Hiroshi Uchimiya

Inhibition of Metastasis of Tumor Cells Overexpressing Thymidine Phosphorylase by 2-Deoxy-l-Ribose

Thymidine phosphorylase (TP) catalyzes the reversible conversion of thymidine to thymine, thereby generating 2-deoxy-d-ribose-1-phosphate, which upon dephosphorylation forms 2-deoxy-d-ribose (d-dRib), a degradation product of thymidine. We have previously shown that d-dRib promotes angiogenesis and chemotaxis of endothelial cells and also confers resistance to hypoxia-induced apoptosis in some cancer cell lines. 2-Deoxy-l-ribose (l-dRib), a stereoisomer of d-dRib, can inhibit d-dRib anti-apoptotic effects and suppressed the growth of KB cells overexpressing TP (KB/TP cells) transplanted into nude mice. In this study, we examined the ability of l-dRib to suppress metastasis of KB/TP cells using two different models of metastasis. The antimetastatic effect of l-dRib was first investigated in a liver-metastasis model in nude mice inoculated with KB/TP cells. Oral administration of l-dRib for 28 days at a dose of 20 mg/kg/day significantly reduced the number of metastatic nodules in the liver and suppressed angiogenesis and enhanced apoptosis in KB/TP metastatic nodules. Next, we compared the ability of l-dRib and tegafur alone or in combination to decrease the number of metastatic nodules in organs in the abdominal cavity in nude mice receiving s.c. of KB/TP cells into their backs. l-dRib (20 mg/kg/day) was significantly (P < 0.05) more efficient than tegafur (100 mg/kg/day) in decreasing the number of metastatic nodules in organs in the abdominal cavity. By in vitro invasion assay, l-dRib also reduced the number of invading KB/TP cells. l-dRib anti-invasive activity may be mediated by its ability to suppress the enhancing effect of TP and d-dRib on both mRNA and protein expression of vascular endothelial growth factor and interleukin-8 in cultured KB cells. These findings suggest that l-dRib may be useful in a clinical setting for the suppression of metastasis of tumor cells expressing TP.

Thymidine phosphorylase inhibits apoptosis induced by cisplatin.

An angiogenic factor, platelet-derived endothelial cell growth factor/thymidine phosphorylase (PD-ECGF/TP), stimulates the chemotaxis of endothelial cells and confers resistance to apoptosis induced by hypoxia. 2-Deoxy-D-ribose, a degradation product of thymidine generated by TP, partially prevents hypoxia-induced apoptosis. TP is expressed at higher levels in tumor tissues compared to the adjacent non-neoplastic tissues in a variety of human carcinomas. High expression of TP is associated with an unfavorable prognosis. To investigate the effect of TP on cisplatin-induced apoptosis, human leukemia Jurkat cells were transfected with wild-type or mutant (L148R) TP cDNA. TP inhibited a number of steps in the cisplatin-induced apoptotic pathway, activation of caspases 3 and 9 and mitochondrial cytochrome c release. These findings suggest a mechanism by which TP confers resistance to apoptosis induced by cisplatin. Moreover, mutant TP that has no enzymatic activity also suppressed cisplatin-induced apoptosis. These findings indicate that TP has cytoprotective functions against cytotoxic agents which are independent of its enzymatic activity.

Estrogen Dermatitis: A Dendritic-Cell-Mediated Allergic Condition

Background: Most estrogen dermatitides are induced by local or systemic contact dermatitis where dendritic cells are central, and tamoxifen has a blocking effect on dendritic cells. Methods: We present 5 cases of estrogen dermatitis in which the clinical features were prurigo, urticaria, acneiform eruption and annular erythema. Results: Tamoxifen was effective in 3 of 4 cases. Three of 4 biopsy specimens showed the formation of Langerhans cell nests in the epidermis and hair follicles and perivascular infiltration of CD4+ and CD8+ lymphocytes in the dermis. Conclusion: These results suggest that a dendritic-cell-mediated allergic mechanism is involved in estrogen dermatitis.

