Yuri Masui

Serum Levels of Galectin-3: Possible Association with Fibrosis, Aberrant Angiogenesis, and Immune Activation in Patients with Systemic Sclerosis

Objective. Galectin-3 is a multifunctional protein implicated in a variety of biological processes including fibrosis, angiogenesis, and immune activation, all of which are associated with the development of systemic sclerosis (SSc). We investigated the clinical significance of serum galectin-3 levels in SSc. Methods. Serum galectin-3 levels were determined by a specific ELISA in 58 patients with SSc and 19 healthy controls. Results. Serum galectin-3 levels were significantly lower in patients with diffuse cutaneous SSc (dcSSc) than in controls (3.29 ± 3.27 ng/ml vs 4.91 ± 2.67 ng/ml, respectively; p < 0.05), while being comparable between limited cutaneous SSc (3.70 ± 2.39 ng/ml) and healthy controls. In dcSSc, serum galectin-3 levels significantly correlated with total skin score (r = 0.45, p < 0.05). Serum galectin-3 levels were significantly decreased in early dcSSc (disease duration < 1 year; 1.64 ± 1.74 ng/ml; p < 0.05), but not in mid-stage dcSSc (1 to 6 years; 3.22 ± 3.16 ng/ml) or late-stage dcSSc (> 6 years; 4.86 ± 4.10 ng/ml), compared with controls. Serum galectin-3 levels were higher in SSc patients with both digital ulcers (DU) and elevated right ventricular systolic pressure (RVSP) than in those without each symptom (DU: 5.44 ± 3.74 ng/ml vs 2.99 ± 2.36 ng/ml, p < 0.05; elevated RVSP: 4.44 ± 3.14 ng/ml vs 2.82 ± 2.64 ng/ml, p < 0.05). Conclusion. Galectin-3 may be related to the developmental process of skin sclerosis in dcSSc and of DU and pulmonary vascular involvements in total SSc.

Serum adiponectin levels inversely correlate with the activity of progressive skin sclerosis in patients with diffuse cutaneous systemic sclerosis

Backgrounds  Adiponectin has been demonstrated to be one of anti‐inflammatory and anti‐fibrotic factors, suggesting the potential of this cytokine to be involved in the developmental process of systemic sclerosis (SSc).

Clinical significance of serum retinol binding protein‐4 levels in patients with systemic sclerosis

Background  Retinol binding protein‐4 (RBP‐4) is a member of adipocytokines, which is potentially associated with fibrosis, vasodilation, and angiogenesis in addition to insulin resistance.

Serum apelin levels: clinical association with vascular involvements in patients with systemic sclerosis

Background  Apelin is a bioactive peptide exerting its pro‐angiogenic and pro‐fibrotic effects in a context‐dependent manner through the activation of its receptor APJ, which is ubiquitously expressed on the surface of various cell types. The activation of apelin/APJ signalling appears to be involved in the pathological process of fibrotic disorders, including liver cirrhosis.

Serum Tie2 levels: clinical association with microangiopathies in patients with systemic sclerosis.

Background  Tie2 and its ligand, angiopoietins (Ang), regulate the transition between vascular quiescence and angiogenesis. Although defective angiogenesis is one of the major causes of microangiopathies in systemic sclerosis (SSc), the role of Ang/Tie2 signalling in the development of SSc has never been examined.

A possible contribution of visfatin to the resolution of skin sclerosis in patients with diffuse cutaneous systemic sclerosis via a direct anti-fibrotic effect on dermal fibroblasts and Th1 polarization of the immune response

OBJECTIVE Visfatin is a member of the adipocytokines with pro-fibrotic, pro-inflammatory and immunomodulating properties potentially implicated in the pathogenesis of certain fibrotic and inflammatory autoimmune diseases. In this study, we investigated THE CLINICAL SIGNIFICANCE OF SERUM VISFATIN LEVELS AND ITS CONTRIBUTION TO THE DEVELOPMENTAL PROCESS IN SSC. METHODS Serum visfatin levels were determined by a specific ELISA in 57 SSc patients and 19 healthy controls. The mRNA levels of target genes were determined in normal and SSc fibroblasts by real-time RT-PCR. The levels of IL-12p70 produced by THP-1 cells were measured by a specific ELISA. RESULTS Serum visfatin levels were comparable among total SSc, diffuse cutaneous SSc (dcSSc), limited cutaneous SSc and healthy controls. The only finding in a series of analyses regarding the correlation of serum visfatin levels with clinical symptoms and laboratory data was the significantly longer disease duration in dcSSc with elevated serum visfatin levels than in those with normal levels. Consistently, serum visfatin levels were significantly elevated in late-stage dcSSc (disease duration >6 years), but not in early and mid-stage dcSSc compared with healthy controls. In in vitro experiments, visfatin reversed the pro-fibrotic phenotype of SSc dermal fibroblasts and induced the expression of IL-12p70 in THP-1 cells treated with IFN-γ plus lipopolysaccharide. CONCLUSION Visfatin may contribute to the resolution of skin sclerosis in late-stage dcSSc via a direct anti-fibrotic effect on dermal fibroblasts and Th1 polarization of the immune response.

