Cutaneous angioimmunoblastic T-cell lymphoma: Epstein-Barr virus positivity and its effects on clinicopathologic features.

BACKGROUND: Epstein-Barr virus (EBV) positivity frequently presents in patients with nodal angioimmunoblastic T-cell lymphoma (AITL). However, the presence of EBV in skin lesions and its clinicopathologic significance have not been evaluated. OBJECTIVE: To analyze the clinical and histopathologic features of cutaneous AITL and evaluate EBV positivity in skin tissue and its effects on clinicopathologic features of AITL. METHODS: Clinicopathologic variables in patients with cutaneous AITL were analyzed and compared depending on EBV in situ hybridization status in skin lesions by using patients' medical records. RESULTS: Of the 86 patients with AITL, 42 had a cutaneous presentation. In situ hybridizations positive for EBV were noted in 19 of 42 patients with cutaneous AITL. EBV positivity was more common in papular and nodular skin lesions than other cutaneous morphologies, such as nonspecific rash or purpuric patches. An EBV-positive in situ hybridization was associated with a pattern of dense, superficial and deep infiltrates of pleomorphic, large-sized, atypical lymphocytes. EBV positivity in skin lesions was an independent negative prognostic factor in patients with AITL. LIMITATIONS: Retrospective study at a single institution. CONCLUSION: EBV-positive cutaneous AITL is associated with distinctive clinicopathologic features.

Novel regulation of melanogenesis by adiponectin via the AMPK/CRTC pathway.

Several studies observed that adiponectin, an important adipokine that improves glucose metabolism by regulating AMP-activated protein kinase (AMPK) signaling, is dermatologically beneficial. In our recent microarray data, we found that adiponectin expression was lower in lesional skin than in non-lesional skin of melasma patients. Given that AMPK is a key adiponectin signaling mediator, we investigated the role of adiponectin and AICAR, a cell-permeable AMPK activator, in melanogenesis. We herein showed that adiponectin and AICAR downregulated MITF, tyrosinase, TRP-1, and DCT expression and reduced melanin content in normal human and mouse melanocytes. The depigmenting effect of adiponectin was mediated via AMPK activation, which induced the inhibitory phosphorylation of CREB-regulated transcription co-activators (CRTCs) and subsequent suppression of the novel CRTC/CREB pathway in melanocytes. These findings suggest that adiponectin and its analogs are useful as a clinical strategy for treating hyperpigmentation disorders.

A prospective, split-face, double-blinded, randomized study of the efficacy and safety of a fractional 1064-nm Q-switched Nd:YAG laser for photoaging-associated mottled pigmentation in Asian skin.

BACKGROUND: Laser toning using low-fluence 1064-nm Q-switched neodymium-doped yttrium aluminum laser (QSNY) has gained popularity in the treatment of photoaging-associated mottled pigmentation (PMP). However, hypopigmentation or lack of efficacy has been reported depending on the fluences used. OBJECTIVE: To compare a novel fractional 1064-nm QSNY with conventional 1064-nm QSNY for the treatment of photoaging-associated mottled pigmentary lesions except epidermal lesions of lentigines and freckles through a randomized, split-face, double-blind study. MATERIALS AND METHODS: Thirteen Asian women were treated every week for 6 weeks with fractional 1064-nm QSNY on one side of the face and conventional 1064-nm QSNY on the other side. We evaluated the pigmentation area and severity index (PSI), melanin index, erythema index, and the patient's global assessment of improvement. RESULTS: At three months post-treatment, the PSI score improved compared with baseline, by 14.48% on the conventional 1064-nm QSNY side and 21.81% on the fractional 1064-nm QSNY side. Both groups showed improvements in the melanin index. CONCLUSION: Both fractional 1064-nm QSNY and strictly low-fluence conventional 1064-nm QSNY are moderately effective against PMP and other photoaging signs. Fractional laser toning shows better subjective outcomes than conventional toning.

Successful treatment of multiple vemurafenib-induced keratoacanthomas by topical application of imiquimod cream: Confirmation of clinical clearance by dermoscopy.

