Randomized Trial of Four Treatment Approaches for Actinic Keratosis.

BACKGROUND: Actinic keratosis is the most frequent premalignant skin disease in the white population. In current guidelines, no clear recommendations are made about which treatment is preferred. METHODS: We investigated the effectiveness of four frequently used field-directed treatments (for multiple lesions in a continuous area). Patients with a clinical diagnosis of five or more actinic keratosis lesions on the head, involving one continuous area of 25 to 100 cm2, were enrolled at four Dutch hospitals. Patients were randomly assigned to treatment with 5% fluorouracil cream, 5% imiquimod cream, methyl aminolevulinate photodynamic therapy (MAL-PDT), or 0.015% ingenol mebutate gel. The primary outcome was the proportion of patients with a reduction of 75% or more in the number of actinic keratosis lesions from baseline to 12 months after the end of treatment. Both a modified intention-to-treat analysis and a per-protocol analysis were performed. RESULTS: A total of 624 patients were included from November 2014 through March 2017. At 12 months after the end of treatment, the cumulative probability of remaining free from treatment failure was significantly higher among patients who received fluorouracil (74.7%; 95% confidence interval [CI], 66.8 to 81.0) than among those who received imiquimod (53.9%; 95% CI, 45.4 to 61.6), MAL-PDT (37.7%; 95% CI, 30.0 to 45.3), or ingenol mebutate (28.9%; 95% CI, 21.8 to 36.3). As compared with fluorouracil, the hazard ratio for treatment failure was 2.03 (95% CI, 1.36 to 3.04) with imiquimod, 2.73 (95% CI, 1.87 to 3.99) with MAL-PDT, and 3.33 (95% CI, 2.29 to 4.85) with ingenol mebutate (P≤0.001 for all comparisons). No unexpected toxic effects were documented. CONCLUSIONS: At 12 months after the end of treatment in patients with multiple actinic keratosis lesions on the head, 5% fluorouracil cream was the most effective of four field-directed treatments. (Funded by the Netherlands Organization for Health Research and Development; ClinicalTrials.gov number, NCT02281682.).

Reorganising dermatology care: predictors of the substitution of secondary care with primary care.

BACKGROUND: The substitution of healthcare is a way to control rising healthcare costs. The Primary Care Plus (PC+) intervention of the Dutch 'Blue Care' pioneer site aims to achieve this feat by facilitating consultations with medical specialists in the primary care setting. One of the specialties involved is dermatology. This study explores referral decisions following dermatology care in PC+ and the influence of predictive patient and consultation characteristics on this decision. METHODS: This retrospective study used clinical data of patients who received dermatology care in PC+ between January 2015 and March 2017. The referral decision following PC+, (i.e., referral back to the general practitioner (GP) or referral to outpatient hospital care) was the primary outcome. Stepwise logistic regression modelling was used to describe variations in the referral decisions following PC+, with patient age and gender, number of PC+ consultations, patient diagnosis and treatment specialist as the predicting factors. RESULTS: A total of 2952 patients visited PC+ for dermatology care. Of those patients with a registered referral, 80.2% (N = 2254) were referred back to the GP, and 19.8% (N = 558) were referred to outpatient hospital care. In the multivariable model, only the treating specialist and patient's diagnosis independently influenced the referral decisions following PC+. CONCLUSION: The aim of PC+ is to reduce the number of referrals to outpatient hospital care. According to the results, the treating specialist and patient diagnosis influence referral decisions. Therefore, the results of this study can be used to discuss and improve specialist and patient profiles for PC+ to further optimise the effectiveness of the initiative.

Mendelian Disorders of Cornification Caused by Defects in Intracellular Calcium Pumps: Mutation Update and Database for Variants in ATP2A2 and ATP2C1 Associated with Darier Disease and Hailey-Hailey Disease.

