Melanoma-associated leukoderma and vitiligo cannot be differentiated based on blinded assessment by experts in the field.

BACKGROUND: Melanoma-associated leukoderma (MAL) is a depigmenting disorder that can occur spontaneously in patients with melanoma. The differences in clinical presentation between MAL and vitiligo are not well defined. This may lead to misdiagnosing MAL as vitiligo, resulting in delayed detection of melanoma. OBJECTIVE: The objective of this study was to assess whether experts in the field can distinguish between MAL and vitiligo, and to assess if discriminative features can be identified. METHODS: We designed an image comparison study in which 4 experts in the field blindly assessed photographs followed by medical history of 11 patients with MAL and 33 with vitiligo. RESULTS: The assessors misdiagnosed 72.7% of MAL cases and marked 80.0% of them as typical vitiligo. The median age at onset of the leukoderma was higher (55 years, P = .001) in MAL. No discriminative features were found. LIMITATIONS: Sampling bias because of inclusion in tertiary referral center is a limitation. CONCLUSION: The clinical presentation of leukoderma in patients with melanoma resembles that of vitiligo. We propose "melanoma-associated vitiligo" as the more appropriate term for leukoderma in patients with melanoma. Clinicians should be aware that depigmentation in vitiligo can also be caused by melanoma-associated vitiligo and a total body inspection should be performed.

Back to the roots - dermatology in ancient Egyptian medicine.

Although ancient Greek and Roman medicine is generally considered the origin of European medicine, there is evidence in ancient Egyptian texts suggesting a precursor role of ancient Egyptian medicine in this regard. What did Greek and Roman physicians learn from their Egyptian counterparts? Of the medical papyri discovered to date, the largest and most significant - the Ebers papyrus and the Smith papyrus - originate from the beginning of the New Kingdom, however, they were - at least in part - already written during the Old Kingdom. Considering the times, the spectrum of diseases treated as well as the range of conservative and surgical treatment methods was truly astounding. Taking a medical history, performing a thorough manual examination, and assessing clinical findings constituted key components in establishing a diagnosis. Apart from hygienic aspects, skin and hair disorders, the treatment of acute and chronic wounds and injuries as well as cosmetic procedures took on an important role. Even back then, physicians sought to assess inflammatory processes with respect to their cardinal features, implement graded wound therapy, and treat diseases with allopathic drugs. The 'channel theory' prevalent at that time, in which the unimpeded flow of bodily fluids was considered a fundamental prerequisite for health, may likely be regarded as precursor of ancient Greek humoral pathology. The latter became the basis for the subsequently established theory of the four humors, and was thus essential for the entire field of medieval medicine.

Transplantation of autologous keratinocyte suspension in fibrin matrix to chronic venous leg ulcers: improved long-term healing after removal of the fibrin carrier.

BACKGROUND: The transplantation of keratinocytes suspended in fibrin carrier represents a candidate regimen for chronic ulcer treatment in an outpatient setting. We evaluated the integration and survival of autologous individualized keratinocytes applied within fibrin matrix onto chronic venous leg ulcers in vivo. Parallel in vitro culture was used to validate keratinocyte survival and apoptosis in fibrin compared to collagen matrix carrier. METHODS: Seven patients with chronic venous leg ulcers were transplanted with autologous keratinocytes suspended in fibrin sealant after isolation and expansion from full-skin biopsy. The fibrin carrier was removed in three patients after 7 days, whereas four patients served as control with fibrin remaining. In parallel in vitro cultures, primary keratinocyte movement in fibrin as well as viability in three-dimensional (3D) fibrin versus collagen lattices was examined. RESULTS: Complete ulcer healing was observed in four of seven ulcers after a mean duration of 14.5 weeks. If the fibrin layer was removed, complete wound healing occurred in three of three patients, compared to one of four in the control group. In vitro, keratinocytes formed a monolayer underneath but remained isolated and nonmobile within the fibrin matrix, suggesting reepithelialization along the lower fibrin interphase. Keratinocyte culture in 3D fibrin at clinically used concentration (90 mg/mL) caused high levels of apoptosis, similar to 3D collagen, which was prevented by diluting fibrin concentration to 3 mg/mL. CONCLUSIONS: Transplantation of autologous keratinocytes suspended in fibrin is efficient in the treatment of chronic venous leg ulcers. Due to an antimigratory and survival-compromising effect, the presently used fibrin carrier should be removed after a few days of transplantation.

