Comparison of the Distribution of Morphological Disorganization of Pigmented Lesions in a Community-based Practice versus a University-based Clinical Setting as Measured by a Multispectral Digital Skin Lesion Analysis Device: Impact on Diagnosis

Objective: To observe how a multispectral digital skin lesion analysis device was used by dermatologists in a community-based clinical setting and determine differences from a university-based environment. Design: Use of multispectral digital skin lesion analysis was incorporated into a community-based practice by 12 dermatologists across six clinics over seven consecutive days with the data provided by the device integrated as an adjuvant to their clinical evaluation for their pigmented lesion management decisions. Multispectral digital skin lesion analysis results were collected electronically for lesions prior to biopsy, and histopathological evaluation was performed for the biopsied lesions. Multispectral digital skin lesion analysis and pathology results were then compared to assess the degree of morphological disorganization. Setting/participants: Study of 160 consecutive patients in community-based clinical setting. Measurements: Proportion of “low” and “high” disorganization lesions identified by multispectral digital skin lesion analysis. Results: Of the 344 pigmented skin lesions analyzed by multispectral digital skin lesion analysis, 255 were high disorganization, 113 of which were biopsied. Of the 89 lesions evaluated by multispectral digital skin lesion analysis to be low disorganization, seven were biopsied and all pathology was benign. Data demonstrate a higher rate of multispectral digital skin lesion analysis low disorganization readings for pigmented skin lesions (32% for single use per patient lesions, p<0.0001; 26% for all lesions, p<0.0001) than observed in the pigmented lesions clinics providing data for the university-based clinical study (10%). Conclusion: Multispectral digital skin lesion analysis in the community-based clinical setting may outperform specificity results from the university-based clinical trial study, perhaps because of a higher proportion of subtle lesions encountered at high-risk pigmented lesion clinics of participating major academic centers as compared with those in a community-based practice settingEarly diagnosis of melanoma is critical for patient survival. New technology may improve the accuracy of dermatologist decisions to biopsy suspicious pigmented lesions.1 Multispectral digital skin lesion analysis (MSDSLA) (MelaFind®; MELA Sciences Inc., Irvington, New York) provides objective information about the morphological disorganization of clinically ambiguous pigmented skin lesions. Dermatologists then incorporate the additional information provided by MSDSLA into their biopsy decision. Objective probability information provided by this device has been studied for its potential to enhance the accuracy of dermatologists evaluating suspicious lesions for biopsy.2MSDSLA uses narrow bands of visual and near-infrared light (430-950nm) to capture data from the skin surface down to 2.5mm in depth. At a 20-micron resolution (∼ diameter of 3 melanocytes), individual cellular atypia is not evaluable by MSDSLA. Alternatively, the device uses 75 analytical parameters to determine the level of morphological disorder within a clinically atypical pigmented skin lesion and generate a classifier score (CS).3 Using a binary output, a CS greater than or equal to 0 is considered to have “high” disorganization and scores less than 0 have “low” disorganization. High disorganization was associated with 98-percent sensitivity to melanoma and severely dysplastic nevi. Low disorganization was associated with significantly higher specificity than study dermatologists (10% vs. 4%, p=0.022) and a 98 percent negative predictive value.4The safety and effectiveness of MSDSLA were originally established from data analyzing 1,632 skin lesions collected by physicians at multiple major academic centers.4 In this primarily academic pigmented lesion center based study, 10 percent of the lesions had low disorganization results. However, the sampling of benign lesions from that study may not be representative of what would be seen in the general population. The use of MSDSLA and the distribution of high and low disorganization lesions in the community-based practice clinical setting have not yet been studied. The purpose of this study is to observe how the MSDSLA device was used by dermatologists in a multi-physician, multi-clinic, community-based clinical setting and to measure the distribution of high and low morphological disorganization to determine if a difference exists from what was found in academic-based centers.     

The Impact of Multispectral Digital Skin Lesion Analysis on German Dermatologist Decisions to Biopsy Atypical Pigmented Lesions with Clinical Characteristics of Melanoma

Objective: To determine the impact of multispectral digital skin lesion analysis on German dermatologist biopsy decisions of atypical pigmented skin lesions. Design: Participants were shown high-resolution clinical images of 12 atypical pigmented skin lesions previously analyzed by multispectral digital skin lesion analysis. Participants were asked if they would biopsy the lesion based on clinical images and high-resolution dermoscopy images and again when subsequently shown multispectral digital skin lesion analysis probability information. Setting/participants: Forty-one dermatologists at a skin cancer conference in Germany in September 2014. Measurements: Sensitivity, specificity, diagnostic accuracy, percent biopsying all melanomas, and overall biopsy rates. Results: Sensitivity for the detection of melanoma following clinical evaluation was 64 percent. After receipt of multispectral digital skin lesion analysis probability information, sensitivity decreased nonsignificantly to 62 percent. Specificity with clinical evaluation was 57 percent and increased to 73 percent using multispectral digital skin lesion analysis. Overall biopsy accuracy increased from 60 percent with clinical evaluation to 68 percent with multispectral digital skin lesion analysis. The percentage of low-grade dysplastic nevi chosen for biopsy decreased from 43 percent after clinical evaluation to 27 percent with multispectral digital skin lesion analysis. Finally, the overall percentage of lesions biopsied decreased from 52 percent with clinical evaluation to 42 percent after multispectral digital skin lesion analysis. Conclusion: Multispectral digital skin lesion analysis can be used reliably to detect melanoma as well as clinical evaluation. Dermatologists can confidently use multispectral digital skin lesion analysis to significantly improve specificity and reduce their overall number of biopsies while increasing overall diagnostic accuracy.The use of technology has dramatically altered the landscape of clinical practice in the last few decades giving the opportunity to enhance cost-effective, quality care. Within the field of dermatology, early diagnosis of melanoma is critical to survival.1 Therefore interventions to enhance timely diagnosis are needed, multispectral digital skin lesion analysis (MSDSLA)2,3 is currently being studied in the United States4 and Germany5 for its use in noninvasively augmenting dermatologist decisions to biopsy suspicious pigmented lesions.MSDSLA employs visible and near-infrared light (430-950nm) to image lesions up to 2.5mm below the skin surface. MSDSLA then analyzes pigmented lesions across 10 spectral bands using 75 unique analytical algorithms to determine a “classifier score” based on the degree of morphological disorganization. Validated on a database of 1,632 pigmented lesions, MSDSLA also provides the probability of an analyzed lesion being melanoma and melanoma, atypical melanocytic hyperplasia (AMH) or a high-grade dysplastic nevus (DN) to the clinician.4The MSDSLA device is available for purchase commercially. Following some training on how to properly acquire an image immersed in isopropyl alcohol, the handheld device takes approximately 30 seconds to image and analyze each pigmented lesion per patient sitting. The additional objective information provided by MSDSLA about a suspicious pigmented lesion is then integrated into a dermatologist’s biopsy decision. MSDSLA is not meant to be followed blindly. For example, if the additional probability information suggests a low probability of melanoma, AMH, or high-grade DN, the final biopsy decision is still up to the experienced dermatologist evaluating the entire clinical picture. The purpose of this study was to determine how physicians’ biopsy decisions are affected by integration of this objective data.     

Impact of Guidance Provided by a Multispectral Digital Skin Lesion Analysis Device Following Dermoscopy on Decisions to Biopsy Atypical Melanocytic Lesions

