Konosuke Nagae

Tumor thickness as a prognostic factor in extramammary Paget's disease

Extramammary Pagets disease (EMPD) is a rare tumor and a widely accepted classification system specific for the disease has not been established. To elucidate prognostic factors of EMPD, we conducted a retrospective review of 145 patients with 155 EMPD lesions and investigated clinicopathological factors using univariate and multivariate analyses. We also explored tumor thickness and metastatic lymph nodes using detection analysis to determine cut‐off points for survival. All patients were Japanese (88 men and 57 women), with EMPD in the genital (82.8%), perianal (3.4%) and axillary regions (1.4%). In the remaining cases (12.4%), there were lesions at two or more regions. Univariate analysis revealed the following prognostic factors: perianal location, presence of nodules, invasion depth, tumor thickness, number of metastatic nodes and serum carcinoembryonic antigen level. Both tumor thickness and perianal location retained statistical significance in multivariate analysis (hazard ratio, 1.39; 95% confidence interval, 1.12–1.72; P = 0.0024; hazard ratio, 50.72; 95% confidence interval, 4.20–612.63; P = 0.0020; respectively). The signal detection analysis indicated tumor thickness of more than 3 mm and three or more metastatic lymph nodes as cut‐off points for survival. In conclusion, tumor thickness and the number of metastatic lymph nodes closely correlated with patient outcome and these factors could be suitable for the tumor and node classification.

Upregulation of S100P, receptor for advanced glycation end products and ezrin in malignant melanoma.

S100P is a member of the S100 family. Increased levels of S100P have been documented in various malignancies. Binding of extracellular S100P to receptor for advanced glycation end products (RAGE) or coupling of intracellular S100P with a cytoskeletal protein, ezrin, play a crucial role in tumor growth, invasion and metastasis. However, little is known about the expression of S100P, RAGE and ezrin in malignant melanoma. We immunostained these three molecules in 20 primary and 20 metastatic melanomas. Samples of 20 benign nevus pigmentosus and 10 of normal skin were tested as controls. The expression levels (percentage of positively stained cells) of S100P, RAGE and ezrin were significantly higher in melanomas than in nevus pigmentosus. Moreover, slightly but significantly higher expression levels were observed in metastatic than in primary melanomas. Significant positive correlations were evident between the expression levels of S100P and RAGE, S100P and ezrin, and RAGE and ezrin, respectively. In conclusion, the coordinate upregulation of S100P, RAGE and ezrin may possibly facilitate malignant transformation of melanoma.

Narrow‐margin excision is a safe, reliable treatment for well‐defined, primary pigmented basal cell carcinoma: an analysis of 288 lesions in Japan

Complete excision is the most promising treatment for basal cell carcinoma (BCC) and a surgical margin of at least 4 mm is recommended. However, little is known about the appropriate surgical margin of pigmented BCC.

Triple-marker PCR assay of sentinel lymph node as a prognostic factor in melanoma

Metastasis of sentinel lymph node (SLN) is generally evaluated on histopathological examination and controversy still exists over the usefulness of PCR assay of SLN.

Disseminated protothecosis manifesting with multiple, rapidly-progressing skin ulcers: Successful treatment with amphotericin B

Protothecosis is a rare infection caused by Prototheca species, which are achlorophyllous algae found ubiquitously in nature [1]. Herein, we report a case of disseminated P. wickerhamii infection in a patient with systemic lupus erythematosus (SLE). The disease presented as multiple, rapidly-progressing skin ulcers and was successfully treated with systemic antifungal agents.A 65-year-old Japanese woman was referred to our hospital with a two-week history of extensive ulcerative lesions on the right [...]

6-Formylindolo[3,2-b]Carbazole Accelerates Skin Wound Healing via Activation of ERK, but Not Aryl Hydrocarbon Receptor

Wound healing is an elaborate process composed of overlapping phases, such as proliferation and remodeling, and is delayed in several circumstances, including diabetes. Although several treatment strategies for chronic wounds, such as growth factors, have been applied, further alternatives are required. The skin, especially keratinocytes, is continually exposed to UV rays, which impairs wound healing. 6-Formylindolo[3,2-b]carbazole (FICZ) is a tryptophan photoproduct formed by UV exposure, indicating that FICZ might be one of the effectors of UV radiation. In contrast, treatment with tryptophan, the precursor for FICZ, promoted wound closure in keratinocytes. Therefore, the aim of our study was to determine the role of FICZ in wound healing. Here we showed that FICZ enhanced keratinocyte migration through mitogen-activated protein kinase/extracellular signal-regulated kinase activation, and promoted wound healing in various mouse models, including db/db mice, which exhibit wound healing impairments because of type 2 diabetes. Moreover, FICZ, the endogenous ligand of an aryl hydrocarbon receptor, accelerated migration even in the aryl hydrocarbon receptor knockdown condition and also promoted wound healing in DBA/2 mice, bearing a low-affinity aryl hydrocarbon receptor, suggesting that FICZ enhanced keratinocyte migration in a mitogen-activated protein kinase/extracellular signal-regulated kinase-dependent, but aryl hydrocarbon receptor-independent, manner. The function of FICZ might indicate the possibility of its clinical use for intractable chronic wounds.

