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Background: Skin cancer screening is routinely performed for members of melanoma-prone families, but longitudinal studies evaluating the efficacy of surveillance in this high-risk population are lacking. Methods: We evaluated thickness for first primary melanomas diagnosed in melanoma-prone families (≥2 individuals with melanoma) enrolled in NCT00040352 (NCI familial melanoma study) from 1976 through 2014; enrolled patients received routine skin cancer screening and education about skin self-exams. We used linear and ordinal logistic regression models adjusted for gender and age with a generalized estimating equations approach to report changes in thickness and tumor (T) stage over time, comparing outcomes for NCI cases diagnosed before (pre-study) versus after study participation (prospective) and for NCI cases versus nonfamilial cases [Surveillance, Epidemiology, and End Results (SEER) 9 registries]. Results: Tumor thickness was evaluated for 293 NCI (pre-study = 246; prospective = 47) patients. Compared with NCI pre-study cases, NCI prospective melanomas were thinner (0.6 vs. 1.1 mm; P < 0.001) and more likely to be T1 stage [39/47 (83%) vs. 98/246 (40%); P < 0.001]. Similar findings (P < 0.05) were observed for familial cases with and without germline CDKN2A and CDK4 mutations. Peters–Belson modeling suggested that calendar period effects of decreasing thickness in the general population (SEER 9) did not fully explain thickness trends in NCI families. Conclusions: Participation in a longitudinal surveillance program providing skin cancer screening and education about skin self-exams was associated with thinner melanomas for members of melanoma-prone families. Impact: The study findings support the clinical benefit of screening (physician and self) for this high-risk population.

BACKGROUND: CDKN2A, CDK4, and POT1 are well-established melanoma-susceptibility genes. OBJECTIVE: We evaluated melanoma histopathology for individuals with germline mutations of CDKN2A, CDK4, and POT1. METHODS: We assessed histopathology for melanomas diagnosed in melanoma-prone families (≥2 individuals with melanoma) from the United States, Italy, and Spain. Comparisons between mutation carriers and non-carriers (no mutation) were adjusted for age, sex, Breslow depth, and correlations among individuals within the same family. RESULTS: Histologic slides were evaluated for 290 melanomas (139 from 132 non-carriers, 122 from 68 CDKN2A carriers, 10 from 6 CDK4 carriers, 19 from 16 POT1 carriers). Superficial spreading was the predominant subtype for all groups. Spitzoid morphology (>25% of tumor) was observed in the majority of invasive melanomas from POT1 carriers (10 of 15 [67%], P

The characterization of the effects of solar UVR on a broad set of circulating markers in systemic immunity and inflammation may provide insight into the mechanisms responsible for the UVR associations observed for several benign and malignant diseases. We examined the associations between exposure to solar UVR and circulating levels of 78 markers among 1,819 individuals aged 55–74 years who participated in the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial using multiplex assays. Solar UVR was derived by linking the geocoded locations of 10 screening centers across the continental United States and the date of blood draw to the National Solar Radiation Database from 1993 to 2005. We assessed associations between ambient solar UVR and dichotomized marker levels using adjusted weighted logistic regression models and applied a 5% false discovery rate criterion to P-values. UVR exposure was associated (P < 0.05) with 9 of the 78 markers. CCL27, CCL4, FGF2, GM-CSF, IFN-γ, soluble IL4R, IL-7, and IL-11 levels were lower with increasing UVR tertile, with adjusted ORs ranging from 0.66 to 0.80, and the significant association for CCL27 withstood multiple comparison correction. In contrast, CRP levels were elevated with increasing UVR. Solar UVR was associated with alterations in systemic immune and inflammation marker levels., Graphical abstract