Objective: To determine how a multispectral digital skin lesion analysis (MSDSLA) device data affects the biopsy performance of dermatologists and non-dermatologist practitioners following clinical and dermoscopic pigmented lesion evaluation. Design: MSDSLA employs near infrared light to image and analyze pigmented skin lesions. MSDSLA generates a “classifier score” based on morphological disorganization. Using a logistical regression model, 1) a probability of being melanoma and, 2) a probability of being melanoma, atypical melanocytic hyperplasia, or a high grade dysplastic nevus is computed. Participants were shown clinical images of 12 lesions (2 melanomas in situ, 3 invasive melanomas, and 7 low grade DNs). They were asked first if they would biopsy the lesion based on clinical images, again after observing dermoscopy images, and once more when presented with MSDSLA probability information. Setting: National dermoscopy conference. Participants: Sixty-four healthcare providers; 30 dermatologists and 34 non-dermatologist practitioners. Measurements: Sensitivity, specificity, diagnostic accuracy, biopsy rates Results: For the 30 dermatologists, sensitivity was 65 percent after clinical evaluation (C) and 65% post-dermoscopy (D) but improved to 91% after MSDSLA. For the 34 non-dermatologist practitioners, sensitivity improved from 66 percent (C) to 70 percent (D) to 95 percent after MSDSLA. With MSDSLA information, dermatologist specificity increased from 40 percent (D) to 58 percent while non-dermatologist practitioners specificity increased from 34 percent (D) to 55 percent. Diagnostic accuracy of malignant and benign lesions decreased for both groups 55 percent (C) to 51 percent (D) for dermatologists and 54 percent (C) to 49 percent (D) for non-dermatologist practitioners. However, diagnostic accuracy increased to 72 percent for dermatologists and 72 percent for non-dermatologist practitioners with MSDSLA data. Non-melanoma biopsy percentages by dermatologists increased from 53 percent (C) to 60 percent (D), but decreased to 42 percent when provided with MSDSLA data. Similarly, non-dermatologist practitioners’ biopsy percentages of nonmelanomas increased from 55 percent (C) to 66 percent (D) and decreased to 45 percent with MSDSLA. Conclusion: Decisions to biopsy atypical melanocytic lesions were more sensitive and specific when MSDSLA information was provided for both dermatologists and nondermatologist practitioners. Both groups were also less likely to biopsy nonmelanomas after MSDSLA evaluation. The authors’ results suggest providing practitioners with MSDSLA data leads to improved biopsy accuracy decreasing the number of nonessential biopsies for nonmelanocytic lesions even after dermoscopic evaluation.Early detection of melanoma improves survival.1 Suspicious pigmented lesions are typically evaluated by clinical examination and sometimes dermoscopy.2 New technologies may provide additional clinically significant information to augment accurate biopsy decisions.3,4This study was designed to determine how information provided by a multispectral digital skin lesion analysis (MSDSLA) device (MelaFind, MELASciences Inc, Irvington, New York)4,5 affects the biopsy decisions of dermatologists and non-dermatologist practitioners (NDPs) following clinical and dermoscopic pigmented skin lesion evaluation. MSDSLA employs visible and near-infrared light (430-950nm) to image lesions up to 2.5mm below the skin surface. MSDSLA then analyzes pigmented lesions across 10 spectral bands using 75 unique analytical algorithms to determine a “classifier score” based on the degree of morphological disorganization. Validated on a database of 1,632 pigmented lesions,5 MSDSLA also provides the probability of an analyzed lesion being melanoma and melanoma, atypical melanocytic hyper¬plasia (AMH) or a high-grade dysplastic nevus (DN) to the clinician.     

Correlation Between the Evaluation of Pigmented Lesions by a Multi-spectral Digital Skin Lesion Analysis Device and the Clinical and Histological Features of Melanoma

Objective: To correlate Multi-spectral Digital Skin Lesion Analysis classifier scores with histopathological severity of pigmented lesions and clinical features of melanoma. Design: Classifier scores were computed for 1,632 skin lesions. Dermatologists evaluated the same lesions for Asymmetry, Border Irregularity, Color variegation, Diameter >6mm, Evolution, Patient’s Concern, Regression, and/or “Ugly Duckling” sign. Classifier scores were correlated to the number of clinical risk features and for six histopathological severity levels of pigmented lesions. Measurements: Average classifier score, Welch’s t-test, and chi-square analysis. Results: Melanomas had higher mean classifier scores (3.5) than high-grade dysplastic nevi (2.7, p=0.002), low-grade dysplastic nevi (1.7, p<0.0001), non-dysplastic nevi (1.6, p<0.0001), and benign non-melanocytic lesions (2.0, p<0.0001). Classifier score and the number of clinical risk characteristics directly correlated (Pearson coefficient 0.32, p<0.0001). Conclusion: Correlation of classifier scores to clinical and histological melanoma features supports the effectiveness of Multi-spectral Digital Skin Lesion Analysis in assessing the risk of pigmented lesions requiring biopsy. Optimizing outcomes of dermatologist decisions to biopsy suspicious pigmented lesions may be enhanced utilizing Multi-spectral Digital Skin Lesion Analysis.The incidence of malignant melanoma has increased an average of four percent per year in the United States since the early 1970s.1 Today, over one American dies every hour from melanoma.2 Detected in its earliest stage, melanoma is almost completely curable with simple excision. However, the five-year survival rate drops to <10 percent with stage IV disease. Therefore, the key challenge for early diagnosis is to determine which atypical pigmented skin lesions require biopsy. Technology has been shown to augment the biopsy decision accuracy of dermatologists evaluating suspicious pigmented lesions.3Multi-spectral Digital Skin Lesion Analysis (MSDSLA, MELA Sciences Inc, Irvington, New York) uses narrow bands of visual and near-infrared light (430-950nm) to capture data from the skin surface down to 2.5mm in depth. At a 20-micron resolution (~diameter of 3 melanocytes), individual cellular atypia is not evaluable by MSDSLA. Instead, the device uses 75 analytical parameters to determine the level of morphological disorder within an atypical pigmented skin lesion to generate a classifier score (CS).3 Using the CS, MSDSLA provides objective data that can be integrated into the dermatologist’s biopsy decision. Knowledge of the CS was shown to improve the average biopsy sensitivity for melanoma of 179 dermatologists from 69 to 94 percent (p<0.001).4The purpose of this study was to further characterize the MSDSLA CS for levels of histologic severity of atypical and banal pigmented lesions and its level of correlation to independently evaluated clinical features of the same lesions.     

Assessment of a Diagnostic Predictive Probability Model Provided by a Multispectral Digital Skin Lesion Analysis Device for Melanoma and Other High-risk Pigmented Lesions and its Impact on Biopsy Decisions

Objective: Risk prediction models for primary malignant melanoma thus far have relied on qualitative patient information. The authors propose a quantitative diagnostic predictive probability model using Multispectral Digital Skin Lesion Analysis for melanoma and other high-risk pigmented lesions and evaluate its effectiveness optimizing biopsy decisions by dermatologists. Design: Data from 1,632 pigmented lesions analyzed by a Multispectral Digital Skin Lesion Analysis device were used to perform a logistic regression analysis. This new quantitative melanoma or melanoma/atypical melanocytic hyperplasia/high-grade dysplastic nevus probability model was then evaluated to determine its impact on dermatologist decisions to biopsy pigmented lesions clinically suggestive of melanoma. Participants were given an electronic keypad and answered “yes” or “no” if they would biopsy each of 12 pigmented lesions when presented first with patient history, clinical images, and dermoscopic images and again when subsequently shown Multispectral Digital Skin Lesion Analysis data. Setting/participants: Study of 191 dermatologists at a medical conference. Measurements: Sensitivity, specificity, biopsy accuracy, overall biopsy rate, and percentage dermatologists biopsying all five melanomas. Results: Dermatologists were significantly more sensitive, specific, and accurate while decreasing overall biopsy rates with Multispectral Digital Skin Lesion Analysis probability information. Conclusion: Integration of Multispectral Digital Skin Lesion Analysis probability information in the biopsy evaluation and selection process of pigmented lesions has the potential to improve melanoma sensitivity of dermatologists without the concomitant costs associated with additional biopsies being performed.Risk prediction models are often used to help identify individuals at higher risk of cancer in the general population. Developing statistical models to evaluate the probability of developing cancer over a defined period of time allows for enhanced early detection, patient education, and intervention. Several studies have attempted to assess a binary outcome for melanoma (MM) diagnosis, but have not proposed device-based models for MM diagnostic assessment.1Several diagnostic tools for MM have emerged in the past decade, including confocal scanning laser microscopy, electrical impedance spectroscopy, noninvasive genomic detection, and multispectral imaging2 suggesting there is interest in improving MM diagnosis with quantifiable data. The authors propose a quantitative diagnostic predictive probability model for MM and other high-risk pigmented lesions using a Multispectral Digital Skin Lesion Analysis (MSDSLA) device (MelaFind^®, MelaSciences, Inc., Irvington, New York) and evaluate its effectiveness optimizing biopsy decisions by dermatologists.     

