Manabu Yoshioka

Type of skin eruption is an independent prognostic indicator for adult T-cell leukemia/lymphoma

Cutaneous involvement is seen in ~ 50% of adult T-cell leukemia/lymphoma (ATLL) patients. We investigated the association between skin eruption type and prognosis in 119 ATLL patients. ATLL eruptions were categorized into patch (6.7%), plaque (26.9%), multipapular (19.3%), nodulotumoral (38.7%), erythrodermic (4.2%), and purpuric (4.2%) types. When the T stage of the tumor-node-metastasis-blood (TNMB) classification of mycosis fungoides/Sézary syndrome was applied to ATLL staging, 16.0% were T1, 17.7% T2, 38.7% T3, and 4.2% T4, and the remaining 23.5% were of the multipapular and purpuric types. For the patch type, the mean survival time (median survival time could not be estimated) was 188.4 months. The median survival times (in months) for the remaining types were as follows: plaque, 114.9; multipapular, 17.3; nodulotumoral, 17.3; erythrodermic, 3.0; and purpuric, 4.4. Kaplan-Meier curves of overall survival showed that the erythrodermic type had the poorest prognosis, followed by the nodulotumoral and multipapular types. The patch and plaque types were associated with better survival rates. Multivariate analysis demonstrated that the hazard ratios of the erythrodermic and nodulotumoral types were significantly higher than that of the patch type, and that the eruption type is an independent prognostic factor for ATLL. The overall survival was worse as the T stage became more advanced: the multipapular type and T2 were comparable, and the purpuric type had a significantly poorer prognosis than T1.

Galectin-7, induced by cis-urocanic acid and ultraviolet B irradiation, down-modulates cytokine production by T lymphocytes

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.

Leptin controls hair follicle cycling

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.

Nivolumab in the treatment of malignant melanoma: review of the literature

Nivolumab was developed as a monoclonal antibody against programmed death receptor-1, an immune checkpoint inhibitor which negatively regulates T-cell proliferation and activation. Intravenous administration of nivolumab was approved for the treatment of unresectable malignant melanoma in 2014 in Japan. When advanced melanoma patients were treated with nivolumab, median overall survival became longer. Overall survival rate was significantly better in nivolumab-treated melanoma patients than dacarbazine-treated melanoma patients. Nivolumab had an acceptable long-term tolerability profile, with 22% of patients experiencing grade 3 or 4 adverse events related to the drug. Therefore, nivolumab can become an alternative therapy for advanced malignant melanoma.

Increased circulating Th17 cell in a patient with tinea capitis caused by Microsporum canis

Tinea capitis is a relatively common superficial fungal infection. In the infection ofMicrosporum canis (M. canis), the lesion is around a hair shaft and eventually the hairs break off 1e3 mm above the scalp. The patients sometimes experience permanent hair loss, especially after longstanding inflammation. However, the detail mechanism of severe inflammation leading to subcutaneous pustular formation and hair loss caused by tinea capitis remains unclear. Recently, IL-17-producing Th17 cells, which are comprised in established CD4þ T helper cell subsets, exacerbate skin inflammation,

Combination of skin-directed therapy and oral etoposide for smoldering adult T-cell leukemia/lymphoma with skin involvement

Abstract Approximately 50% of patients with adult T-cell leukemia/lymphoma (ATLL) have skin involvement, and the smoldering, skin lesion-bearing cases are often treated with various skin-directed therapies, such as phototherapy and radiation therapy. Daily oral administration of etoposide plus prednisolone (EP) is also used for smoldering-type ATLL. However, it remains unclear whether these therapies improve patients’ survival. We retrospectively analyzed the prognosis of patients with smoldering, skin lesion-bearing ATLL (n = 62), who were treated, as first therapy, with one skin-directed therapy (n = 29), oral EP alone (n = 14) or a combination of skin-directed therapy and oral EP (n = 19). Multivariate analysis revealed that the hazard ratios (HRs) for the overall survival (OS) and progression-free survival (PFS) with the combination therapy were significantly lower than those with the skin-directed therapy (HR 0.1, p = 0.001; HR 0.2, p = 0.002, respectively). These results suggest that the combination of skin-directed therapy and oral EP improves the clinical outcome of patients with smoldering, skin lesion-bearing ATLL.

