Downregulation of Src-family tyrosine kinases by Srcasm and c-Cbl: A comparative analysis.

AIM: Elevated Src-Family tyrosine kinase (SFK) activity drives carcinogenesis in vivo and elevated SFK activity is found ubiquitously in human cancers. Although human squamous cell carcinomas (SCCs) demonstrate increased SFK activity, in silico analysis of SCCs demonstrates that only 0.4% of lesions contain mutations that could potentially increase SFK activity; similarly, a low frequency of activating SFK mutations is found in other major cancers. These findings indicate that SFK activation in cancers likely is not due to activating mutations but alternative mechanisms. To evaluate potential alternative mechanisms, we evaluated the selectivity of c-Cbl and Srcasm in downregulating native and activated mutant forms of SFKs. MATERIALS AND METHODS: We co-transfected native and activated forms of Src and Fyn with c-Cbl and Srcasm into HaCaT cells and monitored the ability of Srcasm and c-Cbl to downregulate native and activated forms of SFKs by Western blotting. The mechanism of downregulation was probed using mutant forms of Srcasm and c-Cbl and using proteosomal and lysosomal inhibition. RESULTS: The data indicate that Srcasm downregulates native Fyn and Src more effectively than c-Cbl, whereas c-Cbl preferentially downregulates activated SFK mutants, including Fyn Y528F, more effectively than Srcasm. Srcasm downregulates SFKs through a lysosomal-dependent mechanism while c-Cbl utilizes a proteosomal-dependent mechanism. CONCLUSION: Given the rarity of activating SFK mutations in human cancer, these data indicate that decreasing Srcasm level/function may represent a mechanism for increasing SFK activity in SCC and other human tumors.

Papillary Dermal Elastolysis Secondary to Combination Nivolumab and Cabiralizumab Therapy: Histiocytes and Dermal Mucin as Clues to the Diagnosis.

ABSTRACT: Papillary dermal elastolysis has been described in the setting of experimental combination nivolumab and cabiralizumab immunotherapy. We report a third patient with distinctive, generalized atrophic macules that developed after a morbilliform eruption during a clinical trial for treatment of metastatic pancreatic adenocarcinoma. Histopathological findings demonstrated diminished elastic fibers in the papillary dermis, associated with a histiocyte-rich infiltrate and increased dermal mucin, features that should clue the dermatopathologist to this condition.

Efficacy Using a Modified Technique for Tissue Stabilized-Guided Subcision for the Treatment of Mild-to-Moderate Cellulite of the Buttocks and Thighs.

BACKGROUND: Cellulite can be significantly improved using vacuum-assisted tissue stabilized-guided subcision (TS-GS). However, the treatment of shallow and linear cellulite has remained problematic. OBJECTIVE: In this retrospective study, we describe a modified technique of vacuum-assisted TS-GS. The aim is to demonstrate that this new limited-release technique is an effective treatment for long ripples and interconnected shallow dimples, which are characteristic of mild-to-moderate cellulite. METHODS: Patients with mild-to-moderate cellulite were treated with limited-release vacuum-assisted TS-GS. All subcisions were performed at the 6-mm depth and a minimum of 3 mm between each dimple. Using a 4-point scale, 2 raters graded cellulite improvement on evaluation of prephotographs and postphotographs. RESULTS: A total of 23 female patients were included in this study. The pre- and post-treatment photographs were correctly identified in 22 of the 23 patients (95.6%). The average cellulite improvement was 2.9 of 4 for the buttocks and 2.8 of 4 for the posterior thighs. Global cellulite improvement was reported at 3.1 of 4. CONCLUSION: The results demonstrate that modified, limited-release, vacuum-assisted TS-GS can be an effective and safe method for the treatment of long ripples and shallow dimples that are characteristics of mild-to-moderate cellulite.

Demographic and Tumor Characteristics of Patients Younger Than 50 Years With Nonmelanoma Skin Cancer Referred for Mohs Micrographic Surgery.

