Yoji Hirai

Hydroa Vacciniforme Is Associated with Increased Numbers of Epstein–Barr Virus–Infected γδT Cells

Hydroa vacciniforme (HV) is a rare photosensitivity disorder of childhood associated with Epstein-Barr virus (EBV)(+) T-cell infiltration. We have summarized clinical manifestations of HV, and analyzed EBV(+) T-cell subsets as well as EBV DNA load in lymphocyte fractions, in comparison with hypersensitivity to mosquito bites (HMB), an EBV-associated T/natural killer (NK) lymphoproliferative disorder. We found that 31 of 33 (93.9%) HV lesions were composed of EBV(+) T cells and reactive EBV(-) cytotoxic T cells, without significant CD56(+) cell infiltration, whereas many CD56(+) cells were present in 8 of 9 (88.9%) HMB lesions. Of 13 (20.6%) HMB patients with or without HV, 12 (92.3%) showed increased percentages (>32%) of NK cells in the peripheral blood, whereas in the 16 patients with HV alone, 14 (87.5%) showed no increase. Of the 11 HV patients, 10 (90.9%) had increased percentages (>5%) of circulating γδT cells, with a mean value of 15.7 ± 2.9%, and the γδT-cell fractions contained larger amounts of EBV DNA than non-γδT-cell fractions. A triple-labeling method revealed that all three HV patients examined had increased percentages of EBER(+), T-cell receptor (TCR)γδ(+), and TCRαβ(-) cells. Our observations indicate that HV is associated with increased numbers of EBV(+) γδT cells, whereas HMB is associated with EBV(+) NK cells.

Survival rates and prognostic factors of Epstein-Barr virus-associated hydroa vacciniforme and hypersensitivity to mosquito bites.

Epstein‐Barr virus (EBV)‐associated T/natural‐killer lymphoproliferative disorders form a group of diseases that includes classical and systemic hydroa vacciniforme (HV) and hypersensitivity to mosquito bites (HMB). Patients with systemic HV (sHV) and HMB often have a poor prognosis, although little is known about the prognostic factors.

Comparative study on driver mutations in primary and metastatic melanomas at a single Japanese institute: A clue for intra- and inter-tumor heterogeneity

BACKGROUND Searching for driver mutations in melanoma is critical to understanding melanoma genesis, progression and response to therapy. OBJECTIVES We aimed to investigate the frequency and pattern of driver mutations in Japanese primary and metastatic melanomas including cases of unknown primary origin, in relation to their clinicopathologic manifestations. METHODS Seventy-seven samples from 60 patients with melanoma were screened for 70 driver mutations of 20 oncogenes by Sequenom MelaCarta MassARRAY, and the results for primary and metastatic melanomas were compared. RESULTS Of 77 tissue samples, BRAF V600E was detected in 21 samples (27%), CDK4 R24C in 7, EPHB6 G404S in 6, BRAF V600K in 2, NEK10 E379K in 2, and CDK4 R24H, NRAS Q61K, NRAS Q61R, KRAS G12A, KIT L576P, KIT V559A, ERBB4 E452K, and PDGFRA E996K in one sample each. No driver mutations related to the MAPK cascade including RAS and BRAF were detected in the chronically sun-damaged (CSD) group of melanoma. Dual or triple driver mutations were found in four of 40 (10%) samples from the primary melanomas, and three of 37 (8%) of the metastatic melanomas. Fourteen of 26 (54%) samples of non-CSD melanoma, and 3 of 6 (50%) melanomas of unknown primary origin had the BRAF V600E mutation. Mutations in membrane-bound receptors including KIT, ERBB4 and EPHB6 were detected in 8 of 77 (10%) samples. Of 17 pairs of primary and metastatic melanomas from the same patient, the primary mutation pattern was changed to a novel one in three cases, and only one of the plural mutations in the primary melanoma was found in the metastatic lesions in two cases. CONCLUSIONS BRAF V600E is a predominant mutation in non-CSD melanoma and melanomas of unknown primary origin. Mutational heterogeneity may exist in the primary melanoma (intra-tumor heterogeneity), and between the primary and metastatic lesions (inter-tumor heterogeneity).

