Sanehito Haruyama

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.

Connexin 26 (GJB2) mutations in keratitis-ichthyosis-deafness syndrome presenting with squamous cell carcinoma.

Dear Editor, We report a 58-year-old Japanese woman with keratitis–ichthyosis– deafness (KID) syndrome (Online Mendelian Inheritance in Man: 148210). The patient had been provisionally diagnosed as having ectodermal dysplasia since childhood. She had also suffered from keratitis since 30 years of age. Her twin sister had the same skin conditions. She had a 4-year history of a tumor on the scalp. Physical examination disclosed a sessile, erosive tumor on her scalp (Fig. 1a,b). She had alopecia, sparse eyebrows, and dry and scaly face (Fig. 1a). Another small tumor was present on the right upper eyelid (Fig. 1c). There was hyperkeratosis on the palms (Fig. 1d) and soles (Fig. 1e) and nail dystrophy (Fig. 1f). Audiometry revealed bilateral sensorineural deafness (data not shown). The surgically removed scalp and eyelid tumors showed the presence of invading epithelial lobules, consisting of atypical epithelial cells with squamoid eddies (Fig. 1g). The eyelid tumor had virtually the same histological findings (Fig. 1h). A biopsy specimen taken from the palm showed orthokeratotic hyperkeratosis of the cornified layer (Fig. 1i). After the operation, subcutaneous induration was noticed in her left breast. By mammography, echography and computed tomography, a 17 mm · 15 mm tumor was histopathologically as invasive scirrhous ductal carcinoma of the breast (T1cN1M0, stage IIA). She received a course of chemotherapy (epirubicin, cyclophosphamide and 5-fluorouracil) and is currently on follow up. There was no metastasis or relapse of squamous cell carcinoma (SCC) in our case. Although our patient had no follicular occlusion triad with hidradenitis suppurativa, acne conglobate and dissecting cellulitis of the scalp, a long-term follow up will be needed in this respect. Furthermore, we analyzed connexin-26 (CX26) (National Center for Biotechnology Information: NM_004004), the responsible mutated gene for KID syndrome. After informed consent, genomic DNA was extracted from the patient’s lesional skin. The CX26 exon 2 (819 bp) was amplified via polymerase chain reaction (PCR) and sequencing analysis was performed using a primer pair (CX26 F, 5¢-AgAgCAAACCgCCCAgAgT-3¢, and CX26 R, 5¢-gggAAATgCTAg CgACTgAg-3¢). We identified three heterozygous missense mutations (Fig. 1j): (i) c.79G>A mutation (valinefiisoleucine, V27I); (ii) c.148G > A mutation (aspartic acidfiasparagine, D50N); and (iii) c.341A > G mutation (glutamic acidfiglycine, E114G). Two healthy volunteers had none of these mutations, although one healthy subject possessed a homozygous V27I mutation. The patient was diagnosed with KID syndrome based on the well-characterized D50N mutation. V27I and E114G missense mutations have been identified in patients with non-syndromic hearing loss (NSHL). However, V27I is the most frequent type of polymorphic mutation, suggesting that V27I is not related to pathogenesis in this patient. In immunohistochemical study of the plantar skin, keratinocytes of the prickle to granular layers were strongly stained for CX26 in a normal subject (Fig. 1k), and the staining intensity of those cells in our patient was weaker (Fig. 1l). In the scalp SCC lesion of a non-KID syndrome patient, the neoplastic cells were weakly positive for CX26 (Fig. 1m), but the SCC cells in our patient were negative for CX26 (Fig. 1n), suggesting that D50N and E114G mutations induced a low expression or a conformational change of CX26. However, CX26 expression of breast cancer cells in our patient was positive (Fig. 1o), suggesting that its expression depends on the epithelial cells. To our knowledge, there have been 12 cases of KID syndrome reported with SCC (Table 1). It is possible that epidermal keratinocytes with CX26 dysfunction are prone to transform to neoplastic cells, or the skin losing CX26 function provides a circumstance where SCC easily grows. Especially, the D50N mutation may induce the SCC. Mutations other than D50N have been reported in several Table 1. Reported cases of KID syndrome with SCC

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,

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

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

Bullous Pemphigoid Associated with the Dipeptidyl Peptidase-4 Inhibitor Sitagliptin in a Patient with Liver Cirrhosis Complicated with Rapidly Progressive Hepatocellular Carcinoma

A 78-year-old man presented with cutaneous blisters of the limbs and abdominal distension. He had been treated for various diseases, including liver cirrhosis. He had begun receiving sitagliptin, a dipeptidyl peptidase-4 (DPP-4) inhibitor, for diabetes mellitus three years before the hospitalization. A skin biopsy demonstrated bullous pemphigoid. Ultrasonography (US) revealed multiple liver tumors, although he had been receiving regular US studies. We stopped sitagliptin and started insulin and corticosteroids. However, his renal dysfunction progressed, and he died 14 days after the hospitalization. We should therefore be careful of various complications, including bullous pemphigoid and progression of tumors, when using DPP-4 inhibitors.

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 [...]

Development of a prominent granulomatous eruption after interferon-gamma therapy in a patient with mycosis fungoides.

© 2010 The Authors. doi: 10.2340/00015555-0788 Journal Compilation

Acute Generalized Exanthematous Pustulosis Caused by Faropenem: A Possible Pathogenetic Role for Interleukin-23.

© 2016 The Authors. doi: 10.2340/00015555-2225 Journal Compilation

CD30-positive Cutaneous Pseudolymphoma Caused by Tocilizumab in a Patient with Rheumatoid Arthritis: Case Report and Literature Review

Tocilizumab is a biological disease-modifying anti-rheumatic drug (DMARD) that targets interleukin 6 (IL-6) receptor, blocking IL-6 signalling (1). Tocilizumab has shown efficacy in the treatment of rheumatoid arthritis (2); however, it sometimes induces cutaneous adverse reactions. We report here a case of pseudolymphoma caused by tocilizumab, manifesting as an unusual cutaneous eruption. We also review the literature concerning drug eruption caused by tocilizumab, and pseudolymphoma caused by biologics in general.