BACKGROUND: An increase in nonmelanoma skin cancer (NMSC) in younger patients has been reported. Many are treated with Mohs micrographic surgery (MMS). OBJECTIVE: Investigate patient and tumor characteristics in patients less than 50 years undergoing MMS for NMSC at a large, referral-based practice. METHODS & MATERIALS: Retrospective chart review of 1,332 tumors occurring in 1,018 consecutive patients over a five-year period. RESULTS: 81.7% of tumors were BCC and 55.3% occurred in women. Patients less than 30 years were more likely to be female (P equals 0.016) and women were more likely to have BCC (P equals 0.010). SCCs were more likely with increasing age (P less than 0.001). Of all tumors, 3.6% were recurrent, 2.7% had diameters ≥ 2 centimeters, and 5.5% of all BCCs had a high-risk histologic subtype. Women were more than twice as likely as men to be referred to plastic surgery for repair (P equals 0.020). CONCLUSION: Patients < 50 years with NMSC may represent a growing population referred for MMS, especially young women with BCC. High-risk tumor features were rare among young patients, and female gender was associated with an increased rate of referral for repair by a plastics subspecialty. Study was performed at the Laser & Skin Surgery Center of New York. IRB STATUS: Approved by Essex Institutional Review Board, Protocol #MOHS40-65

J Drugs Dermatol. 2018;17(5):499-505.

Microneedling: A Comprehensive Review.

BACKGROUND: Microneedling is a minimally invasive procedure that uses fine needles to puncture the epidermis. The microwounds created stimulate the release of growth factors and induce collagen production. The epidermis remains relatively intact, therefore helping to limit adverse events. The indications for microneedling therapy have grown significantly, and it is becoming a more widely used treatment in dermatology. OBJECTIVE: A comprehensive review of microneedling in human subjects and its applications in dermatology. METHODS AND MATERIALS: A search was performed using PubMed/MEDLINE and Science Direct databases. Search terms included "microneedling," "needling," and "percutaneous collagen induction." All available studies involving human subjects were included in the discussion, with priority given to prospective, randomized trials. RESULTS: Studies demonstrate microneedling efficacy and safety for the treatment of scars, acne, melasma, photodamage, skin rejuvenation, hyperhidrosis and alopecia and for facilitation of transdermal drug delivery. While permanent adverse events are uncommon, transient erythema and postinflammatory hyperpigmentation are more commonly reported. CONCLUSION: Microneedling appears to be an overall effective and safe therapeutic option for numerous dermatologic conditions. Larger and more randomized controlled trials are needed to provide greater data on the use of microneedling for different dermatologic conditions in different skin types.

Annular Elastolytic Giant Cell Granuloma Successfully Treated With Adalimumab Subsequently Complicated by Drug-Induced Lupus.

We report a 51-year-old female with a 3-year history of recalcitrant annular elastolytic giant cell granuloma (AEGCG) who was effectively treated with the anti-tumor necrosis factor (TNF)-alpha antibody, adalimumab. Her disease was refractory to topical glucocorticoids, intralesional glucocorticoids, narrow-band ultraviolet light (UV)-B phototherapy and cyclosporine. During her treatment with adalimumab she developed a positive anti-nuclear-antibody and double-stranded-DNA antibody and her treatment was terminated. Our findings suggest that adalimumab is an efficacious therapeutic alternative for the treatment of annular elastolytic giant cell granuloma unresponsive to standard therapies, however drug-induced lupus is a potential side effect that clinicians must be cognizant of. To our knowledge, this is the first time adalimumab has successfully been used in the treatment of AEGCG.

J Drugs Dermatol. 2017;16(2):169-171.

Safety of a picosecond laser with diffractive lens array (DLA) in the treatment of Fitzpatrick skin types IV to VI: A retrospective review.