Maculopapular type drug eruption caused by silodosin

Silodosin is one of the a1-adrenergic receptor antagonists and is commonly used to treat male lower urinary tract symptoms due to benign prostatic hypertrophy.1 The incidence of silodosin-related adverse events was 69.7%,1 and themost common adverse event after silodosin treatment was abnormal ejaculation.1 However, to our knowledge, there has been no case report on cutaneous drug eruption caused by silodosin in English literature. Herein, we report the first case of silodosin-induced drug eruption. A 58-year-old male, who had suffered from benign prostatic hypertrophy for 5 years, developed his erythematous plaques andwas referred to our department for evaluation of his eruption. Physical examination revealed that papules and erythematous eruption had developed on his trunk (Fig. 1AeC) and extremities without mucosal involvement after the 3rd administration of silodosin for his benign prostatic hypertrophy. Laboratory and biochemical examinations were within normal ranges. At the first visit, a skin biopsy specimen taken from an erythematous lesion on his trunk revealed lymphocyte infiltration around vessels in dermis (Fig. 1D) with less epidermal change. We performed lymphocyte stimulation test (LST) with silodosin as described previously.2,3

Expression of AID in malignant melanoma with BRAFV600E mutation

BRAF‐activating somatic mutations often exist in malignant melanoma. The underlying molecular mechanism of somatic BRAF mutation inductions remained to be clear. Activation‐induced cytidine deaminase (AID), a member of a cytidine deaminase family, and APOBEC3B induce somatic mutations and recently have been indicated to be involved in the pathomechanism of several kinds of cancers. The aim of this study was to explore the expression level of AID and APOBEC3B in BRAF‐mutation‐ containing malignant melanoma. Immunohistochemical study demonstrated that 9 of 10 malignant melanomas with high AID expression had BRAFV600E mutation. Eight of them developed multiorgan metastases or multiple lymph node metastases afterwards. Although the size of the patient panel was small, the results indicate that there might be an association between AID expression and BRAF mutation in melanoma.

Hypopituitarism and hypothyroidism following atrioventricular block during nivolumab treatment

Dear Editor, Nivolumab is a blocking antibody against programmed death receptor-1 (PD-1), which inhibits T-cell proliferation and cytokine production. Nivolumab has exhibited a favorable therapeutic response in patients with malignancies, such as malignant melanoma and lung cancer. Although various sideeffects, such as hematological toxicity and respiratory disease, have been reported, we report an extremely rare case of hypopituitarism and hypothyroidism following atrioventricular block (AV block) possibly due to nivolumab. An 85-year-old Japanese male noticed a black plaque on his head 9 months prior, and the lesion gradually developed. He visited the dermatology clinic, and a skin biopsy from his black plaque was obtained. The histopathological diagnosis was malignant melanoma (Fig. 1a–d). He was referred to our department for evaluation of his skin eruption. A chest computed tomography examination revealed that multiple metastatic tumors were observed in both lungs. Therefore, he was diagnosed with stage IV malignant melanoma, and nivolumab (2 mg/kg) was administrated i.v. for his malignant melanoma every 3 weeks. Three months after the treatment, his heart rate decreased to approximately 50 b.p.m., and an electrocardiogram revealed first-degree AV block (Fig. 1e). Therefore, cardiac pacemaker insertion was performed. Five months after the treatment, lung metastasis lesions decreased in size; however, he suffered from fatigue and loss of appetite. His blood pressure was 96/58 mmHg, indicating hypotension. Laboratory findings revealed lower levels of adrenocorticotropic hormone (ACTH) (2.0 pg/mL; normal range, 7.2– 63.3) and cortisol (0.4 lg/dL; normal range, 2.7–18.0), whereas serum levels of all other anterior pituitary hormones were within normal ranges. Therefore, we suspected that he might be suffering from adrenal insufficiency due to hypopituitarism, and we performed a corticotropin-releasing hormone (CRH) test for the diagnosis. As expected, ACTH and cortisol exhibited no significant responses under CRH stimulation. Furthermore, laboratory examination revealed an increased level of thyroid-stimulating hormone (9.5 mIU/mL; normal range, 0.34–6.50) and a reduced level of free T4 (0.87 ng/dL; normal range, 0.97–1.79). We diagnosed the patient with hypothyroidism and adrenal insufficiency due to hypopituitarism after nivolumab treatment. His symptoms due to hypothyroidism were relatively mild without any treatment. His symptoms dramatically improved after administration of hydrocortisone (15 mg/day). Nivolumab administration was continued without other additional treatments. Although previous studies reported that patients treated with nivolumab occasionally exhibit adverse events, such as

Drug eruption caused by secukinumab

The Th17 cell is a pro-inflammatory T helper cell subset defined by the production of IL-17, which plays an important role in various inflammatory diseases [1]. IL-17 exacerbates inflammatory responses through activation of various immune cells, such as neutrophils and keratinocytes. Therefore, the IL-17 axis is a key therapeutic target for the regulation of inflammatory diseases, such as psoriasis and rheumatoid arthritis [2]. Secukinumab is an IL-17 neutralizing antibody, and widely used for the [...]