Mitsuru Setoyama

Defect of Hepatocyte Growth Factor Activator Inhibitor Type 1/Serine Protease Inhibitor, Kunitz Type 1 (Hai-1/Spint1) Leads to Ichthyosis-Like Condition and Abnormal Hair Development in Mice

Hepatocyte growth factor activator inhibitor type 1 (HAI-1)/serine protease inhibitor, Kunitz type 1 (SPINT1) is a membrane-bound, serine proteinase inhibitor initially identified as an inhibitor of hepatocyte growth factor activator. It also inhibits matriptase and prostasin, both of which are membrane-bound serine proteinases that have critical roles in epidermal differentiation and function. In this study, skin and hair phenotypes of mice lacking the Hai-1/Spint1 gene were characterized. Previously, we reported that the homozygous deletion of Hai-1/Spint1 in mice resulted in embryonic lethality attributable to impaired placental development. To test the role of Hai-1/Spint1 in mice, the placental function of Hai-1/Spint1-mutant mice was rescued. Injection of Hai-1/Spint1(+/+) blastocysts with Hai-1/Spint1(-/-) embryonic stem cells successfully generated high-chimeric Hai-1/Spint1(-/-) embryos (B6Hai-1(-/-High)) with normal placentas. These embryos were delivered without apparent developmental abnormalities, confirming that embryonic lethality of Hai-1/Spint1(-/-) mice was caused by placental dysfunction. However, newborn B6Hai-1(-/-High) mice showed growth retardation and died by 16 days. These mice developed scaly skin because of hyperkeratinization, reminiscent of ichthyosis, and abnormal hair shafts that showed loss of regular cuticular septation. The interfollicular epidermis showed acanthosis with enhanced Akt phosphorylation. Immunoblot analysis revealed altered proteolytic processing of profilaggrin in Hai-1/Spint1-deleted skin with impaired generation of filaggrin monomers. These findings indicate that Hai-1/Spint1 has critical roles in the regulated keratinization of the epidermis and hair development.

New entity, definition and diagnostic criteria of cutaneous adult T-cell leukemia/lymphoma : Human T-lymphotropic virus type 1 proviral DNA load can distinguish between cutaneous and smoldering types

Adult T‐cell leukemia/lymphoma (ATLL) has been divided into four subtypes up to now: (i) acute; (ii) lymphoma; (iii) chronic; and (iv) smoldering. Skin lesion(s) may be present and the cases showing less than 5% abnormal T‐lymphocytes in peripheral blood without involvement of other organs, have been classified as smoldering ATLL. However, this type of ATLL with skin manifestations had a worse prognosis than that without skin lesions. This study aimed to define and distinguish cutaneous ATLL lacking nodal lymphoma and leukemic change from smoldering ATLL. We propose an entity of cutaneous ATLL, which has less than 5% abnormal T lymphocyte in peripheral blood, a normal lymphocyte count (i.e. <4 × 109/L), no hypercalcemia and lactate dehydrogenase values of up to 1.5 times the normal upper limit. At least one of the histologically proven skin lesions should be present accompanying monoclonal integration of human T‐cell lymphotropic virus type 1 (HTLV‐1) proviral DNA in the skin lesion. Blood samples were collected from 41 HTLV‐1‐infected patients, 21 asymptomatic carriers, 16 patients with cutaneous ATLL and four patients with smoldering ATLL. HTLV‐1 proviral loads, soluble interleukin‐2 receptors and other parameters were examined in each case. HTLV‐1 proviral DNA loads in smoldering ATLL group are significantly higher than those in asymptomatic carrier and cutaneous ATLL group. Cutaneous ATLL may be a distinct entity that should be separated from smoldering ATLL clinically and virologically.

Two Japanese cases of lichen planus pigmentosus-inversus.

Case 1 was a 51‐year‐old Japanese woman. She presented with an asymptomatic brown macule located on the right axilla of 2 months’ duration. The smooth macule was 2 cm in diameter with a sharp demarcation ( Fig. 1A ).

Human T-lymphotropic Virus 1 (HTLV-1) infection – dermatological implications

Human T‐lymphotropic virus type 1 (HTLV‐1) is a type C retrovirus primarily endemic to Japan, Central and South America, the Middle East, regions of Africa, and the Caribbean. Currently, an estimated 10–20 million people worldwide are infected with this virus. Although the majority of infected individuals remain asymptomatic, HTLV‐1 is the causative agent of a number of disorders, notably adult T‐cell leukemia/lymphoma (ATLL) and a progressive demyelinating neurological disorder, HTLV‐1‐associated myelopathy/tropical spastic paraparesis (HAM/TSP). In addition to ATLL and HAM/TSP, HTLV‐1 has been associated with a spectrum of skin disorders, such as infective dermatitis associated with HTLV‐1, crusted scabies, and leprosy. The understanding of the interaction between virus and host response has improved markedly, but there are still few treatment options.

Guidelines for the management of cutaneous lymphomas (2011): A consensus statement by the Japanese Skin Cancer Society - Lymphoma Study Group

In 2010, the first Japanese edition of guidelines for the management of cutaneous lymphoma was published jointly by the Japanese Dermatological Association (JDA) and the Japanese Skin Cancer Society (JSCS) – Lymphoma Study Group. Because the guidelines were revised in 2011 based on the most recent data, we summarized the revised guidelines in English for two reasons: (i) to inform overseas clinicians about our way of managing common types of cutaneous lymphomas such as mycosis fungoides/Sézary syndrome; and (ii) to introduce Japanese guidelines for lymphomas peculiar to Asia, such as adult T‐cell leukemia/lymphoma and extranodal natural killer/T‐cell lymphoma, nasal type. References that provide scientific evidence for these guidelines have been selected by the JSCS – Lymphoma Study Group. These guidelines, together with the degrees of recommendation, have been made in the context of limited medical treatment resources, and standard medical practice within the framework of the Japanese National Health Insurance system.

