Fumihiko Maeda

Loss of Class III β-Tubulin Induced by Histone Deacetylation Is Associated with Chemosensitivity to Paclitaxel in Malignant Melanoma Cells

Overexpression of class III beta-tubulin (TUBB3) is an important mechanism of taxane resistance. Using 7 melanoma cell lines, 2 normal neonatal human epidermal melanocyte (NHEM) cultures, and 49 primary melanomas, we investigated TUBB3 expression, its relationship to chemosensitivity to taxane derivatives, and the epigenetic mechanism controlling TUBB3 gene expression. Normal melanocytes in vitro and in vivo strongly expressed TUBB3 protein. NHEMs exhibited marked chemoresistance to paclitaxel-induced apoptosis. A subset (10 of 49, 20%) of primary malignant melanomas was TUBB3 negative. The incidence of TUBB3-negative melanomas increased with stage of progression. TUBB3 protein expression varied among cell lines; one (HMV-I) of the seven cell lines exhibited an extremely low endogenous level. TUBB3 protein expression correlated well with chemosensitivity to paclitaxel-induced apoptosis (P<0.05). Treatment with a histone deacetylase (HDAC) inhibitor restored TUBB3 expression in HMV-I. Chromatin immunoprecipitation assays revealed that histones H3 and H4 were hypoacetylated at the TUBB3 gene in HMV-I as compared with a TUBB3-overexpressing cell type (HMV-II). Treatment with the HDAC inhibitor induced gain of histone acetylation only in HMV-I. These results suggest that loss of TUBB3 protein may be induced by histone deacetylation in a subset of malignant melanomas, and may be associated with chemosensitivity to taxane.

Nucleus Accumbens-Associated 1 Contributes to Cortactin Deacetylation and Augments the Migration of Melanoma Cells

We investigated the prognostic significance and post-transcriptional acetylation-modification of cortactin (CTTN) via the nucleus accumbens-associated 1 (NACC1)-histone deacetylase 6 (HDAC6) deacetylation system in primary melanomas and melanoma cell lines. Overexpression of CTTN protein was observed in 56 (73%) of 77 stage I-IV melanomas, and was significantly correlated with tumor thickness, lymph node metastasis, distant metastasis, and disease outcome. The patients whose tumors exhibited CTTN overexpression had a poorer outcome than patients without this feature (P=0.028, log-rank test). NACC1 and CTTN proteins, but not HDAC6, were overexpressed in four melanoma cell lines in comparison with a primary culture of normal human epidermal melanocytes. Knockdown of both NACC1 and HDAC6 markedly downregulated the migration activity of all melanoma cell lines (P<0.05), and induced a gain of CTTN protein acetylation status. Confocal microscopy showed that hyperacetylation of CTTN modulated by depletion of both NACC1 and HDAC6 induced disappearance of CTTN protein at the leading edge of migrating cells, resulting in stabilization of the focal adhesion structure and development of actin stress fibers. These data suggest that the acetylation status of CTTN modulated by the NACC1-HDAC6 deacetylation system induces acceleration of melanoma cell migration activity via an actin-dependent cellular process, possibly contributing to aggressive behavior (invasion/metastasis) of the melanoma cells.

Multiple vascular eccrine spiradenomas: A case report and published work review of multiple eccrine spiradenomas

Eccrine spiradenoma (ES) usually occurs as a solitary small nodule. It presents rarely as multifocal or multiple localized tumors arranged in a linear, zosteriform or nevoid distribution. We present a rare case of a 55‐year‐old woman who had a 48‐year history of multiple vascular eccrine spiradenomas (VES) localized on the left side of the submandibular region and neck. All five tumors were skin‐colored or pinkish‐purple, and ranged in size 1.5–2.5 cm. Histologically, each tumor was composed of two characteristic cell types and many dilated vascular spaces were noted in the stroma. Contrast‐enhanced computed tomography showed irregularly shaped, enhanced areas at the center of the tumors. A published work search revealed 35 cases of multiple ES, but multiple VES was extremely rare. We summarized the features of previously reported multiple ES and discuss the clinical and histological classification of ES.