Keratoacanthomas (KAs) are a well-known cutaneous side effect of BRAF inhibitors and multiple lesions continue to develop throughout the course of therapy. We present a case of an 81-year old women diagnosed with metastatic melanoma who underwent six weeks of vemurafenib therapy. She developed multiple vemurafenib-induced KAs and applied a 5% imiquimod cream three times a week. KAs successfully treated with topical application of imiquimod cream and clearance of these lesions was further confirmed by dermoscopic examination. Topical imiquimod can be an effective treatment option for the noninvasive management of multiple KAs induced by vemurafenib treatment.

Fractional 532-nm Q-switched Nd:YAG laser: One of the safest novel treatment modality to treat café-au-lait macules.

Café-au-lait macules (CALMs) are benign epidermal basilar hyperpigmentations that can be found in an isolated form or in association with neurocutaneous syndromes. Frequency-doubled Q-switched neodymium-doped yttrium aluminum garnet laser (532-nm QSNYL) does not penetrate deeply into the skin and is therefore suitable for epidermal pigmented lesion. Fractional photothermolysis (FP) targets only very small areas of the skin, without injuring adjacent areas of healthy, normal skin. Herein, we report a case of CALMs successfully treated with fractional 532-nm QSNYL. By applying FP to 532-nm QSNYL, we could treat CALMs safely with less downtime as compared to conventional laser treatments and expect more energy delivery for each microscopic hole, thereby allowing higher response rate.

Secondary Cutaneous Diffuse Large B-cell Lymphoma has a Higher International Prognostic Index Score and Worse Prognosis Than Diffuse Large B-cell Lymphoma, Leg Type.

Diffuse large B-cell lymphoma (DLBCL) can be separated into 2 groups: nodal and extranodal disease. The aim of this study was to analyse the clinical features of skin lesions and survival outcomes of cutaneous DLBCL according to the primary tumour site. A total of 44 patients with cutaneous DLBCL were classified as primary cutaneous DLBCL, leg type or cutaneous DLBCL secondary to primary disease. Although skin lesion characteristics did not differ significantly between groups, extensive cutaneous lesions were more often observed in secondary cutaneous DLBCL compared with DLBCL, leg type. Secondary cutaneous DLBCL was more commonly associated with an advanced stage and higher International Prognostic Index score than DLBCL, leg type. DLBCL, leg type demonstrated a better survival outcome than secondary cutaneous DLBCL. The multiplicity of skin lesions and time-point of cutaneous involvement were associated with prognosis in secondary cutaneous DLBCL. Survival outcomes and prognostic factors differ depending on the primary tumour site of cutaneous DLBCL.

A Case of Metastatic Gastric Adenocarcinoma Mimicking Preseptal Cellulitis.

Cutaneous metastasis from gastric adenocarcinoma is uncommon, and the eyelid is a rare metastatic site. Three patterns of clinical presentation of eyelid metastasis have been described: nodular, infiltrative, and ulcerated. The infiltrative pattern, also known as an inflammatory diffuse pattern or mask-like metastasis, can be easily misdiagnosed as cellulitis or contact dermatitis. Here, we report a case of gastric adenocarcinoma in a 75-year-old man who presented with a localized erythematous plaque on his eyelid that developed four months earlier. The patient had been treated with an antimicrobial agent owing to suspicion of preseptal cellulitis. Gastric adenocarcinoma metastasis was diagnosed on the basis of histopathological examination and immunophenotyping (i.e., cytoplasmic epithelial membrane antigen, cytokeratin- 7, cytokeratin-20, and carcinoembryonic antigen). For patients with malignant neoplasms, persistent skin lesions similar to cellulitis or contact dermatitis should be suspected of metastasis derived from an internal malignancy, even for very rare sites of metastasis.

Usefulness of Skin Explants for Histologic Analysis after Fractional Photothermolysis.