Epstein-Barr virus reactivation is induced, but abortive, in cutaneous lesions of systemic hydroa vacciniforme and hypersensitivity to mosquito bites

BACKGROUND Epstein-Barr virus (EBV)-associated T/natural killer (NK)-lymphoproliferative disorders (LPDs) include hydroa vacciniforme (HV) and hypersensitivity to mosquito bites (HMB). The pathomechanisms of these diseases are still unclear. OBJECTIVE To understand the inflammatory process, we examined EBV reactivation markers, BZLF1 and BDRF1 mRNA in the tissue and blood from patients with EBV-associated T/NK-LPDs. METHODS Sixty-four patients with EBV-associated LPDs and epithelial neoplasms, and EBV+ cell line cells were studied. DNase-treated and resistant EBV DNA load in blood and cell culture supernatants were calculated. An EBV reactivation signal was analyzed in the tissue, blood and cell line cells. RESULTS In the tissue, BZLF1 mRNA was detected in 5 of 6 (83%) samples of EBV+ epithelial neoplasms, 16 of 21 (76%) of EBV+ lymphomas, and 5 of 15 (33%) of systemic HV and/or HMB, but negative in all 15 patients with classical HV. In the blood, BZLF1 mRNA was detected in only one of 19 (5.3%) samples of EBV-associated T/NK-LPDs. A down-stream reactivation signal, BDRF1 mRNA was expressed in all 6 samples of EBV+ epithelial neoplasms, but it was positive in only one of 15 (6.7%) samples from systemic HV and HMB in the tissue. EBV+ T/NK-cell line cells treated with phorbol 12-myristate 13-acetate produced BZLF1 and BDRF1 mRNA, and encapsidated EBV DNA was detected in the culture supernatants of cell line cells. CONCLUSION Stimulation-induced EBV reactivation occurred both in vivo and in vitro, but it was almost abortive in vivo. Reactivation-related EBV antigens might be responsible for induction of systemic HV and HMB.

Oculomucosal and gastrointestinal involvement in Epstein-Barr virus-associated hydroa vacciniforme

In a series of patients with Epstein-Barr virus (EBV)-associated hydroa vacciniforme (HV) and related disorders, we reviewed the incidence of oculomucosal and gastrointestinal involvement. Of 63 patients with EBV-related HV and/or hypersensitivity to mosquito bites (HMB), 11 patients (17.5%) presented with mucosal lesions such as aphthous stomatitis and ulcerative gingivitis, 3 patients (4.8%) had ocular symptoms including iritis, conjunctival hyperemia and corneal erosions, and 2 patients (3.2%) presented with severe HV complicated gastrointestinal involvement. Oculomucosal lesions are sometimes complicated in patients with EBV-related HV and HMB, and gastrointestinal involvement may occur in the severe form.

Epstein–Barr virus‐positive mucocutaneous ulcer in a patient with polycythemia vera treated with oral hydroxyurea

Dear Editor, Epstein–Barr virus (EBV)-positive mucocutaneous ulcer (EMU), a proposed entity, is one of the EBV-positive lymphoproliferative disorders that arise in individuals with various immunosuppressive conditions. EMU is characterized by clinically localized disease with an indolent course and Hodgkin-like histopathological features. We present a case of EMU caused by oral hydroxyurea. In June 2013, a 79-year-old Japanese man was referred to us because of a 9-month history of a gradually developing perioral tumor (Fig. 1a). In 1994, he had been diagnosed as having polycythemia vera, and he was treated with oral hydroxyurea, which resulted in a favorable clinical course. Our physical examination of him revealed a 15-mm indurated erythemic nodule on his lower lip. No mucosal ulcer was observed in his oral cavity. No swollen node was detected in his neck. The laboratory findings were as follows: lactate dehydrogenase, 381 U/L (normal, 120–240); and soluble interleukin-2 receptor, 493 U/mL (normal, 122–496). Blood EBV DNA load was not determined. No significant accumulation was detected by F-fluorodeoxyglucose positron emission tomography. A biopsy specimen from the tumor showed dense infiltration of lymphoid, plasmacytoid and large abnormal lymphoid cells, suggestive of malignant lymphoma (Fig. 1b). The infiltrating large cells mimicked Hodgkin cells, with expressions of CD20, CD30 and EBV-encoded RNA (Fig. 1c,d). CD3 was not expressed on these large tumor cells. A diagnosis of EMU was made. However, clonal B-cell populations were not detected by polymerase chain reaction amplification of immunoglobulin genes, using DNA extracted from the biopsy specimen. We stopped the patient’s oral hydroxyurea regimen, resulting in spontaneous tumor regression within 2 weeks. However, the oral hydroxyurea was restarted 3 weeks later, when marked leukocytosis and thrombocytosis were observed. Again, a perioral tumor gradually recurred on the same lesion as before (Fig. 1e). Histopathological findings of a biopsy specimen from the recurrent tumor were similar to the previous findings. He was successfully treated with four rounds of polychemotherapy with rituximab, pirarubicin, cyclophosphamide, vincristine and prednisone, followed by radiation therapy (30 Gy) for the involved site. However, in April 2014 during the follow up after the radio-chemotherapy, the patient died of an unknown cause independent of the EMU. Usually, EMU presents as a solitary nodule with or without ulcer, preferentially at the transition site of mucosa and skin.

