Indocyanine green fluorescence-guided sentinel lymph node biopsy in dermato-oncology

Background: Sentinel lymph node biopsy (SLNB) for cutaneous malignancies usually carried out with radioactive nanocolloids (Tc‐99m). The SLNE is controversially discussed internationally. This is especially given to the high false‐negative rate up to 44 %. An alternative could be the fluorescent dye indocyanine green (ICG). Material and Methods: We investigated the advantage of intraoperative fluorescence detection of lymphatic vessels and SLN with a Near‐Infrared (NIR) camera in comparison to conventional methods using preoperative lymphoscintigraphy and SPECT/CT in 22 patients with malignant melanoma. Results: A total of 61 SLNs were removed in 22 operative procedures. In 7 SLN (10.3 %; 7/68) the histopathological assessment could demonstrate a metasta‐tic involvement. 11 additional SLN (19.1 %) in 8 patients were only identified using the fluorescent labeling. Two of these additional SLN (9.1 %; 2/22) showed metastatic involvement. Conclusion: The ICG fluorescence‐guided SLNB is an innovative imaging technique for dermato‐oncology, reliable and providing additional information in the detection of SLN. Therefore SLNB with fluorescence‐dye is an attractive option with intraoperative real‐time lymphoscintigraphy to improve the detection of SLN in cutaneous malignancies and potential reduction of the false negative rate in SLN.     

Is there a relationship between homocysteine and vitiligo? A pilot study

Background Pigmentary dilution is observed in patients with homocystinuria. Therefore, it is possible that an increase of local homocysteine (Hcy) interferes with normal melanogenesis and plays a role in the pathogenesis of vitiligo. Vitamin B₁₂ and folic acid, levels of which are decreased in vitiligo, are important cofactors in the metabolism of Hcy. Consequently, a nutritional deficiency in either of these two vitamins will result in an increase in homocysteine in the circulation, a finding that we expect to find in vitiligo. Objective To determine the level of Hcy in the blood of patients with vitiligo as a first step in revealing if it has any relationship with the pathogenesis of vitiligo and consequently if this will have an impact on the treatment of vitiligo. Methods Twenty‐six patients of both sexes with vitiligo (age range 20–50 years, mean 31·4 ± 8·09) and 26 age‐matched healthy controls were included in the study. After excluding factors that may affect serum Hcy levels, blood samples from patients and controls were obtained for homocysteine determination by enzyme immunoassay. Results The mean serum level of Hcy was significantly higher in patients with vitiligo than in controls (21·61 ± 13·28 vs. 13·1 ± 4·88 μmol L^?1; P < 0·001). The Hcy level was significantly higher in male patients than in female patients (28·67 ± 15·95 vs. 15·56 ± 6·2 μmol L^?1; P < 0·001) and in male controls compared with female controls (15·07 ± 4·61 vs. 12·05 ± 4·82 μmol L^?1; P < 0·001). The homocysteine level was related to the activity of vitiligo and was significantly higher in patients with progressive disease than in controls (25·4 ± 14·99 vs. 13·1 ± 4·88 μmol L^?1; P < 0·001). No significant difference in Hcy levels was found between either untreated vitiligo patients (22·77 ± 13·36 μmol L^?1) or patients receiving ultraviolet therapy (20·45 ± 13·73 μmol L^?1) and the total patient group (21·62 ± 13·28 μmol L^?1). Conclusion An elevated homocysteine level may be a precipitating factor for vitiligo in predisposed individuals. In view of the biological role of vitamin B₁₂ and folic acid in Hcy metabolism, we present our recommendations regarding the investigation and treatment of this common disease.     