The two disorders of cornification associated with mutations in genes coding for intracellular calcium pumps are Darier disease (DD) and Hailey-Hailey disease (HHD). DD is caused by mutations in the ATP2A2 gene, whereas the ATP2C1 gene is associated with HHD. Both are inherited as autosomal-dominant traits. DD is mainly defined by warty papules in seborrheic and flexural areas, whereas the major symptoms of HHD are vesicles and erosions in flexural skin. Both phenotypes are highly variable. In 12%-40% of DD patients and 12%-55% of HHD patients, no mutations in ATP2A2 or ATP2C1 are found. We provide a comprehensive review of clinical variability in DD and HHD and a review of all reported mutations in ATP2A2 and ATP2C1. Having the entire spectrum of ATP2A2 and ATP2C1 variants allows us to address the question of a genotype-phenotype correlation, which has not been settled unequivocally in DD and HHD. We created a database for all mutations in ATP2A2 and ATP2C1 using the Leiden Open Variation Database (LOVD v3.0), for variants reported in the literature and future inclusions. This data may be of use as a reference tool in further research on treatment of DD and HHD.

Aesthetic outcome and complications of simple interrupted versus running subcuticular sutures in facial surgery: A randomized controlled trial.

BACKGROUND: The suturing technique and its associated complications could affect cosmetic outcome after facial surgery. Literature on this topic is limited. OBJECTIVE: To compare the cosmetic results 12 months after treatment and complications associated with simple interrupted sutures (SIS) versus running subcuticular sutures (RSS) in facial surgery. METHODS: A randomized, controlled multicenter trial was performed. Adults receiving dermatologic surgery on the face were randomized to receive SIS or RSS for wound closure. The primary outcome was the overall opinion score on the Patient and Observer Scar Assessment Scale (POSAS) 12 months after surgery. Secondary outcomes were the complication rates and scores according to alternative methods for assessment of cosmetic outcome. The observer of cosmetic outcome was blinded to treatment assignment. RESULTS: 142 patients were randomized to receive SIS (n = 73) or RSS (n = 69). Twelve months after surgery, the median score of the overall opinion on the POSAS was 2.0 (range 1-8) according to the patients and 3.0 (range 1-8) according to the observer in both groups. In the RSS group, hyper- or hypoesthesia was reported more often. LIMITATIONS: The cosmetic result was assessed by 1 observer. CONCLUSION: SIS and RSS in facial surgery resulted in comparable cosmetic outcomes. RSS was more often associated with hyper- or hypoesthesia.

Comprehensive analysis of the gene encoding filaggrin uncovers prevalent and rare mutations in ichthyosis vulgaris and atopic eczema.

We recently reported two common filaggrin (FLG) null mutations that cause ichthyosis vulgaris and predispose to eczema and secondary allergic diseases. We show here that these common European mutations are ancestral variants carried on conserved haplotypes. To facilitate comprehensive analysis of other populations, we report a strategy for full sequencing of this large, highly repetitive gene, and we describe 15 variants, including seven that are prevalent. All the variants are either nonsense or frameshift mutations that, in representative cases, resulted in loss of filaggrin production in the epidermis. In an Irish case-control study, the five most common European mutations showed a strong association with moderate-to-severe childhood eczema (chi2 test: P = 2.12 x 10(-51); Fisher's exact test: heterozygote odds ratio (OR) = 7.44 (95% confidence interval (c.i.) = 4.9-11.3), and homozygote OR = 151 (95% c.i. = 20-1,136)). We found three additional rare null mutations in this case series, suggesting that the genetic architecture of filaggrin-related atopic dermatitis consists of both prevalent and rare risk alleles.

Correlation between histological findings on punch biopsy specimens and subsequent excision specimens in cutaneous squamous cell carcinoma.

Diagnosis and subsequent treatment of cutaneous squamous cell carcinoma are frequently based on punch biopsies. Regarding the current TNM classification and stage grouping for cutaneous squamous cell carcinoma, it is important to identify the high-risk features (infiltration depth > 4 mm, perineural and/or lymphovascular invasion and poor differentiation). This study investigates the agreement of histological high-risk features and TNM grouping stage on 3 mm punch biopsies and subsequent surgical excision in 105 patients diagnosed with cutaneous squamous cell carcinoma. On punch biopsy, infiltration depth > 4 mm is not identified in 83.3% (30/36), perineural invasion in 90.9% (10/11) and poor differentiation in 85.7% (6/7) of cases. The TNM stage was underestimated on punch biopsy in 15.4% (16/104). This study shows that on a 3 mm punch biopsy, high-risk features in cSCC can remain undetected and that the actual TNM stage is not identified in 1 out of 6 tumours.