BACKGROUND: Recent genome-wide association meta-analysis for melanoma doubled the number of previously identified variants. We assessed the performance of an updated polygenic risk score (PRS) in a population of older individuals, where melanoma incidence and cumulative ultraviolet radiation exposure is greatest. METHODS: We assessed a PRS for cutaneous melanoma comprising 55 variants in a prospective study of 12 712 individuals in the ASPirin in Reducing Events in the Elderly Trial. We evaluated incident melanomas diagnosed during the trial and prevalent melanomas diagnosed preenrolment (self-reported). Multivariable models examined associations between PRS as a continuous variable (per SD) and categorical (low-risk [0%-20%], medium-risk [21%-80%], high-risk [81%-100%] groups) with incident melanoma. Logistic regression examined the association between PRS and prevalent melanoma. RESULTS: At baseline, mean participant age was 75 years; 55.0% were female, and 528 (4.2%) had prevalent melanomas. During follow-up (median = 4.7 years), 120 (1.0%) incident cutaneous melanomas occurred, 98 of which were in participants with no history. PRS was associated with incident melanoma (hazard ratio = 1.46 per SD, 95% confidence interval [CI] = 1.20 to 1.77) and prevalent melanoma (odds ratio [OR] = 1.55 per SD, 95% CI = 1.42 to 1.69). Participants in the highest-risk PRS group had increased risk compared with the low-risk group for incident melanoma (OR = 2.51, 95% CI = 1.28 to 4.92) and prevalent melanoma (OR = 3.66, 95% CI = 2.69 to 5.05). When stratifying by sex, only males had an association between the PRS and incident melanoma, whereas both sexes had an association between the PRS and prevalent melanoma. CONCLUSIONS: A genomic risk score is associated with melanoma risk in older individuals and may contribute to targeted surveillance.

Importance Risk of sebaceous carcinoma (SC), a rare skin cancer associated with Muir-Torre syndrome, is elevated among solid organ transplant recipients (SOTRs). However, population studies evaluating this association and assessing survival for posttransplant cases are lacking, and further understanding of SC epidemiology in this immunosuppressed population could provide etiologic and clinical insights. Objective To assess SC incidence and patient survival after solid organ transplantation. Design, Setting, and Participants This cohort study, conducted from January 1, 1987, to December 31, 2017, used data from the Transplant Cancer Match Study, which links transplant and cancer registry data for 17 states and 1 metropolitan area in the United States. Altogether, these registries account for approximately 46% of all US transplants. Data on demographic and transplant characteristics as well as induction and initial maintenance immunosuppressive therapies were obtained from the transplant registry. Standardized incidence ratios (SIRs) comparing SC incidence among SOTRs to the general population were calculated. Incidence rate ratios (IRRs) comparing SC risk between SOTR subgroups were calculated using multivariate Poisson regression. Cox regression was used to compare overall survival between SC cases in SOTRs and other individuals. Main Outcomes and Measures Sebaceous carcinoma incidence and overall patient survival after transplantation compared with the general population. Results A total of 326 282 transplant procedures were performed for 301 075 patients (No. [%] age at transplant, 126 550 [38.8%] aged 0-44 years; 82 394 [25.3%] aged 45-54 years; 82 082 [25.5%] aged 55-64 years; 35 256 [10.8%] aged ≥65 years; 201 354 male patients [61.7%]; 202 557 White patients [62.1%]). A total of 102 SCs were diagnosed in 301 075 SOTRs, corresponding to a 25-fold increased incidence (SIR, 24.8; 95% CI, 20.2-30.1). Incidence was especially elevated among lung recipients (SIR, 47.7; 95% CI, 20.6-94.0) and after a posttransplant diagnosis of cutaneous squamous cell carcinoma (SIR, 104.0; 95% CI, 62.8-163.0). Among SOTRs, factors independently associated with SC risk included male sex (IRR, 2.46; 95% CI, 1.48-4.07; P

Sebaceous carcinoma is an aggressive skin cancer with a 5-year overall survival rate of 78% for localized/regional disease and 50% for metastatic disease. The incidence of this cancer has been increasing in the United States for several decades, but the underlying reasons for this increase are unclear. In this article, we review the epidemiology and genetics of sebaceous carcinoma, including recent population data and tumor genomic analyses that provide new insights into underlying tumor biology. We further discuss emerging evidence of a possible viral etiology for this cancer. Finally, we review the clinical implications of recent advances in sebaceous carcinoma research for screening, prevention, and treatment.

