Todd V. Cartee

Epidermal growth factor receptor inhibition augments the expression of MHC class I and II genes.

Purpose: Diverse immune-related effects occur with the use of epidermal growth factor receptor inhibitors (EGFRI). In addition to the cutaneous inflammation induced by EGFRIs, these agents have been associated with the exacerbation of autoimmune skin disease and contact hypersensitivity, antiviral effects, and fatal alveolar damage in the setting of lung transplantation. Because EGFR ligands can modulate MHC class I (MHCI) and II (MHCII) molecule expression, we hypothesized that some of the immune-related effects of EGFRIs are due to direct effects on the expression of MHCI and/or MHCII molecules. Experimental Design: Primary human keratinocytes and a malignant keratinocyte cell line (A431) were treated with EGFRIs alone or prior to IFN-γ, a potent inducer of MHCI and MHCII molecule expression. CIITA, MHCI, and MHCII RNA expression was measured using quantitative real-time reverse transcriptase PCR, and cell surface MHCI and MHCII protein expression was measured using flow cytometry. Skin biopsies from patients were analyzed for MHCI and MHCII protein expression before and during therapy with an EGFRI using immunohistochemistry. Results: Both EGFR tyrosine kinase inhibitors and ligand-blocking antibodies (cetuximab) augmented the induction of MHCI and MHCII molecules by IFN-γ in primary and malignant human keratinocytes. Unexpectedly, the increase in MHCI protein expression did not require the presence of IFN-γ. Consistent with these in vitro findings, skin biopsies from cancer patients exhibited increased epidermal MHCI protein expression during therapy with an EGFRI as well as increases in MHCI and MHCII molecule RNA. Conclusions: These studies suggest that EGFRIs may influence immune/inflammatory responses by directly modulating MHC expression. Clin Cancer Res; 17(13); 4400–13. ©2011 AACR.

Melanoma reporting to central cancer registries by US dermatologists: An analysis of the persistent knowledge and practice gap

BACKGROUND Every state requires diagnosing physicians to report new cases of melanoma to its central cancer registry. Previous regional studies and anecdotal experience suggest that few dermatologists are cognizant of this obligation. This oversight could result in a large number of unreported melanomas annually and, in turn, US melanoma statistics that markedly underestimate the true incidence of the disease. OBJECTIVE We sought to quantify the percentage of dermatologists who are unaware of melanoma reporting requirements (the knowledge gap) and who are not reporting melanoma diagnoses (the practice gap). We also sought to delineate factors predictive of reporting knowledge and behavior. METHODS A survey was administered to attendees of the Cutaneous Oncology Symposium at the 2010 American Academy of Dermatology annual meeting. RESULTS In all, 104 of 419 eligible attendees completed surveys (response rate 26%). Fifty percent of respondents do not believe they are required to report melanomas and 56% do not actively report their diagnoses to a registry. Practice duration of less than 10 years was significantly associated with both a knowledge gap (P = .047) and practice gap (P = .056). Similarly, dermatologists who diagnosed fewer than 10 melanomas per year were more likely to possess a knowledge gap (P = .096) and a practice gap (P = .087) than those who diagnosed more than 10. LIMITATIONS Limitations include small sample size and low response rate. CONCLUSION A majority of dermatologists are not reporting melanomas they diagnose to a cancer registry, and half of those surveyed were not aware that diagnosing physicians are required to report melanoma.

An Overview of Botulinum Toxins: Past, Present, and Future

Although the mechanism of action of botulinum toxin (BTX) has been intensively studied, many unanswered questions remain regarding the composition and clinical properties of the two formulations of BTX currently approved for cosmetic use. In the first half of this review, these questions are explored in detail, with emphasis on the most pertinent and revelatory studies in the literature. The second half delineates most of the common and some not so common uses of BTX in the face and neck, stressing important patient selection and safety considerations. Complications from neurotoxins at cosmetic doses are generally rare and usually technique dependent.

Hypoxia and hypoxia mimetics inhibit TNF-dependent VCAM1 induction in the 5A32 endothelial cell line via a hypoxia inducible factor dependent mechanism

BACKGROUND We previously reported that iron chelators inhibit TNFα-mediated induction of VCAM-1 in human dermal microvascular endothelial cells. We hypothesized that iron chelators mediate inhibition of VCAM-1 via inhibition of iron-dependent enzymes such as those involved with oxygen sensing and that similar inhibition may be observed with agents which simulate hypoxia. OBJECTIVE We proposed to examine whether non-metal binding hypoxia mimetics inhibit TNFα-mediated VCAM-1 induction and define the mechanisms by which they mediate their effects on VCAM-1 expression. METHODS These studies were undertaken in vitro using immortalized dermal endothelial cells, Western blot analysis, ELISA, immunofluorescence microscopy, quantitative real-time PCR, and chromatin immunoprecipitation. RESULTS Hypoxia and the non-iron binding hypoxia mimetic dimethyl oxallyl glycine (DMOG) inhibited TNFα-mediated induction of VCAM-1. DMOG inhibition of VCAM-1 was dose-dependent, targeted VCAM-1 gene transcription independent of NF-κB nuclear translocation, and blocked TNFα-mediated chromatin modifications of relevant elements of the VCAM-1 promoter. Combined gene silencing of both HIF-1α and HIF-2α using siRNA led to a partial rescue of VCAM expression in hypoxia mimetic-treated cells. CONCLUSION Iron chelators, non-metal binding hypoxia mimetics, and hypoxia all inhibit TNFα-mediated VCAM-1 expression. Inhibition is mediated independent of nuclear translocation of NF-κB, appears to target TNFα-mediated chromatin modifications, and is at least partially dependent upon HIF expression. The absence of complete VCAM-1 expression rescue with HIF silencing implies an important regulatory role for an Fe(II)/α-ketoglutarate dioxygenase distinct from the prolyl and asparagyl hydroxylases that control HIF function. Identification of this dioxygenase may provide a valuable target for modulating inflammation in human tissues.