In-office Painless Aminolevulinic Acid Photodynamic Therapy: A Proof of Concept Study and Clinical Experience in More Than 100 Patients

Objective: To evaluate the efficacy, safety, and pain of in-office “painless” aminolevulinic acid photodynamic therapy aimed at decreasing treatment-associated pain in patients undergoing removal of actinic keratoses. Design: Prospective split-face study comparing short aminolevulinic acid incubation times of 15 minutes followed by extended exposure (60 minutes) of continuous blue light versus conventional aminolevulinic acid photodynamic therapy. Prospective assessment of pain in patients undergoing in-office “painless” aminolevulinic acid photodynamic therapy. Setting: Clinical practice office. Participants: Three patients with actinic keratoses participated in the split-face study and 101 in the pain assessment study. Measurements: Evaluations in the split-face study included removal of actinic keratoses, skin temperature, and pain measured on a 10-point visual analog scale. Pain was assessed using the visual analog scale in the pain assessment study. Results: In the split-face study, in-office “painless” aminolevulinic acid photodynamic therapy resulted in a 52-percent reduction in lesions versus 44 percent for conventional aminolevulinic acid photodynamic therapy. Maximum pain scores of in-office “painless” aminolevulinic acid photodynamic therapy were all 0 at each time point, and the average score for conventional aminolevulinic acid photodynamic therapy was 7. Baseline skin temperatures increased from a baseline of 29 to 32°C to 34 to 35°C by minute 10 of blue light activation on both sides of the face. Results from the pain assessment study indicated no or minimal (scores 0-2) pain in nearly all patients who received in-office “painless” aminolevulinic acid photodynamic therapy as monotherapy or in combination with 5-fluoruacil or imiquimod used as pretreatments. Conclusions: In-office “painless” aminolevulinic acid photodynamic therapy appears to be effective for removing actinic keratoses and is associated with little or no pain in nearly all patients. This procedure should be evaluated in large-scale controlled trials.Actinic keratoses (AKs) are part of the spectrum between photodamaged skin and invasive squamous cell carcinoma (SCC).1-5 They are a major health care concern because of their increasing prevalence worldwide,6-10 economic impact,9-11 and decreased quality of life of affected individuals.10,12 Results from observational studies have indicated that AKs evolve into primary invasive SCC or in situ SCC at a rate ranging between 1/1,000 lesions per year13 to 0.60 percent at one year and 2.57 percent at four years.14 It is recommended that all AKs be treated because it is not currently possible to predict which will evolve into invasive SCC.15-17A variety of therapeutic modalities are used to treat AKs.1,18-20 Focally destructive therapies, such as cryotherapy,21 electrodessication and curettage,22 and shave excision23 are most often used to treat individual AKs. Large areas of actinically damaged skin require “field therapies” such as 5-fluoruacil (5-FU),24-26 imiquimod,26-30 diclofenac gel,31-33 ingenol mebutate,34,36 aminolevulinic acid photodynamic therapy (ALA PDT)35,37 and methyl-aminolevulinic acid PDT (MAL PDT),38,39 chemical peels,40 dermabrasion,41-43 and laser resurfacing.44,45PDT produces reactive oxygen species that result in tissue destruction46 and it destroys AKs because of the preferential accumulation of the photosensitizing molecule, protoporphyrin IX (PpIX) within AKs following topical application of pro-drugs ALA47 and MAL.48 PDT is safe and effective for treatment of large surface skin areas, provides good adherence because it is performed under supervision in a clinic setting, has minimal post-treatment downtime versus other AK field therapies, and produces good-to-excellent cosmetic outcomes with minimal potential for scarring.49,50 PDT also has several drawbacks, most notably pain during the first few minutes of light activation phase.51-53 Nearly two-thirds of patients undergoing ALA PDT report this pain as “moderate-severe” following 1, 2, or 3-hour ALA incubations.54 Pain with PDT has been related to cellular destruction and inflammation and possibly a direct effect of PDT on nerve fibers55-57; it has now become clear that PDT-related pain is associated with PpIX tissue accumulation based on fluorescence and the fluence rate of the activating light source.58 Topical anesthetics,55 cooling devices,59-61 nerve blockade,61,62 and treatment interruption63 have limited efficacy in managing PDT-related pain, which can lead to reluctance of patients to undergo future PDT treatments.A novel approach to minimizing discomfort during PDT, daylight-mediated PDT, uses a brief (30-minute) incubation period followed by 1.5 to 2.5 hours of daylight exposure.64-66 The shortened incubation period is designed to minimize PpIX build-up in the targeted tissue prior to daylight PpIX activation, and photobleaching prevents further buildup of PpIX and minimizes patient discomfort.67,68 Limitations to daylight-mediated PDT include dependence on favorable weather conditions and patient adherence to the treatment protocol outside the clinic.65Based on the efficacy and improved tolerability of daylight-mediated PDT, an in-office painless (IOP) ALA PDT protocol was developed. It involves applying ALA topically to actinically damaged skin, incubating without occlusion for 15 minutes, and then 60 minutes of continuous blue light activation. This report summarizes results from a split-face comparison of IOP ALA PDT and a standard short (75 minute) ALA incubation protocol followed by the standard 1,000 seconds of blue light activation carried out in three patients, and assessment of pain associated with this treatment in 101 patients undergoing 121 treatments over a two-year time period. In the latter study, IOP ALA PDT was employed as either a full-face monotherapy or in combination with one week of prior treatment with 5% and 0.5% 5-FU and 3.75% and 5% imiquimod.     

Evaluation of Optical Coherence Tomography as a Means of Identifying Earlier Stage Basal Cell Carcinomas while Reducing the Use of Diagnostic Biopsy

Objective: To determine the diagnostic accuracy of optical coherence tomography for basal cell carcinoma and the proportion of biopsies that could be avoided if optical coherence tomography is used to rule-in surgery. Design: Multicenter, prospective, observational study. Setting: Dermatology clinics. Participants: Consecutive patients with clinically challenging pink lesions suspicious for basal cell carcinoma. Measurements: Clinical, dermoscopic, and optical coherence tomography images were obtained for all subjects. At each stage, the clinician made a diagnosis (pathology + subtype if applicable), and assessed his/her own confidence in the diagnosis. Results: Optical coherence tomography significantly (p<0.01) improved sensitivity and specificity over clinical or dermoscopic evaluation. The percentage of correct diagnoses was 57.4 percent (clinical), 69.6 percent (dermoscopy), and 87.8 percent (optical coherence tomography). Optical coherence tomography significantly increased the certainty of diagnosis; clinicians indicated they were certain (>95% confident) in 17 percent of lesions examined clinically, in 38.6 percent examined with dermoscopy, and in 70 percent examined with optical coherence tomography. With the use of optical coherence tomography in the diagnosis of basal cell carcinoma, more than 1 in 3 patients could avoid a diagnostic biopsy. Conclusion: In a population of clinically challenging lesions, optical coherence tomography improved diagnostic certainty by a factor of four over clinical examination alone and improved diagnostic accuracy by 50 percent (57-88%). The addition of optical coherence tomography to other standard assessments can improve the false-positive rate and give a high degree of certainty for ruling in a positive diagnosis for basal cell carcinoma. A reduction of 36 percent in overall biopsies could be achieved by sending high certainty basal cell carcinoma positive optical coherence tomography diagnoses straight to surgery.Nonmelanoma skin cancers (NMSC) comprising basal cell carcinomas (BCC) and squamous cell carcinomas (SCC) constitute 80 percent of all skin cancers,1 with BCC forming the vast majority of those.2,3 There were an estimated total number of NMSCs in the United States population in 2012 of 5,434,193, and the total number of persons in the United States treated for NMSC in 2012 was 3,315,554.4 In the United States, the prevalence of NMSC exceeds that of all other cancers combined.4,5The incidence of BCC has been increasing annually by between two and eight percent since 1960.6 A recently published study, based on US Medicare fee-for-service population data, indicated an increase in procedures of 14 percent between 2006 and 2012, a 2.2 percent per year increase in this population.4 As the incidence of BCC also rises with age,3,7 it is becoming a serious problem in the growing elderly population of the United States.Clinical evaluation of BCC lesions is subject to error, and as such, biopsies are the gold standard for diagnosis. However, biopsies are invasive and can lead to poor cosmetic outcomes particularly for lesions on the face or neck. Furthermore, biopsies are costly: The national average Medicare cost in 2013 for a skin biopsy was $104.40, with each additional biopsy costing $32.89, along with an additional $72.94 for the pathologist.8 Due to the high volume of NMSCs in the United States, an increasing focus on novel diagnostic modalities is appropriate.Optical coherence tomography (OCT) is a noninvasive imaging technique that provides a cross-sectional image of the tissue microarchitecture down to a depth of approximately 1.5mm.9-11 Recent studies have established that the images are sufficiently detailed to enable identification of morphological criteria for different NMSC, such as actinic keratosis (AK), SCC, and BCC.9,11-13OCT has the potential to be a noninvasive alternative to biopsy. Noninvasive technology, such as OCT, could provide value by helping to “rule-in” lesions that are suspicious of skin cancer and require treatment. This could be particularly valuable where the patient has more lesions than could be clinically or ethically biopsied providing the opportunity to scan many suspicious lesions in a single session to determine those which require further attention. Further, by improving sensitivity in difficult lesion populations, lesions could be identified earlier and treated more successfully.Diagnosis and surgery could potentially take place on the same visit, improving the experience for the patient, and there may also be cost savings. As increasing portions of the Medicare payment pool will be used to pay for alternative payment models, an integrated approach to diagnosis and treatment during the same encounter may be attractive to many stakeholders. The key criterion for success in this application is for the technique to have low false-positive rates in order to minimize the number of benign lesions being unnecessarily treated.This multicenter, prospective, observational study aimed to determine the sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) for OCT in the diagnosis of BCC. The proportion of biopsies that could be avoided using OCT as a noninvasive alternative to biopsies taken to rule-in surgery was assessed. In addition, the relationship between diagnostic certainty and diagnostic accuracy for clinical examination, dermoscopic-assisted diagnosis, and OCT-assisted diagnosis was also investigated.     

