Treatment of xanthelasma palpebrarum with a 1064-nm, Q-switched Nd:YAG laser.

BACKGROUND: Xanthelasma palpebrarum is the most common cutaneous xanthoma characterized by soft, yellow papules or plaques that arise on the periorbital skin. As these lesions can be cosmetically disfiguring, many patients seek medical help to remove these lesions. OBJECTIVE: To determine the effectiveness and minimum number of treatment sessions with a 1064-nm, Q-switched neodymium-doped yttrium aluminum garnet (Nd:YAG) laser for the treatment of xanthelasma. METHODS: A retrospective review of patients with xanthelasma consecutively treated with Q-switched Nd:YAG laser was conducted. Forty-six patients with 103 lesions were identified from January 2012 through August 2015. Photographs taken of patients immediately before treatment and 4-8 weeks after treatment were independently evaluated by 2 dermatologists. RESULTS: After a single treatment session, 93.2% of lesions had some degree of clearance. All lesions had excellent-to-complete clearance after at least 4 treatment sessions. Patients usually required 4 treatment sessions for optimal results. LIMITATIONS: This was a retrospective study. Treatment parameters varied, follow-up periods were not uniform, and response was not assessed with a validated scale. CONCLUSION: The Q-switched Nd:YAG laser is effective and well tolerated in the treatment of xanthelasma in our study population.

CuboCube: Student creation of a cancer genetics e-textbook using open-access software for social learning.

Student creation of educational materials has the capacity both to enhance learning and to decrease costs. Three successive honors-style classes of undergraduate students in a cancer genetics class worked with a new software system, CuboCube, to create an e-textbook. CuboCube is an open-source learning materials creation system designed to facilitate e-textbook development, with an ultimate goal of improving the social learning experience for students. Equipped with crowdsourcing capabilities, CuboCube provides intuitive tools for nontechnical and technical authors alike to create content together in a structured manner. The process of e-textbook development revealed both strengths and challenges of the approach, which can inform future efforts. Both the CuboCube platform and the Cancer Genetics E-textbook are freely available to the community.

Contact sensitivity to preservatives in Singapore: frequency of sensitization to 11 common preservatives 2006-2011.

BACKGROUND: Preservatives are indispensable agents used to prevent bacterial and fungal contamination of cosmetics, personal care products, domestic preparations, and industrial products. OBJECTIVE: We evaluated patch-test data at the National Skin Centre, Singapore, from 2006 to 2011 to identify the trends in preservative contact allergies. METHODS: All patients with suspected contact dermatitis were patch tested to 4 preservatives within the modified European standard series. Patients were also tested with 7 preservatives from our special series if clinically indicated. RESULTS: Three thousand one hundred seventy-seven patients were tested to preservatives in the standard series. Sensitization frequencies were all greater than 1%: parabens (2.58%), methylchloroisothiazolinone/methylisothiazolinone (1.75%), quaternium 15 (1.43%), and methyldibromoglutaronitrile (1.2%). There was no change in trends in sensitization frequencies from 2006 to 2011, with no increase in sensitization frequency to methylchloroisothiazolinone/methylisothiazolinone. The sensitization frequencies for methyldibromoglutaronitrile/phenoxyethanol and diazolidinylurea were 2.03% and 1.37%, respectively, and remained less than 1% for bronopol, imidazolidinyl urea, and 2-phenoxyethanol. A rate of 0% was seen for 1,3-dimethylol-5,5-dimethyl hydantoin and formaldehyde; 9.4% of positive patch-test results became positive only at day 7. CONCLUSIONS: Preservatives are common causes of allergic contact dermatitis. This should be considered when introducing new preservatives into the market. Day 7 readings are important to detect late reactions.

Safety and efficacy of vemurafenib in BRAF(V600E) and BRAF(V600K) mutation-positive melanoma (BRIM-3): extended follow-up of a phase 3, randomised, open-label study.