Indocyanine green-augmented diode laser treatment of port-wine stains: clinical and histological evidence for a new treatment option from a randomized controlled trial

Background Complete clearance of port‐wine stains (PWS) is difficult to achieve, mainly because of the resistance of small blood vessels to laser irradiation. Indocyanine green (ICG)‐augmented diode laser treatment (ICG+DL) may overcome this problem. Objectives To evaluate the feasibility of ICG+DL therapy of PWS and to compare the safety and efficacy of ICG+DL with the standard treatment, flashlamp‐pumped pulsed dye laser (FPDL). Methods In a prospective randomized controlled clinical study, 31 patients with PWS were treated with FPDL (λ_em = 585 nm, 6 J cm^?2, 0·45 ms pulse duration) and ICG+DL (λ_em = 810 nm, 20–50 J cm^?2, 10–25 ms pulse duration, ICG‐concentration: 2 mg kg^?1 body weight) in a split‐face modus in one single treatment setting that included histological examination (haematoxylin and eosin, CD34). Two blinded investigators and the patients assessed clearance rate, cosmetic appearance and side‐effects up to 3 months after treatment. Results ICG+DL therapy induced photocoagulation of medium and large blood vessels (> 20 μm diameter) but not of small blood vessels. According to the investigators’ assessment, clearance rates and cosmetic appearance were better after ICG+DL therapy than after FPDL treatment (P = 0·114, P = 0·291, respectively), although not up to a statistically significant level, whereas patients considered these parameters superior (P = 0·003, P = 0·006, respectively). On a 10‐point scale indicating pain during treatment, patients rated ICG+DL to be more painful (5·81 ± 2·12) than FPDL treatment (1·61 ± 1·84). Conclusion ICG+DL represents a new and promising treatment modality for PWS, but laser parameters and ICG concentration need to be further optimized.     

Aberrant hypermethylation in primary tumours and sentinel lymph node metastases in paediatric patients with cutaneous melanoma

Background Debate on how to manage paediatric patients with cutaneous melanoma continues, particularly in those with sentinel lymph node (SLN) metastases who are at higher risk of poor outcomes. Management is often based on adult algorithms, although differences in clinical outcomes between paediatric and adult patients suggest that melanoma in paediatric patients differs biologically. Yet, there are no molecular prognostic studies identifying these differences. Objectives We investigated the epigenetic (methylation) regulation of several tumour‐related genes (TRGs) known to be significant in adult melanoma progression in histopathology(+) SLN metastases (n = 17) and primary tumours (n = 20) of paediatric patients with melanoma to determine their clinical relevance. Methods Paediatric patients (n = 37; ≤ 21 years at diagnosis) with American Joint Committee on Cancer stage I–III cutaneous melanoma were analysed. Gene promoter methylation of the TRGs RASSF1A, RARβ2, WIF1 and APC was evaluated. Results Hypermethylation of RASSF1A, RARβ2, WIF1 and APC was found in 29% (5/17), 25% (4/16), 25% (4/16) and 19% (3/16) of histopathology(+) SLNs, respectively. When matched to adult cutaneous melanomas by Breslow thickness and ulceration, hypermethylation of all four TRGs in SLN(+) paediatric patients with melanoma was equivalent to or less than in adults. With a median follow‐up of 55 months, SLN(+) paediatric patients with melanoma with hypermethylation of > 1 TRG vs. ≤ 1 TRG had worse disease‐free (P = 0·02) and overall survival (P = 0·02). Conclusions Differences in the methylation status of these TRGs in SLN(+) paediatric and adult patients with melanoma may account for why SLN(+) paediatric patients have different clinical outcomes. SLN biopsy should continue to be performed; within SLN(+) paediatric patients with melanoma, hypermethylation of TRGs can be used to identify a subpopulation at highest risk for poor outcomes who warrant vigilant clinical follow‐up.     