Development of a core outcome set for clinical trials in rosacea: study protocol for a systematic review of the literature and identification of a core outcome set using a Delphi survey

BackgroundRosacea is a chronic inflammatory disorder affecting millions of individuals worldwide. Diagnosis is based on signs and symptoms with management and treatment aimed to suppress inflammatory lesions, erythema, and telangiectasia. While many clinical trials of rosacea exist, the lack of consensus in outcome reporting across all trials poses a concern. Proper evaluation and comparison of treatment modalities is challenging. In order to address the inconsistencies present, this project aims to determine a core set of outcomes which should be evaluated in all clinical trials of rosacea.Methods/designThis project will utilize a methodology similar to previous core outcome set research. A long list of outcomes will be extracted over four phases: (1) systematic literature review, (2) patient interviews, (3) other published sources, and (4) stakeholder involvement. Potential outcomes will be examined by the Steering Committee to provide further insight. The Delphi process will then be performed to prioritize and condense the list of outcomes generated. Two homogenous groups of physicians and patients will participate in two consecutive rounds of Delphi surveys. A consensus meeting, composed of physicians, patients, and stakeholders, will be conducted after the Delphi exercise to further select outcomes, taking into account participant scores. By the end of the meeting, members will vote and decide on a final recommended set of core outcomes. For the duration of the study, we will be in collaboration with both the Core Outcome Measures in Effectiveness Trials (COMET) and Cochrane Skin Group - Core Outcome Set Initiative (CSG-COUSIN).DiscussionThis study aims to develop a core outcome set to guide assessment in clinical trials of rosacea. The end-goal is to improve the reliability and consistency of outcome reporting, thereby allowing sufficient evaluation of treatment effectiveness and patient satisfaction.

How Many Sections Are Required to Clear a Tumor? Results from a Web‐Based Survey of Margin Thresholds in Mohs Micrographic Surgery

BACKGROUND Mohs micrographic surgery (MMS) offers an unparalleled cure rate for cutaneous malignancy. Its success hinges on achieving reliably negative histologic margins. When assessing margins, Mohs surgeons generally examine multiple histologic sections per Mohs stage. In some cases, the most‐peripheral section or sections are clear, but tumor is identified in deeper sections within the same tissue block. OBJECTIVE To explore approaches to margin analysis in these scenarios. METHODS A web‐based survey was administered to members of the American College of Mohs Surgery investigating their standard practice when definitively tumor‐free section(s) are examined during a Mohs stage before finding cancer in a deep section. Factors influencing the decision were explored. RESULTS The number of clear sections required to declare margin negativity and terminate MMS (margin threshold) varied widely among respondents; 25% were comfortable with one clear section, whereas 19% would obtain an additional layer with eight clear sections. Margin thresholds depended on tumor type but were independent of surgeon experience. CONCLUSION Although no consensus emerged, a majority of respondents would not take an additional layer with four clear sections if resecting basal cell carcinoma. Prospective outcomes data are needed to standardize management of this important oncologic issue.

Granuloma Annulare Arising in Tumescent Anesthesia Injection Sites After Endovenous Ablation.

Granuloma annulare (GA) is a benign, often selflimiting disorder characterized most commonly by erythematousdermal papules thatmay coalesce to form annular plaques.Here, the authors report a unique case of GA developing as an isomorphic response at sites where tumescent anesthesia was injected for endovenous ablation. The etiology of GA is unknown but likely involves a delayed-type hypersensitivity reaction. Granuloma annulare has been rarely associated with the isomorphic or Koebner phenomenon (KP). Previous reports of physical trauma incitingGA include events such as 1 case after sunburn, 3 cases where arthropod bites were suspected but not clearly linked, 5 cases associated with vaccination, 1 case after collagen injection, and only 1 previous case in a surgical scar. Contrasting with this previous experience, the patient developed a striking eruption of firm reddish brown linear papules precisely at each injection point without any generalization of the GA or apparent immunologic stimulus, a presentation not previously described to the authors’ knowledge.

Quantification of noninvasive fat reduction: A systematic review

Noninvasive fat reduction appears effective, but there are various methods for quantifying changes. The objective of this review is to assess comparative utility measures of subcutaneous fat.

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.

Nodules developing after radiofrequency ablation of varicosities: A potential clinical and histopathologic mimic of polyarteritis nodosa

HBV: hepatitis B virus PAN: polyarteritis nodosa PDL: pulsed dye laser RFA: radiofrequency ablation INTRODUCTION Endothermal ablation is the standard of care for symptomatic saphenous reflux. This minimally invasive treatment uses thermal energy to produce irreversible damage to the vein wall, complete venous occlusion, and eventual fibrosis. We report on a woman in whom multiple regional subcutaneous nodules developed shortly after radiofrequency ablation (RFA) of her great saphenous veins. The clinical and biopsy findings mimicked cutaneous polyarteritis nodosa (PAN). Extensive laboratory evaluation failed to find evidence of systemic involvement. We bring this interesting and uncommon phenomenon to the attention of pathologists and clinicians to facilitate accurate and timely diagnosis.