BACKGROUND: Laser therapy in patients with skin of color is associated with an increased rate of complications. The 755-nm picosecond laser with the diffractive lens array (DLA) has been used for the treatment of scars, striae, and rejuvenation. By delivering high energy to focused areas, the DLA minimizes complications. OBJECTIVE: This study explores the adverse events associated with treatment with the 755-nm picosecond laser with DLA in individuals with Fitzpatrick skin type IV to VI. METHOD: A retrospective chart review of patients treated with the 755-nm picosecond laser with DLA with a standardized spot size of 6 mm, fluence of 0.71 J/cm(2), and pulse width of 750 to 850 picoseconds was performed. Standard clinical photographs were obtained before treatment and at follow-up. Treatment sites were assessed for dyspigmentation, erythema, edema, and herpetic lesions. RESULTS: A total of 56 patients with Fitzpatrick skin type IV to VI, atrophic and hypertrophic scars, and pigmented lesions or striae were included. Ten patients (17.9%) were lost to follow-up. Transient adverse events, most commonly erythema and hyperpigmentation, were reported after therapy; these resolved in all cases. LIMITATIONS: Retrospective design is a limitation. CONCLUSION: The 755-nm picosecond laser with the DLA device may be a safe therapeutic alternative for unwanted scars, pigmented lesions, and striae in patients with skin of color.

microRNA-214 contributes to melanoma tumour progression through suppression of TFAP2C.

Malignant melanoma is fatal in its metastatic stage. It is therefore essential to unravel the molecular mechanisms that govern disease progression to metastasis. MicroRNAs (miRs) are endogenous non-coding RNAs involved in tumourigenesis. Using a melanoma progression model, we identified a novel pathway controlled by miR-214 that coordinates metastatic capability. Pathway components include TFAP2C, homologue of a well-established melanoma tumour suppressor, the adhesion receptor ITGA3 and multiple surface molecules. Modulation of miR-214 influences in vitro tumour cell movement and survival to anoikis as well as extravasation from blood vessels and lung metastasis formation in vivo. Considering that miR-214 is known to be highly expressed in human melanomas, our data suggest a critical role for this miRNA in disease progression and the establishment of distant metastases.

Patient perspectives on medical photography in dermatology.

BACKGROUND: Clinical photography enhances medical care, research, and teaching. Empirical data are needed to guide best practices regarding dermatologic photography. OBJECTIVE: To investigate patient opinion about clinical photography and identify demographic factors that influence these opinions. METHODS AND MATERIALS: Four hundred patients representing a broad range of ages, self-identified ethnic/racial groups, and socioeconomic levels were recruited from 4 dermatology settings in New York City. Patients were administered a survey about perceptions of photography, willingness to allow photographs to be used in a variety of settings, preferences for photographer and photographic equipment, and methods of consent. RESULTS: Eighty-eight percent of patients agreed that photography enhanced their quality of care. Most patients would allow their photographs to be used for medical, teaching, and research purposes with significantly more acceptance when patients were not identifiable. Patients preferred photographs taken by a physician rather than a nurse or student, photographers of the same gender, clinic-owned cameras to personal cameras or cell phones, and written consent to verbal consent. There were significant racial/ethnicity and age-related variations in responses, with white and older patients being more permissive than other groups. CONCLUSION: We use the results of this study to recommend best practices for photography in dermatology.

Indeterminate cell histiocytosis that presented clinically as benign cephalic histiocytosis.

Indeterminate cell histiocytosis (ICH) is a rare, heterogeneous disorder that is characterized by immunophenotypic features of both Langerhans cell histiocytosis (LCH) and non-LCH. We describe a 12-month-old boy with a four-month history of asymptomatic, small, pink-tan papules on his face. Histopathologic evaluation showed a superficial, dermal infiltrate of histiocytes that was positive for S100, CD1a, CD68, and Factor XIIIa. To our knowledge, this represents the first report of the clinical presentation of benign cephalic histiocytosis with immunohistochemical findings of ICH. We review the classification of histiocytic disorders and the clinical and immunohistochemical features of both ICH and benign cephalic histiocytosis.

