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Immune checkpoint inhibitors (ICIs) have become the standard of care for the treatment of non‐small cell lung cancer (NSCLC). With the increasing use of ICIs, clinicians should be familiar with their immune‐related adverse events, including sarcoid‐like reactions, which have been associated with the use of ICIs in patients with cancer. Sarcoid‐like reactions are caused by uncontrolled T helper 1‐mediated immune responses resulting from ICIs, but their pathophysiology is not fully understood. Sarcoid‐like reactions are often clinically important because they mimic metastases from treated cancer. According to previous reports, sarcoid‐like reactions are typically observed in intrathoracic locations (lung and/or mediastinal lymph nodes) and the skin. In this study, we report an extremely rare case of extrathoracic sarcoid‐like reaction in the right external iliac lymph node following two cycles of pembrolizumab therapy in a patient with lung adenocarcinoma. The laboratory data and computed tomography images suggested that infectious and autoimmune diseases were not considered to be the causative agents. Residual bone metastasis might have caused T helper 1‐mediated immune responses by pembrolizumab, and contributed to sarcoid‐like reactions in the right external iliac lymph node. Sarcoid‐like reactions should be considered in the differential diagnosis of patients with lung cancer treated with ICIs who exhibit worsening extrathoracic lymph node swelling. Clinicians should be cautious not to mistake extrathoracic sarcoid‐like reactions of the lymph nodes for progression of the treated disease., Sarcoid‐like reactions are sometimes caused by immune checkpoint inhibitor through uncontrolled T helper 1‐mediated immune responses. Here, we report an extremely rare case of extrathoracic sarcoid‐like reaction in the right external iliac lymph node following two cycles of pembrolizumab therapy in a patient with lung adenocarcinoma. Clinicians should be cautious not to mistake extrathoracic sarcoid‐like reactions of the lymph nodes for progression of the treated disease.

Psoriatic arthritis (PsA) is an inflammatory arthritis with as yet unclear pathophysiology. This retrospective, multicenter, cross-sectional study was conducted in 19 facilities in western Japan and aimed to identify patients' characteristics and factors that affect the results of treatment with biologic agents. Of 2116 patients with psoriasis, 285 (13.5%) had PsA. Skin manifestations preceded joint manifestations in 69.8%, the onset was simultaneous in 17.2%, whereas PsA preceded skin manifestations in 2.5%. Peripheral arthritis was most common, occurring in 73.7%, compared with axial disease in 21.8%, enthesitis in 23.5% and dactylitis in 35.4%. Patients with severe skin manifestations were significantly younger at onset (P = 0.02) and more frequently had axial disease (P

There is a range of psoriasis treatments available, from topical applications to biologic therapy, with corresponding cost variations. The efficacy of each treatment is usually evaluated by objective measures such as the Psoriasis Area and Severity Index (PASI) or subjective measures such as the Dermatology Life Quality Index (DLQI). However, the social and economic impacts of psoriasis, including cost-effectiveness, have not been assessed in Japan. The EuroQol 5-Dimension (EQ-5D) is a generic instrument used worldwide to calculate quality-adjusted life years, on which calculations of treatment cost-effectiveness are based. We conducted a pilot study to determine the cost-effectiveness of psoriasis treatment in Japan. We administered a questionnaire to 133 patients with psoriasis (105 men and 28 women) who visited four university hospitals in Fukuoka Prefecture. The questionnaire covered medical costs, satisfaction and willingness to pay (WTP), and we investigated the relationships between these items. PASI was evaluated by physicians. More participants indicated satisfaction with treatment in the group paying less than ¥5000/month. WTP, PASI and EQ-5D showed little correlation. However, the DLQI and EQ-5D showed a moderate correlation (r = 0.472). WTP seemed more dependent on participants' economic backgrounds. We found that it was difficult to reflect the PASI with the EQ-5D. However, the DLQI may be used to estimate the cost-benefit relationship in patients with psoriasis. This is the first study to evaluate the EQ-5D in patients with psoriasis in Japan.

