an advantage of RCF dosimetry over other methods. This research investigated the ability of 2D X-ray CT dose evaluation using RCF and film-folding phantom.

A 24-year-old Japanese female presented to our department complaining of redness of eyes and pain in the mouth and throat. She had no particular medical history. She was treated in dentistry of our hospital, but there was no improvement. Stomatitis was exacerbated, and conjunctival hyperemia and hoarseness appeared, so she was referred to otolaryngology and ophthalmology of our hospital. At that time, she had hyperemia and blistering of the bulbar conjunctiva and pseudomembrane formation in the palpebral conjunctiva, and multiple ulcerative lesions of the oral cavity, pharynx and larynx (Fig.1a-d). Her symptom was suspected pemphigus vulgaris (PV), so she was referred to a dermatologist. Biopsy specimen from the lip revealed blisters and acantholytic cells in the epidermis with the infiltration of lymphocytes and neutrophils (Fig.1e). In the direct fluorescent antibody method, IgG and C3 are weak-positive deposited between epidermal cells (Fig.1f).

Generalized pustular psoriasis (GPP) is a rare variant of psoriasis with severe clinical symptoms. However, the quality of life (QoL) of the patients is largely unknown. We conducted a nationwide cross‐sectional survey of Japanese GPP patients using the 36‐Item Short‐Form Health Survey version 2 (SF‐36v2) to elucidate patients’ QoL and how their QoL had changed over the last decade. We analyzed QoL data of 83 patients obtained from 2016 to 2019 (present group) and compared it with that of 105 patients collected in a previous survey conducted between 2003 and 2007 (past group). Although the QoL of the present patients was still largely impaired in comparison with the standard Japanese population, substantial improvement was found in some SF‐36v2 subscales including “general health”, “vitality”, “social functioning” and “mental health” as compared with that of the past group. Advances in treatment may contribute to this QoL improvement.

Pustulotic arthro-osteitis (PAO) is an osteoarticular complication of palmoplantar pustulosis (PPP). Although guselkumab, an anti-interleukin-23p19 antibody, has been shown to be effective for PPP, its efficacy for PAO is still not well understood. We conducted a retrospective observational study to evaluate the effectiveness of 28-week guselkumab treatment for five PAO patients in daily clinical practice. Four patients had sternoclavicular arthritis, and one had only sacroiliitis. Guselkumab improved pain visual assessment scale scores in all five patients by 54.2% (11.1-87.5%) on average at week 28 compared with baseline, and discontinuation or dose reduction of analgesics was possible in four of them. Three patients showed clinically significant improvement in Bath Ankylosing Spondylitis Disease Activity Index of 2 or more. On the other hand, beneficial change in Ankylosing Spondylitis Disease Activity Score of 1.1 or more was observed in only one patient. Bone scintigraphy demonstrated decreased uptake in sternoclavicular joints after guselkumab treatment in all four patients with sternoclavicular arthritis. Improvement of Palmoplantar Pustulosis Area and Severity Index was also confirmed. Guselkumab can be a treatment option for intractable PAO.

Secukinumab, a fully human monoclonal antibody that selectively neutralizes interleukin‐17A, has been available for the treatment of moderate to severe psoriasis and psoriatic arthritis since February 2015 in Japan. Because there was a time gap after the previous approval of biologics for psoriatic disease indication, it was suggested that patients to be treated with secukinumab at its launch might have refractory disease symptoms. In order to assess the safety and effectiveness of secukinumab in those patients, a 52‐week, open‐label, multicenter, observational cohort study was conducted. In total, 306 and 250 patients were included in the safety and effectiveness analysis sets, respectively. Over half of patients had previously received biologics (56.9%). Adverse events, serious adverse events and adverse reactions were reported in 41.2%, 7.2% and 24.2% of patients, respectively. The most commonly reported adverse reactions were oral candidiasis (2.9%), consistent with those reported in clinical studies. In addition, none of the patient characteristics assessed for the effect on safety of secukinumab increased the occurrence of adverse reactions. Psoriasis Area and Severity Index score (mean ± standard deviation) improved from baseline (14.7 ± 12.3) to week 12 (1.78 ± 3.3), which was maintained up to week 24 (1.59 ± 3.0). The proportion of patients with a Dermatology Life Quality Index score of 0/1 improved from baseline (2.2%) to week 12 (64.7%) and sustained up to week 24 (71.4%). In addition to the skin symptoms, improvement was observed in all psoriatic arthritis disease‐related assessments. The current study reaffirmed the safety and effectiveness of secukinumab with broader patients than those in the clinical studies.