Clinical and Laboratory Markers Associated With Relapse in Cutaneous Polyarteritis Nodosa

Importance In cutaneous polyarteritis nodosa (CPAN), less aggressive treatments can be selected, because CPAN is not associated with life-threatening or progressive outcomes. Although patients with a recurrent clinical course may require additional immunosuppressive therapies, no pretreatment factors associated with a worse prognosis in CPAN have been reported. Objective To identify clinical or laboratory markers associated with relapse of CPAN. Design, Setting, and Participants This retrospective case series was performed at a dermatology clinic of a tertiary referral center in Okayama, Japan, from October 1, 2001, through April 30, 2017. Of 30 patients identified with CPAN, the 21 with histopathologic evidence of disease were eligible and enrolled in the study. Main Outcomes and Measures The medical database was examined for sex, age at diagnosis, affected anatomical sites, type and extent of skin lesion, laboratory data, initial therapies, duration of follow-up, and current status. Relapse was defined as the first reoccurrence or new onset of cutaneous disease that required further escalation of treatment with prednisolone at a dosage of greater than 20 mg/d and/or add-on use of immunosuppressant therapy, more than 6 months after initial treatment. The pretreatment factors were statistically evaluated between the groups without and with relapse. Results The 21 patients included 5 males and 16 females with a median age of 49 years (range, 11-74 years) at diagnosis. The median follow-up was 42 months (range, 8-374 months). Pretreatment cutaneous ulcer was significantly associated with relapse between the 2 groups (0 of 11 in the nonrelapse group vs 4 of 10 in the relapse group; &khgr;21 = 4.67; P < .05). In the laboratory test results, significantly higher mean (SD) values were observed in the relapse group for C-reactive protein level (0.23 [2.00] vs 6.03 [3.10] mg/dL; standard error of the mean [SEM], 3.40 mg/dL; 95% CI, 0.01-10.8 mg/dL; P = .01), absolute neutrophil count (ANC) (3.4 × 103/&mgr;L [1.1 × 103/&mgr;L] vs 6.0 × 103/&mgr;L [3.2 × 103/&mgr;L]; SEM, 2.9 × 103/&mgr;L; 95% CI, 1.9 × 103/&mgr;L to 14.6 × 103/&mgr;L; P = .001), neutrophil-to-lymphocyte ratio (1.4 [0.8] vs 2.8 [0.9]; SEM, 1.2; 95% CI, 1.1-4.9; P = .002), and systemic immune-inflammation index (5.1 × 105 [3.9 × 105] vs 11.7 × 105 [7.7 × 105]; SEM, 7.3 × 105; 95% CI, 3.3 × 105 to 31.1 × 105; P = .007). The estimated 2-year cumulative relapse rate was significantly high in the patients with blood ANC of greater than 4.9 × 103/&mgr;L compared with 4.9 × 103/&mgr;L or less (9 of 10 [90%] vs 2 of 11 [18%]; 95% CI, 6%-72%). Conclusions and Relevance Pretreatment status of cutaneous ulcer, the serum C-reactive protein level, the blood ANC, the neutrophil-to-lymphocyte ratio, and the systemic immune-inflammation index are associated with a worse prognosis in CPAN.

An effective and promising treatment with adalimumab for impetigo herpetiformis with postpartum flare-up

In November 2016, a 32-year-old Japanese pregnant woman (18 weeks into her third pregnancy) noticed an itchy eruption on her legs. Topical corticosteroid twice daily had not shown much efficacy for her eruption. In January 2017, she was referred to our clinic because of a rapidly developing eruption mainly on the extremities. She had not had psoriasis and had no familial history of it. She had not received any medication. Our physical examination revealed multiple erythemic pustules on her extremities, coalesced into annular erythemic plaques, without any fever (Fig. 1a,b). Severe pain on her legs was interfering with her ability to walk. Routine laboratory test results revealed a white blood cell count (WBC) of 10,310/ll. Blood chemistry test results showed a decreased serum level of albumin at 3.3 g/dl (normal: 4.1–5.1). No abnormal findings were observed in the serum calcium levels. A biopsy specimen from the pustule showed infiltration of neutrophils in the epidermis with a formation of Kogoj’s spongiform pustule (Fig. 1c,d). No immune deposits were detected by direct immunofluorescence study. A diagnosis of IH was made. In February 2017, we performed five rounds of GMA therapy at 7-day intervals because oral prednisone 30 mg daily and dapsone 50 mg daily had no apparent effects. In this report, we used the GPP score as an index of IH severity, as proposed by the Japanese Dermatological Association in 2010 (Fig. 2). In this patient, GMA therapy had only a mild effect, with a decrease in the GPP score from 5 to 3. The serum level of interleukin (IL)-8 was markedly reduced (Fig. 3). The patient safely gave birth to a full-term, healthy baby girl on day 15 from the end of the GMA therapy. However, 2 weeks after delivery, her IH worsened again with severe leg pain (Fig. 1e). A rapid tapering of prednisone was not performed after delivery (Fig. 3). We selected a biologics treatment for the