BACKGROUND: In the BRIM-3 trial, vemurafenib was associated with risk reduction versus dacarbazine of both death and progression in patients with advanced BRAF(V600) mutation-positive melanoma. We present an extended follow-up analysis of the total population and in the BRAF(V600E) and BRAF(V600K) mutation subgroups. METHODS: Patients older than 18 years, with treatment-naive metastatic melanoma and whose tumour tissue was positive for BRAF(V600) mutations were eligible. Patients also had to have a life expectancy of at least 3 months, an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, and adequate haematological, hepatic, and renal function. Patients were randomly assigned by interactive voice recognition system to receive either vemurafenib (960 mg orally twice daily) or dacarbazine (1000 mg/m(2) of body surface area intravenously every 3 weeks). Coprimary endpoints were overall survival and progression-free survival, analysed in the intention-to-treat population (n=675), with data censored at crossover. A sensitivity analysis was done. This trial is registered with ClinicalTrials.gov, NCT01006980. FINDINGS: 675 eligible patients were enrolled from 104 centres in 12 countries between Jan 4, 2010, and Dec 16, 2010. 337 patients were randomly assigned to receive vemurafenib and 338 to receive dacarbazine. Median follow-up was 12·5 months (IQR 7·7-16·0) on vemurafenib and 9·5 months (3·1-14·7) on dacarbazine. 83 (25%) of the 338 patients initially randomly assigned to dacarbazine crossed over from dacarbazine to vemurafenib. Median overall survival was significantly longer in the vemurafenib group than in the dacarbazine group (13·6 months [95% CI 12·0-15·2] vs 9·7 months [7·9-12·8]; hazard ratio [HR] 0·70 [95% CI 0·57-0·87]; p=0·0008), as was median progression-free survival (6·9 months [95% CI 6·1-7·0] vs 1·6 months [1·6-2·1]; HR 0·38 [95% CI 0·32-0·46]; p<0·0001). For the 598 (91%) patients with BRAF(V600E) disease, median overall survival in the vemurafenib group was 13·3 months (95% CI 11·9-14·9) compared with 10·0 months (8·0-14·0) in the dacarbazine group (HR 0·75 [95% CI 0·60-0·93]; p=0·0085); median progression-free survival was 6·9 months (95% CI 6·2-7·0) and 1·6 months (1·6-2·1), respectively (HR 0·39 [95% CI 0·33-0·47]; p<0·0001). For the 57 (9%) patients with BRAF(V600K) disease, median overall survival in the vemurafenib group was 14·5 months (95% CI 11·2-not estimable) compared with 7·6 months (6·1-16·6) in the dacarbazine group (HR 0·43 [95% CI 0·21-0·90]; p=0·024); median progression-free survival was 5·9 months (95% CI 4·4-9·0) and 1·7 months (1·4-2·9), respectively (HR 0·30 [95% CI 0·16-0·56]; p<0·0001). The most frequent grade 3-4 events were cutaneous squamous-cell carcinoma (65 [19%] of 337 patients) and keratoacanthomas (34 [10%]), rash (30 [9%]), and abnormal liver function tests (38 [11%]) in the vemurafenib group and neutropenia (26 [9%] of 287 patients) in the dacarbazine group. Eight (2%) patients in the vemurafenib group and seven (2%) in the dacarbazine group had grade 5 events. INTERPRETATION: Inhibition of BRAF with vemurafenib improves survival in patients with the most common BRAF(V600E) mutation and in patients with the less common BRAF(V600K) mutation. FUNDING: F Hoffmann-La Roche-Genentech.

Grb2 promotes integrin-induced focal adhesion kinase (FAK) autophosphorylation and directs the phosphorylation of protein tyrosine phosphatase α by the Src-FAK kinase complex.