Histological regression in primary melanoma: not a predictor of sentinel lymph node metastasis in a cohort of 397 patients

Background Regression has been proposed as a potential marker of dissemination in thin melanomas. Previous studies have shown conflicting results. Objective To determine if regression in melanoma is associated with an increased risk of sentinel lymph node (SLN) metastasis. Methods A cohort analysis was conducted. Data on all patients were collected on a standardized case report form during 10 years. A total of 397 consecutive patients with melanoma who underwent a SLN biopsy were analysed. All cases of melanoma and SLN biopsies were examined by the same two pathologists. Differences between melanomas with and without SLN metastasis were compared using Fisher’s exact test or the two‐sample t‐test and the χ² test. Multivariable logistic regression was used to adjust for possible confounding factors. Results We analysed 397 patients (411 melanomas) who underwent a SLN biopsy. The median Breslow index was 1·8 mm (interquartile range 1·1–3). Regression was observed in 23% (n = 94). SLN metastases were observed in 26% (n = 106). The frequency of SLN metastasis was 16% in melanomas with regression and 29% without regression (P = 0·012). The adjusted odds ratio (OR) for regressive melanoma was 0·9 [95% confidence interval (CI) 0·4–1·9; P = 0·777]. The risk of SLN metastasis was increased in melanoma cases with a Breslow index from 1·5 to < 2·0 mm (adjusted OR 3·1; 95% CI 1·4–7·1; P = 0·006) and ≥ 2·0 mm (adjusted OR 3·5; 95% CI 1·7–7·4; P = 0·001) and ulceration of the melanoma (adjusted OR 1·8; 95% CI 1·1–3·2; P = 0·03). Conclusion Regression is not an independent predictor of the risk of SLN metastasis in melanoma.     

Allergy‐inducing nickel concentration is lowered by lipopolysaccharide at both the sensitization and elicitation steps in a murine model

Background Nickel (Ni) is the major cause of contact allergy. We previously found that lipopolysaccharide (LPS, a cell‐surface component of Gram‐negative bacteria) markedly promotes Ni allergy in a murine model. Establishing the minimum concentration or amount of Ni needed to induce allergic responses may help us to prevent or reduce such responses. Objectives Using the above murine model, we examined the influence of LPS on the minimum allergy‐inducing concentrations of Ni (Ni‐MAICs) at the sensitization step and at the elicitation step. Methods BALB/c mice were sensitized by intraperitoneal injection of a mixture containing various concentrations of LPS and NiCl₂. Ten days later, their ear pinnas were challenged intradermally with a mixture containing various concentrations of LPS and NiCl₂, and ear swelling was measured. Results Without LPS, the Ni‐MAICs at the sensitization and elicitation steps were around 1 × 10^?2 mol L^?1 and 1 × 10^?5 mol L^?1, respectively. Sensitization with NiCl₂ + LPS did not alter the value at elicitation. Surprisingly, LPS markedly reduced these Ni‐MAICs (to around 1 × 10^?6 mol L^?1 at sensitization, with 25 μg mL^?1 LPS, and 1 × 10^?12 mol L^?1 at elicitation, with 0·5 μg mL^?1 LPS). The effect of LPS depended on its concentration and the timing of its injection. Conclusions Our findings suggest that: (i) Ni‐MAIC is higher at sensitization than at elicitation; (ii) once sensitization is established, Ni allergy can easily be induced by a low concentration of Ni; and (iii) a bacterial milieu or infection may greatly facilitate the establishment and elicitation of Ni allergy.     

Comparison of narrowband ultraviolet B exposure and oral vitamin D substitution on serum 25-hydroxyvitamin D concentration

Summary Background A short course of narrowband ultraviolet B (NB‐UVB) exposures increases the serum 25‐hydroxyvitamin D [25(OH)D] concentration in patients with psoriasis and healthy subjects. Objectives To compare the effects of NB‐UVB and oral vitamin D substitution in healthy subjects in winter. Methods Healthy adult hospital employees and medical students were screened for serum 25(OH)D concentration. Those with 25(OH)D below 75 nmol L^?1 were randomly given either 12 NB‐UVB exposures or 20 μg of oral cholecalciferol daily for 4 weeks. The NB‐UVB exposures were given with a Waldmann UV 7001 cabin and the mean cumulative dose was 48·4 standard erythema doses. Serum 25(OH)D was measured before and after the treatments by radioimmunoassay. Results The baseline serum 25(OH)D concentrations were 52·9 ± 10·4 (mean ± SD) in the 33 NB‐UVB‐treated and 53·5 ± 12·7 nmol L^?1 in the 30 oral cholecalciferol‐treated subjects. The mean increase in serum 25(OH)D was 41·0 nmol L^?1 [95% confidence interval (CI) 34·8–47·2; P < 0·001] in the NB‐UVB group and 20·2 nmol L^?1 (95% CI 14·6–26·0; P < 0·001) in the cholecalciferol group. The difference between the two treatments was significant at 2 weeks (P = 0·033) and at 4 weeks (P < 0·001). One month after the treatments the 25(OH)D concentrations had increased further. Conclusions The present study shows that 12 NB‐UVB exposures given during 4 weeks increase serum 25(OH)D concentration significantly more than 20 μg of oral cholecalciferol daily. A short NB‐UVB course is an effective way to improve vitamin D balance in winter and the response is still evident 2 months after the course.     