Clinical significance of serum decoy receptor 3 levels in patients with systemic sclerosis

Decoy receptor 3 (DcR3) is associated with autoimmunity and altered angiogenesis in certain pathological conditions. We herein measured serum DcR3 levels in 51 patients with systemic sclerosis (SSc) and 19 healthy controls and evaluated their clinical significance in this disorder. Serum DcR3 levels were significantly higher in diffuse cutaneous SSc (dcSSc) patients than in limited cutaneous SSc patients and in healthy controls. In dcSSc, serum DcR3 levels were significantly elevated in patients with disease duration of ≤6 years compared with healthy controls, but not in those with disease duration of >6 years. Serum DcR3 levels correlated negatively with the percentage of predicted diffusion lung capacity for carbon monoxide and positively with right ventricular systolic pressure. Furthermore, serum DcR3 levels positively correlated with C-reactive protein, erythrocyte sedimentation rate and immunoglobulin G. Collectively, the elevation of serum DcR3 levels is associated with the development of pulmonary arterial hypertension and systemic inflammation in SSc.

Sézary syndrome treated with narrowband ultraviolet B: time‐course measurement of serum levels of CCL17/CCL27

We describe a patient with Sézary syndrome (SS) who was successfully treated with topical steroid and narrowband UVB. Sézary cells in peripheral blood correlated with severity of skin lesions. In addition, serum levels of CCL17 and CCL27 decreased as disease activity improved. These chemokines may be important for the pathogenesis of SS.

Proliferating tricholemmal cystic carcinoma: a case containing differentiated and dedifferentiated parts

A 46‐year‐old man had a cystic mass on the right side of his scalp. Histological examination revealed a cystic dermal nodule composed of relatively circumscribed lobules of proliferating squamous epithelium, with atypical mitoses and dyskeratotic cells of invasive structure, which was diagnosed as proliferating tricholemmal cystic carcinoma (PTCC). Most of the cyst was composed of thick layers of highly proliferating, atypical, dedifferentiated epithelium (dedifferentiated part), which was attached to a highly proliferative but mildly differentiated part. A completely differentiated, tricholemmal cyst (TC)‐like part was also attached to the main cyst, which supports the idea of PTCC beginning in a pre‐existing TC. The dedifferentiated and mildly differentiated parts exhibited a high frequency of proliferating cell nuclear antigen (PCNA)‐positive cells both in the basal and the suprabasal layers, while PCNA staining was almost negative in the TC‐like part. Expression of cytokeratin (CK)10 and CK16 suggested disturbed epidermal differentiation in dedifferentiated part, while TC‐like part showed well‐differentiated trichilemmal epithelium and the mildly differentiated part was in the middle of these two.

Perianal and Vulvar Extramammary Paget Disease: A Report of Six Cases and Mapping Biopsy of the Anal Canal

Treatment of perianal and vulvar extramammary Paget disease (EMPD), rare intraepithelial malignancies, is often challenging because of its potential to spread into the anal canal. However, there is still no consensus regarding the optimal resection margin within the anal canal. Between 2004 and 2014, six patients (three with perianal EMPD and three with vulvar EMPD) in which the spread of Paget cells into the anal canal was highly suspected were referred to our department. To evaluate the disease extent within the anal canal, preoperative mapping biopsy of the anal canal was performed in five out of six patients. Two patients were positive for Paget cells within the anal canal (one at the dentate line and the other at 0.5 cm above the dentate line), whereas in three patients, Paget cell were present only in the skin of the anal verge. Using 1 cm margin within the anal canal from the positive biopsy sites, we performed anal-preserving wide local excision (WLE), and negative resection margins within the anal canal were confirmed in all five patients. The remaining one patient with perianal EMPD did not undergo mapping biopsy of the anal canal because preoperative colonoscopy revealed that the Paget cells had spread into the lower rectum. Therefore, WLE with abdominoperineal resection was performed. During the median follow-up period of 37.3 months, no local recurrence was observed in all patients. Our small case series suggest the usefulness of mapping biopsy of the anal canal for the treatment of perianal and vulvar EMPD.