Immunohistochemistry for histone h3 lysine 9 methyltransferase and demethylase proteins in human melanomas.

Abstract:Methylation and demethylation of histone H3 lysine 9 (H3K9) play a role in the transcriptional regulation of several cancer-related genes and are closely associated with malignant tumor behavior. A novel study has recently demonstrated that SETDB1, a member of the H3K9 methyltransferases, accelerates tumor formation significantly in a zebrafish melanoma model. However, the expression of H3K9 methyltransferases including SETDB1 and demethylases has not been systematically examined in samples of human melanoma. Here, we used immunohistochemistry to examine the expression of the H3K9 methyltransferases, EHMT2 and SETDB1, and a H3K9 demethylase, LSD1, in 67 patients with melanoma. Overexpression of EHMT2, SETDB1, and LSD1 was observed in 14 (21%), 38 (57%), and 53 (79%) of the 67 patients, respectively. A significant relationship was observed between overexpression of EHMT2 or SETDB1 and aggressive tumor behavior such as lymph node metastasis and/or distant metastasis (P < 0.05), whereas no significant relationship was evident for LSD1 immunoreactivity. Univariate log-rank tests demonstrated that patients with melanoma overexpressing EHMT2 had a poorer outcome (P < 0.001), whereas overexpression of SETDB1 or LSD1 had no prognostic impact. These results suggest that overexpression of EHMT2 might be a prognostic marker in patients with melanoma.

Childhood-onset psoriatic onycho-pachydermo-periostitis treated successfully with infliximab

An 8-year-old girl presented with a two-year history of nail changes and alopecia areata on the scalp. Although the alopecia was improved by topical applications of corticosteroids, nail changes developed on all fingers and toes. After six months, all fingers and toes showed redness and swelling; physical examination revealed onycholysis with subungueal debris (figure 1A). Erythematous swelling of the soft tissues of the distal interphalangeal (DIP) joint was evident on all fingers and toes, which [...]

Monitoring serum cytokeratin 19 fragment 21-1 to determine the efficacy of docetaxel chemotherapy in advanced extramammary Paget's disease

Dear Editor, Most Extramammary Paget’s disease (EMPD) tumors are limited to the epidermis. However, invasive EMPD tumors cause metastases to the regional lymph nodes or other organs. The treatments for metastatic EMPD include chemotherapy and radiotherapy, but it is necessary to evaluate the therapeutic effects. Previous research showed that serum cytokeratin (CK)19 fragment 21-1 (CYFRA) is a useful tumor marker and can be used to evaluate tumor progression and treatment efficacy in patients with EMPD. A 65-year-old Japanese woman presented to our hospital with a 5-month history of bilateral leg edema and genital bleeding. Physical examination revealed irregular erythema on both labia majora and an ulcerative tumor on the right labium (Fig. 1a). The right inguinal lymph nodes were enlarged. The serum carcinoembryonic antigen (CEA) level was mildly

A Case of Cellular Fibrous Histiocytoma on the Right Elbow with Repeated Relapse within a Short Period

Cellular fibrous histiocytoma, a variant of fibrous histiocytoma, is a designation used for lesions showing increased cellularity with a fascicular growth pattern and frequent extension into the subcutis. Here we describe a case of cellular fibrous histiocytoma showing repeated recurrence in a 36-year-old woman who initially presented with a 2-cm cutaneous tumor on her right elbow. Histopathologically, the first resected specimen demonstrated irregularly arranged collagen fibers mixed with scattered proliferating plump to spindle-shaped fibrohistiocytes. However, examination of the resected specimens obtained after recurrence showed that the cellularity had increased, the spindle-shaped cells showing monomorphic proliferation with a fascicular and storiform growth pattern extending into the subcutis, as well as an increase of Ki-67 positivity. Since the lesion showed repeated relapse within a short period, we performed wide-field resection of the tumor with a 3-cm margin. Currently, 48 months after surgery, there has been no local recurrence or metastasis, but continuous strict follow-up will be necessary.