Repigmentation of pretibial vitiligo with calcineurin inhibitors under occlusion.

Treatment of vitiligo is a challenge, especially in children. Recently, topical calcineurin inhibitors have been introduced in the management of vitiligo, but significant repigmentation is not achieved except on the face. Large pretibial lesions of a 15-year-old female with progressive vitiligo were treated twice daily over six months with 0.1% tacrolimus ointment on the right and 1% pimecrolimus cream on the left side without effect. Additional overnight occlusion with polyurethane and hydrocolloid foils during the following 18 months led to substantial repigmentation on both sides (tacrolimus-treated side, 88% repigmented area; pimecrolimus-treated side, 73%). Tacrolimus serum levels measured at four different time points did not exceed 1.8 ng/ml. This case report on a direct comparison of topical tacrolimus and pimecrolimus in vitiligo shows that on the shins considerable improvement could be induced with both agents only by additional long-term occlusion and that tacrolimus was somewhat more effective than pimecrolimus.

Vitiligo and melanoma-associated hypopigmentation (MAH): shared and discriminative features.

BACKGROUND: It is unclear if differences between melanoma-associated hypopigmentation (MAH) and classical vitiligo exist. PATIENTS AND METHODS: Hypopigmented areas and associated lesions (halo nevi, hypopigmented scars) in 15 melanoma patients and 31 patients with classical vitiligo were analyzed by digital photography. The activity of the respective lesions was assessed by the vitiligo disease activity (VIDA) score. Associated diseases were recorded by history and serological tests;genotyping of HLA class I antigens as well as histology/immunohistology were performed. RESULTS: MAH were diagnosed in 12 of 15 melanoma patients; mean onset was 4.8 years after the primary diagnosis of the melanoma. Three melanoma patients reported hypopigmentation more than 15 years before diagnosis of melanoma. In the history and family history of vitiligo patients, autoimmune diseases were much more frequent and haplotype HLA-A2 was twice as common compared to MAH patients. MAH lesions were most often distributed in a bilateral symmetrical pattern, corresponding to vitiligo. MAH was less progressive compared to classical vitiligo; however, it was more often associated with other acquired leukodermas. In both groups hypopigmentation spread centripetally to the trunk. Histological and immunohistological differences were not found. CONCLUSIONS: Whereas differences exist concerning associated autoimmune diseases, MAH and vitiligo shared many common clinical and histological features. Further studies are needed to assess the clinical relevance of vitiligo-like alterations in melanoma patients.

Genome-wide association studies of autoimmune vitiligo identify 23 new risk loci and highlight key pathways and regulatory variants.

Vitiligo is an autoimmune disease in which depigmented skin results from the destruction of melanocytes, with epidemiological association with other autoimmune diseases. In previous linkage and genome-wide association studies (GWAS1 and GWAS2), we identified 27 vitiligo susceptibility loci in patients of European ancestry. We carried out a third GWAS (GWAS3) in European-ancestry subjects, with augmented GWAS1 and GWAS2 controls, genome-wide imputation, and meta-analysis of all three GWAS, followed by an independent replication. The combined analyses, with 4,680 cases and 39,586 controls, identified 23 new significantly associated loci and 7 suggestive loci. Most encode immune and apoptotic regulators, with some also associated with other autoimmune diseases, as well as several melanocyte regulators. Bioinformatic analyses indicate a predominance of causal regulatory variation, some of which corresponds to expression quantitative trait loci (eQTLs) at these loci. Together, the identified genes provide a framework for the genetic architecture and pathobiology of vitiligo, highlight relationships with other autoimmune diseases and melanoma, and offer potential targets for treatment.