The Use of Noninvasive Optical Coherence Tomography to Monitor the Treatment Progress of Vismodegib and Imiquimod 5% Cream in a Transplant Patient with Advanced Basal Cell Carcinoma of the Nose

Immunosuppressed transplant recipients have increased risk for the development of basal cell carcinoma skin cancers. While oral vismodegib therapy has been successful in treating locally advanced basal cell tumors, few studies document its use and efficacy in organ transplant patients. In this immunocompromised population, topical imiquimod 5% cream has been shown to be an effective and well-tolerated option for superficial and nodular basal cell carcinomas. To the authors’ knowledge, no data documents the use of optical coherence tomography, a noninvasive imaging technique, to monitor progress of such combined therapies on in vivo skin. The authors report the successful treatment of an extensive basal cell carcinoma on the nose of an immunosuppressed 54-year-old Caucasian man with a history of kidney and pancreas transplantations. By combining continuous noninvasive lesion monitoring with vismodegib 150mg/d therapy and adjuvant imiquimod 5% topical cream, the patient showed complete disease clearance on clinical, optical coherence tomography, and histological evaluation. This report supports the feasibility and efficacy of nonsurgical treatment of basal cell lesions in complicated transplant patients and the need for individualized treatment plans. A noninvasive follow-up tool, especially during nonsurgical therapy, is of critical value to ensure the best possible treatment outcome for the patient.Basal cell carcinoma (BCC) is the most common malignancy in individuals of mixed European descent, and accounts for approximately 80 percent of all skin malignancies.1-3 The risk for developing BCC is greatly increased in organ transplant recipients who use a combination of immunosuppressive drug therapies for prolonged periods of time.4-6 BCC is the second most frequent skin cancer assoiated with immunosuppression and more commonly metastasizes in this population than patients who have human immunodeficiency virus/acquired immune deficiency syndrome (HIV/AIDS) or iatrogenic images of tissue micro-architecture down to a depth of immunodeficiency.4,6,7 The management of extensive BCC in immunosuppressed organ transplant recipients can be a challenge for dermatologists.The current gold standard of diagnosis and management of extensive and infiltrative BCC is clinical and histopathological evaluation followed by surgical excision.3. Such invasive procedures often lead to poor cosmetic outcomes and/or functional impairment8 and there has been increased focus on alternative nonsurgical diagnostic, follow-up and treatment modalities for these patients.Optical coherence tomography (OCT), a noninvasive maging technique, allows for real-time detection and assessment of skin lesions. OCT uses near-infrared light to generate high-resolution black and white cross-sectional 2mm.9-12 These images depict cellular components in the same plane as traditional histological cuts, and studies have established that they are sufficiently detailed for identification of morphological criteria for BCC and other nonmelanoma skin cancers (NMSC).8,9,11,13,15 The OCT diagnostic sensitivity and specificity for NMSC varies by study, but ranges from 79 to 94 percent and 85 to 96 percent, respectively, whereas the clinical diagnostic sensitivity and specificity for NMSC ranges from 56 to 90 percent and 75 to 90 percent, respectively.12,14,15 Regardless of the reported sensitivities and specificities, these studies have all shown OCT to improve diagnostic accuracy. More recently, the diagnostic value of OCT, specifically for BCC, was demonstrated in a population of clinically challenging lesions.15 OCT improved diagnostic certainty by a factor of four over clinical examination alone, and improved diagnostic accuracy by 50 percent.15 With OCT imaging, 48 percent more BCCs were detected than by clinical examination alone, and sensitivity in this population increased from 62.9 to 92.9 percent.15 As such, OCT offers a powerful diagnostic tool for NMSC and can be used to monitor lesion treatment progress.12Nonsurgical treatment options for locally advanced or metastatic BCCs include vismodegib (Erivedge, Genentech-Curis), the first and only available oral hedgehog pathway inhibitor drug.2,16-18 While this novel treatment is efficacious in treating metastasized, recurrent, and inoperable BCCs, adverse side effects such as nausea, vomiting, muscle cramps, decreased appetite, weight loss, and alopecia can preclude long-term use.16,18 Furthermore, efficacy of vismodegib treatment has not been determined in organ transplant recipients. More established topical field treatments, such as imiquimod 5% cream (Aldara, 3M Pharmaceuticals), have been shown to be effective treatments for superficial and nodular BCCs in the immunosuppressed population.20Herein, the authors present an immunocompromised transplant recipient monitored noninvasively with OCT imaging to assess tissue morphology throughout nonsurgical combination therapy with oral vismodegib and imiquimod cream. To their knowledge, there is limited literature on the use of vismodegib in transplant patients, and this is the first reported case of its combination with imiquimod cream for advanced BCC in an immunosuppressed transplant patient that shows complete lesion clearance.     

Combination of Peritubular C4d and Transplant Glomerulopathy Predicts Late Renal Allograft Failure

The histologic associations and clinical implications of peritubular capillary C4d staining from long-term renal allografts are unknown. We identified 99 renal transplant patients who underwent an allograft biopsy for renal dysfunction at least 10 yr after transplantation, 25 of whom were C4d-positive and 74 of whom were C4d-negative. The average time of the index biopsy from transplantation was 14 yr in both groups. Compared with C4d-negative patients, C4d-positive patients were younger at transplantation (29 ± 13 versus 38 ± 12 yr; P < 0.05) and were more likely to have received an allograft from a living donor (65 versus 35%; P < 0.001). C4d-positive patients had more inflammation, were more likely to have transplant glomerulopathy, and had worse graft outcome. The combined presence of C4d positivity, transplant glomerulopathy, and serum creatinine of >2.3 mg/dl at biopsy were very strong predictors of rapid graft loss. C4d alone did not independently predict graft loss. Retrospective staining of historical samples from C4d-positive patients demonstrated C4d deposition in the majority of cases. In summary, these data show that in long-term renal allografts, peritubular capillary staining for C4d occurs in approximately 25% of biopsies, can persist for many years after transplantation, and strongly predicts graft loss when combined with transplant glomerulopathy.Advances in understanding immunologic mechanisms underlying acute renal allograft rejection have enabled the development of efficient diagnostic tools and therapeutic strategies directed against early immune-mediated graft loss. This led to an increase of 1-yr graft survival rates to >90%; however, long-term graft survival has not improved to a similar degree.^1,2 A steady decline of renal function over years is still the rule in the majority of cases after renal transplantation. Multiple factors can influence graft outcome in the late posttransplantation setting, including acute and or chronic rejection; patient compliance with immunosuppressive therapy; and other medical conditions, such as cardiovascular disease, hypertension, diabetes, infections, drug toxicities, and recurrent disease. Evaluation of renal biopsies may reveal changes related to calcineurin inhibitor toxicity, immune-mediated injury, BK nephropathy, thrombotic microangiopathy, hypertension, diabetes, and recurrent disease, which can help guide appropriate therapy.There is a growing awareness of the contribution of chronic immune-mediated injury and alloantibodies in late renal allograft dysfunction. Immunohistochemical detection of the complement degradation product C4d in peritubular capillaries (PTCs) of renal allograft biopsies has gained considerable attention because of its diagnostic and prognostic importance in early acute antibody-mediated rejection (AMR). Detection of C4d is regarded as indirect evidence (a “footprint”) of a host''s antibody response to a renal allograft and is one of the key criteria used to diagnose AMR.³ C4d deposition has also been implicated in more chronic immune injury of allograft kidneys. Transplant glomerulopathy (TG), a cause of renal dysfunction in longstanding renal allografts, has an estimated prevalence of 1.6 to 12% in renal transplant populations.^4–9 TG is often associated with evidence of AMR, such as the presence of donor-specific antibodies (DSAs) and positive PTC C4d staining, and is considered to be a hallmark of chronic AMR.^4,9–13 The combination of circulating alloantibodies, glomerular and PTC basement membrane multilamination, PTC C4d, and duplication of the glomerular basement membrane has been termed the “ABCD tetrad” of late AMR by Halloran et al.⁴Many reports have diffused that PTC C4d deposition predicts poor graft survival in both early (<1 yr) and late (>1 yr) posttransplantation periods.^12,14–23 Several reports also have shown C4d staining has little impact on graft survival. Satoskar et al.²⁴ examined 80 cases of late allograft rejection that occurred >1 yr after transplantation. They followed patients for 20 mo and found no difference in outcome between C4d⁺ and C4d⁻ groups. Nickeleit et al.²⁵ analyzed 400 transplant biopsies, at a median of 38 d after transplantation (range 7 to 5646 d) and found no differences between C4d⁺ and C4d⁻ groups in serum creatinine or graft survival at 1 yr of follow-up. A European study including protocol biopsy samples from early and late time points found no reduction in allograft survival in C4d⁺ versus C4d⁻ biopsy samples.¹³ Recently, a study by Haas et al.²⁶ of ABO-incompatible renal allografts showed that diffuse PTC C4d deposition without histologic evidence of AMR or cellular rejection in their initial protocol biopsies was associated with a lower risk for scarring at 1 yr. Several factors may explain the conflicting conclusions in these studies, including limitations as a result of highly selected patient groups,¹² short follow-up,^24–26 and the inclusion of both early and late allograft biopsies.^13,22,23,25In this study, we identified a unique cohort of renal transplant recipients with allografts surviving ≥10 yr after transplantation with biopsies performed for evaluation of graft dysfunction with or without proteinuria at these later time points. The aim of this study was to assess the prevalence of C4d staining and to clarify the clinical and pathologic significance of C4d positivity in long-term renal allografts.     