Osteomalacia induced by a phosphaturic mesenchymal tumor secreting fibroblast growth factor 23

Tumor-induced osteomalacia (TIO) is a rare paraneoplastic condition characterised by the presence of a tumor, hypophosphatemia caused by renal phosphate wasting and low serum concentration of 1,25-dihydroxyvitamin D [1,25(OH)2D], with clinical and histological evidence of osteomalacia [1-4]. Hypophosphatemia subsequently causes muscle weakness, bone pain and multiple fractures [1]. Most cases of TIO are associated with mesenchymal tumors secreting fibroblast growth factor 23 (FGF23) [1], which was [...]

Two Cases of Cutaneous Squamous Cell Carcinoma Arising in Immunosuppressed Patients with Chronic Human Papillomavirus Infection

Increasing evidence has suggested that human papillomaviruses (HPVs) are linked to a large subset of numerous malignant tumors, including mucosal squamous cell carcinoma (SCC); however, its involvement in cutaneous SCC has not fully been elucidated. Cutaneous SCC is the second most common type of skin cancer and is increasing in frequency every year. Since we have no satisfactory treatment for advanced SCC, it is important to provide a definitive diagnosis and appropriate therapeutic intervention at an early stage. Here, we present two cases of SCC arising in immunosuppressed patients. In these cases, we suspected the association between SCC and HPV infection histopathologically and succeeded in proving the presence of high-risk type HPV by PCR analysis (HPV 14 in case 1 and HPV 23 and 38 in case 2). Although it is unclear whether HPV actually induced SCC in our cases, our cases showed rapid progression comparing to typical courses of actinic keratosis (AK)/SCC. SCC and AK are common diseases; in daily practice, dermatologists examine many patients with immunosuppression of various causes. We should apply increased oncological vigilance to these patients to prevent an aggressive course of SCC/AK.

Hybrid perineurioma-neurofibroma in a patient with neurofibromatosis type 1, clinically mimicking malignant peripheral nerve sheath tumor

Perineurioma is a rare benign peripheral nerve sheath tumor (BPNST) featuring perineurial differentiation. Sporadic case reports of hybrid tumors of BPNST have been reported; hybrid perineurioma-neurofibroma in neurofibromatosis type 1 (NF-1) is extremely rare [1-3]. Here, we present a hybrid tumor arising in a diffuse plexiform neurofibroma on the face of an NF-1 patient.A 30-year-old Japanese man presented with a two-month history of subcutaneous nodules in a diffuse plexiform neurofibroma on the [...]

Glucagon-like peptide-1 analogue liraglutide facilitates wound healing by activating PI3K/Akt pathway in keratinocytes

AIMS Diabetes induces various skin troubles including foot ulcer. This type of skin ulcer is refractory but the pathogenesis is not so certain. Recent study show that glucagon-like peptide-1 (GLP-1) analogues reduce foot complications with diabetes (Pérez et al., 2015), however, the role of GLP-1/GLP-1R axis is not fully understood, and clear evidence of GLP-1 to facilitate wound closure is still lacking. In this study, we investigated whether a potent GLP-1R agonist liraglutide affects wound healing process. METHODS The expression of GLP-1R in HaCaT cells were indentified by quantitative reverse-transcription polymerase chain reaction (qRT-PCR) and immunoblotting analysis. To assess the effect on wound closure in keratinocytes, we performed in vitro scratch assay using the IncuCyte system (Essen BioSciences, Ann Arborm MI). We applied ointment containing liraglutide on full-thickness wounds in the dorsum of female balb/c mice (n = 6) until healing. To investigate the effect on PI3K/Akt pathway, we used IncuCyte system in HaCaT treated with PI3K inhibitor and Akt inhibitor. RESULTS Keratinocytes expressed GLP-1R and liraglutide induced their migration. Liraglutide facilitated the wound healing in mice. Liraglutide upregulated keratinocyte migration via PI3K/Akt activation. CONCLUSIONS Our study suggests that liraglutide may be a potential target drug to improve skin ulcer with diabetes through its specific receptor GLP-1.