A case of follicular mucinosis treated successfully with minocycline.

q 2000 British Association of Dermatologists, British Journal of Dermatology, 142, 812±851 For general consideration regarding the ecology and taxonomy of Alternaria spp. the reader is referred to Acland et al. A. tenuissima, together with A. alternata and A. chartarum, are the species most involved in human pathology, but other rarer Alternaria spp. have also been reported. Factors such as immunosuppression, local wounds or systemic disease are generally present, but cases without predisposing factors are described, and are probably due to factors inherent to the fungus. Formerly said to be rare, cutaneous alternariosis could be more frequent than thought, and we suspect that it is under-diagnosed. This might be due to either extreme variability and non-specificity of the appearance of infected skin, or to insufficient use of mycological investigations. Alternatively, it may be apparently under-reported simply because many case reports are spread in a myriad of either low-impact or vernacular journals of various ages. Treatment of cutaneous Alternaria infections is not standardized, and lack of consensus will probably persist, owing to the fact that such cases are relatively infrequent and multicentre case±control studies are not easily feasible. However, these patients, who often are in a critical condition, have to be treated immediately. Following examples of treatment of systemic dematiaceous fungal infections with terbinafine, we propose the use of this well-tolerated and rapid-acting drug in cutaneous alternariosis.

Purpuric drug eruption with leukocytoclastic vasculitis due to gefitinib

Figure 2. Histopathological examination of patient 1 showing extravasation and perivascular lymphocytes and neutrophils and nuclear debris in the papillary dermis (hematoxylin–eosin stain, original magnification ·200). Dear Editor, Gefitinib (Iressa; AstraZeneca, London, UK) is an p.o. administrated selective epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor that blocks signal transduction pathways implicated in the proliferation and survival of cancer cells and other hostdependent processes that promote cancer growth. EGFR is expressed on basal epidermal keratinocytes, the outer root sheath cells of hair follicles, and sebaceous and eccrine sweat gland cells as well as various cancer cells. Gefitinib treatment can elicit adverse cutaneous effects and although many patients with acneiform drug eruption due to gefitinib have been reported, our search of the published work found only four patients with purpuric eruption. We encountered two patients with leukocytoclastic vasculitis (LCV) manifesting as purpuric lesions during gefitinib treatment. Patient 1 was a 74-year-old woman with advanced lung cancer who was referred for the evaluation of palpable purpuric lesions and erosions on both lower legs (Fig. 1) that appeared after 1 month of treatment with gefitinib (250 mg ⁄day). She had no complaints of arthralgia or abdominal pain. Urine analysis was normal. A skin biopsy specimen from a purpuric papule on her right lower leg showed degenerated epidermis, lymphocytes, neutrophils and nuclear debris in the vicinity of the capillaries, and extravasated erythrocytes in the papillary dermis (Fig. 2). These histopathological findings were consistent with LCV. The deposit of immunoglobulin (Ig)A to the small vessel wall was not detected by direct immunofluorescence. Gefitinib was discontinued 1 week later because she complained of severe leg pain and her purpuric eruptions disappeared in the course of 2 weeks. We subsequently administrated gefitinib intermittently and she developed no further purpuric eruptions.