sRAGE and Risk of Diabetes,Cardiovascular Disease,and Death

Advanced glycation end products (AGEs) and their receptors are strongly implicated in the development of diabetes complications. When stimulated by AGEs, the receptors for AGEs (RAGEs) induce inflammation and are thought to fuel disease progression. Soluble circulating RAGE (sRAGE) may counteract the detrimental effects of RAGE. We measured sRAGE in stored plasma from a random sample of 1,201 participants in the Atherosclerosis Risk in Communities (ARIC) Study who were aged 47–68 years, had normal kidney function, and had no history of cardiovascular disease. In cross-sectional analyses, black race, male sex, higher BMI, and higher C-reactive protein were independently associated with low sRAGE. The racial difference was striking, with blacks approximately three times more likely to have low sRAGE compared with whites even after adjustment. During ~18 years of follow-up, there were 192 incident coronary heart disease events, 53 ischemic strokes, 213 deaths, and 253 cases of diabetes (among the 1,057 persons without diabetes at baseline). In multivariable Cox models comparing risk in the first quartile with that in the fourth quartile of baseline sRAGE, low levels of sRAGE were significantly associated with risk of diabetes (hazard ratio 1.64 [95% CI 1.10–2.44]), coronary heart disease (1.82 [1.17–2.84]), and mortality (1.72 [1.11–2.64]) but not ischemic stroke (0.78 [0.34–1.79]). In conclusion, we found that low levels of sRAGE were a marker of future chronic disease risk and mortality in the community and may represent an inflammatory state. Racial differences in sRAGE deserve further examination.Advanced glycation end products (AGEs) are strongly implicated in the development of diabetic vascular disease (1–3) and are of particular interest as novel biomarkers because they are a postulated etiologic link between hyperglycemia and diabetes complications (3–8). It is also thought that AGEs contribute to the development of vascular disease in nondiabetic people through their pro-oxidant activities (4,5). AGEs bind a variety of receptors, and circulating levels of AGE receptors are thought to be influenced by a number of endogenous (e.g., glucose, inflammation) and exogenous (e.g., smoking, diet) factors. The most widely studied AGE receptor is receptor for AGEs (RAGE), which is expressed in the vasculature, retina, kidney, and inflammatory cells. RAGE is considered a multiligand receptor of the immunoglobulin superfamily, binding, in addition to AGEs, S100/calgranulins, high-mobility group box-1, amyloid-β peptide, and other molecules (9). The COOH terminus of the protein is located on the extracellular surface. The NH₂-terminus of RAGE is essential in activating proinflammatory nuclear factor (NF)-κB–mediated signaling. When stimulated by AGEs, RAGE induces inflammation, contributes to tissue injury, and fuels the progression of chronic disease through NF-kB–mediated signaling (10–13). The soluble receptor for AGEs (sRAGE) is the isoform of RAGE found in serum and is primarily formed by proteolytic cleavage of RAGE and secondarily by endogenously secreted RAGE (esRAGE). esRAGE can be measured independently, comprises roughly one-quarter of total serum RAGE (14,15), and is highly correlated with total sRAGE levels (14,16). sRAGE has been described as a “sponge” for AGEs and may have protective functions, as it lacks the NH₂-terminus and cannot activate NF-κB signaling. Levels are primarily dependent on cell-surface RAGE levels (17).Recent studies have demonstrated inverse associations of serum sRAGE with clinical outcomes in persons with diabetes or kidney disease (18–21) and inverse cross-sectional associations with measures of coronary heart disease or atherosclerosis in more general populations (15,22–24). However, few prospective studies have been conducted in diverse, community-based populations using robust ELISA methods for measurement of sRAGE. The objective of this study was to characterize the association of sRAGE with risk of diabetes, coronary heart disease, stroke, and all-cause mortality in a community-based population.     

A Meta-analysis to Investigate the Relation Between Fitzpatrick Skin Types and Tolerability of Adapalene-Benzoyl Peroxide Topical Gel in Subjects with Mild or Moderate Acne

The overall goal of acne management for all patients is to select treatments that effectively address as many pathogenic factors as possible while minimizing side effects. Acne therapy in darker skin patients presents unique challenges due to differences in the risk of postinflammatory hyperpigmentation, which may develop in response to acne itself or to irritation secondary to treatment. One combination treatment currently available is a gel formulation containing a retinoid (adapalene 0.1%) in fixed combination with an antimicrobial (benzoyl peroxide 2.5%). Results from three randomized, double-blind, vehicle-controlled, clinical trials of adapalene-benzoyl peroxide were combined in a retrospective meta-analysis that included 909 patients treated for 12 weeks and assessed at each visit for erythema, scaling, dryness, and stinging/burning. Only Week 1 results were included in the meta-analysis because the worst severity of cutaneous irritation was found to occur at this timepoint in all three trials. For each study, and for the meta-analysis, comparisons were made using the Cochran-Mantel-Haenszel test. There were no statistically significant differences in dryness, scaling, and stinging/burning with adapalene-benzoyl peroxide treatment when subjects with Fitzpatrick skin types I to III were compared to subjects with Fitzpatrick skin types IV to VI (P=NS). Erythema assessments were statistically different based on skin types, as subjects with Fitzpatrick skin types IV to VI were rated as having “none” more often than those with Fitzpatrick skin types I to III (P<0.001). This could be due to the difficulty in visualizing erythema in patients with darker skin types, mainly Fitzpatrick skin types VI. Acne patients with Fitzpatrick skin types IV to VI were not found to be more susceptible to cutaneous irritation from treatment with the adapalene-benzoyl peroxide gel than patients with Fitzpatrick skin types I to III.Acne affects individuals of all races and ethnicities. The pathogenesis of acne is multifactorial, and the same factors are probably involved across the spectrum of skin types: sebaceous follicle obstruction, excessive sebum production due to hormonal stimulation of sebaceous glands, and proliferation of Propionibacterium acnes, which produces chemotactic factors and proinflammatory mediators that, in turn, generate an inflammatory response, followed by follicular rupture and extension of inflammation into the dermis, resulting in the formation of inflammatory lesions.^1,2The overall goal of acne management in all patients is to select treatment that effectively addresses as many of the pathogenic factors as possible while minimizing side effects.^3,4 Using multiple agents at the same time during treatment (concomitant therapy) has been recommended as a rational means to achieve this goal.^5,6 Acne therapy in skin of color (high melanin content) presents unique challenges due to differences relating to acne sequelae in these skin types, especially the presence or risk of postinflammatory hyperpigmentation (PIH) and keloidal scarring,^7–10 which are more prevalent in darker skin.^11–13Current acne treatment recommendations include combining gentle cleansing, effective moisturization, and sun protection, along with lower concentrations of benzoyl peroxide (BPO, 2.5%, 5%) and topical retinoids (adaplene 0.1%, tretinoin microsphere 0.04%, tazarotene 0.05%).^6,7,14 These agents can then be titrated up to higher concentrations if tolerated by the patient. Recently, a fixed-dose combination product containing a retinoid (adapalene) in combination with an antimicrobial (BPO) became available. Retinoids, such as adapalene, tretinoin, and tazarotene, are ideally suited for acne therapy because they target key factors in hyperkeratinization and comedogenesis, and are anti-inflammatory.¹⁵ Adapalene itself possesses anticomedogenic, comedolytic, and anti-inflammatory properties.^16–19 Some studies have documented that retinoids in skin of color, in addition to effectively treating noninflammatory and inflammatory acne, may also improve PIH.^20–23 Antimicrobials, such as BPO, provide additional benefits. BPO is an oxidizing agent with antibacterial and keratolytic effects and is used in acne treatment for its activities in decreasing the bacterial population of P. acnes.^24–27 In addition, the nonclinical and clinical safety profile of BPO is well established.²⁸Despite the benefits of combination therapy, the potential for increased cutaneous irritation is a concern. Although it has not been established that skin of color is more or less sensitive to irritants,²⁹ PIH may be triggered in darker skinned patients by skin irritation independent of cause (i.e., a disease or iatrogenic cause).^11,21,30 This issue has led some physicians to believe that skin of color is more sensitive to irritation from therapy. Because acne-related PIH is caused by a response to skin inflammation,^7,8 minimizing inflammation and reducing potential irritation and dryness is also a key goal in treating acne in skin of color. This is why dermatologists who treat acne patients with darker skin strive for a balance between effectively treating acne lesions and recognizing the importance of tolerability.This meta-analysis of the cutaneous irritation of adapalene-BPO gel was conducted to investigate possible differences in the incidence and severity of irritation among patients with different skin types. Three randomized, double-blind, vehicle- and placebo-controlled, clinical trials involving 3,855 patients have established the safety and efficacy of adapalene-BPO gel in the treatment of acne for all skin types.^31–33 The present retrospective meta-analysis is based on the tolerability data from those patients who were assigned to the adapalene 0.1%–BPO 2.5% treatment arm in each of the three randomized trials.     