BACKGROUND: Fractional laser resurfacing treatment has been extensively investigated and is widely used. However, the mechanism underlying its effects is poorly understood because of the ethical and cosmetic problems of obtaining skin biopsies required to study the changes after laser treatment. OBJECTIVE: To evaluate the usefulness of human skin explants for the investigation of fractional photothermolysis. METHODS: Full-thickness discarded skin was treated in 4 ways: no treatment (control), fractional carbon dioxide laser, fractional Er:YAG laser, and fractional 1,550-nm erbium-doped fiber laser. Both treated and non-treated skin samples were cultured ex vivo at the air-medium interface for 7 days. Frozen tissue was sectioned and stained with hematoxylin & eosin for histologic examination and nitro blue tetrazolium chloride for viability testing. RESULTS: Skin explants cultured for up to 3 days exhibited histologic changes similar to those observed in in vivo studies, including microscopic treatment zones surrounded by a thermal coagulation zone, re-epithelialization, and formation of microscopic epidermal necrotic debris. However, the explant structure lost its original form within 7 days of culture. The viability of skin explants was maintained for 3 days of culture but was also lost within 7 days. CONCLUSION: The skin explant model may be a useful tool for investigating the immediate or early changes following fractional photothermolysis, but further improvements are required to evaluate the long-term and dermal changes.

Clinical evaluation of 368 patients with nasal rosacea: subtype classification and grading of nasal rosacea.

BACKGROUND: The clinical features of nasal rosacea have not been described in detail. OBJECTIVE: To describe the clinical features of nasal rosacea. METHODS: 599 patients were classified into those with rosacea in both the nasal and extra-nasal areas (group A), localized nasal rosacea (group B) and rosacea without nasal involvement (group C). RESULTS: The mixed subtype was more common in group A (n = 337) than in group C (n = 231). The severity score was higher in group A than in group C. Erythematotelangiectatic rosacea was the most common subtype in group B (n = 31) and was more common in group B than in group A. Rosacea mainly affected the lower half of the nose in group B, but affected the entire nose in group A. CONCLUSION: Nasal involvement may be an index of severe rosacea. Localized nasal rosacea is a separate spectrum with different clinical features.

Comparison of acquired bilateral nevus of Ota-like macules in men and women.

BACKGROUND: The clinical and histopathological characteristics of acquired bilateral nevus of Ota-like macules in men are poorly documented due to its rarity. AIMS: To compare the clinical and histopathological characteristics of acquired bilateral nevus of Ota-like macules in men with the condition in women. METHODS: We studied 11 men and 62 women, all with a clinical diagnosis of acquired bilateral nevus of Ota-like macules. Biopsies were taken from 5 men and 10 women and their clinical and histopathological features were compared. RESULTS: The most frequently affected site in men was the forehead [8 (73%) out of 11 patients]. Lesions on the forehead were more common in men than women (P = 0.001). In contrast to women, there was no apparent tendency of the lesions to become more blue with age in men. Concurrent melasma was observed in 14 (23%) out of 62 women, but not in men. Extra-facial acquired dermal melanocytosis was noted in 2 (18%) out of 11 men and in none of the 62 women. CONCLUSION: Significant differences were noted between men and women in the appearance of concurrent pigmentary lesions and the distribution of lesions. Extra-facial acquired dermal melanocytosis was noted in men.

Effect of azelastine on cardiac repolarization of guinea-pig cardiomyocytes, hERG K⁺ channel, and human L-type and T-type Ca²âº channel.