The integrin-activated Src-focal adhesion kinase (FAK) kinase complex phosphorylates PTPα at Tyr789, initiating PTPα-mediated signaling that promotes cell migration. Recruitment of the BCAR3-Cas complex by PTPα-phospho-Tyr789 at focal adhesions is one mechanism of PTPα signaling. The adaptor protein Grb2 is also recruited by PTPα-phospho-Tyr789, although the role of the PTPα-Grb2 complex in integrin signaling is unknown. We show that silencing Grb2 expression in fibroblasts abolishes PTPα-Tyr789 phosphorylation and that this is due to two unexpected actions of Grb2. First, Grb2 promotes integrin-induced autophosphorylation of FAK-Tyr397. This is impaired in Grb2-depleted cells and prohibits FAK activation and formation of the Src-FAK complex. Grb2-depleted cells contain less paxillin, and paxillin overexpression rescues FAK-Tyr397 phosphorylation, suggesting that the FAK-activating action of Grb2 involves paxillin. A second distinct role for Grb2 in PTPα-Tyr789 phosphorylation involves Grb2-mediated coupling of Src-FAK and PTPα. This requires two phosphosites, FAK-Tyr925 and PTPα-Tyr789, for Grb2-Src homology 2 (SH2) binding. We propose that a Grb2 dimer links FAK and PTPα, and this positions active Src-FAK in proximity with other, perhaps integrin-clustered, molecules of PTPα to enable maximal PTPα-Tyr789 phosphorylation. These findings identify Grb2 as a new FAK activator and reveal its essential role in coordinating PTPα tyrosine phosphorylation to enable downstream integrin signaling and migration.

Protein tyrosine phosphatase α phosphotyrosyl-789 binds BCAR3 to position Cas for activation at integrin-mediated focal adhesions.

Integrin-mediated focal adhesions connect the extracellular matrix and cytoskeleton to regulate cell responses, such as migration. Protein tyrosine phosphatase α (PTPα) regulates integrin signaling, focal adhesion formation, and migration, but its roles in these events are incompletely understood. The integrin-proximal action of PTPα activates Src family kinases, and subsequent phosphorylation of PTPα at Tyr789 acts in an unknown manner to promote migration. PTPα-null cells were used in reconstitution assays to distinguish PTPα-Tyr789-dependent signaling events. This showed that PTPα-Tyr789 regulates the localization of PTPα and the scaffolding protein Cas to adhesion sites where Cas interacts with and is phosphorylated by Src to initiate Cas signaling. Linking these events, we identify BCAR3 as a molecular connector of PTPα and Cas, with phospho-Tyr789 PTPα serving as the first defined cellular ligand for the BCAR3 SH2 domain that recruits BCAR3-Cas to adhesions. Our findings reveal a novel role of PTPα in integrin-induced adhesion assembly that enables Src-mediated activation of the pivotal function of Cas in migration.

Co-development of a companion diagnostic for targeted cancer therapy.

Oncology drug development is a long and costly process associated with a success rate of 5-10%. The parallel development of companion diagnostic tests that will identify patients most likely to receive benefit has the potential to increase the success rate for oncology drugs and decrease development time and associated costs. Metastatic melanoma is a challenging disease that has been associated with poor survival. Identification of a mutated BRAF kinase gene in many cases of melanoma provided a promising therapeutic target. Here we describe the successful co-development of vemurafenib, a first-in-class selective inhibitor of oncogenic BRAF kinase, and its companion diagnostic, the cobas(®) 4800 BRAF V600 Mutation Test. Key success factors in the development process included early identification of the BRAF V600E biomarker, early development of the diagnostic test, and early and close collaboration between the pharmaceutical and diagnostic development teams. This focused and integrated process resulted in the first personalized medicine for the treatment of metastatic melanoma less than five years after the Investigational New Drug Application, a remarkably short time.

Interventions for erosive lichen planus affecting mucosal sites.