Prevention of Diabetes With Pioglitazone in ACT NOW: Physiologic Correlates

We examined the metabolic characteristics that attend the development of type 2 diabetes (T2DM) in 441 impaired glucose tolerance (IGT) subjects who participated in the ACT NOW Study and had complete end-of-study metabolic measurements. Subjects were randomized to receive pioglitazone (PGZ; 45 mg/day) or placebo and were observed for a median of 2.4 years. Indices of insulin sensitivity (Matsuda index [MI]), insulin secretion (IS)/insulin resistance (IR; ΔI_0–120/ΔG_0–120, ΔIS rate [ISR]_0–120/ΔG_0–120), and β-cell function (ΔI/ΔG × MI and ΔISR/ΔG × MI) were calculated from plasma glucose, insulin, and C-peptide concentrations during oral glucose tolerance tests at baseline and study end. Diabetes developed in 45 placebo-treated vs. 15 PGZ-treated subjects (odds ratio [OR] 0.28 [95% CI 0.15–0.49]; P < 0.0001); 48% of PGZ-treated subjects reverted to normal glucose tolerance (NGT) versus 28% of placebo-treated subjects (P < 0.005). Higher final glucose tolerance status (NGT > IGT > T2DM) was associated with improvements in insulin sensitivity (OR 0.61 [95% CI 0.54–0.80]), IS (OR 0.61 [95% CI 0.50–0.75]), and β-cell function (ln IS/IR index and ln ISR/IR index) (OR 0.26 [95% CI 0.19–0.37]; all P < 0.0001). Of the factors measured, improved β-cell function was most closely associated with final glucose tolerance status.The prevalence of type 2 diabetes mellitus (T2DM) has risen to epidemic proportions in the United States and worldwide (1), and is being driven by the epidemic of obesity (2). In high-risk individuals, it is reasonable to consider interventions that reduce the incidence of T2DM. Impaired glucose tolerance (IGT) and impaired fasting glucose (IFG) are “high-risk” states with annual diabetes conversion rates ranging from 3 to 11% per year (3). Individuals with IGT have moderate-to-severe insulin resistance (IR) in muscle and impaired second-phase insulin secretion (IS), while those with IFG are characterized by hepatic IR and impaired first-phase IS with intact second-phase IS and normal/near-normal muscle insulin sensitivity (4–7). IGT conversion to T2DM is associated with a further and progressive decline in β-cell function with little worsening of IR, which is near maximally established in IGT (4,5,8–10). Treatment with thiazolidinediones improves IS (11) and IR (12–15), ameliorates lipotoxicity (12,14), and redistributes fat from muscle/liver/β-cells to subcutaneous fat depots (12,16). Therefore, they represent a logical choice for the treatment of IGT and IFG.In the ACT NOW Study (17,18), over a 2.4-year period, the annual conversion rate of IGT to T2DM was 7.6% in placebo-treated vs. 2.1% in pioglitazone (PGZ)-treated subjects (hazard ratio 0.28, P < 0.0001) (18). PGZ is a potent insulin-sensitizing agent in muscle, liver, and adipocytes (reviewed in 12–14); augments IS; and preserves β-cell function (11,19). These effects are mediated, in part, via peroxisome proliferator–activated receptor-γ (PPAR-γ) receptor (13,20) and via reversal of lipotoxicity (12,14) and changes in adipocytokines (20). PGZ reduces plasma free fatty acid (FFA) levels, mobilizes fat out of muscle (21) and liver (22), and redistributes fat from visceral to subcutaneous depots (12,16).In the current study, we examined which physiologic/metabolic/anthropometric changes (end-of-study versus baseline) in the ACT NOW Study (18) were associated with IGT progression to diabetes and reversion to normal glucose tolerance (NGT) in PGZ- and placebo-treated subjects.     

Tanning Bed Perception Survey: A Questionnaire-based Study

Objective: This study was intended to investigate the perception of tanning bed use among college students. Design: A 15-question survey was given to young adults regarding tanning perceptions. Setting: Rochester Community College in Rochester, Minnesota. Participants: Forty-four respondents between 18 and 51 years of age. Measurements: Data was collected via a self-reported questionnaire. Results: In this study, 50 percent of participants were not educated on the risks of melanoma, and 68 percent were not interested in receiving information on melanoma and completing a follow-up survey. More specifically, 63 percent versus 89 percent of participants with no tanning bed versus some tanning bed use did not want information regarding melanoma, respectively. This study also shows that more tanning bed users believe tanning helps prevent burning than non-tanning bed users. Fifty-seven percent of the 35 participants who had never used a tanning bed thought that they never prevent sunburn, while only 11 percent of the nine participants who had used a tanning bed in the past thought that they never prevent sunburn, which was statistically significant.Nearly 30 million people tan indoors in the United States every year.1 It is notably significant in younger patients. In a study of more than 10,000 boys and girls aged 12 to 18,2 tanning bed use increased from seven percent among 14-year-old girls to 16 percent by age 15, and more than doubled again by age 17. Tanning bed users’ reasons for use can include the following: “to look better,” “to feel healthy,” “tanning is accomplished in less time,” “salons have a pleasant atmosphere,” “burning is avoided.” Words associated with tanning salons include “relaxation,” “easy,” “nice,” “friendly.”3 Tanning bed use among girls reporting that it was worth getting burned was nearly double than for those without this belief (22.3% vs. 11.3%).2There are significant dangers associated with artificial tanning use. Karagas et al4 reported that any use of tanning devices was associated with an odds ratio of 2.5 for squamous cell carcinoma and a 1.5 higher odds ratio for basal cell carcinoma. Indoor ultraviolet tanners are also 74 percent more likely to develop melanoma than are those who have never tanned indoors.5 There is a ban on tanning bed use in people under the age of 18 in many countries and seven American states.6 Brazil banned tanning beds altogether in 2009,7 and Australia has banned tanning beds in most areas with plans to end all commercial tanning by the end of 2015.6Knowledge about tanning bed safety needs to be improved. On YouTube, there are more advertisements for tanning salons than total number of videos purveying the dangers of tanning.8 Providing patients with tanning bed safety information may alter tanning bed usage. Robinson et al2 reported on 100 young adults and found that knowledge of melanoma/skin cancer was associated with a change in tanning bed usage from 1988 (42%) to 1994 (38%) to 2007 (87%). Knowledge of the association of tanning and melanoma increased from 1988 (25%) to 1994 (77%), but decreased from 1994 to 2007 (67%). Although physicians, especially dermatologists, were sources of information about tanning and were considered the most trusted source, only 14 percent of respondents in 1994 and 2007 reported ever talking to a doctor about indoor tanning. Physicians should be conscious of actively counseling patients about the safety of tanning bed use. Hession et al9 reported that among 137 pediatricians who responded through an online survey in New York State, 45 percent counseled at least one percent of their patients between the ages of 11 and 18 years on indoor tanning, while only four percent counsel 50 percent or more, despite the fact that 92 percent agreed that indoor tanning is an important preventive health issue. Lack of time was the most frequently cited obstacle to counseling; 59 percent agreed that given the limited time during a visit, other topics seem more important.Education regarding tanning salon dangers is still insufficient. This questionnaire study was designed to investigate the perception of tanning bed use among college students. Specifically, the authors sought to understand if users were educated or willing to be educated on the safety of tanning beds, frequency of tanning bed use, history of a family member using a tanning bed, and if the patient had a history of any skin cancer.     