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.

BackgroundZNF597, encoding a zinc-finger protein, is the human-specific maternally expressed imprinted gene located on 16p13.3. The parent-of-origin expression of ZNF597 is regulated by the ZNF597:TSS-DMR, of which only the paternal allele acquires methylation during postimplantation period. Overexpression of ZNF597 may contribute to some of the phenotypes associated with maternal uniparental disomy of chromosome 16 (UPD(16)mat), and some patients with UPD(16)mat presenting with Silver-Russell syndrome (SRS) phenotype have recently been reported.MethodsA 6-year-old boy presented with prenatal growth restriction, macrocephaly at birth, forehead protrusion in infancy and clinodactyly of the fifth finger. Methylation, expression, microsatellite marker, single nucleotide polymorphism array and trio whole-exome sequencing analyses were conducted.ResultsIsolated hypomethylation of the ZNF597:TSS-DMR and subsequent loss of imprinting and overexpression of ZNF597 were confirmed in the patient. Epigenetic alterations, such as UPD including UPD(16)mat and other methylation defects, were excluded. Pathogenic sequence or copy number variants affecting his phenotypes were not identified, indicating that primary epimutation occurred postzygotically.ConclusionWe report the first case of isolated ZNF597 imprinting defect, showing phenotypic overlap with SRS despite not satisfying the clinical SRS criteria. A novel imprinting disorder entity involving the ZNF597 imprinted domain can be speculated.

Hidradenitis suppurativa (HS) is a chronic relapsing skin disease localized mainly on the apocrine gland‐bearing areas. In Japan, HS is yet to be fully understood, and no criteria have been established for its diagnosis or severity assessment. The purpose of this study was to investigate and characterize HS in Japan. We conducted a nationwide questionnaire‐based study, in which Japanese diagnostic criteria were proposed. Question items included age, sex, disease duration, past history, family history, smoking status, disease severity scores (Hurley stage, modified Sartorius score and Physician Global Assessment [PGA] score), treatments, comorbidities and prognosis. We analyzed 300 patients (219 males and 81 females) diagnosed with HS based on our criteria. Average disease duration was 92.3 ± 6.82 months. Only 12 (4%) patients had a family history of HS. Disease severity was classified by PGA score (mild, 100 [33.3%]; moderate, 133 [44.3%]; severe, 34 [11.3%]; most severe, 29 [9.7%]) and Hurley stage (I, 69 [23%]; II, 109 [36.3%]; III, 121 [40.3%]). Disease severities based on PGA score and Hurley stage were positively correlated to modified Sartorius score using the Kruskal–Wallis test (P

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.

The 14 authors of the first review article on hidradenitis suppurativa (HS) pathogenesis published 2008 in EXPERIMENTAL DERMATOLOGY cumulating from the 1st International Hidradenitis Suppurativa Research Symposium held March 30-April 2, 2006 in Dessau, Germany with 33 participants were prophetic when they wrote "Hopefully, this heralds a welcome new tradition: to get to the molecular heart of HS pathogenesis, which can only be achieved by a renaissance of solid basic HS research, as the key to developing more effective HS therapy." (Kurzen et al. What causes hidradenitis suppurativa? Exp Dermatol 2008;17:455). Fifteen years later, there is no doubt that the desired renaissance of solid basic HS research is progressing with rapid steps and that HS has developed deep roots among inflammatory diseases in Dermatology and beyond, recognized as "the only inflammatory skin disease than can be healed". This anniversary article of 43 research-performing authors from all around the globe in the official journal of the European Hidradenitis Suppurativa Foundation e.V. (EHSF e.V.) and the Hidradenitis Suppurativa Foundation, Inc (HSF USA) summarizes the evidence of the intense HS clinical and experimental research during the last 15 years in all aspects of the disease and provides information of the developments to come in the near future., info:eu-repo/semantics/published