Hypopigmentary skin disorders: current treatment options and future directions.

Alterations of skin and hair pigmentation are important features that have warranted treatment from ancient history on up to modern time. In some cultures, even today patients with vitiligo are regarded as social outcasts and are affected considerably both emotionally and physically. This article presents current options and future directions for the treatment of hypopigmentary disorders. Whereas with congenital disorders, such as albinism and phenylketonuria, no causal therapy has been established up to now, several treatment options for acquired hypopigmentary disorders have been investigated. In particular, in vitiligo, one of the most prevalent hypopigmentary disorders, a number of treatment modalities have been employed in the past 30 years. However, most of them are only able to palliate, not cure, the disease. Depending on the distribution of the hypopigmented lesions (localised or generalised) and the state of the disease (active or stable), several therapeutic options, for example phototherapy, surgical skin grafts, autologous melanocyte transplantation and immunomodulators, can be applied alone or in combination. For phototherapy, because of unfavourable results and adverse effects, ultraviolet (UV) A has been largely replaced by narrow-band UVB for repigmentation of generalised vitiligo. Although immunomodulators, such as corticosteroids, have been used both topically and systemically over the past 3 decades for the treatment of disseminated vitiligo, they are only suitable for the treatment of acrofacial and localised forms because of adverse effects. Hence, new immunomodulatory agents, such as calcineurin antagonists, have recently been introduced as new promising tools to treat acquired hypopigmentary disorders. However, all therapeutic approaches are hampered by the fact that the pathophysiology of hypopigmentary disorders is still poorly understood.

Treatment of vitiligo using targeted UVB-Intense Pulsed Light (IPL)- phototherapy: evaluation of variables affecting therapeutic success.

BACKGROUND: Targeted UVB intense pulsed light (IPL)-phototherapy has gained interest for repigmentation of vitiligo as it allows selective treatment, sparing the surrounding skin. However, optimal treatment frequency and duration are not known. OBJECTIVES: We compared the efficacy and safety of two treatment protocols, weekly and every two weeks, for a maximum of 12 months. Variables affecting treatment response were evaluated. PATIENTS & METHODS: 22 patients (16 female, 6 male; aged 15 - 67 years) with generalised vitiligo were evaluated retrospectively. UVB-IPL had been administered weekly (13 patients, group A), or every second week (9 patients, group B). In cases of no response, treatment stopped after 6 months. Regimentation was evaluated qualitatively and quantitatively. RESULTS: After 6 months, 12/13 patients (A), 3/9 patients (B) showed repigmentation. Due to lack of success, treatment was stopped after 6 months in 1 group A patient and 6/9 group B patients. After 12 months, lesions on the face and trunk in group A showed a mean of 70 ± 27% and 60 ± 29% repigmentation, respectively. Moderate to good repigmentation was seen in 78% of group A patients on the ulnar region on the forearms and the shins. Side effects were minimal. Treatment success depended on treatment frequency, number of treatments and the anatomical site of lesions. CONCLUSIONS: UVB-IPL phototherapy seems to be effective and well-tolerated in non-segmental vitiligo. A treatment frequency of weekly intervals rather than every two weeks appears preferable. Our observations will help in designing a sufficiently powered prospective clinical trial to test this hypothesis.

Development of a postsurgical patient-reported outcome instrument for women with vulvar neoplasia.

