Hisashi Kokuba

Expression of phosphorylated Stat3, cyclin D1 and Bcl-xL in extramammary Paget disease

Background  Stat3 (Signal transducer and activator of transcription‐3) is an oncogene that plays a critical role in regulating fundamental processes associated with malignant transformation and cell survival. It participates in oncogenesis through upregulation of genes encoding apoptosis inhibitors (Bcl‐xL) and cell cycle regulators (cyclin D1). The expression of Stat3, Bcl‐xL and cyclin D1 protein has not been investigated in extramammary Paget disease (EMPD).

Expression of insulin-like growth factor-1 receptor, p-AKT and p-ERK1/2 protein in extramammary Paget's disease.

Background  The insulin‐like growth factor‐1 (IGF‐1) receptor (R)‐induced phosphatidylinositol 3‐kinase (PI3K)/AKT and mitogen‐activated protein kinase (MAPK)/ERK signal transduction cascade, which have critical roles in prevention of apoptosis and regulation of cell cycle progression, plays an important role in tumorigenesis. The expression of IGF‐1R, AKT and ERK1/2 has been described in some human malignancies, but not in extramammary Pagets disease (EMPD).

Expression of p16 and hTERT protein is associated with the presence of high-risk human papillomavirus in Bowenoid papulosis.

Background:  High‐risk human papillomavirus (hrHPV) type E6 and E7 oncoproteins contribute to oncogenesis in multiple ways by modulating the activities of host components in cell‐cycle regulation including the expression of p16 protein (p16) and human telomerase reverse transcriptase (hTERT). The expression of p16 and hTERT protein in Bowenoid papulosis (BP) has not been studied.

Bullous pemphigoid followed by pustular psoriasis showing Th1, Th2, Treg and Th17 immunological changes

Psoriasis vulgaris is occasionally accompanied by autoimmune bullous diseases, but the opposite is very rare. We document here the first reported case of generalized pustular psoriasis that appeared during steroid therapy for bullous pemphigoid. The serum cytokine levels and the results of an immunohistochemical study over the disease course suggest that the immunological state was consistent with a shift from Th2-dominance to Th1-dominance. IL-17-producing cells appeared in the skin lesions when each disease was most exacerbated and disappeared after remission. Thus, the present case demonstrated a dynamic immunological state in which the appearances of Th1 and Th2 as well as Th17 varied during the course of the disease.

Expression of minichromosome maintenance 5 protein in proliferative and malignant skin diseases.

Background  The entire minichromosome maintenance (MCM) family (MCM2–7) play roles in the initiation and elongation of DNA replication. Many studies have demonstrated that MCM proteins may be better indicators of a wide variety of proliferative or cancer cells in malignant tissues.

Prolonged severe pancytopenia preceding the cutaneous lesions of juvenile xanthogranuloma

We report a case of juvenile xanthogranuloma (JXG) having progressive pancytopenia for 6 months until the proliferating skin lesions. A 2‐month‐old infant presented recurrent fever, anemia, and hepatosplenomegaly mimicking hemophagocytic lymphohistiocytosis (HLH) or juvenile myelomonocytic leukemia (JMML). At 8 months of age, the biopsy of a growing papule on the elbow made the diagnosis. Bone marrow (BM) specimens showed clustering foamy cells including hemophagocytosis by histiocytes. Treatment with etoposide followed by vinblastine plus prednisolone (PSL) therapy improved the disease. Although JXG is a benign non‐Langerhans cell histiocytosis, the multisystem‐visceral form should be considered as a potential aggressive disease when associated with BM failure in early infancy.