25-Hydroxyvitamin D levels in African-American and Caucasian/Hispanic subjects with cutaneous lupus erythematosus

Background Because exposure to ultraviolet radiation accounts for a significant portion of endogenous vitamin D production, subjects with cutaneous lupus (CLE) who practise sun‐protective measures are at risk for vitamin D insufficiency. Previous studies have shown light‐skinned subjects with CLE to have lower serum 25‐hydroxy (25‐OH) vitamin D levels than normal controls. Objectives To assess the status of vitamin D insufficiency in dark‐skinned individuals with CLE. Methods We performed a cross‐sectional study comparing serum 25‐OH vitamin D levels in 25 African‐American (AA) subjects with CLE and 26 normal AA subjects matched by age, sex and season in Dallas, Texas. A questionnaire on demographics, medical history and lifestyle habits was administered to determine factors potentially affecting vitamin D levels. Findings were contrasted to a similar comparison in 26 Caucasian and Hispanic (C/H) subjects with CLE and 24 normal C/H subjects matched by age, sex and season. Results We found similar mean ± SD 25‐OH vitamin D levels in AA subjects with CLE (52·0 ± 18·5 nmol L^?1) and normal AA subjects (54·8 ± 21·2 nmol L^?1) (P = 0·62). Almost half of AA subjects in both groups were vitamin D insufficient. A larger difference in 25‐OH vitamin D levels was found between C/H subjects with CLE (59·4 ± 21·0 nmol L^?1) and normal C/H subjects (70·5 ± 27·4 nmol L^?1) (P = 0·12). Two‐way anova demonstrated that skin colour (AA vs. C/H) had a significant effect on 25‐OH vitamin D levels (P = 0·008), although CLE status (CLE vs. normal) did not (P = 0·13). Conclusions Providers are encouraged to address vitamin D insufficiency concerns in all dark‐skinned individuals. Future studies should stratify subjects by skin colour in determining differences between subjects with CLE and normal controls.     

Evaluation of zinc level in skin of patients with necrolytic acral erythema

Summary Background Necrolytic acral erythema (NAE) is considered a cutaneous sign of hepatitis C virus infection. Its exact pathogenesis is still not fully understood, with some reports about decreased serum zinc levels but none about its level in the skin. Objectives To assess skin (lesional and perilesional) and serum zinc levels in patients with NAE and compare them with levels in control subjects. Methods Fifteen patients with NAE and 10 healthy controls were included in this study. Assessment of zinc level, in serum by graphite furnace atomic absorption spectrophotometry and in lesional and perilesional skin biopsies by flame atomic absorption spectrometry, was done in all subjects. Re‐evaluation of serum and lesional skin zinc level was done after oral zinc treatment. Results Mean ± SD zinc levels were significantly lower in patients (serum 0·44 ± 0·13 mg L^?1; lesional skin 42·6 ± 18·9 mg L^?1; perilesional skin 32·5 ± 17·2 mg L^?1) than controls (serum 1·17 ± 0·29 mg L^?1; skin 100·1 ± 2·77 mg L^?1), with a positive correlation between lesional and perilesional skin zinc (r = 0·91, P < 0·01). Oral zinc supplementation significantly increased serum and skin zinc levels (by 159% and 4%, respectively; P < 0·05). Conclusions NAE is associated with decreased serum and skin zinc levels. Oral zinc supplementation corrects decreased levels of plasma and skin zinc much earlier than the desired clinical benefits appear.     