Bilateral lichen striatus.

We describe a very rare case of bilateral lichen striatus on the lower extremities with a history of more than ten years. Histopathologically, the lesions demonstrated a lichenoid tissue reaction with foci of spongiosis and perivascular inflammatory cell infiltration. In addition, the finding of lymphocytic infiltrations around the eccrine duct was observed. They were treated successfully with topical application of corticosteroid ointment. To the best of our knowledge, no other lichen striatus case has been reported with bilateral distribution and such long‐term persistence.

Phase I/II study of the oral retinoid X receptor agonist bexarotene in Japanese patients with cutaneous T-cell lymphomas

Safety, tolerability, pharmacokinetics and efficacy of bexarotene, a novel retinoid X receptor (RXR)‐selective retinoid, were evaluated in Japanese patients with stage IIB–IVB and relapsed/refractory stage IB–IIA cutaneous T‐cell lymphomas (CTCL). This study was conducted as a multicenter, open‐label, historically controlled, single‐arm phase I/II study. Bexarotene was p.o. administrated once daily at a dose of 300 mg/m2 for 24 weeks in 13 patients, following an evaluation of safety and tolerability for 4 weeks at a dose of 150 mg/m2 in three patients. Eight of 13 patients (61.5%) with an initial dose of 300 mg/m2 met the response criteria using the modified severity‐weighted assessment tool (mSWAT) at 24 weeks or discontinuation. Dose‐limiting toxic effects (DLT) were present in four of 13 patients (31%) at a dose of 300 mg/m2: two neutropenia, one abnormal hepatic function and one hypertriglyceridemia. No DLT was observed in patients received 150 mg/m2 bexarotene. In the 13 patients at 300 mg/m2, common drug‐related adverse events (AE) included hypothyroidism (92%), hypercholesterolemia (77%), leukopenia or neutropenia (39%), nasopharyngitis or anemia (31%). The treatment‐related grade 3 AE included hypertriglyceridemia (4/16 patients, 25%), increased alanine aminotransferase, increased aspartate aminotransferase, dyslipidaemia, leukopenia and neutropenia (1/16 patients, 6%), and one of 16 patients experienced grade 4 hypertriglyceridemia. No patients discontinued bexarotene due to the AE during the study, but dose reduction or suspension was required. Bexarotene was shown to be well tolerated at 300 mg/m2 once daily and effective in Japanese patients with CTCL.

An autopsy case of chemical burns by hydrochloric acid

A 34-year-old man was discovered by his coworkers in a tank filled with 35% (w/w) hydrochloric acid. Despite undergoing intensive treatment, he died one and a half days later. An autopsy revealed generalized high tensity, overall grayish brown skin color, heavy gastric submucosal hemorrhage and heavy pulmonary edema. We concluded that death was caused by burn shock due to wide, generalized chemical burn. Microscopic investigation of the burn in the area with grayish brown skin considered coagulation necrosis of full-thickness of the skin (third-degree or deep burn), revealed that the burn was judged to cover the partial thickness of the skin (second-degree or dermal burn). These findings suggest that chemical burn by hydrochloric acid results in a change of skin color due to chemical reaction so that the appearance of the chemical burn is more severe than the degree assigned by histological examination.

A case of pemphigus vulgaris accompanied by multiple myeloma

Pemphigus is a mucocutaneous intraepithelial blistering disease caused by autoantibodies to epithelial cell adhesion molecules (desmoglein). The association between pemphigus and malignant neoplasm is well recognized. We present the case of a 62‐year‐old woman with pemphigus vulgaris accompanied by multiple myeloma. To the best of our knowledge, this is the first report of a case of pemphigus vulgaris concomitant with multiple myeloma. From the results of immunoblotting using normal human epidermal extracts and indirect immunofluorescence using rat bladder sections, and her clinical manifestations, our case does not seem to be one of paraneoplastic pemphigus.

The detection of Propionibacterium acnes signatures in granulomas of lupus miliaris disseminatus faciei

Lupus miliaris disseminatus faciei (LMDF) is a papular eruption that occurs on adults faces, predominantly on the lower eyelids. Histologically, the granulomatous lesions are primarily situated around the hair follicles, particularly the superficial region/infundibula. Its etiology remains to be elucidated. Recently, Propionibacterium acnes (P. acnes) has been suspected as a cause of sarcoidosis. In light of the sarcoid‐like reactions that are present in LMDF, we hypothesized that P. acnes may also be implicated in granulomas associated with the disease. We evaluated nine DNA samples from granulomatous lesions from the skin of patients with LMDF. We used laser capture microdissection to extract DNA from these regions. Polymerase chain reaction was performed to amplify segments of the 16S ribosomal RNA of P. acnes, and the P. acnes gene was clearly detectable in all nine DNA samples. The gene was also detected in samples from normal‐appearing skin, but these bands were faint in all samples. The results of the present study suggest that P. acnes plays a pathogenetic roles in LMDF.