SummaryBackground It is unclear whether hair washing is effective against scalp eruption and pruritus caused by seborrheic dermatitis or psoriasis vulgaris. Aims To assess whether a proper hair-washing regimen, including the use of antibacterial shampoo, can ameliorate scalp eruption symptoms and alter the composition of the scalp microflora. Methods Eighteen patients with seborrheic dermatitis or psoriasis vulgaris scalp eruptions were instructed in proper techniques of daily hair washing, rinsing, and shampooing, which they underwent for 12 weeks. They used control shampoo in weeks 1–4 and 9–12, and an antibacterial shampoo during weeks 5–8. At the start of the test period and at weeks 4, 8, and 12, we assessed scalp symptoms (erythema, scaling/desquamation, dryness, itchiness, and scratching scars); microbial DNA levels from lesion and nonlesion areas; and levels of interleukin (IL)-1α, IL-1ra, and total protein in the scalp's horny layer. Results Compared to baseline values, scaling/desquamation and itchiness improved significantly at weeks 8 and 12. Other observed skin symptoms also improved over time. Malassezia colonization levels in lesion and nonlesion areas decreased gradually; the decrease was significant at week 8 in lesion areas and at weeks 4 and 8 in nonlesion areas. Bacterial colonization levels also decreased gradually, achieving significance in lesion areas at week 4. Gradual decreases in IL-1ra/IL-1α level showed statistical significance at weeks 4 and 12, while the protein quantity significantly decreased at week 12. Conclusion Proper hair washing improved scalp condition symptoms, and possibly the underlying etiology.

The pathobiology of alopecia areata (AA), one of the most frequent autoimmune diseases and a major unsolved clinical problem, has intrigued dermatologists, hair biologists and immunologists for decades. Simultaneously, both affected patients and the physicians who take care of them are increasingly frustrated that there is still no fully satisfactory treatment. Much of this frustration results from the fact that the pathobiology of AA remains unclear, and no single AA pathogenesis concept can claim to be universally accepted. In fact, some investigators still harbour doubts whether this even is an autoimmune disease, and the relative importance of CD8+ T cells, CD4+ T cells and NKGD2+ NK or NKT cells and the exact role of genetic factors in AA pathogenesis remain bones of contention. Also, is AA one disease, a spectrum of distinct disease entities or only a response pattern of normal hair follicles to immunologically mediated damage? During the past decade, substantial progress has been made in basic AA-related research, in the development of new models for translationally relevant AA research and in the identification of new therapeutic agents and targets for future AA management. This calls for a re-evaluation and public debate of currently prevalent AA pathobiology concepts. The present Controversies feature takes on this challenge, hoping to attract more skin biologists, immunologists and professional autoimmunity experts to this biologically fascinating and clinically important model disease.

Enzalutamide is an androgen receptor inhibitor. We report a new cutaneous eruption to this drug and review cases of drug eruptions caused by androgen receptor inhibitors.

Acute kidney injury (AKI) is not recognized as a major complication at the maintenance phase after kidney transplantation (KTx). Moreover, it is not clear whether the onset of AKI leads to graft failure. We examined the incidence of AKI that developed three months or later after KTx at our institute. We examined whether the incidence of AKI defined by the Risk of renal dysfunction, Injury to the kidney, Failure of kidney function, Loss of kidney function and End-stage kidney disease criteria associates with graft failure by matched-pair Cox regression analysis. A total of 289 patients were available for the final analysis. The overall incidence of AKI was 20.4%, and the common etiology of AKI was bacterial infectious diseases. The group that developed AKI had significantly lower graft survival than non-AKI group independently of acute rejection. AKI Risk represented a high risk for graft failure and AKI Injury/Failure represented a higher risk for graft failure. The analysis by the AKIN classification yielded the similar results. These results indicate that AKI is a relatively common complication of KTx and represents the major risk for graft failure. We should make every effort in the prevention and early detection to avoid the occurrence of AKI and the subsequent graft failure after KTx.