Vitamin D deficiency in patients with cutaneous lupus erythematosus is prevalent throughout the year

Background Vitamin D mediates immunomodulatory functions and its deficiency has been associated with an increased prevalence of immunological diseases including systemic lupus erythematosus (SLE). Chronic discoid or subacute cutaneous lupus erythematosus (CLE) are ultraviolet (UV)‐triggered skin diseases. As vitamin D is mostly UV‐derived and not from nutrition, its deficiency is frequent especially during the UV‐deprived winter months. Objective To compare the vitamin D status of patients with CLE with patients with type I allergy and healthy individuals during the summer or winter months. Methods The vitamin D status of patients with CLE (n = 41) was compared with patients with type I allergy (n = 24), healthy individuals (n = 25) and a reference pool (n = 1951) by means of concentrations of circulating storage metabolite 25‐hydroxyvitamin D in the summer and winter. Results Serum 25‐hydroxyvitamin D concentrations were lower during the winter in the reference population, and type I allergic and healthy individuals (29·2–35·5 nmol L^?1) compared with the summer months (56·3–89·8 nmol L^?1) and paralleled by the prevalence of vitamin D deficiency (serum 25‐hydroxyvitamin D < 50 nmol L^?1; winter: 70·8–73·4%, summer: 34·9–39·4%). In contrast, vitamin D deficiency in patients with CLE was prevalent throughout the year (summer: 85·7%, winter: 97·1%). In patients with CLE with concomitant prednisolone treatment, the 25‐hydroxyvitamin D serum levels were comparable with (mean daily intake 877 IU) or without vitamin D supplementation during summer or winter (P = 0·75 and P = 0·14, respectively). Conclusions  Our data identify vitamin D deficiency in patients with CLE throughout the year and indicate that monitoring and correcting the vitamin D status should be considered to prevent bone demineralization and fractures and to modulate beneficially immunological dysfunction.     

Activation of blood coagulation in bullous pemphigoid: role of eosinophils, and local and systemic implications

Background Bullous pemphigoid (BP) is a blistering skin disease caused by autoantibodies to hemidesmosomal proteins, with eosinophils participating in blister formation. Eosinophils are a source of tissue factor (TF), an initiator of blood coagulation. Objectives To evaluate the local and systemic activation of coagulation in BP. Methods We studied 20 patients with active BP (eight re‐evaluated during remission) and 40 controls. The coagulation markers prothrombin fragment F1+2 and d ‐dimer were measured in the plasma of all subjects and in both plasma and blister fluid of patients with BP. TF was evaluated immunohistochemically in skin specimens from the 20 patients and in 20 normal samples. Results F1+2 and d ‐dimer levels were higher in plasma of patients with BP (649 ± 96 pmol L^?1 and 18·52 ± 3·44 nmol L^?1, respectively) than in plasma of controls (157 ± 7 pmol L^?1 and 1·42 ± 0·06 nmol L^?1; P = 0·0001), and were very high in blister fluid (40 449 ± 3491 pmol L^?1 and 1532·32 ± 262·81 nmol L^?1; P = 0·0001). Plasma and blister fluid F1+2 and d ‐dimer levels paralleled blood and tissue eosinophilia and disease severity. In the eight patients re‐evaluated during remission, there was a marked reduction in F1+2 (from 1127 ± 144 to 287 ± 52 pmol L^?1; P = 0·005) and d ‐dimer (from 24·03 ± 4·08 to 4·69 ± 1·51 nmol L^?1; P = 0·029). Immunohistochemistry revealed strong TF reactivity in BP skin (P = 0·0001), and colocalization studies confirmed eosinophils as a source of TF. Conclusions The coagulation cascade is activated in BP and correlates with the severity of the disease and with eosinophilia, indicating that eosinophils play a role in coagulation activation via TF. The hypercoagulability may contribute to inflammation, tissue damage, blister formation and possibly thrombotic risk in BP.     