TypeD(CD8+) lymphomatoid papulosis in a patient with classic (CD4+) mycosis fungoides

EJD, vol. 28, n◦ 2, March-April 2018 267 a daily practice cohort of AD patients treated with CsA were reported to discontinue treatment due to side effects [4]. This is also in line with a recent prospective randomised, non-inferiority trial comparing MTX with CsA in 97 patients [3] which showed that the MTX-related adverse events were significantly less frequent than with CsA: 30% vs 55%, respectively (p<0.0001) [3]. Although the initial efficacy of oral MTX at 15 mg/week was inferior to oral CsA at 2.5 mg/kg/day at Week 8, the up-dosing of MTX to 25 mg/week induced a significant improvement versus the up-dosing of CsA to 5 mg/kg/day at Week 20. Therefore, we recommended initiating MTX at 20 or 25 mg/week, depending on patient weight and disease severity; and using the subcutaneous route to increase bioavailability and efficacy. These findings, which were obtained here in a real life situation, are of interest, since 75% of our patients showed a SCORAD of 50 after one year, whereas only 49% of the patients from the study of Politiek et al. [5] exhibited a good response after a one-year treatment with MTX, evaluated by Physician’s Global Assessment score (PGA1). This discrepancy can be explained by: (1) subcutaneous administration in only 11% of patients from the study of Politiek et al. vs 75% in our cohort; and (2) a lower initial mean dose of MTX in the study of Politiek et al. (13 mg/week) compared with our study (21 mg/week). Although MTX acts more slowly than CsA, the absence of major side effects makes MTX an excellent systemic option in AD treatment. Thus, due to its good efficacy, tolerance, and low medico-economic impact, MTX should be a systemic anti-inflammatory molecule of choice, before switching to new biologics. In conclusion, MTX could be a first-line systemic treatment, in combination with local treatments, for patients with moderate-to-severe AD. For this indication, we strongly recommend initiating MTX using the subcutaneous route at 20 or 25 mg/week in AD adults, in order to obtain a good balance between tolerance and efficacy. Disclosure. Financial support: none. Conflict of interest: none.

Clinical outcomes of primary cutaneous anaplastic large cell lymphoma: data from a single Japanese centre

aspect of the fingers; this was associated with drug-resistant chronic angular stomatitis and typical seborrheic dermatitis. Laboratory findings, including complete blood count, erythrocyte sedimentation rate, urea, creatinine, thyroid stimulating hormone, fasting glucose, transaminases, and total bilirubin, were within the normal range. HBV and HCV serology were negative. Immunological work up, including antinuclear antibodies, anti-Ro/SSA and La/SSB antibodies, and rheumatoid factor, was normal. Liver ultrasound and Doppler ultrasound of the upper limbs were also normal; in addition, the electromyogram performed did not show any abnormalities. Serological tests for syphilis were negative, however, HIV antibodies were detected using an enzyme-linked immunosorbent assay, confirmed by western blotting. The blood CD4-lymphocyte count was 392/ L; HIV RNA viral load reached 107,000 copies/ L. The patient attributed his primary HIV infection to sexual intercourse, two years before. A combination of anti-HIV therapy with darunavir (a protease inhibitor), ritonavir (a booster for other protease inhibitors), and tenofovir/emtricitabine (a combination of two nucleoside inhibitors) was initiated. Marked improvement of the PE and resolution of dysesthesia were seen within two months. The viral load decreased significantly after treatment initiation. PE can be a manifestation of various infectious diseases, including HBV or HCV [1, 3, 4], arboviruses [5], and myelopathy associated with human T-lymphotrophic virus type 1 infection [6, 7]. PE has also been described in patients with brucellosis and trichinellosis [8, 9], however, to our knowledge, PE secondary to HIV infection has never been described before. A similar syndrome called “red-finger syndrome”, manifesting with well-demarcated distal erythema of the fingers and toes, has been described in patients co-infected with HIV and HCV [10]. The authors speculated that vascular reactions might be induced by immunological disturbances induced by HCV and liver disease. The physiopathology of PE is unknown. It could be due to capillary dilatation in the palms and high circulating oestrogen levels, or to stimulation of parasympathetic nerve fibres due to neuropathy secondary to some viral infections (such as HIV). PE can be a manifestation of HIV infection. Its recognition as a cutaneous sign of HIV infection is important, as HIV screening could lead to early diagnosis, early control of the disease, and could prevent further infections.