Topical retinoid and antibiotic combination therapy is an integral part of acne treatment and is considered the appropriate first-line therapy according to the Japanese guideline for moderate and severe acne. In this combination, clindamycin or doxycycline are mostly used as antibiotics, but there have been no reports on the effectiveness of nadifloxacin, a widely used antibiotic in Japan and European countries for acne, in combination with topical retinoid. To confirm the efficacy and safety of adapalene gel and nadifloxacin cream in the treatment of Japanese patients with acne vulgaris, a total of 50 patients were randomized to the two groups, the combination therapy and the adapalene monotherapy, and each therapy was tested for 8 weeks. The percentage reduction in the number of inflammatory acne lesions was evaluated and the safety was monitored through adverse events. The combination of adapalene gel and nadifloxacin cream produced a significantly higher reduction in the inflammatory lesions at 2 weeks (P = 0.047) and at 8 weeks (P = 0.011) after the starting than did adapalene gel monotherapy. The combination did not elevate the side effects of erythema and scale scores, but rather significantly depressed erythema at 1 week. This study showed the efficacy and safety of the combination therapy of nadifloxacin cream with adapalene gel for the inflammatory acne.

Background/Objective Acute generalized exanthematous pustulosis (AGEP) is a diffuse pustular disorder that usually begins in intertriginous folds with widespread erythema. The causes in the majority of the cases are drugs. T cells and interleukin (IL)-8 play roles in the development of AGEP, but the mechanism remains to be elucidated. We investigated the involvement of Th17 cells and their cytokine IL-22 in the pathogenesis. Methods Three patients with AGEP were enrolled in this study. The percentages of IL-17+ Th17 cells, interferon γ+ T cells and IL-4+ T cells were measured in the patients’ peripheral blood lymphocytes by intracellular cytokine staining and flow cytometry. The concentration of IL-22 in the sera was measured by enzyme-linked immunosorbent assay. Results The percentages of Th17 cells were markedly higher in all three patients than healthy control individuals. The frequencies of interferon γ+ T cells were slightly high in the patients compared with the control, and there was no definite tendency in IL-4+ T-cell frequencies. The concentration of IL-22 was remarkably high in all patients when compared with normal subjects with levels under detection. Conclusion Th17 cells and their produced cytokine IL-22 were elevated in the peripheral blood of patients with AGEP. As IL-17 and IL-22 cooperatively stimulate keratinocytes to produce IL-8, IL-8 may contribute to the accumulation of neutrophils in the lesional epidermis of AGEP.

Urocanic acid (UCA) is an epidermal chromophore that undergoes trans to cis isomerization after UVB irradiation. cis-UCA is a potent inhibitor of cutaneous acquired immunity. The aim of this study was to explore the genes, which are upregulated by cis-UCA in normal human epidermal keratinocytes (NHEK) and investigated its role in vitro using human T-lymphocyte cell line, Jurkat cells. DNA microarray analysis and real-time PCR investigation revealed that cis-UCA, not trans-UCA, increased the expression of a gene encoding a β-galactoside-binding lectin, galectin-7, LGALS7B. Immunohistochemical study demonstrated that galectin-7 was highly expressed in the epidermis in the patients with actinic keratosis. Galectin-7 administration upregulated apoptosis and inhibited the expression of interleukin-2 (IL2) and interferon-γ (IFNG) mRNA in Jurkat cells. Taken together, galectin-7 may play important roles in downregulating the functions of T lymphocytes after UVB irradiation and can be developed into novel immunosuppressive therapies for inflammatory skin diseases.