Sarcoidosis: a comprehensive review and update for the dermatologist: part I. Cutaneous disease.

Sarcoidosis is a common systemic, noncaseating granulomatous disease of unknown etiology. The development of sarcoidosis has been associated with a number of environmental factors and genes. Cutaneous sarcoidosis, the "great imitator," can baffle clinicians because of its diverse manifestations and its ability to resemble both common and rare cutaneous diseases. Depending on the type, location, and distribution of the lesions, treatment can prevent functional impairment, symptomatic distress, scarring, and disfigurement. Numerous therapeutic options are available for the treatment of cutaneous sarcoidosis, but there are few well designed trials to guide practitioners on evidence-based, best practice management. In part I, we review the current knowledge and advances in the epidemiology, etiology, pathogenesis, and genetics of sarcoidosis, discuss the heterogeneous manifestations of cutaneous sarcoidosis, and provide a guide for treatment of cutaneous sarcoidosis.

Sarcoidosis: a comprehensive review and update for the dermatologist: part II. Extracutaneous disease.

Sarcoidosis is a multisystemic, granulomatous disease with protean manifestations and variable prognosis. Because the skin can be the only organ in which the disease is recognized, dermatologists may be responsible for the care of sarcoidosis patients. Therefore, dermatologists should be cognizant of the disease's extracutaneous manifestations to assure appropriate evaluation and treatment. Part II of this review describes the diagnostic approach and management of the extracutaneous manifestations of sarcoidosis.

Glomangioma.

A 22-year-old man presented with a 9-year history of multiple blue nodules on the medial aspect of his right arm. A biopsy specimen showed a cystic space with a cuboidal cellular lining that stained positive for α-smooth-muscle actin; these findings were consistent with multiple glomangiomas. We review the clinical and histopathologic characteristics of this rare entity.

Self-reported Patient Motivations for Seeking Cosmetic Procedures.

Importance: Despite the growing popularity of cosmetic procedures, the sociocultural and quality-of-life factors that motivate patients to undergo such procedures are not well understood. Objective: To estimate the relative importance of factors that motivate patients to seek minimally invasive cosmetic procedures. Design, Setting, and Participants: This prospective, multicenter observational study was performed at 2 academic and 11 private dermatology practice sites that represented all US geographic regions. Adult patients presenting for cosmetic consultation or treatment from December 4, 2016, through August 9, 2017, were eligible for participation. Exposures: Participants completed a survey instrument based on a recently developed subjective framework of motivations and a demographic questionnaire. Main Outcomes and Measures: Primary outcomes were the self-reported most common motivations in each quality-of-life category. Secondary outcomes were other frequently reported motivations and those associated with specific procedures. Results: Of 529 eligible patients, 511 agreed to participate, were enrolled, and completed the survey. Typical respondents were female (440 [86.1%]), 45 years or older (286 [56.0%]), white (386 [75.5%]), and college educated (469 [91.8%]) and had previously received at least 2 cosmetic procedures (270 [52.8%]). Apart from motivations pertaining to aesthetic appearance, including the desire for beautiful skin and a youthful, attractive appearance, motives related to physical health, such as preventing worsening of condition or symptoms (253 of 475 [53.3%]), and psychosocial well-being, such as the desire to feel happier and more confident or improve total quality of life (314 of 467 [67.2%]), treat oneself or celebrate (284 of 463 [61.3%]), and look good professionally (261 of 476 [54.8%]) were commonly reported. Motivations related to cost and convenience were rated as less important (68 of 483 [14.1%]). Most motivations were internally generated, designed to please the patients and not others, with patients making the decision to undergo cosmetic procedures themselves and spouses seldom being influential. Patients younger than 45 years were more likely to undertake procedures to prevent aging (54 of 212 [25.5%] vs 42 of 286 [14.7%] among patients ≥45 years; P < .001). Patients seeking certain procedures, such as body contouring (19 of 22 [86.4%]), acne scar treatment (36 of 42 [85.7%]), and tattoo removal (8 of 11 [72.7%]), were more likely to report psychological and emotional motivations. Conclusions and Relevance: This initial prospective, multicenter study comprehensively assessed why patients seek minimally invasive cosmetic procedures. Common reasons included emotional, psychological, and practical motivations in addition to the desire to enhance physical appearance. Differences relative to patient age and procedures sought may need further exploration.

