Hiroo Hata

Specific Filaggrin Mutations Cause Ichthyosis Vulgaris and Are Significantly Associated with Atopic Dermatitis in Japan

Mutations in the gene encoding filaggrin (FLG) have been identified as the cause of ichthyosis vulgaris (IV) and shown to be major predisposing factors for atopic dermatitis (AD). However, these studies have been mainly carried out in European populations. In early 2007, we identified two Oriental-specific FLG mutations in four Japanese families with IV and reported that filaggrin mutations were also significant predisposing factors for AD in Japan. However, the frequency of FLG mutations observed in our Japanese AD cohort (5.6%), was much lower than that seen in Europeans (up to 48%). Here, we studied a further seven Japanese families with IV and identified two additional nonsense mutations in FLG, S2889X, and S3296X. We found that more than 20% of patients in our Japanese AD case series carry FLG mutations, and there is significant statistical association between the four mutations and AD (chi(2) P=8.4 x 10(-6); heterozygote odds ratio 7.57, 95% CI 2.84-23.03). These data emphasize that skin-barrier impairment due to reduced filaggrin expression plays an important role in the pathogenesis of AD and sheds further light on the genetic architecture of atopy in Japan.

Usefulness of real‐time tissue elastography for detecting lymph‐node metastases in squamous cell carcinoma

We report a case of invasive SCC arising from multiple lesions of Bowen’s disease with right inguinal lymph‐node metastasis. Assessment of superficial lymph‐node involvement by real‐time tissue elastography before surgery was found to be more useful than other noninvasive conventional methods. Histologically, the metastatic tumour cells were located asymmetrically in a small section of the cortical area of the right node, and this result was comparable with the elastographic findings. Additionally, we found that the presence of an asymmetrical cortical area with high elasticity should be included in the determination of metastatic involvement in small lymph nodes. It has high predictive values in the differentiation of benign and malignant superficial lymph nodes in patients with clinically node‐negative skin cancer. More cases are needed to validate this efficiency in differentiating benign from malignant lymph‐node status, but if confirmed, it may have an important role in the diagnosis of high‐risk cutaneous squamous cell carcinoma.

A novel splice site mutation in NCSTN underlies a Japanese family with hidradenitis suppurativa

Background  Hidradenitis suppurativa (HS) is a chronic follicular occlusive disease with characteristic recurrent draining sinuses, skin abscesses and disfiguring scars, mainly involving the axilla, groin, perianal and perineal regions. While most HS cases are nonfamilial, familial cases showing autosomal dominant inheritance have been reported. Recently, loss‐of‐function mutations in the genes encoding γ‐secretase have been identified as a cause of familial HS in the Chinese and British populations.

The spectrum of cutaneous lymphomas in Japan: a study of 62 cases based on the World Health Organization Classification

Background:  The relative incidence of malignant lymphoma subtypes differs according to geographic location. This study investigated the epidemiology of cutaneous lymphoma subtypes in Japan and compared it with other countries.

Eccrine porocarcinoma and Bowen's disease arising in a seborrhoeic keratosis

An association between seborrhoeic keratosis (SK) and malignant tumours is considered to be rare. We observed a case of eccrine porocarcinoma and Bowens disease (BD) occurring synchronously, forming one lesion in a SK on the abdomen. It is controversial whether malignant neoplasms arising in SK occur only by chance or if pre‐existing SK plays a role in pathogenesis. This case suggests an implication of pre‐existing SK in the subsequent development of both BD and eccrine porocarcinoma. 

Sequential local injection of low-dose interferon-beta for maintenance therapy in stage II and III melanoma: a single-institution matched case-control study.

Objective: To determine the beneficial effect of maintenance therapy in stage II and III melanoma by sequential local injection of low-dose interferon-β. Methods: We reviewed 46 patients with stage II and III primary melanoma at our institution from 2004 through 2009. Twenty-one patients were treated with interferon-β maintenance therapy consisting of subcutaneous injection of natural interferon-β at a dose of 3 × 106 IU/day for 10 consecutive days, and 25 patients underwent observation alone. Results: Compared with all patients, overall survival and relapse-free survival were significantly worse in the observation group than in the interferon-β group (p = 0.024 and 0.029, respectively). In stage II, a significant difference in overall survival, but not in relapse-free survival, was seen between the two groups (p = 0.041). When the interferon-β group was stratified by subgroup, there was a statistical difference only between dosage and duration (p = 0.027 and p < 0.001, respectively). Conclusions: This study demonstrates that maintenance therapy by interferon-β is beneficial in the outcome of the disease without substantial toxic effects, especially in patients with stage II melanoma. Extension of the duration of treatment beyond 2 years could further improve the therapeutic efficacy of interferon-β.