Objective: To assess the functional results, health-related quality of life (QOL) outcomes, and complications in patients with an ileal neobladder in comparison to those with cutaneous diversion (ileal conduit and cutaneostomy). Methods: Between September 1992 and February 2003, we consecutively performed an ileal neobladder (the Studer method) in 30 patients and cutaneous diversion in 38 patients. In August 2004, questionnaires were mailed to 54 patients. The questionnaire included the validated health-related quality of life (QOL) questionnaire, SF-36 General Health Survey, and a urinary incontinence questionnaire. We also evaluated the functional results in patients with an ileal neobladder and the postoperative complications in patients with both urinary diversions. Results: The data from 41 patients (21 ileal neobladder procedures and 20 cutaneous diversions) were available for the analysis. No differences in the overall QOL were observed between the two groups. Complete daytime and night-time urinary continence was achieved in the 21 patients (100%) and 13 patients (61.9%), respectively. The mean value of the maximum flow rate was 15 ± 12 mL/min in the 21 neobladder patients. There were 19 early complications in 18 patients (60.0%) and seven late complications in six patients (20.0%) with an ileal neobladder. However, there were 15 early complications in 14 patients (36.8%) and eight late complications in six patients (15.8%) with cutaneous diversions. Conclusion: The findings regarding the health-related QOL and the frequency of complications in the neobladder group and those in the cutaneous diversion group were similar. However, the functional results and the status of urinary continence in the neobladder patients were satisfactory.

Members of the transforming growth factor beta/bone morphogenetic protein (TGF-beta/BMP) family are involved in the control of hair follicle (HF) morphogenesis and cycling. The activities of several members of this family activins and BMP-2, -4, -7, and -11) are controlled by antagonists such as follistatin. Because follistatin-deficient mice show abnormalities in vibrissae development, we explored the role of follistatin and activin in pelage HF development and cycling. We show here that during HF development follistatin mRNA was prominently expressed by hair matrix and outer root sheath keratinocytes as well as by interfollicular epidermal cells, whereas activin betaA mRNA was mainly expressed in dermal papilla cells. Compared with age-matched wild-type controls, both follistatin knockout mice and activin betaA transgenic mice showed a significant retardation of HF morphogenesis. Treatment of wild-type embryonic skin explants with follistatin protein stimulated HF development. This effect was inhibited by addition of recombinant activin A protein. Activin betaA transgenic mice demonstrated retardation of catagen entry, down-regulation of BMP-2, and up-regulation of expression of its antagonist matrix GLA protein. These observations suggest that follistatin and activin interaction plays an important role in both HF development and cycling, possibly in part by regulating expression of BMP-2 and its antagonist.

We report on the first case of pyogenic granulomas caused by afatinib. We also review the current literature concerning pyogenic granulomas caused by epidermal growth factor receptor tyrosine kinase inhibitors.

Topical immunotherapy is effective for severe alopecia areata. However, there are patients with alopecia areata refractory to topical immunotherapy alone. We tried SADBE (squaric acid dibutylester) topical immunotherapy combined with topical dry ice cryotherapy, carpronium chloride (a parasympathetic nerve stimulant) and/or oral cepharanthin (a biscoclaur alkaloid) in alopecia areata refractory to topical SADBE. Seventeen patients with alopecia areata (3 multiple, 3 ophiasis, 5 totalis and 6 universalis) were treated with SADBE in our department in 1999 to 2001. In 3 cases (2 multiple and 1 universalis) out of the 17 cases, cosmetically acceptable regrowth of hair was observed in several months with topical SADBE alone. In the other 14 cases, the SADBE therapy alone for several months (mean: 6.9 months) resulted in no or poor regrowth of hair. However, with subsequent combination therapy of topical SADBE for several months (mean: 7.6 months), satisfactory regrowth of hair was observed in 6 of the 14 cases. Our cases indicate that combination therapy of topical SADBE with other therapies can be a choice for alopecia areata which is refractory to topical SADBE therapy alone.