Glucagon is a 29 amino acid peptide hormone secreted by pancreatic α−cells and interacts with specific receptors located in various organs. Glucagon tends to form gel-like fibril aggregates that are cytotoxic because they activate apoptotic signaling pathways. To understand mechanism of fibril formation, we investigated the structure and kinetics of glucagon fibril formation using 13C solid-state NMR spectroscopy. In aqueous acetic acid solution at pH 3.3, distorted α−helical structure appeared around Gly4, Leu14, Ala19 and Leu26 in the monomeric form. In contrast, Gly4 and Ala19 were involved in β-sheet structures in the fibril form. The fibrillation process can be explained by a two-step autocatalytic reaction mechanism in which the first step is a homogeneous nuclear formation (k1), and the second step is an autocatalytic heterogeneous fibrillation process (k2). The rate constants k1 and k2 were separately determined in the acetic acid solution. Fibril formation was further investigated in the presence of lipid bilayers to mimic the physiological condition. We used bicelles which form discoidal nano-particles as the bilayer system and observed that the N-terminal α-helix did not change to β-sheet when fibrils formed in the presence of bicelles. Rate constant k1 became faster and k2 became slower in the presence of bicelles compared to the case in the absence of bicelles. Our findings reveal that the structure and kinetics of fibril formation by glucagon are altered in the presence of lipid bilayers.

Emerging evidence has demonstrated that Toll-like receptors (TLRs) are associated with autoimmune diseases. In this study, we investigated the role of TLR2 in psoriasis using imiquimod-induced psoriasis-like dermatitis. Although TLR2 signaling is known to play a critical role in the induction of proinflammatory cytokines by immune cells, such as dendritic cells (DCs), macrophages, and monocytes, TLR2 deficiency unexpectedly exacerbated psoriasiform skin inflammation. Importantly, messenger RNA (mRNA) levels of Foxp-3 and IL-10 in the lesional skin were significantly decreased in TLR2 KO mice compared with wild-type mice. Furthermore, flow cytometric analysis of the lymph nodes revealed that the frequency of regulatory T cells (Tregs) among CD4-positive cells was decreased. Notably, stimulation with Pam3CSK4 (TLR2/1 ligand) or Pam2CSK4 (TLR2/6 ligand) increased IL-10 production from Tregs and DCs and the proliferation of Tregs. Finally, adoptive transfer of Tregs from wild-type mice reduced imiquimod-induced skin inflammation in TLR2 KO mice. Taken together, our results suggest that TLR2 signaling directly enhances Treg proliferation and IL-10 production by Tregs and DCs, suppressing imiquimod-induced psoriasis-like skin inflammation. Enhancement of TLR2 signaling may be a new therapeutic strategy for psoriasis.

Since the publication of the Japanese "Guidelines for the management of cutaneous lymphomas" in 2011, the World Health Organization (WHO) classification of hematolymphoid neoplasms and the WHO-European Organisation for Research and Treatment of Cancer classification for primary cutaneous lymphomas were updated and a number of novel systemic drugs for cutaneous T-cell lymphoma had been approved in Japan. In 2020, we revised the Japanese guidelines for the management of cutaneous lymphomas with consideration of the recent advances in the understanding of the pathophysiology and classification of cutaneous lymphomas together with the update of treatment strategies reflecting the advent of novel drugs. In addition to a brief explanation of epidemiology, diagnosis, staging system, prognosis and management of each subtype of cutaneous lymphomas, the recommendations for nine clinical questions regarding treatment options that can vary even among experts are also described. A systematic review process and determination of recommendations in answer to each clinical question have been performed in accordance with the Grading of Recommendations, Assessment, Development and Evaluation scheme by a multidisciplinary expert panel consisting of dermatologists, a hematologist and a radiation oncologist. In this article, we present the outlines of the revised Japanese "Guidelines for the management of cutaneous lymphomas".

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"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.

Generalized pustular psoriasis (GPP) is a rare disease characterized by recurrent fever and systemic flushing accompanied by extensive sterile pustules. The committee of the guidelines was founded as a collaborative project between the Japanese Dermatological Association and the Study Group for Rare Intractable Skin Diseases under the Ministry of Health, Labour, and Welfare Research Project on Overcoming Intractable Diseases. The aim of the guidelines was to provide current information to aid in the treatment of patients with GPP in Japan. Its contents include the diagnostic and severity classification criteria for GPP, its pathogenesis, and recommendations for the treatment of GPP. Since there are few clinical trial data with high levels of evidence for this rare disease, recommendations by the committee are described in the present guidelines.