Photodynamic therapy versus topical imiquimod versus topical fluorouracil for treatment of superficial basal-cell carcinoma: a single blind, non-inferiority, randomised controlled trial.

BACKGROUND: Superficial basal-cell carcinoma is most commonly treated with topical non-surgical treatments, such as photodynamic therapy or topical creams. Photodynamic therapy is considered the preferable treatment, although this has not been previously tested in a randomised control trial. We assessed the effectiveness of photodynamic therapy compared with imiquimod or fluorouracil in patients with superficial basal-cell carcinoma. METHODS: In this single blind, non-inferiority, randomised controlled multicentre trial, we enrolled patients with a histologically proven superficial basal-cell carcinoma at seven hospitals in the Netherlands. Patients were randomly assigned to receive treatment with methylaminolevulinate photodynamic therapy (MAL-PDT; two sessions with an interval of 1 week), imiquimod cream (once daily, five times a week for 6 weeks), or fluorouracil cream (twice daily for 4 weeks). Follow-up was at 3 and 12 months post-treatment. Data were collected by one observer who was blinded to the assigned treatment. The primary outcome was the proportion of patients free of tumour at both 3 and 12 month follow up. A pre-specified non-inferiority margin of 10% was used and modified intention-to-treat analyses were done. This trial is registered as an International Standard Randomised controlled trial (ISRCTN 79701845). FINDINGS: 601 patients were randomised: 202 to receive MAL-PDT, 198 to receive imiquimod, and 201 to receive fluorouracil. A year after treatment, 52 of 196 patients treated with MAL-PDT, 31 of 189 treated with imiquimod, and 39 of 198 treated with fluorouracil had tumour residue or recurrence. The proportion of patients tumour-free at both 3 and 12 month follow-up was 72.8% (95% CI 66.8-79.4) for MAL-PDT, 83.4% (78.2-88.9) for imiquimod cream, and 80.1% (74.7-85.9) for fluorouracil cream. The difference between imiquimod and MAL-PDT was 10.6% (95% CI 1.5-19.5; p=0.021) and 7.3% (-1.9 to 16.5; p=0.120) between fluorouracil and MAL-PDT, and between fluorouracil and imiquimod was -3.3% (-11.6 to 5.0; p=0.435. For patients treated with MAL-PDT, moderate to severe pain and burning sensation were reported most often during the actual MAL-PDT session. For other local adverse reactions, local skin redness was most often reported as moderate or severe in all treatment groups. Patients treated with creams more often reported moderate to severe local swelling, erosion, crust formation, and itching of the skin than patients treated with MAL-PDT. In the MAL-PDT group no serious adverse events were reported. One patient treated with imiquimod and two patients treated with fluorouracil developed a local wound infection and needed additional treatment in the outpatient setting. INTERPRETATION: Topical fluorouracil was non-inferior and imiquimod was superior to MAL-PDT for treatment of superficial basal-cell carcinoma. On the basis of these findings, imiquimod can be considered the preferred treatment, but all aspects affecting treatment choice should be weighted to select the best treatment for patients. FUNDING: Grant of the Netherlands Organization for Scientific Research ZONMW (08-82310-98-08626).

Effectiveness of a patient decision aid for patients with superficial basal cell carcinoma: A pre- and post-implementation study.

OBJECTIVE: This study evaluates whether using a patient decision aid (PDA) for patients with superficial basal-cell carcinoma (sBCC) results in a decreased decisional conflict level and increased knowledge. METHODS: In a prospective multicentre study, patient groups were included before and after implementation of a PDA. Decisional conflict levels were compared directly after making the treatment decision, measured once as the mean score on the decisional conflict scale (DCS). Higher scores correspond with higher conflict levels (0-100). Secondary outcomes were knowledge on treatment options, recognizing a BCC, and risk factors for developing a BCC measured on an adapted version of a validated knowledge questionnaire for melanoma patients, and patient satisfaction with the PDA. RESULTS: Data was available for 103 patients in the control-group and 109 in the PDA-group. The mean DCS score in the control-group was 22.78 (SD 14.76) compared to 22.34 (SD 14.54) in the PDA-group; the decrease was non-significant (p = 0.828). The average percentage correct answers on the knowledge questionnaire increased from 76.5% in the control-group to 80.5% in the PDA-group (p = 0.044). According to the majority of patients in the PDA-group (73.7%) the PDA had added value. CONCLUSION: Using the PDA had no significant effect on decisional conflict levels, but increased overall knowledge on relevant issues concerning sBCC. PRACTICE IMPLICATIONS: The PDA can be used as an informational tool by patients with sBCC.

