Taiki Isei

Cytokine biomarkers to predict antitumor responses to nivolumab suggested in a phase 2 study for advanced melanoma

Promising antitumor activities of nivolumab, a fully humanized IgG4 inhibitor antibody against the programmed death‐1 protein, were suggested in previous phase 1 studies. The present phase 2, single‐arm study (JAPIC‐CTI #111681) evaluated the antitumor activities of nivolumab and explored its predictive correlates in advanced melanoma patients at 11 sites in Japan. Intravenous nivolumab 2 mg/kg was given repeatedly at 3‐week intervals to 35 of 37 patients enrolled from December 2011 to May 2012 until they experienced unacceptable toxicity, disease progression, or complete response. Primary endpoint was objective response rate. Serum levels of immune modulators were assessed at multiple time points. As of 21 October 2014, median response duration, median progression‐free survival, and median overall survival were 463 days, 169 days, and 18.0 months, respectively. The overall response rate and 1‐ and 2‐year survival rates were 28.6%, 54.3%, and 42.9%, respectively. Thirteen patients remained alive at the end of the observation period and no deaths were drug related. Grade 3–4 drug‐related adverse events were observed in 31.4% of patients. Pretreatment serum interferon‐γ, and interleukin‐6 and ‐10 levels were significantly higher in the patients with objective tumor responses than in those with tumor progression. In conclusion, giving repeated i.v. nivolumab had potent and durable antitumor effects and a manageable safety profile in advanced melanoma patients, strongly suggesting the usefulness of nivolumab for advanced melanoma and the usefulness of pretreatment serum cytokine profiles as correlates for predicting treatment efficacy.

Xeroderma pigmentosum variant associated with multiple cancers

A 62‐year‐old Japanese man with xeroderma pigmentosum (XP) variant is reported. The patient had developed at least 6 basal cell carcinomas, a squamous cell carcinoma, and a malignant melanoma on sun‐exposed areas, and an atypical carcinoid on the right lung. In vivo phototesting showed a normal response. The minimal erythema dose of ultraviolet B (UVB) was not lowered and no delayed peaking of the erythema reaction was observed. His skin fibroblasts exhibited higher sensitivity to UV irradiation, but a normal level of unscheduled DNA and RNA synthesis. Cell fusions with XP group A, C, D, E, F, and G cells after UV irradiation were all complemented. Previous reports together with this case suggest that older XP variant patients have a high frequency of not only skin cancers, but also internal malignancies.

Occult HIV infection in Japanese rupioid psoriasis

Dear Editor, Recently, the number of HIV-infected patients has been rising in Japan; however, HIV screening is not mandatory for biologic therapies of psoriasis. We herein report a patient with psoriasis who was found to have a HIV infection by a screening test before the initiation of biologic therapy. A 45-year-old Japanese man had sex with an unspecified large number of women while he worked overseas. He developed erythema on the forehead and the extremities 6 months prior to his initial visit that spread all over his body within the next 3 months. Due to the exacerbation of the skin lesions and a persistent fever above 38°C, he visited the Department of Dermatology at Osaka University Hospital in March 2015. At the first visit, he presented with erythroderma (Psoriasis Area and Severity Index [PASI] score, 58.6), and dark-purple rupioid scales and crusts were distributed over the trunk and extremities (Fig. 1a,b). A skin biopsy performed on the scaling erythema plaque on the forearm revealed hyperkeratosis, parakeratosis, moderate acanthosis and loss of the granular layer (Fig. 1c). The upper dermis also showed edema and lymphocyte infiltration. Although the pathological hallmarks of psoriasis are neutrophilic microabscesses, these were not observed in our patient. However, we considered that he had psoriasis based on the clinical observation, and histologically psoriasiform dermatitis. Therefore, we planned to start biologic therapy. The laboratory data revealed that CD4 T-lymphocyte cell count (4 cells/lL) was low. His HIV RNA viral load was 1 826 962 copies/mL, confirming a diagnosis of HIV infection.

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 – 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.