Establishment of a novel experimental model of human angiosarcoma and a VEGF-targeting therapeutic experiment

BACKGROUND Angiosarcoma is one of the most life-threatening neoplasms with strong resistance to conventional chemotherapy/radiotherapy; consequently, alternative therapeutic agents are urgently required. One factor in delaying the therapy development is the limitation of experimental models. OBJECTIVE We established a novel experimental angiosarcoma model. METHODS From surgically resected tissue, human AS cell line was established. Using xenograft of AS cell line, we performed therapeutic experiments with the anti-human VEGF Ab or the receptor tyrosine kinase inhibitor. RESULTS First we generated an angiosarcoma cell line, HAMON (human angiosarcoma, monoclonal), which expresses CD31 and produces tumors in immunodeficient mice. HAMON expresses VEGFR2 and that exogenous VEGF leads to HAMON proliferation in vitro. Anti-human VEGF Ab bevacizumab treatment failed to suppress HAMON proliferation in vitro and in vivo. Furthermore, the receptor tyrosine kinase inhibitor sunitinib did not suppress HAMON proliferation in vitro. Similarly, in in vivo therapeutic experiments, even high doses of sunitinib failed to inhibit tumor growth. Finally, we checked whether compensatory activation of VEGF signaling occurred after sunitinib addition. VEGF protein secretion, VEGF mRNA synthesis and VEGFR2 phosphorylation all were unaffected in HAMON after sunitinib treatment. CONCLUSION A novel in vitro and in vivo experimental model of human angiosarcoma has been successfully established. With this model, we were able to perform therapeutic experiments. In addition, our angiosarcoma cell line, HAMON, is quite useful for identifying key molecules in angiosarcoma.

Context-Dependent Regulation of Collagen XVII Ectodomain Shedding in Skin

Pemphigoid is a common autoimmune blistering disorder in which autoantibodies target transmembrane collagen XVII (COL17), a component of hemidesmosomes in basal keratinocytes. The ectodomain of COL17 can be cleaved from the cell surface within the juxtamembranous extracellular NC16A domain, and, interestingly, certain autoantibodies of pemphigoid patients preferentially react with the shed ectodomain. These findings suggest that COL17 ectodomain shedding generates neoepitopes on the shed form; however, the regulatory mechanism of the shedding in in vivo skin and the pathogenicity of the neoepitope-targeting antibodies still are uncertain. To address these issues, we produced rabbit antibodies specifically reacting with N-terminal cleavage sites of the shed COL17 ectodomain. The antibodies showed that certain amounts of the human COL17 ectodomain are cleaved physiologically at Gln(525) in in vivo skin. In contrast, migrating human keratinocytes cleave COL17 at Leu(524) but not at Gln(525). The passive transfer of antibodies reacting with an N-terminal cleavage site of the mouse COL17 ectodomain into neonatal wild-type mice failed to induce blister formation, even though the antibodies bound to the dermal-epidermal junctions, indicating that cleavage site-specific antibodies have reduced or absent pathogenicity for blister formation. This study shows the ectodomain shedding of COL17 to be a physiological event in in vivo human skin that probably generates nonpathologic epitopes on the cleavage sites.

Controlling the histological margin for non‐melanoma skin cancer conveniently using a double‐bladed scalpel

In some countries, intraoperative histological evaluation to control the surgical margin for non‐melanoma skin cancer is widely used instead of Mohs micrographic surgery. Nevertheless, this evaluation by frozen section analysis is usually limited to suspicious areas.

Severe rash associated with vemurafenib administration following nivolumab therapy.

poly-chemotherapy, only one paper reported an occurrence of Steve-Johnson syndrome in a patient treated with rituximab. However, no case of TEN have been reported in humans, but only in two Rhesus Macaques (Macaca Mulatta). The pathogenesis of TEN is still unclear. It was observed that activated T cells secrete a large amount of TNF-a and interferon-c, resulting in a Fas-ligand (FasL) up-regulation and Fasmediated keratinocyte apoptosis. This pathway could explain the pathogenesis of TEN after rituximab administration, since rituximab induces a sensitization to Fas-mediated apoptosis through the activation of caspase-8. At the same time, etanercept blocks this inflammatory pathway via TNF-a inhibition. As reported in a previous paper 7, only a 50 mg sub-cutaneous administration of etanercept was needed to block TEN. TEN can be a serious, sudden, and unexpected side effect in patients treated with rituximab, as well as with other drugs. The current report highlights how etanercept is a useful and manageable drug to treat this dangerous skin condition.