Increased levels of circulating platelet‐derived microparticles are associated with metastatic cutaneous melanoma

We investigated the plasma levels of PMPs in patients with 45 stage III and 45 stage IV melanoma. PMPs were characterised by flow cytometry and their thrombogenic activity. We also investigated the link between PMPs circulating levels and tumor burden. The circulating levels of PMPs were significantly higher in stage IV (8500 μL^?1) than in patients with stage III (2041 μL^?1) melanoma (P=.0001). We calculated a highly specific (93.3%) and predictive (91.7%) cut‐off value (5311 μL^?1) allowing the distinction between high‐risk stage III and metastatic stage IV melanoma. The thrombogenic activity of PMPs was significantly higher in patients with stage IV melanoma (clotting time: 40.7 second vs 65 second, P=.0001). There was no significant association between the radiological tumoral syndrome and the plasma level of PMPs. Our data suggest the role of PMPs in metastatic progression of melanoma.     

Narrowband ultraviolet B course improves vitamin D balance in women in winter

Background Vitamin D insufficiency is common in winter in the Nordic countries. Objectives  To examine whether a short course of narrowband ultraviolet B (NB‐UVB) improves vitamin D balance. Methods Fifty‐six healthy, white women (mean age 41 years) volunteered and 53 completed the study. NB‐UVB exposures were given on seven consecutive days either on the whole body (n = 19), on the head and arms (n = 9) or on the abdomen (n = 14). Similarly, seven solar simulator exposures were given on the face and arms (n = 11). The cumulative UVB dose was 13 standard erythema doses in all regimens. Serum calcidiol (25‐hydroxyvitamin D) concentration was measured by radioimmunoassay before and after the NB‐UVB exposures. Follow‐up samples were taken from the whole‐body NB‐UVB group at 2 months. Results At onset 41 women (77%) had vitamin D insufficiency (calcidiol < 50 nmol L^?1) and six (11%) had vitamin D deficiency (calcidiol < 25 nmol L^?1). Calcidiol concentration increased significantly, by a mean of 11·4 nmol L^?1 when NB‐UVB was given on the whole body, by 11·0 nmol L^?1 when given on the head and arms and by 4·0 nmol L^?1 when given on the abdomen. Solar simulator exposures given on the face and arms increased calcidiol by 3·8 nmol L^?1. After 2 months serum calcidiol was still higher than initially in the group who received NB‐UVB exposures on the whole body. Conclusions NB‐UVB exposures given on seven consecutive days on different skin areas of healthy women significantly improved serum calcidiol concentration. A short low‐dose NB‐UVB course can improve vitamin D balance in winter.     

A costly revolution for a subgroup of patients with metastatic melanoma

ORIGINAL ARTICLE: Hauschild A, Grob JJ, Demidov LV et al. Dabrafenib in BRAF‐mutated metastatic melanoma: a multicentre, open‐label, phase 3 randomised controlled trial. Lancet 2012; 380: 358–65. Background Dabrafenib, an inhibitor of mutated BRAF, has clinical activity with a manageable safety profile in phase I and II studies in patients with BRAF (V600)‐mutated metastatic melanoma. Hauschild et al. aimed to assess the efficacy of dabrafenib in a phase III trial of patients with BRAF (V600)‐mutated metastatic melanoma. Methods Patients were enrolled into a phase III trial between December 2010 and September 2011. This report is based on the cut‐off date of 19 December 2011. Patients with previously untreated stage IV or unresectable stage III BRAF (V600)‐mutated melanoma were randomly assigned (3:1) to receive dabrafenib (150 mg twice daily, orally) or dacarbazine (1000 mg m^?2 intravenously every 3 weeks). Patients were stratified according to American Joint Committee on Cancer stage. The primary endpoint was investigator‐assessed progression‐free survival (PFS) and was analysed by intention to treat. Safety was assessed per protocol. Findings Of the 733 patients screened, 250 were randomly assigned to receive either dabrafenib (187 patients) or dacarbazine (63 patients). Median PFS was 5·1 months for dabrafenib and 2·7 months for dacarbazine, with a hazard ratio of 0·30 (95% confidence interval 0·18–0·51, P < 0·0001). At cut‐off, 107 (57%) patients in the dabrafenib group and 14 (22%) in the dacarbazine group remained on randomized treatment. Treatment‐related adverse events (grade 2 or higher) occurred in 100 (53%) of the 187 patients who received dabrafenib and in 26 (44%) of the 59 patients who received dacarbazine. The most common adverse events with dabrafenib were skin‐related toxic effects, fever, fatigue, arthralgia and headache. The most common adverse events with dacarbazine were nausea, vomiting, neutropenia, fatigue and asthenia. Grade 3–4 adverse effects were uncommon in both groups. Interpretation Dabrafenib significantly improved PFS compared with dacarbazine.     