Multiple giant pilomatricoma

Dear Editor, Pilomatricoma (PM) is a benign adnexal tumor with differentiation toward hair matrix cells. It usually manifests as a firm, solitary lesion measuring 0.5–3.0 cm in diameter on the face and upper extremities. We report a 16-year-old girl with multiple giant PM. The patient was referred to Saiseikai Sendai Hospital for the evaluation of three large tumors on her back and right shoulder. She had first noticed the lesions 1 year earlier and they gradually enlarged. On physical examination, we noted two domeshaped hard tumors, 5 cm × 5 cm and 4 cm × 3 cm, on her back and a similar 7 cm × 6 cm tumor on her right shoulder. They were movable and slightly tender. The color of the overlying skin was moderately violaceous (Fig. 1). All the lesions were surgically excised. On histopathological examination, the tumors showed demarcation from the dermis and subcutaneous tissue; they were composed of eosinophilic shadow cells with basaloid cells and calcium deposits in some areas (Fig. 2). Based on these findings, a diagnosis of PM was made. She returned to our clinic 2 years after excision of the three tumors because seven new PM had appeared on her back and neck. Considering the association of multiple PM with systemic disorders such as myotonic dystrophy, Rubinstein–Taybi, Gardner, and Turner syndromes, we performed extensive neurological, mycological, gastrointestinal, hormonal and radiological examinations. No abnormalities were discovered. There was no family history of PM. Julian and Bowers, who reviewed 209 PM, reported that the size of these tumors ranged from 0.5–6.0 cm; most of them were between 1.0 and 1.5 cm. Our case is remarkable in that the lesions were much larger (7 cm × 6 cm, 5 cm × 5 cm and 4 × 3 cm) and that new lesions appeared after their resection. In their published work search, Jang et al., who presented two patients with multiple giant PM, found only one previously reported case. Our patient developed a total of 10 PM. An association of multiple PM with some systemic disorders has been reported. According to Chan et al., who

Squamous Cell Carcinoma of the Skin Associated with Sarcoid Reactions in the Regional Lymph Nodes

Sarcoid reactions in lymph nodes with or without metastasis from a primary malignant neoplasm are well‐known. However, it is extremely rare to find these reactions associated with cutaneous solid tumors; only one such case has appeared in the literature. Here we describe a case of an 83‐year‐old man with cutaneous squamous cell carcinoma accompanied by sarcoid reactions and metastatic foci in the regional lymph nodes. The possibilities of systemic sarcoidosis and tuberculosis were excluded after extensive examinations specific for these diseases. Some authors regard the sarcoid reaction to be a sign of a good prognosis on the basis of studies of a few patients with solid tumors. In our case, however, the patient died of pulmonary metastasis with pleuritis carcinomatosa shortly after surgery.

Extramammary Paget’s disease with prominent signet-ring cells

Figure 2. Histopathological examination showed prominent signet-ring cells invaded in the epidermis and dermis (HE stain, original magnification ·200). Figure 1. Photograph showing indurated erythematous lesions on the lower abdomen, scrotum and penis. Dear Editor, Extramammary Paget’s disease (EMPD), characterized histologically by the intraepidermal proliferation of Paget cells, is a relatively common skin cancer. Signet-ring cells are neoplastic cells with abundant cytoplasm; their nuclei are eccentrically located. Primary cutaneous signet-ring cell carcinoma (SRCC), mammary Paget’s disease and EMPD are primary carcinomas of the skin exhibiting signet-ring morphology. We encountered a 63-year-old man with EMPD on the scrotum and lower abdomen comprised primarily of signet-ring cells. One year prior to his current admission to our hospital, he noticed an erythematous plaque in his genital region. Skin biopsy, positron emission tomography (PET) and computed tomography (CT) of the whole body were performed elsewhere and a non-specific diagnosis of adenocarcinoma was made based on biopsy findings. PET and CT study detected a metastatic liver lesion. After 6-month treatment with tegafur and cisplatin he was referred to our hospital. Examination revealed an irregularly-shaped erythematous lesion with induration involving his scrotum, penis and lower abdomen, showing a trunk-like distribution (Fig. 1). Although this type of distribution is often observed in a retrograde metastatic lesion from inguinal lymph nodes, his inguinal lymph nodes were not palpable nor detected by PET and CT. Biopsy specimens from his scrotum and lower abdomen disclosed prominent signet-ring cells with mucinous cytoplasm both in the epidermis and dermis. Signet-ring cells are distributed prominently in the dermis (Fig. 2). Lymphatic invasion was revealed by staining with D2-40, a specific marker for lymph vessels (Fig. 3). The invasion level of tumor cells and the distribution of signet-ring cells are evenly seen in the lesion. Immunohistochemical examination showed that the cells were positive for carcinoembryonic antigen