BACKGROUND: Erosive lichen planus (ELP) affecting mucosal surfaces is a chronic autoimmune disease of unknown aetiology. It is often more painful and debilitating than the non-erosive types of lichen planus. Treatment is difficult and aimed at palliation rather than cure. Several topical and systemic agents have been used with varying results. OBJECTIVES: To assess the effects of interventions in the treatment of erosive lichen planus affecting the oral, anogenital, and oesophageal regions. SEARCH METHODS: We searched the following databases up to September 2009: the Cochrane Skin Group Specialised Register, the Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library, MEDLINE (from 2005), EMBASE (from 2007), and LILACS (from 1982). We also searched reference lists of articles and online trials registries for ongoing trials. SELECTION CRITERIA: We considered all randomised controlled trials (RCTs) that evaluated the effectiveness of any topical or systemic interventions for ELP affecting either the mouth, genital region, or both areas, in participants of any age, gender, or race. DATA COLLECTION AND ANALYSIS: The primary outcome measures were as follows:(a) Pain reduction using a visual analogue scale rated by participants; (b) Physician Global Assessment; and (c) Participant global self-assessment.Changes in scores at the end of therapy compared with baseline were analysed. MAIN RESULTS: A total of 15 RCTs were identified, giving a total of 473 participants with ELP. All studies involved oral ELP only. Six of the 15 studies included participants with non-erosive lichen planus. In these studies, only the erosive subgroup was included for intended subgroup analysis. We were unable to pool data from any of the nine studies with only ELP participants or any of the six studies with the ELP subgroup, due to small numbers and the heterogeneity of the interventions, design methods, and outcome variables between studies. One small study involving 50 participants found that 0.025% clobetasol propionate administered as liquid microspheres significantly reduced pain compared to ointment (Mean difference (MD) -18.30, 95% confidence interval (CI) -28.57 to -8.03), but outcome data was only available in 45 participants. However, in another study, a significant difference in pain was seen in the small subgroup of 11 ELP participants, favouring ciclosporin solution over 0.1% triamcinolone acetonide in orabase (MD -1.40, 95% CI -1.86 to -0.94). Aloe vera gel was 6 times more likely to result in at least a 50% improvement in pain symptoms compared to placebo in a study involving 45 ELP participants (Risk ratio (RR) 6.16, 95% CI 2.35 to 16.13). In a study involving 20 ELP participants, 1% pimecrolimus cream was 7 times more likely to result in a strong improvement as rated by the Physician Global Assessment when compared to vehicle cream (RR 7.00, 95% CI 1.04 to 46.95).There is no overwhelming evidence for the efficacy of a single treatment, including topical steroids, which are the widely accepted first-line therapy for ELP. Several side-effects were reported, but none were serious. With topical corticosteroids, the main side-effects were oral candidiasis and dyspepsia. AUTHORS' CONCLUSIONS: This review suggests that there is only weak evidence for the effectiveness of any of the treatments for oral ELP, whilst no evidence was found for genital ELP. More RCTs on a larger scale are needed in the oral and genital ELP populations. We suggest that future studies should have standardised outcome variables that are clinically important to affected individuals. We recommend the measurement of a clinical severity score and a participant-rated symptom score using agreed and validated severity scoring tools. We also recommend the development of a validated combined severity scoring tool for both oral and genital populations.

Analytical performance of a real-time PCR-based assay for V600 mutations in the BRAF gene, used as the companion diagnostic test for the novel BRAF inhibitor vemurafenib in metastatic melanoma.

Melanomas frequently harbor BRAFV600 mutations. Vemurafenib (RG7204/PLX4032), a small-molecule inhibitor of mutant BRAF, has shown striking clinical efficacy in BRAFV600 mutant melanoma, creating the need for a well-validated companion diagnostic to select patients for treatment. We describe analytic performance characteristics of the cobas 4800 BRAF V600 Mutation Test, the test used to select patients for the pivotal vemurafenib trials. This real-time polymerase chain reaction assay was designed to detect the V600E (1799T>A) mutation DNA from formalin-fixed paraffin-embedded tissue samples. Sensitivity was assessed using blends of cell lines or tumor DNA, and tumor specimens with low levels of mutant alleles, as determined by 454 sequencing (a quantitative next-generation pyrosequencing method). A >96% hit rate was obtained across all specimen types with 5% mutant alleles at a DNA input of 125 ng, an amount readily obtained from one 5-µm section. The cobas test showed a higher sensitivity and specificity than direct bidirectional sequencing in a panel of 219 melanoma specimens. Cross reactivity with V600K and V600D was observed. Repeated testing of 5 specimens by 2 operators, using different instruments and reagent lots, yielded correct calls in 158/160 tests (98.8%). A set of 26 highly pigmented samples were identified that gave invalid test results. A simple 1:2 dilution resulted in a valid test result of 76% in such cases. The cobas test is a reproducible assay that detects some non-V600E mutations and is more accurate than direct sequencing in detecting BRAFV600E.