Backgrounds IFN regulatory factor (IRF)-2 is one of the potential susceptibility genes for psoriasis, but how this gene influences psoriasis pathogenesis is unclear. Topical application of imiquimod (IMQ), a TLR7 ligand, induces psoriasis-like skin lesions in mice. Objective The aim of this study was to investigate whether IRF-2 gene status would influence severity of skin disease in IMQ-treated mice. Methods Imiquimod-induced psoriasis-like skin inflammation was assessed by clinical findings, histology, and cytokine expression. The effects of imiquimod or IFN on peritoneal macrophages were analyzed in vitro. Results IMQ-induced skin inflammation assessed by clinical findings and histology was more severe in IRF-2+/− mice than in wild-type mice. In inflamed skin, mRNA expression levels of tumor necrosis factor (TNF)-α, IL-12/23p40, IL-17A, and IL-22 were significantly elevated in IRF-2+/− mice compared to wild-type mice. Stimulation of peritoneal macrophages by IMQ significantly increased mRNA levels of TNF-α, IL-12/23p40, IL-23p19, IL-12p35, and IL-36. Interestingly, macrophages from IRF-2+/− mice expressed higher levels of TNF-α, IL-12/23p40, and IL-36 compared to those from wild-type mice 24 h after stimulation, while they expressed similar levels of IL-12p35 and IL-23p19. Moreover, elevated mRNA expression of inducible nitric oxide synthase was observed only in IMQ-stimulated macrophages derived from IRF-2+/− mice, which correlated with angiogenesis in IMQ-treated ears of IRF-2+/− mice. Conclusions These results suggest that IRF-2 haploinsufficiency creates heightened biologic responses to IFN-α that phenotypically lead to enhanced angiogenesis and psoriasis-like inflammation within skin.

Summary Background Dupilumab, a human monoclonal antibody, blocks the shared receptor unit for interleukin‐4 and interleukin‐13. International phase II and III studies have evaluated the efficacy and safety of dupilumab in adults with moderate‐to‐severe atopic dermatitis (AD), but the effects of dupilumab in Japanese patients have not been reported. Objectives To evaluate the efficacy and safety of dupilumab in Japanese patients with moderate‐to‐severe AD. Methods We analysed the efficacy and safety of dupilumab in the Japanese cohorts of a 16‐week, phase IIb dose‐finding trial (AD‐1021; NCT01859988); a 16‐week, phase III, placebo‐controlled monotherapy trial (LIBERTY AD SOLO 1; NCT02277743) and a 52‐week, phase III, placebo‐controlled study of dupilumab with topical corticosteroids (LIBERTY AD CHRONOS; NCT02260986). Results Twenty‐seven, 106 and 117 Japanese patients were enrolled in AD‐1021, SOLO 1 and CHRONOS, respectively. Baseline disease severity was numerically higher in the Japanese cohort than in the overall study population. Generally, dupilumab significantly improved signs and symptoms of AD, including pruritus and patient quality of life, compared with placebo in the Japanese cohort, consistent with the overall study population. The combined safety profile of dupilumab in the Japanese cohort was similar to that in the total study populations; dupilumab was associated with an increased incidence of injection‐site reactions and conjunctivitis compared with placebo. Dupilumab was associated with rapid reduction in thymus and activation‐regulated chemokine and gradual IgE reductions. Conclusions Dupilumab alone or with topical corticosteroids improved signs and symptoms of AD, had an acceptable safety profile, and suppressed biomarkers of type 2 inflammation compared with placebo in Japanese adult patients with moderate‐to‐severe AD. What's already known about this topic? Differences in atopic dermatitis (AD) pathology have been reported between Asian and Western populations, in which distinct helper T‐cell activation profiles have been observed.International clinical studies in adults with moderate‐to‐severe AD have evaluated the efficacy and safety of dupilumab, which blocks interleukin‐4 and interleukin‐13, key molecules in type 2 inflammation.The effects of dupilumab in Japanese patients specifically have not yet been reported. What does this study add? Dupilumab alone or with topical corticosteroids improved signs and symptoms of AD and had an acceptable safety profile compared with placebo in Japanese patients with moderate‐to‐severe AD.The effects were comparable with those observed in the overall study population.Reported immunological differences in AD pathology in Asian patients may be secondary to type 2 immune activation., Plain language summary available online Respond to this article