Sirt5 is dispensable for BrafV600E‐mediated cutaneous melanoma development and growth in vivo

Sirt5 is known to functionally regulate mitochondrial proteins by altering posttranslational modifications, including lysine desuccinylation. While roles for Sirt5 as either a tumor promoter or suppressor, or in chemoresistance, have been implicated in other cancers, the function of Sirt5 in cutaneous melanoma has not been well examined. Therefore, to determine whether Sirt5 is necessary for Braf^V600E‐mediated melanoma formation and/or disease progression, we crossed a genetically engineered murine melanoma model (Tyr^CreERT2/+; Braf^{LSL‐V600E/+}; Pten^flox/flox) to Sirt5^?/? knockout animals. In addition, we tested for synergism with a selective BRAF (V600E) inhibitor in Sirt5^?/? mouse melanoma cells. Taken together, this report demonstrates that, in these models, Sirt5 is dispensable for Braf^V600E‐mediated cutaneous melanoma formation and growth in vivo, and does not improve sensitivity to a selective BRAF inhibitor.     

Sentinel lymph node biopsy for 102 patients with primary cutaneous melanoma at a single Japanese institute

Sentinel lymph node biopsy (SLNB) is a widely accepted standard procedure for patients with clinically localized melanoma. Melanoma prevalence and Clark's subtype differ between Asians and Caucasians. Here, we evaluated our experience on SLNB for cutaneous melanoma in a Japanese population. SLNB was performed for patients with melanoma between July 2000 and June 2014. We retrospectively analyzed 102 patients regarding association of clinicopathological features with sentinel lymph node (SLN) status, melanoma‐specific survival (MSS) and disease‐free survival (DFS). A positive SLN was significantly associated with primary Breslow thickness. Compared with 43 patients with negative SLN, 59 patients with positive SLN had significantly shorter MSS (5‐year survival rate, 94.3% vs 63.2%; P = 0.0002) and DFS (5‐year survival rate, 92.7% vs 63.4%; P = 0.0004). According to our subgroup analyses, nine patients with positive non‐SLN had significantly shorter MSS compared with 32 patients with negative non‐SLN (5‐year survival rate, 32.4% vs 68.5%; P = 0.0273). The survival of 51 Japanese patients with acral lentiginous melanoma (ALM) was not inferior to the survival of patients with other Clark's subtype. Breslow thickness is an important factor for both MSS and DFS, and the status of SLN is the most predictive prognostic factor in Japanese patients with clinically localized melanomas, as in case of Caucasians. Features of ALM may be different between Asians and Caucasians.     