PURPOSE/OBJECTIVES: To (a) develop the Women With Vulvar Neoplasia-Patient-Reported Outcome (WOMAN-PRO) instrument as a measure of women's post-vulvar surgery symptom experience and informational needs, (b) examine its content validity, (c) describe modifications based on pilot testing, and (d) examine the content validity of the revised instrument. DESIGN: Mixed-methods research project. SETTING: One Swiss and two German university hospitals. SAMPLE: 10 patients and 6 clinicians participated in the pilot test. METHODS: The instrument was developed based on literature searches, clinician feedback, and patient interviews. Thirty-seven items were first pilot tested by patients and clinicians. The revised 36 items were pilot tested by patients. The content validity index (CVI) for each item and the entire instrument was calculated. MAIN RESEARCH VARIABLES: Symptom experience and informational needs of patients with vulvar neoplasia. FINDINGS: The initial pilot test showed excellent scale CVI based on feedback from patients (CVI = 0.98) and clinicians (CVI = 0.92). After revising six items based on low individual CVIs and participant comments, the revised WOMAN-PRO showed excellent item and scale content validity (CVI = 1). CONCLUSIONS: The newly developed WOMAN-PRO instrument can guide patients and clinicians in assessing symptoms, informational needs, and related distress. IMPLICATIONS FOR NURSING: Use of the WOMAN-PRO instrument in clinical practice can offer patients guidance in self-assessment and early recognition of symptoms. The instrument also can provide clinicians with systematic information about key symptoms from a patient perspective, as well as women's unmet informational needs. If the results of additional psychometric testing are promising, the WOMAN-PRO tool may provide an outcome measure for clinical trials.

Genome-wide association analyses identify 13 new susceptibility loci for generalized vitiligo.

We previously reported a genome-wide association study (GWAS) identifying 14 susceptibility loci for generalized vitiligo. We report here a second GWAS (450 individuals with vitiligo (cases) and 3,182 controls), an independent replication study (1,440 cases and 1,316 controls) and a meta-analysis (3,187 cases and 6,723 controls) identifying 13 additional vitiligo-associated loci. These include OCA2-HERC2 (combined P = 3.80 × 10(-8)), MC1R (P = 1.82 × 10(-13)), a region near TYR (P = 1.57 × 10(-13)), IFIH1 (P = 4.91 × 10(-15)), CD80 (P = 3.78 × 10(-10)), CLNK (P = 1.56 × 10(-8)), BACH2 (P = 2.53 × 10(-8)), SLA (P = 1.58 × 10(-8)), CASP7 (P = 3.56 × 10(-8)), CD44 (P = 1.78 × 10(-9)), IKZF4 (P = 2.75 × 10(-14)), SH2B3 (P = 3.54 × 10(-18)) and TOB2 (P = 6.81 × 10(-10)). Most vitiligo susceptibility loci encode immunoregulatory proteins or melanocyte components that likely mediate immune targeting and the relationships among vitiligo, melanoma, and eye, skin and hair coloration.

Occlusive treatment enhances efficacy of tacrolimus 0.1% ointment in adult patients with vitiligo: results of a placebo-controlled 12-month prospective study.

Topical tacrolimus was recently introduced as a novel therapeutic option in vitiligo. Excellent results were seen mainly on the face and neck areas. We treated 30 adult vitiligo patients with tacrolimus 0.1% ointment twice daily, and compared the results with those of placebo ointment. In 20 patients, defined areas on the right arm or leg were occluded overnight with 3 different dressings. Repigmentation was evaluated quantitatively and qualitatively. Quality of life changes were assessed with the Dermatology Life Quality Index. After 6 months, treatment was stopped in 7 of 30 patients as they did not show any repigmentation, 5 of them had no occlusive therapy. After 12 months, 17 of 21 patients (81%) with facial involvement showed repigmentation of the face. Although no or minimal repigmentation occurred on the extremities when using tacrolimus ointment alone, 80% of the patients showed repigmentation on the arms when using additional occlusive, especially hydrocolloid dressings. Hands, feet and lower legs were unresponsive. The best results were obtained in patients with long-standing vitiligo. Only minimal side-effects were noted. There was no significant elevation in tacrolimus blood levels, taking into account that occlusion was performed only on limited parts of the body. In conclusion, tacrolimus 0.1% ointment proved an effective and safe treatment option for adult patients with vitiligo. Beyond the face and neck areas, repigmentation could be achieved only by additional occlusion.

Confocal reflection imaging of 3D fibrin polymers.