Alopecia, neurological defects, and endocrinopathy syndrome caused by decreased expression of RBM28, a nucleolar protein associated with ribosome biogenesis.

Single-gene disorders offer unique opportunities to shed light upon fundamental physiological processes in humans. We investigated an autosomal-recessive phenotype characterized by alopecia, progressive neurological defects, and endocrinopathy (ANE syndrome). By using homozygosity mapping and candidate-gene analysis, we identified a loss-of-function mutation in RBM28, encoding a nucleolar protein. RBM28 yeast ortholog, Nop4p, was previously found to regulate ribosome biogenesis. Accordingly, electron microscopy revealed marked ribosome depletion and structural abnormalities of the rough endoplasmic reticulum in patient cells, ascribing ANE syndrome to the restricted group of inherited disorders associated with ribosomal dysfunction.

Reorganization of the nuclear lamina and cytoskeleton in adipogenesis.

A thorough understanding of fat cell biology is necessary to counter the epidemic of obesity. Although molecular pathways governing adipogenesis are well delineated, the structure of the nuclear lamina and nuclear-cytoskeleton junction in this process are not. The identification of the 'linker of nucleus and cytoskeleton' (LINC) complex made us consider a role for the nuclear lamina in adipose conversion. We herein focused on the structure of the nuclear lamina and its coupling to the vimentin network, which forms a cage-like structure surrounding individual lipid droplets in mature adipocytes. Analysis of a mouse and human model system for fat cell differentiation showed fragmentation of the nuclear lamina and subsequent loss of lamins A, C, B1 and emerin at the nuclear rim, which coincides with reorganization of the nesprin-3/plectin/vimentin complex into a network lining lipid droplets. Upon 18 days of fat cell differentiation, the fraction of adipocytes expressing lamins A, C and B1 at the nuclear rim increased, though overall lamin A/C protein levels were low. Lamin B2 remained at the nuclear rim throughout fat cell differentiation. Light and electron microscopy of a subcutaneous adipose tissue specimen showed striking indentations of the nucleus by lipid droplets, suggestive for an increased plasticity of the nucleus due to profound reorganization of the cellular infrastructure. This dynamic reorganization of the nuclear lamina in adipogenesis is an important finding that may open up new venues for research in and treatment of obesity and nuclear lamina-associated lipodystrophy.

Correlation between histologic findings on punch biopsy specimens and subsequent excision specimens in recurrent basal cell carcinoma.

BACKGROUND: The type of treatment for a basal cell carcinoma (BCC) depends on the histologic subtype. Histologic examination is usually performed on incisional biopsy specimens. In primary BCC, the histologic subtype is correctly identified with a punch biopsy in 80.7% of cases. In recurrent BCC, correct identification is more difficult because of discontinuous growth caused by scar formation. Because an aggressive histologic subtype has a significantly higher risk for recurrence in these tumors, the histologic subtype is at least as important in recurrent BCC as it is in primary BCC. OBJECTIVE: To investigate the correlation between histologic findings on punch biopsy specimens and subsequent excision specimens in recurrent BCC. Furthermore, we sought to clarify how often an aggressive histologic subtype was missed, based on the punch biopsy specimen. METHODS: We compared the histologic subtype in a punch biopsy specimen with the subsequent excision specimen in recurrent BCC. All BCCs were coded and judged randomly by the same dermatopathologist. RESULTS: In 24 of 73 investigated BCCs (32.9%), the histologic subtype of the initial biopsy did not match with the histologic subtype of the subsequent excision. Of the 37 excised BCCs with an aggressive histologic subtype, 7 (19%) were missed by the initial punch biopsy. LIMITATIONS: Intraobserver variation may have affected the results of this study. CONCLUSIONS: Discriminating tumors with any aggressive growth is relevant for treatment. However, in recurrent BCC, the histology of the biopsy specimen does not always correlate with the histology of the definitive excision. This may have important therapeutic implications.