The Efficacy and Tolerability of a Fixed Combination Clindamycin (1.2%) and Benzoyl Peroxide (3.75%) Aqueous Gel in Adult Female Patients with Facial Acne Vulgaris

Objective: To investigate the efficacy and tolerability of clindamycin phosphate 1.2%/benzoyl peroxide 3.75% gel or vehicle monotherapy in adult female acne patients. Methods: A post hoc analysis in 72 adult female patients (aged ≥25 years) with moderate-to-severe acne receiving clindamycin phosphate 1.2%/benzoyl peroxide 3.75% gel or vehicle for 12 weeks. Results: The efficacy of clindamycin phosphate 1.2%/benzoyl peroxide 3.75% gel was significantly greater than vehicle. The mean percent change from baseline in inflammatory and noninflammatory lesion counts and the percentage of patients who achieved a 2-grade reduction in the Evaluator’s Global Severity Score was 68.7%, 60.4, and 52.7 percent, respectively (P=0.019, 0.020 and 0.074 versus vehicle). In addition, 44 percent of patients reported their acne to be “clear” or “almost clear” at Week 12 (P=0.026 versus vehicle). No substantive differences were seen in cutaneous tolerability among treatment groups, and no patients discontinued treatment because of adverse events. Limitations: It is not possible to determine the contributions of the individual active ingredients, and this study was not set up specifically to investigate the treatment of adult female acne. Conclusion: Clindamycin phosphate 1.2%/benzoyl peroxide 3.75% gel provides statistically significant greater efficacy than vehicle in treating acne in adult female patients and has a favorable safety and tolerability profile.Acne vulgaris is a very common skin disease that usually presents in adolescence, but frequently continues into adulthood. An increasing number of older women are seeking acne treatment from dermatologists.1,2 A recent study of almost 3,000 women taken from a general population showed that although acne peaked in teenage years, 45 percent of women aged 21 to 30, 26 percent aged 31 to 40, and 12 percent aged 41 to 50 suffered from acne.3The pathogenesis of adult acne and its differences from that of teenage acne are unclear. In general, adult women with acne have high levels of sebum. Smoking has also been identified as an aggravating factor for patients with pre-existing acne or with a genetic predisposition.4,5 The majority of patients have a first-degree family history of postadolescent acne,6 a factor known to increase the risk of adult acne by four percent.7 Acne has been shown to be associated with psychiatric comorbidities in adult women. One study reported 40 percent of adult female acne patients suffer from depression,8 and daily stress has been shown to exacerbate the condition.9Postadolescent acne is broadly categorized into two main groups—persistent (the most common) and late-onset acne. Patients with persistent acne are those who developed acne in adolescence and the acne did not resolve.10 Late-onset acne, on the other hand, refers to patients who were clear in their teenage years, but developed acne later in life. Traditionally, adult acne has been described as an inflammatory condition affecting predominantly the lower one-third of the face and jawline. Frequently, patients report a premenstrual flare occurring 1 to 2 weeks prior to menses. However, recent data now challenge this notion. In a recent international study evaluating 374 women, investigators found that in 90 percent of patients, facial acne distribution was similar to that of teenagers. Moreover, acne was characterized not only by inflammatory lesions, but also comedones.11 A cross-sectional, web-based survey of 208 adult women revealed similar data, noting facial acne on the cheeks, chin, and forehead. This study also assessed disease burden, with three of four respondents reporting that their acne was moderately, severely, or very severely troublesome.12Data on the treatment of acne in the adult female population is limited. Recently, efficacy and tolerability data on a new fixed combination product, clindamycin phosphate 1.2%/benzoyl peroxide (BP) 3.75% gel was reported.13 A post hoc analysis was performed to evaluate efficacy and cutaneous tolerability of this product in adult female patients enrolled in the study.     

Pregnancy and Maternal Outcomes Among Kidney Transplant Recipients

Fertility rates, pregnancy, and maternal outcomes are not well described among women with a functioning kidney transplant. Using data from the Australian and New Zealand Dialysis and Transplant Registry, we analyzed 40 yr of pregnancy-related outcomes for transplant recipients. This analysis included 444 live births reported from 577 pregnancies; the absolute but not relative fertility rate fell during these four decades. Of pregnancies achieved, 97% were beyond the first year after transplantation. The mean age at the time of pregnancy was 29 ± 5 yr. Compared with previous decades, the mean age during the last decade increased significantly to 32 yr (P < 0.001). The proportion of live births doubled during the last decade, whereas surgical terminations declined (P < 0.001). The fertility rate (or live-birth rate) for this cohort of women was 0.19 (95% confidence interval 0.17 to 0.21) relative to the Australian background population. We also matched 120 parous with 120 nulliparous women by year of transplantation, duration of transplant, age at transplantation ±5 yr, and predelivery creatinine for parous women or serum creatinine for nulliparous women; a first live birth was not associated with a poorer 20-yr graft or patient survival. Maternal complications included preeclampsia in 27% and gestational diabetes in 1%. Taken together, these data confirm that a live birth in women with a functioning graft does not have an adverse impact on graft and patient survival.One of the many perceived benefits of kidney transplantation has been restoration of pituitary-ovarian function and fertility in women of reproductive age. Prenatal advice for women with a functioning kidney transplant has been primarily based on data derived from observational research,^1–13 and the reported live-birth rates achieved in such women range from 43.2¹⁴ to 82%.¹⁵Although an increased pregnancy event number has been reported for women with a functioning kidney transplant,¹⁶ little is actually known about “pregnancy rate changes” during the past 40 yr. More importantly, long-term graft and maternal survival analyses, referred to when advising women who have undergone transplantation and are considering a pregnancy, have been mostly performed without adequate matching,¹² or, alternatively, matching has been used but outcomes followed up for only brief intervals^14,17,18 and in small cohorts.^19–22 Published graft matching studies to date suggest no adverse impact 10 yr after a live birth.¹⁴In most instances, pregnancies in women with a kidney graft have been encouraged. Historically, renal function,^8,15,17,18 baseline proteinuria,²³ intercurrent hypertension,^1,24 and time from transplantation^{1,3,5,8,14,15,18,24,25} have been used to predict adverse event risks to the mother, kidney, and offspring. To this are added the often unquantifiable inherent risks for genetically transmitted diseases or the problems associated with prematurity.^26,27 More recently, epidemiologic evidence suggests low birth weight may be associated with the development of hypertension,²⁸ cardiovascular disease,²⁹ insulin resistance,³⁰ and end-stage renal failure.³¹ Moreover, low birth weight is associated with an increased risk for hypertension, independent of genetic and shared environmental factors.³²Series published to date have not captured all pregnancy events or their outcomes. Limitations of some of the published studies include short duration of follow-up and studies with no adequate or long-term matching for decade and renal function.We examined fertility rates, pregnancy rates, and pregnancy outcomes over 40 yr in an at-risk population, defined as women who were aged between 15 and 49 and had a functioning kidney transplant, using ANZDATA registry data. In addition, maternal and graft outcomes were analyzed, and, uniquely, a matched cohort analysis of 120 nulliparous and 120 parous women who had undergone transplantation enabled analysis of outcomes at 20 yr.     