A Case of Basal Cell Carcinoma with Outer Hair Follicle Sheath Differentiation.

A 70-year-old Japanese man presented at our hospital with an asymptomatic, blackish, irregularly shaped plaque with a gray nodule in the periphery on his left lower leg. The lesion had been present for 10 years and had recently enlarged, associated with bleeding. Histopathologically, the tumor consisted of three distinct parts: The first part showed massive aggregation of basophilic basaloid cells with peripheral palisading and abundant melanin granules, and was diagnosed as solid-type basal cell carcinoma. The second part showed aggregation of clear cells with squamous eddies, and was diagnosed as proliferating trichilemmal tumor. The third part showed reticular aggregation of basaloid cells with infundibular cysts in the papillary dermis, and was diagnosed as infundibulocystic basal cell carcinoma. We diagnosed this tumor as basal cell carcinoma with various forms of hair follicle differentiation, including differentiation into the outer root sheath.

A case of atypical fibrous histiocytoma with positivity for CD163 and CD44.

Atypical fibrous histiocytoma (AFH) is a variant of der-matofibroma (DF) that was first described by Fukamizu et al. (1) in 1983. Histologically AFH is characterized by proliferation of dermal spindle cells composed mainly of atypical histiocytic cells with striking nuclear pleo-morphism and atypia, in a background of classic fibrous histiocytoma (2). It is known that many cases of AFH follow a benign course if complete excision is carried out (2, 3). However, because the tumour cells are atypical, AFH must be differentiated from tumours of intermediate malignancy, such as dermatofibrosarcoma protuberans (DFSP) or atypical fibrous xanthoma (AFX), as well as more malignant tumours, such as pleomorphic dermal sarcoma (PDS)/malignant fibrous histiocytoma (MFH). We report here a case of AFH on the left upper arm of a 63-year-old woman and describe its immunoreactivity in detail. We also discuss the points of histological and immunohistological differentiation between AFH and other cutaneous spindle cell tumours. A 63-year-old woman presented with an 8-month history of a symptomless, slowly growing swelling on the left upper arm. The patient had no unusual medical or family history. Clinical examination revealed an 8-mm black-purplish hard mass with peripheral erythema (Fig. 1A). The tumour had arisen at a site without any known previous history of injury. A haemangioma was clinically suspected, and surgical excision was performed. Microscopic examination revealed a well-defined lesion, located in the dermis and extending to the subcutaneous tissue, with epidermal hyperplasia and a grenz zone (Fig. 1B). The lesion was composed largely of interlacing fascicles of predominant histiocyte-like eosinophilic spindle cells with elongated or plump vesicular nuclei, arranged in a storiform pattern. Abundant pleomorphic giant cells with huge bizarre nuclei (bi-lobed and multi-lobed) and histiocytes with large vesicular nuclei and prominent eosinophilic nucleoli were observed (Fig. 1C). In the peripheral region of the tumour, fibroblast-like spindle cells arranged in a storiform or fascicular pattern with collagen bundles were observed, resembling the classic features of DF. No necrosis was present. Foci of chronic inflammatory cells, including lympho cytes and plasma cells, were also evident. As a typical feature, we noted individual prominent hyalinized collagen bundles surrounded by tumour cells, predominantly in the periphery of the lesion (Fig. 1D). The mitotic count was 3 per 10 high-power fields (HPF). Immunohistochemical staining revealed diffuse positivity for vimentin, factor XIIIa, CD68, CD163 (Fig. 1E) and CD44 (Fig. 1F). The lesion showed no reactivity for desmin, CD34, AE1/AE3, desmin, S-100 …