Differentiation between basal cell carcinoma and trichoepithelioma by immunohistochemical staining of the androgen receptor: an overview.

Clinical and histopathological differentiation between basal cell carcinoma (BCC) and trichoepithelioma (TE) is a frequent problem. Attempts have been made to identify immunohistochemical markers helpful in differentiating them. A correct diagnosis is important because the tumours are treated differently. Recent studies showed the absence of androgen receptor (AR) expression in benign hair follicle tumours like TE. This study examines whether AR immunostaining is a useful diagnostic test to differentiate between BCC and TE. We randomly selected 75 cases with histological diagnoses of either BCC (subtypes: superficial, nodular or infiltrative) or TE (subtypes: classic or desmoplastic) from the database of the pathology department of Maastricht University Medical Centre. The available haematoxylin & eosin (H&E) slides were reviewed by three independent investigators using predetermined characteristics. Fifty-six slides (38 BCC and 18 TE) with unequivocal histological characteristics of either tumour were used for immunohistochemistry with AR antibodies. Any nuclear expression within the tumour was considered positive. AR expression was present in 5/8 classic TE, 0/10 desmoplastic TE, 22/23 superficial or nodular BCC and in 10/15 infiltrative BCC. Immunohistochemical stain for AR is useful to differentiate between TE and BCC; particularly in desmoplastic TE versus infiltrative BCC (specificity and positive predictive value of 100%).

Mutations in the CDSN gene cause peeling skin disease and hypotrichosis simplex of the scalp.

Peeling skin disease is a rare genodermatosis characterized by superficial exfoliation or peeling of the skin. Peeling skin disease is caused by biallelic mutations in CDSN as an autosomal recessive trait. Monoallelic mutations in CDSN have also been described in an autosomal dominant inherited genodermatosis: hypotrichosis simplex of the scalp. This disease is characterized by progressive hair loss of the scalp with onset after early childhood. Clinical data were obtained from a patient with lifelong generalized skin peeling and both his parents. The patient's parents did not suffer from skin peeling, but the mother had a history of thin scalp hair since early childhood. Mutation analysis in the patient showed compound heterozygous mutations in exon 2 of CDSN, a nonsense mutation c.598C>T (p.[Gln200*]), previously associated with hypotrichosis simplex of the scalp, and a frame-shift mutation c.164_167dup (p.[Thr57Profs*6]), previously described in peeling skin disease. The p.(Gln200*) mutation was also found in the mother of the proband. Our study strengthens the previously established link between mutations in CDSN to peeling skin disease and hypotrichosis simplex of the scalp.

Sjögren-Larsson syndrome: The mild end of the phenotypic spectrum.

Sjögren-Larsson syndrome (SLS) is a rare inborn error of lipid metabolism. The syndrome is caused by mutations in the ALDH3A2 gene, resulting in a deficiency of fatty aldehyde dehydrogenase. Most patients have a clearly recognizable severe phenotype, with congenital ichthyosis, intellectual disability, and spastic diplegia. In this study, we describe two patients with a remarkably mild phenotype. In both patients, males with actual ages of 45 and 61 years, the diagnosis was only established at an adult age. Their skin had been moderately affected from childhood onward, and both men remained ambulant with mild spasticity of their legs. Cognitive development, as reflected by school performance and professional career, had been unremarkable. Magnetic resonance spectroscopy of the first patient was lacking the characteristic lipid peak. We performed a literature search to identify additional SLS patients with a mild phenotype. We compared the clinical, radiologic, and molecular features of the mildly affected patients with the classical phenotype. We found 10 cases in the literature with a molecular proven diagnosis and a mild phenotype. Neither a genotype-phenotype correlation nor an alternative explanation for the strikingly mild phenotypes was found. New biochemical techniques to study the underlying metabolic defect in SLS, like lipidomics, may in the future help to unravel the reasons for the exceptionally mild phenotypes. In the meantime, it is important to recognize these mildly affected patients to provide them with appropriate care and genetic counseling, and to increase our insights in the true disease spectrum of SLS.