Kidney and Recipient Weight Incompatibility Reduces Long-Term Graft Survival

Long-term function of kidney allografts depends on multiple variables, one of which may be the compatibility in size between the graft and the recipient. Here, we assessed the long-term consequences of the ratio of the weight of the kidney to the weight of the recipient (KwRw ratio) in a multicenter cohort of 1189 patients who received a transplant between 1995 and 2006. The graft filtration rate increased by a mean of 5.74 ml/min between the third and sixth posttransplantation months among patients with a low KwRw ratio (<2.3 g/kg; P < 0.0001). In this low KwRw ratio group, the graft filtration rate remained stable between 6 months and 7 years but then decreased at a mean rate of 3.17 ml/min per yr (P < 0.0001). In addition, low KwRw ratios conferred greater risk for proteinuria, more antihypertensive drugs, and segmental or global glomerulosclerosis. Moreover, a KwRw ratio <2.3 g/kg associated with a 55% increased risk for transplant failure by 2 years of follow-up. In conclusion, incompatibility between graft and recipient weight is an independent predictor of long-term graft survival, suggesting that avoiding kidney and recipient weight incompatibility may improve late clinical outcome after kidney transplantation.The effect of nephron reduction has long been described in animal models as well as in humans^1,2 and is thought to be a potential “nonimmunologic” risk factor for chronic graft dysfunction after kidney transplantation.^3,4 The paradigm generally considered to account for the deleterious effect of nephron reduction on graft function is that of “adaptive” hyperfiltration of the remaining glomeruli, ultimately leading to glomerulosclerosis.^5–7 In accordance with this hypothesis, individuals who have undergone nephrectomy have been shown to develop high BP and proteinuria decades after the nephrectomy,^8–11 as in the case of older recipients with a higher body mass index¹²; however, renal insufficiency only appears in the case of a 75% reduction in kidney mass and after at least 10 years of follow-up.⁹ Kidney transplantation has been proposed as an accelerated model of nephron reduction resulting from the accumulation of several unfavorable factors. For example, repeated injuries, from initial brain death of the donor¹³ to ischemia-reperfusion injury,¹⁴ negatively affect the transplant. Moreover, superimposed immunologic and nonimmunologic events further decrease the initial nephron mass of a transplant and serve only to exacerbate the consequences of hyperfiltration related to its single kidney status.Given that kidney weight (Kw) and glomerular volume (but not nephron number) correlate with body surface area (BSA),¹⁵ several studies have already analyzed the effect of donor and recipient BSA mismatches.^7,16–19 The effect of kidney graft size and recipient weight (Rw)^20,21 has also been studied; however, the direct impact of matching the Kw itself (which correlates with both glomerular volume and nephron number)¹⁵ to the Rw has been studied only in relatively small cohorts of <300 patients and only in living donors,^22,23 where the graft does not incur the same accumulating injuries as those from deceased donors.We previously reported on the results of a first study²⁴ focusing on the impact of graft weight on clinical outcome; however, within the relatively short survey period of the latter study (mean 32 months; range 8 days to 94 months), no impact on short-term graft survival was observed. Because renal failure has been described a decade after nephron reduction,^3,10,25 we reappraised our historical cohort to which an additional 47 patients were included (whole population n = 1189) at a mean of 6.2 years from transplantation (range 8 days to 13 years). We now report that the magnitude of the Kw and Rw incompatibility is significantly associated not only with sustained “adaptive” hyperfiltration and early proteinuria but also with an increased risk for hypertension requiring more medication, a higher incidence of segmental or global glomerulosclerosis, and a significantly poorer long-term transplant survival.     

Adipose Tissue Macrophages Function As Antigen-Presenting Cells and Regulate Adipose Tissue CD4+ T Cells in Mice

The proinflammatory activation of leukocytes in adipose tissue contributes to metabolic disease. How crosstalk between immune cells initiates and sustains adipose tissue inflammation remains an unresolved question. We have examined the hypothesis that adipose tissue macrophages (ATMs) interact with and regulate the function of T cells. Dietary obesity was shown to activate the proliferation of effector memory CD4⁺ T cells in adipose tissue. Our studies further demonstrate that ATMs are functional antigen-presenting cells that promote the proliferation of interferon-γ–producing CD4⁺ T cells in adipose tissue. ATMs from lean and obese visceral fat process and present major histocompatibility complex (MHC) class II–restricted antigens. ATMs were sufficient to promote proliferation and interferon-γ production from antigen-specific CD4⁺ T cells in vitro and in vivo. Diet-induced obesity increased the expression of MHC II and T-cell costimulatory molecules on ATMs in visceral fat, which correlated with an induction of T-cell proliferation in that depot. Collectively, these data indicate that ATMs provide a functional link between the innate and adaptive immune systems within visceral fat in mice.Obesity-induced inflammation contributes to the development of type 2 diabetes, metabolic syndrome, and cardiovascular disease (1–3). Accumulation of activated leukocytes in metabolic tissues is a driving force for obesity-associated metabolic inflammation (metainflammation) and insulin resistance (3,4). In adipose tissue, a vast array of leukocytes have been identified and reported to contribute to obesity-induced metainflammation. How adipose tissue leukocytes interact to shape the inflammatory environment within fat is an important unresolved gap in our current understanding of metabolic disease.In humans and rodent models, F4/80⁺ adipose tissue macrophages (ATMs) are the predominant leukocyte found in metabolically healthy and insulin-resistant fat (5). Resident (type 2) ATMs are distributed between adipocytes in healthy adipose tissue throughout development, express anti-inflammatory markers typical of “alternatively activated” or M2 polarized macrophages, and promote tissue homeostasis (6,7). Disruption of macrophage M2 polarization increases the susceptibility to insulin resistance induced by a high-fat diet (HFD) (8–10). Obesity triggers the accumulation of F4/80⁺ ATMs that coexpress the dendritic cell (DC) marker CD11c as well as genes typically expressed by “classically activated” or proinflammatory M1 polarized macrophages (11–13). M1 ATMs form multicellular lipid-laden clusters, known as crown-like structures (CLS), around dead adipocytes in obese fat (6,14,15) and produce inflammatory cytokines (e.g., interleukin [IL]-1β, IL-6, and tumor necrosis factor-α [TNF-α]) that can impair insulin action in adipocytes (16,17). Current models suggest that obesity promotes metainflammation in part by altering the balance between type 2 and type 1 ATMs in visceral fat (13,18).In addition to ATMs, adipose tissue contains lymphocytes (e.g., natural killer T cells [NKTs], conventional CD4⁺ T cells [Tconvs], regulatory CD4⁺ T cells [Tregs], cytotoxic CD8⁺ T cells, and B cells) that are also regulated by metabolic status (19–24). Treg content in visceral fat is inversely correlated with measures of insulin resistance and inflammation (19,25,26), suggesting that Tregs are anti-inflammatory. In contrast, T helper 1 (Th1) CD4⁺ T cells and CD8⁺ adipose tissue T cells (ATTs) accumulate in fat during obesity, promoting IFN-γ and TNF-α production and insulin resistance (20,21,27). Thus, analogous to ATMs, the imbalance between anti-inflammatory Tregs and proinflammatory CD4⁺/CD8⁺ ATTs contributes to metainflammation.The mechanisms that regulate ATTs in adipose tissue are largely unknown. Spectratyping experiments suggest that CD4⁺ ATTs (but not CD8⁺ ATTs) undergo monoclonal expansion within fat and have an effector-memory (CD44^High CD62L^Low) phenotype (19,21,28). This implies that ATT activation and expansion may be an adaptive immune response to an obesity-induced antigen. T-cell activation depends on an intricate relationship between T cells and antigen-presenting cells (APCs) (29). Classically, APCs (specifically, macrophages and DCs) shape CD4⁺ T-cell activation by three signals: 1) presentation of peptide antigens on major histocompatibility complex (MHC) class II (MHC II) molecules (signal 1), 2) expression of T-cell costimulatory molecules (e.g., CD40, CD80, and CD86) (signal 2), and 3) production of cytokines (e.g., transforming growth factor-β, IL-10, or IL-12) (signal 3). These three signals shape the differentiation of naïve CD4⁺ T cells into effector T-cell subsets (e.g., Th1, Th2, Th17, Treg).The APCs that interact with ATTs in fat have not been well characterized but could include ATMs, adipose tissue DCs, adipose tissue B cells, mast cells, and neutrophils (24,30–34). Quantitative changes in ATTs can precede the accumulation of type 1 CD11c⁺ ATMs in visceral fat in obese mice, suggesting that APCs present in lean and obese fat could trigger an adaptive immune response. Because ATMs are the predominant leukocyte population in lean and obese fat and ATMs from obese mice and humans express MHC II molecules (35–37), we tested the hypothesis that ATMs (CD11b⁺ F4/80⁺) are capable of functioning as APCs to regulate CD4⁺ ATT activation and proliferation. We report that ATMs within visceral fat from mice phagocytose and process antigens for presentation, express costimulatory molecules, and induce antigen-specific CD4⁺ T-cell proliferation in vitro and in situ. Furthermore, we found proliferating ATTs localized with ATMs in fat-associated lymphoid clusters (FALCs) where antigen-specific T-cell activation and proliferation may be initiated. Our data indicate that ATMs meet the functional definition of APCs and suggest that MHC II-restricted antigens presented by ATMs in visceral fat regulate Tregs and Tconvs CD4⁺ ATTs in mice.