Mucous membrane pemphigoid with antibodies to the β3 subunit of laminin 332

Dear Editor, Mucous membrane pemphigoid (MMP) is a heterogeneous group of rare autoimmune blistering disease and is characterized by the presence of autoantibodies to various components of the basement membrane zone (BMZ). Laminin-332 is an epidermisspecific, extracellular matrix protein consisting of a3, b3 and c2 subunits. A majority of the patients with anti-laminin-332 MMP have antibodies specific to the a3 subunit of laminin-332. In this report, we describe a rare case of MMP with antibodies only to the b3 subunit. The patient’s medical history included acute myeloblastic leukemia (AML) and graft-versus-host disease (GVHD) that developed after bone marrow transplantation (BMT). A 23-year-old Japanese man noted blisters and erosions on the chest and lower legs and experienced ocular pain in 2005. Physical examination revealed that the blisters and erosions were up to 4 cm in diameter, and vitiligo lesions were noted on the trunk (Fig. 1a). Scleritis and symblepharon were observed in both eyes (Fig. 1b), and nasal or pharyngeal mucosae were not involved. The patient had AML in 1997 and underwent allogeneic BMT from his human leukocyte antigen-identical sister in 1998; the transplantation resulted in complete remission. Thereafter, he developed acute and chronic GVHD; however, he has shown no symptoms of GVHD since 1999. The patient developed vitiligo in 2000. Examination of the biopsy specimen revealed a subepidermal blister containing eosinophils and neutrophils. Direct immunofluorescence showed a linear deposition of immunoglobulin G (IgG) along the epidermal BMZ. Indirect immunofluorescence revealed IgG anti-BMZ antibodies reactive with the dermal side of 1 mol ⁄L sodium chloride split skin (Fig. 1c). Immunoblotting using normal human epidermal and dermal extracts showed that the patient’s serum had no apparent reactivity. However, the patient’s serum reacted with the 140-kDa b3 subunit, but not the a3 or c2 subunits, in an immunoblot test using laminin-332 purified from cultured human keratinocytes (Fig. 1d). On the basis of these findings, the patient was diagnosed with anti-laminin-332 MMP. Computed tomography (CT) of the chest and the abdomen and upper esophagogastroduodenoscopy revealed no coexisting malignant tumor. No clinical (a)

EXPERIMENTAL APPROACHES FOR THE TREATMENT OF MURINE B16 MELANOMAS OF VARIOUS SIZES. I : LOCAL INJECTION OF ETHANOL WITH A COMBINATION OF INTERLEUKIN-2 OR MICROWAVAL HYPERTHERMIA FOR B16 MELANOMAS WITH A SIZE OF LESS THAN 7 MM IN DIAMETER

The effects of local absolute ethanol injection combined with administration of interleukin-2 (IL-2) or microwaval hyperthermia in murine B16 melanomas with a size of approximately 7 mm in diameter were investigated. The groups of melanoma-burdened mice treated with both local ethanol injection and local or intra-abdominal administration of IL-2 showed clear suppression of any recurrence of melanoma once the melanomas had been destroyed by ethanol injection and a concomitant prolongation of the survival times. Also, local injection of ethanol in combination with local microwaval hyperthermia at 43 degrees C for 15 min twice a week caused complete cures in B16 melanomas with a size of less than 7 mm in diameter. The infiltrations of T lymphocytes and NK cells were augmented in the melanomas treated with ethanol injection and local injection of IL-2. However, the melanomas treated with ethanol injection and intra-abdominal injection of IL-2 hardly showed any infiltration of such immune cells, although the growth of melanomas was effectively suppressed. In the case of treatment with ethanol and hyperthermia, slight infiltration of NK cells was observed in the melanoma nests as well as in the interstitials. Thus, the direct injection of absolute ethanol in combination with IL-2 or microwaval hyperthermia is effective or even curative in the treatment of murine B16 melanomas with a size of less than 7 mm in diameter.

Experimental approaches for the treatment of murine B16 melanomas of various sizes. II: Injection of ethanol with combinations of β-interferon and microwaval hyperthermia for B16 melanomas with a size of greater than 10 mm in diameter

Although ethanol injection in combination with microwaval hyperthermia and systemic administration of interleukin-2 was found to be very effective in suppressing the growth of B16 melanoma nodules with a size of less than 7 mm in diameter in our previous experiments, the growth of B16 melanomas with a size of greater than 10 mm in diameter was very difficult to control with any of the therapeutic modalities examined. In subsequent experiments, we investigated whether ethanol injection (150 microliters/injection) in combination with local injection of beta-interferon (2 x 10(4) IU/injection) and local microwaval hyperthermia at 43 degrees C for 15 min was able to suppress the growth of melanoma nodules and to prolong survival times of melanoma-burdened mice. The results were that we successfully suppressed the growth of melanoma nodules of that size for the first time with combinations of the therapeutic modalities described above. Infiltration of immunocompetent cells such as T lymphocytes and NK cells was clearly observed in the melanoma tissues treated with the therapeutic combination. These experimental results should be applied to the treatment of human melanomas in advanced stages which have no indications for surgical operation.

Case of diabetic scleredema: diagnostic value of magnetic resonance imaging.

We report the case of a patient with a 20‐year history of diabetes mellitus type 2 who developed sclerotic skin lesions on his neck and upper back. Physical and histological findings were compatible with diabetic scleredema. T2‐weighted magnetic resonance imaging (MRI) revealed diffuse thickening of the dermis and subcutaneous tissue, with hyperintense signals. The MRI findings in the dermis corresponded with the accumulation of collagen tissue with deposition of glycosaminoglycans.