The reconstruction of extracellular matrix (ECM) by confocal reflection microscopy is a physical approach for monitoring the ECM structure, cell-matrix interactions and changes of ECM structure over time. We here show that confocal reflection imaging is useful in reconstructing the fibrillar architecture of 3D fibrin lattices and fibroblasts embedded therein at high resolution up to 250 nm. Together with confocal fluorescence microscopy of collagen deposited by fibroblasts, this technique allows the monitoring of fibrin remodeling by stromal cells. In conclusion, confocal reflection microscopy is a valuable technique for real-time monitoring of the remodeling of fibrin matrices, such as during thrombus formation, wound healing, and tumor formation.

Narrow-band UVB311 nm vs. broad-band UVB therapy in combination with topical calcipotriol vs. placebo in vitiligo.

BACKGROUND: Recently, it has been shown that UVB phototherapy may be more effective than UVA in the treatment of vitiligo. Currently, however, no studies have compared the efficacy of UVB311 nm and broad-band UVB therapy. Calcipotriol has recently been reported to be effective adjunctive treatment for vitiligo, enhancing the efficacy of 8-methoxypsoralen plus UVA (PUVA) therapy. METHODS: Ten patients were enrolled in the study; nine completed the 12 months of therapy. The upper part of the body was treated twice weekly with UVB311 nm and the lower part with broad-band UVB. Calcipotriol was applied onto the vitiligo lesions of the right side of the body and placebo on the left side. Repigmentation was documented by photography, planimetry, and Vitiligo Disease Activity (VIDA) score. The quality of life was measured by the Dermatology Life Quality Index (DLQI). RESULTS: After 7-16 weeks, six of the nine patients showed initial repigmentation on the side treated with UVB311 nm. After 6 months of treatment, none of the patients showed repigmentation on the areas treated with broad-band UVB, which prompted us to apply UVB311 nm all over the body. At the end of 12 months, two patients showed > 75% repigmentation, two showed 51-75%, two showed 26-50%, and three showed 0-25%. In all patients with progressive vitiligo (seven of the nine patients), disease activity was stopped. Remarkably, vitiligo lesions treated with calcipotriol initially showed delayed repigmentation compared with control areas; however, there was no therapeutic difference between calcipotriol and placebo, both in combination with UVB311 nm, by the end of the study. The DLQI score improved significantly by an average of 28%. Conclusion UVB311 nm therapy was effective in the treatment of vitiligo, whereas broad-band UVB had no effect. Combination with calcipotriol ointment was not superior to UVB311 nm monotherapy. The quality of life significantly improved with narrow-band UVB311 nm phototherapy.

Postnatal confirmation of prenatally diagnosed trisomy 20 mosaicism in a patient with linear and whorled nevoid hypermelanosis.

Linear and whorled nevoid hypermelanosis (LWNH) is characterized by hyperpigmented reticulate macules in a Blaschko linear arrangement without atrophy or preceding inflammation. Underlying chromosomal mosaicism was often assumed, but has been verified in only a few published cases. We report a 7-year-old boy with LWNH associated with congenital ventricular septal defect and psychomotor retardation. Prenatal chromosomal analysis of amniocytes revealed trisomy 20 mosaicism, which was not confirmed in peripheral blood lymphocytes after birth. Histologic sections of skin biopsy specimens taken at age 6 years showed hyperpigmentation of the basal epidermal layer with prominent melanocytes and isolated melanophages in the upper dermis. Cytogenetic analysis of cultured skin fibroblasts revealed an extra chromosome 20 in 5 of the 30 metaphases studied (17%). Mosaic trisomy 20 is one of the most common autosomal mosaicisms identified in amniocytes and is, as a rule, compatible with normal pregnancy outcome. In postnatal analysis of peripheral blood lymphocytes, an extra chromosome 20 could never be detected. However, when confirmed in skin fibroblasts, trisomy 20 mosaicism may be associated with systemic anomalies. The present case shows for the first time an association of LWNH with trisomy 20 mosaicism and emphasizes the importance of analyzing skin fibroblasts in cases of prenatally diagnosed trisomy 20.