Azelastine is a second generation histamine H1-receptor antagonist used as an anti-asthmatic and anti-allergic drug that can induce QT prolongation and torsades de pointes. We investigated the acute effects of azelastine on human ether-a-go-go-related gene (hERG) channels, action potential duration (APD), and L-type (I(Ca,L)) and T-type Ca²âº current (I(Ca,T)) to determine the electrophysiological basis for its proarrhythmic potential. Azelastine increased the APD at 90% of repolarization concentration dependently, with an IC50 of 1.08 nM in guinea-pig ventricular myocytes. We examined the effects of azelastine on the hERG channels expressed in Xenopus oocytes and HEK293 cells using two-microelectrode voltage-clamp and patch-clamp techniques. Azelastine induced a concentration-dependent decrease of the hERG current amplitude at the end of the voltage steps and tail currents. The IC50 for the azelastine-induced block of the hERG currents expressed in HEK293 cells was 11.43 nM, while the drug inhibited I(Ca,L) and I(Ca,T) with IC50 values of 7.60 and 26.21 µM, respectively. The S6 domain mutations, Y652A partially attenuated and F656A abolished hERG current block. These results suggest that azelastine is a potent blocker of hERG channels rather than I(Ca,L) or I(Ca,T), providing molecular mechanisms for the arrhythmogenic side effects during the clinical administration of azelastine.

Clomipramine block of the hERG K+ channel: accessibility to F656 and Y652.

Clomipramine is a tricyclic antidepressant for psychiatric disorders that can induce QT prolongation, which may lead to torsades de pointes. Since blockade of cardiac human ether-a-go-go-related gene (hERG) channels is an important cause of acquired long QT syndrome, we investigated the acute effects of clomipramine on hERG channels to determine the electrophysiological basis for its proarrhythmic potential. We examined the effects of clomipramine on the hERG channels expressed in Xenopus oocytes and HEK293 cells using two-microelectrode voltage-clamp and patch-clamp techniques. Clomipramine induced a concentration-dependent decrease in the current amplitude at the end of the voltage steps and hERG tail currents. The IC50 for clomipramine needed to block the hERG current in Xenopus oocytes decreased progressively relative to the degree of depolarization. The fractional electrical distance was estimated to be delta=0.83. The IC50 for the clomipramine-induced blockade of the hERG currents in HEK293 cells at 36 degrees C was 0.13 microM at +20 mV. Clomipramine affected the channels in the activated and inactivated states but not in the closed states. The clomipramine-induced blockade of hERG was found to be use-dependent, exhibiting a more rapid onset and a greater steady-state block at the higher frequencies of activation. The S6 domain mutations, Y652A and F656A partially attenuated (Y652A) or abolished (F656A) the hERG-current blockade. These results suggest that clomipramine is a blocker of the hERG channels, providing a molecular mechanism for the arrhythmogenic side effects during the clinical administration of clomipramine.

Ginsenoside Rg3 inhibits human Kv1.4 channel currents by interacting with the Lys531 residue.

We have demonstrated previously that the 20(S) but not the 20(R) form of ginsenoside Rg(3) inhibited K(+) currents flowing through Kv1.4 (hKv1.4) channels expressed in Xenopus laevis oocytes, pointing to the presence of specific interaction site(s) for Rg(3) in the hKv1.4 channel. In the current study, we sought to identify this site(s). To this end, we first assessed how point mutations of various amino acid residues of the hKv1.4 channel affected inhibition by 20(S)-ginsenoside Rg(3) (Rg(3)). Lys531 residue is known to be a key site for K(+) activation and to be part of the extracellular tetraethylammonium (TEA) binding site; the mutation K531Y abolished the Rg(3) effect and made the Kv1.4 channel sensitive to TEA applied to the extracellular side of the membrane. Mutations of many other residues, including the pH sensitive-site (H507Q), were without any significant effect. We next examined whether K(+) and TEA could alter the effect of Rg(3) and vice versa. We found that 1) raising [K(+)](o) reduced the inhibitory effect of Rg(3) on hKv1.4 channel currents, whereas Rg(3) shifted the K(+) activation curve to the right, and 2) TEA caused a rightward shift of the Rg(3) concentration-response curve of wild-type hKv1.4 channel currents, whereas Rg(3) caused a rightward shift of the TEA concentration-response curve of K531Y mutant channel currents. The docked modeling revealed that Lys531 plays a key role in forming hydrogen bonds between Rg(3) and hKv1.4 channels. These results indicate that Rg(3) inhibits the hKv1.4 channel current by interacting with residue Lys531.