Paraoxonase 1 (PON1) 55 polymorphism,lipid profiles and psoriasis

Background Paraoxonase 1 (PON1) is a serum high‐density lipoprotein‐bound enzyme with antioxidant function. It hydrolyses lipid peroxides, protecting low‐density lipoproteins from oxidative modifications. Patients with psoriasis are at greater risk of oxidative stress, which is associated with abnormal plasma lipid metabolism. Objectives In this study, association of the PON1 55 M allele with serum arylesterase (ARE) activity, malondialdehyde (MDA), lipid profiles and psoriasis was investigated. Methods The present case–control study consisted of 100 patients with psoriasis with and without cardiovascular diseases (mean age 35·3 years) and 100 sex‐ and age‐matched unrelated healthy controls (mean age 35·7 years) from the population of western Iran. The PON1 55 Met>Leu polymorphism was detected by polymerase chain reaction–restriction fragment length polymorphism. Serum ARE activity, MDA, and lipid and apolipoprotein levels were determined spectrophotometrically, by high‐performance liquid chromatography and by enzyme assay, respectively. Results The presence of the PON1 55 M allele was found to be associated with psoriasis (odds ratio = 1·96, P = 0·017). The patients with psoriasis with the PON1 M (M/L + M/M) allele had higher MDA levels (4·12 ± 0·88 vs. 2·24 ± 0·55 μmol L^?1, P < 0·001), apolipoprotein B (APOB)/APOA1 ratio (0·91 ± 0·66 vs. 0·66 ± 0·35, P = 0·004), APOB (111 ± 38·7 vs. 88·3 ± 22·5 mg mL^?1, P = 0·001) and lipoprotein(a) [LP(a)] (21·9 ± 18·4 vs. 15·8 ± 16·6 mg mL^?1, P = 0·034), but lower ARE activity (39·6 ± 11 vs. 45·9 ± 11·8 U mL^?1, P = 0·031) than the control subjects. ARE activity showed a significant positive correlation with APOA1 and a negative correlation with MDA concentration in patients with psoriasis. Conclusions The PON1 55 M allele is a risk factor for psoriasis. Carriers of this allele have high levels of MDA, APOB and LP(a), a high APOB/APOA1 ratio and low ARE activity. These results indicate that oxidative stress, impairment of the antioxidant system and abnormal lipid metabolism may play a role in the pathogenesis and progression of psoriasis and its related complications. These data suggest that patients with psoriasis are more susceptible to vascular diseases.     

High‐concentration (20 μg g−1) tacalcitol ointment in the treatment of facial psoriasis: an 8‐week open‐label clinical trial

Background Facial psoriasis gives rise to considerable concern because of associated cosmetic problems and psychosocial distress. It requires a treatment approach other than topical corticosteroids, which bear a risk of cutaneous adverse reactions. Recently, topical tacalcitol has been shown to be effective in psoriasis. Objectives The aim of this open‐label single‐centre study is to investigate the efficacy and safety of high‐concentration (20 μg g^?1) tacalcitol ointment (Bonalfa‐high^®, Teijin Pharma, Tokyo, Japan) in patients with facial psoriasis and to evaluate clinical response according to the distribution of facial psoriatic lesions. Patients and methods Thirty‐seven patients were enrolled to this clinical trial. Tacalcitol 20 μg g^?1 ointment was applied once daily to psoriatic lesions of the face over an 8‐week period. Patients were also categorized into three subtypes according to facial lesion distribution. Efficacy was evaluated by the facial Psoriasis Area and Severity Index (facial PASI) and the Physician’s Global Assessment (PGA) score at weeks 2, 4 and 8. The Subjective Global Assessment (SGA) was also determined at the end of the study. Results Thirty‐three patients completed the clinical trial. Mean facial PASI of 33 patients at baseline was 9·58 and after 8 weeks of treatment the mean facial PASI decreased significantly to 3·88. By using PGA, patients showed the following responses to treatment: clearance (n = 1); excellent (6); good (16); fair (4); slight (5); no change (1). The response rate among the three facial psoriasis types showed no difference. Using the SGA, 27 (82%) of the patients presented excellent (15%) or good (67%) effect with tacalcitol 20 μg g^?1 ointment. No serious adverse reactions were observed. Conclusions This is the first clinical study reporting a relevant therapeutic effect and favourable safety profile of tacalcitol 20 μg g^?1 ointment in facial psoriasis. These results suggest that tacalcitol 20 μg g^?1 ointment can be used as the first‐line treatment in patients with facial psoriasis.