Case of giant eccrine hidrocystoma of the scalp

Dear Editor, Eccrine hidrocystomas (EH) are characterized by mature, deformed eccrine sweat units with dilated ducts. They are attributable to retention of sweat and usually measure 1–3 mm. We report a 76-year-old Japanese woman with a giant EH arising in the scalp region. In September 2006, she was referred to Tanoue Hospital for evaluation of a tumor in the occipital region that was first noticed 30 years earlier and subsequently enlarged gradually. On physical examination, it was firm, approximately 8 cm × 4 cm in diameter, elastic hard, relatively immobile, cystic and located in the occipital area (Fig. 1). No other papules or nodules were noted in this area. The results of hematological and serum examinations were within normal limits. The clinical diagnosis was pilar cyst, and the tumor was excised under local anesthesia. Histologically, it was a single cystic cavity located in the deep dermis with extension to the subcutaneous adipose tissue. The overlying epidermis exhibited no relevant abnormalities (Fig. 2a). The cyst wall consisted of two layers of small, cuboidal or flattened epithelial cells (Fig. 2b). No decapitation secretion was noted. Based on these findings, we made a diagnosis of EH. There was no evidence of local recurrence 2 months after surgery. Eccrine hidrocystomas, as first described by Robinson in 1893, is a distinctive cutaneous disease. Although the “classic” case described by Robinson manifested numerous lesions, Smith and Chernosky reported that most patients with EH had solitary lesions. While “Robinson-type” multiple EH are relatively common in Japan, “Smith-type” solitary EH are rare. The etiology of EH reportedly involves occlusion of the intradermal portion of the eccrine duct, however, Murayama et al. suggest that EH is a hamartoma-like disorder that becomes more pronounced as a result of sweat retention. Fifteen cases of solitary EH have been previously reported in Japan. In diameter, these tumors ranged from 1–30 mm and no solitary EH arising on the scalp have been reported in Japan. Ours is the largest EH in the scalp region documented in a Japanese patient. EH should be considered as a differential diagnosis in patients with cystic tumors of the scalp.

A Case of Prurigo‐Type Drug Eruptions Due to UFT

To the Editor: UFT is a mixture of ftorafur, a product of 5-fluorouracil (5-FU), and uracil, which reduces the degradation of 5-FU in organisms (1). The coadministration of 5-FU with uracil was designed to produce a constant reserve of 5-FU and its active metabolites and to minimize the production of inactive and potentially toxic metabolites (2). There is clinical evidence that UFT has significant activity in patients with epithelial malignancies including colon, rectum, stomach, lung, and breast cancers (3). Therefore, UFT has become one of the most widely prescribed anticancer agents. We report what we believe to be the first instance of a patient developing prurigo-type eruptions while on UFT therapy. A 64-year-old woman was referred to our clinic for the evaluation of severely itchy skin eruptions. Three months earlier, she had undergone a mastectomy because of breast cancer. Oral UFT (300 mg/day) was started 75 days prior to her visit to our clinic. The skin lesions appeared two weeks after the introduction of UFT, increased gradually in number, and did not respond to topical corticosteroid (betamethasone valerate). Clinical examination revealed multiple, erythematous papules 5–10 mm in diameter with ulcerated centers on her face, neck, chest, upper back, and upper arms (Fig. 1a). A biopsy specimen obtained from her right arm revealed acanthosis, partial disruption of the epidermis, and infiltration of lymphocytes admixed with eosinophils in the vicinity of capillaries in the dermis. The ulcerated area of the epidermis was filled with a plug consisting of keratin and inflammatory deThe Journal of Dermatology Vol. 30: 762–763, 2003