Sarcoidosis.

Sarcoidosis is a disease characterized by noncaseating granulomatous infiltration of 1 or more organs. In North America, after the lungs and thoracic lymph nodes, the skin is the next most commonly involved organ. Data from multiple studies indicate a coaction between genetic and environmental factors in immunologically susceptible hosts. The disease's many clinical manifestations and course vary greatly and are influenced by race, ethnicity, and gender. In the skin, the lesions of sarcoidosis are classified as specific when noncaseating granulomas are present, and nonspecific when there is an inflammatory reaction pattern devoid of granulomas.

Histology-specific microRNA alterations in melanoma.

We examined the microRNA signature that distinguishes the most common melanoma histological subtypes, superficial spreading melanoma (SSM) and nodular melanoma (NM). We also investigated the mechanisms underlying the differential expression of histology-specific microRNAs. MicroRNA array performed on a training cohort of 82 primary melanoma tumors (26 SSM, 56 NM), and nine congenital nevi (CN) revealed 134 microRNAs differentially expressed between SSM and NM (P<0.05). Out of 134 microRNAs, 126 remained significant after controlling for thickness and 31 were expressed at a lower level in SSM compared with both NM and CN. For seven microRNAs (let-7g, miR-15a, miR-16, miR-138, miR-181a, miR-191, and miR-933), the downregulation was associated with selective genomic loss in SSM cell lines and primary tumors, but not in NM cell lines and primary tumors. The lower expression level of six out of seven microRNAs in SSM compared with NM was confirmed by real-time PCR on a subset of cases in the training cohort and validated in an independent cohort of 97 melanoma cases (38 SSM, 59 NM). Our data support a molecular classification in which SSM and NM are two molecularly distinct phenotypes. Therapeutic strategies that take into account subtype-specific alterations might improve the outcome of melanoma patients.

The novel gamma secretase inhibitor RO4929097 reduces the tumor initiating potential of melanoma.

Several reports have demonstrated a role for aberrant NOTCH signaling in melanoma genesis and progression, prompting us to explore if targeting this pathway is a valid therapeutic approach against melanoma. We targeted NOTCH signaling using RO4929097, a novel inhibitor of gamma secretase, which is a key component of the enzymatic complex that cleaves and activates NOTCH. The effects of RO4929097 on the oncogenic and stem cell properties of a panel of melanoma cell lines were tested both in vitro and in vivo, using xenograft models. In human primary melanoma cell lines, RO4929097 decreased the levels of NOTCH transcriptional target HES1. This was accompanied by reduced proliferation and impaired ability to form colonies in soft agar and to organize in tridimensional spheres. Moreover, RO4929097 affected the growth of human primary melanoma xenograft in NOD/SCID/IL2gammaR-/- mice and inhibited subsequent tumor formation in a serial xenotransplantation model, suggesting that inhibition of NOTCH signaling suppresses the tumor initiating potential of melanoma cells. In addition, RO4929097 decreased tumor volume and blocked the invasive growth pattern of metastatic melanoma cell lines in vivo. Finally, increased gene expression of NOTCH signaling components correlated with shorter post recurrence survival in metastatic melanoma cases. Our data support NOTCH inhibition as a promising therapeutic strategy against melanoma.