Cutaneous ureterostomy cannot be carried out by the retroperitoneal method in cases showing an insufficient length of the available ureter. We therefore proposed and carried out cutaneous ureterostomy transperitoneally on a ureter of minimum length using the transverse mesocolon. The right and left ureters are drawn from the retroperitoneum into the peritoneal cavity in the renal hilus area. The right ureter is then led from the root of the transverse mesocolon to the area attached to the transverse colon under the subserous part of the transverse mesocolon, and penetrates the gastrocolic ligament. The left ureter is led to the area attached to the transverse mesocolon under the subserous part of the transverse mesocolon, and penetrates the transverse mesocolon, bursa omentalis and gastrocolic ligament. Next, both the right and left ureters are drawn up to the abdominal wall and a ureterstoma is constructed. The transverse mesocolon can be used as supporting tissue for the ureter. Furthermore, this also ensures blood flow in the ureter.

The effectiveness of non-interval topical PUVA treatment was studied in four patients with mycosis fungoides at the plaque stage. Five regions of each patient were exposed to UVA immediately, 30 minutes, 60 minutes, 90 minutes, and 120 minutes, after topical application of 8-methoxypsoralen, respectively. The effects of these treatments were evaluated by clinical appearance and histological findings after the 20th treatment. All five regions were more improved clinically and histologically than the control region, which was not given PUVA therapy. There were no clear differences clinically among these five regions. Biopsy specimens from each region revealed the disappearance of epidermotropism and a marked decrease in atypical mononuclear cell infiltrations in the dermis. From these data, we concluded that there were no clear differences between these five treatments clinically or histologically and that non-interval PUVA therapy is useful for the early stages of mycosis fungoides. To our knowledge, this is the first report of non-interval PUVA therapy for mycosis fungoides.

Woolly hair is characterized by fine and tightly curled hair. It has recently been revealed that both LPAR6 and lipase H (LIPH) mutations cause autosomal recessive woolly hair (ARWH)/hypotrichosis. This notion has provided critical evidence to the concept that LPA6 activation by LIPH-catalyzed lipid mediator lysophosphatidic acid has a key role in regulation of hair follicle development. Very recently, novel mutations in exon 6, homozygous 736T>A and compound heterozygous 736T>A and 742C>A have been identified in Japanese ARWH/hypotrichosis patients. Here, we report on siblings (a 7-year-old Japanese girl and her 5-year-old brother) both showing woolly hair. Determination of their genomic sequence showed presence of a homozygous 736T>A transition in exon 6 of the LIPH gene changing cysteine at position 246 to serine, without any mutation in the LPAR6 gene. Additionally, the same mutation was found in one out of a 100 alleles of Japanese healthy controls and identified homozygously in three out of four other Japanese sporadic cases with woolly hair. Collectively, it has been suggested that 736T>A transition is highly specific and common in ARWH/hypotrichosis of Japanese origin.

Leptin is a cytokine well known for its ability to control body weight and energy metabolism. Several lines of evidence have recently revealed that leptin also plays an important role in wound healing and immune modulation in skin. Sumikawa et al. Exp Dermatol 2014 evaluated the effect of leptin on hair follicle cycling using mutant and wild-type mice. They report that leptin is produced in dermal papilla cells in hair follicles and that leptin receptor-deficient db/db mice show an abnormality in hair follicle cycling. Moreover, leptin injection induced the transition into the growth stage of the hair cycle (anagen). On this basis, it now deserves exploration whether leptin-mediated signalling is a key stimulus for anagen induction and whether this may be targeted to manage human hair disorders with defect in the control of hair follicle cycling.

Superficial angiomyxoma is a rare benign multilobulated cutaneous tumor, comprising a prominent myxoid matrix and numerous blood vessels. The tumor usually presents with a nodular lesion on the trunk, head, and neck. We describe a case of superficial angiomyxoma unusually located on the scrotum of a 4-year-old boy.