CD8‐positive granulomatous mycosis fungoides mimicking generalized granuloma annulare

Dear Editor, Patients with malignant lymphoma may develop non-infectious granulomas in both involved and non-involved organs, including the skin and lymph nodes. Cutaneous granulomas in the setting of malignant lymphoma are divided into two types. The first type involves cutaneous granuloma without lymphoma cells, and consists of sarcoid-like granulomas or other granulomatous skin processes. The second type is characterized by granulomatous infiltrates admixed with lymphoma cells within specific skin lesions of malignant lymphoma. A granulomatous variant of mycosis fungoides (MF) is the most typical example. Fewer than 100 cases of granulomatous MF have been reported, and the CD8 phenotype is extremely rare. Herein, we report a case of CD8 granulomatous MF mimicking generalized granuloma annulare (GA). Because the patient had diabetes and previous histopathological examinations had not revealed definite atypical lymphocyte infiltration, generalized GA was suspected as the skin reaction can be related to diabetes. A 62-year-old woman presented with brown annular skin lesions on the waist. GA was diagnosed based on the clinical features and histological examinations at her local city hospital. The patient was treated with topical steroids for 10 years, but no improvement was achieved. Because the skin lesions gradually extended to the abdomen and extremities, she was referred to us for narrow-band ultraviolet B therapy. Physical examination revealed diffuse papules and confluent, brown, annular plaques (Fig. 1), symmetrically involving the extremities, trunk and face. All laboratory investigations yielded results in the normal range with the exception of increased serum glucose (215 mg/dL), glycosylated hemoglobin (6.8%) and soluble interleukin-2 receptor (5350 U/mL). Anti-Human T-cell leukemia virus type 1 antibody was negative. Serum angiotensin-converting enzyme and calcium levels were normal. Histopathology of a plaque on the waist revealed prominent accumulation of lymphocytes admixed with epithelioid cells and numerous Langerhans-type and foreign bodytype multinucleated giant cells (MGC) in the dermis (Fig. 2a). Immunophenotypic study showed that the lesions were comprised of T-lymphocytes (CD3, CD4 , CD8, CD30 , CD45RO, CD56 , CD20 and CD79a ) (Fig. 2b) and CD68 histiocytes. In vitro MGC from peripheral blood monocytes, according to our previously described method, showed a significantly higher rate of MGC formation compared with those from healthy volunteers (78.2 ± 9.3% vs 32.2 ± 7.1%). Total body computed tomography revealed enlarged right cervical, bilateral axillary and bilateral inguinal lymph nodes. Axillary lymph node biopsy showed a granulomatous lesion composed of epithelioid cells and MGC in the absence of necrosis. The patient was diagnosed with CD8 granulomatous MF mimicking GA and treatment was initiated with oral psoralen plus ultraviolet A therapy and 50 mg/day etoposide. While the skin lesions improved, the lymphadenopathy remained unchanged. Granuloma annulare has rarely been reported in association with malignant lymphoma. Barksdale et al. reported 13 patients with GA and lymphoma and concluded that GA with atypical clinical presentation may be associated with underlying hematopoietic malignancy and may represent part of a generalized granulomatous response to malignant lymphoma. The histopathological pattern in such cases was that of GA with no lymphomatous cells, mixed with granulomatous infiltration. Conversely, Jouary et al. reported an unusual case of granulomatous MF mimicking GA with granulomatous changes and lymphoma cell infiltration within the same lesion.

The wound/burn guidelines – 3: Guidelines for the diagnosis and treatment for diabetic ulcer/gangrene

We aimed to prepare guidelines for the management of diabetic ulcer/gangrene with emphasis on the diagnosis and treatment of skin symptoms. They serve as a tool to improve the quality of the diagnosis and treatment in each patient and, further, to improve the level of the care for diabetic ulcer in Japan by systematically presenting evidence‐based recommendations for clinical judgments by incorporating various viewpoints.

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 – 1: Wounds in general

The Japanese Dermatological Association determined to prepare the Wound/Burn Guidelines focusing on treatments, catering to needs for the clinical practice of dermatology. Among these guidelines, “Wounds in General” was intended to explain knowledge necessary “to heal wounds” without specifying particular disorders.

Cutaneous necrotizing vasculitis in a patient with dermatomyositis positive for anti-PL-7 antibody

ejd.2013.2163 Auteur(s) : Ikuko Ueda-Hayakawa1 uedaik@hirakata.kmu.ac.jp, Taro Kusuyama1, Taiki Isei1, Yoshio Ozaki2, Yasuhito Hamaguchi3, Manabu Fujimoto3, Kazuhiko Takehara3, Hiroyuki Okamoto1 1 Department of Dermatology, 2 Department of Rheumatology and Clinical Immunology, Kansai Medical University, 2-3-1 Shinmachi, Hirakata, Osaka 573-1191, Japan 3 Department of Dermatology, Kanazawa University Graduate School of Medical Science, Kanazawa, Japan Autoantibodies against several aminoacyl-tRNA [...]