Sebaceous carcinoma (SC) is an aggressive skin tumor. Although ultraviolet radiation (UVR) is an important risk factor for some skin cancer types, no population-level study has evaluated for an association between UVR and SC risk. Herein, we examined satellite-based ambient UVR in relation to SC incidence using Surveillance, Epidemiology, and End Results 18 cancer registry data (2000–2016). There were 3503 microscopically confirmed cases of SC diagnosed during the study period. For non-Hispanic whites, there was an association between increasing ambient UVR and SC risk (incidence rate ratio [per UVR quartile] = 1.15, 95% confidence interval = 1.11 to 1.19; two-sided P

CDKN2A and CDK4 are well-established melanoma susceptibility genes, but their effect on tumor location and distribution is unknown. We used a case-case study design to assess for differences in tumor location between mutation carriers (CDKN2A = 141 patients, 348 melanomas; CDK4 = 15 patients, 54 melanomas) and noncarriers (104 patients, 157 melanomas) in US melanoma-prone families. Associations between groups were assessed with chi-square tests. Odds ratios (ORs) for tumor location were adjusted for diagnosis age, gender, and superficial spreading subtype. Models included random effects to account for within individual and family correlations. Compared with having a truncal melanoma, CDK4 (vs. noncarriers: lower extremities OR = 14.5, 95% confidence interval [CI] = 5.02-42.0, P0.001; upper extremities OR = 6.88, 95% CI = 2.37-19.9, P0.001; head and neck OR = 18.6, 95% CI = 4.04-85.2, P0.001) and CDKN2A (vs. noncarriers: lower extremities OR = 3.01, 95% CI = 1.56-5.82, P0.05; upper extremities OR = 1.91, 95% CI = 1.03-3.52, P 0.05; head and neck OR = 5.40, 95% CI = 2.10-13.9, P0.001) carriers had higher odds of developing melanoma at all other sites. Similar findings were observed for analyses stratified by gender, age, and first versus subsequent melanoma diagnoses. Further studies are needed to understand the biology underlying these genotype-associated patterns of tumor development, which could provide new insights into melanoma treatment and prevention.

Background Teledermatology may improve dermatologic care access in underserved areas and expand the clinical experience of dermatologists-in-training. The potential for teledermatology to supplement global health curricula in dermatology residency education has not been explored. Methods An international virtual grand rounds (VGR) curriculum was created based on teledermatology cases from Kabul, Afghanistan. The learning objectives included understanding the diagnosis and management of skin diseases in unfamiliar resource-limited settings and highlighting socioeconomic, cross-cultural, and ethical issues. A 17-item, Likert scale questionnaire was used to assess the effectiveness of the curriculum, including specific Accreditation Council for Graduate Medical Education (ACGME) competencies, as well as interest in global health and teledermatology. Results The survey was completed by 85 of 118 VGR attendees (72% response rate). Most respondents considered the curriculum valuable to their education (mean 4.5 on a 5-point Likert scale; standard deviation, 0.5), learned more about diagnosis and treatment of skin diseases in international settings (4.5; 0.6) and in the US (4.1; 0.8), and learned more about socioeconomic, cultural, and ethical issues in skin health (4.6; 0.5). The majority also reported being more interested in global dermatology (4.1; 0.8) and would recommend VGR to a colleague (4.5; 0.6). Conclusion This pilot curriculum provided an innovative platform to enhance undergraduate and graduate medical education in international dermatology. International teledermatology education may be used to address multiple ACGME core competencies and increase resident awareness of sociocultural determinants of skin health.

Trends in the training, supply, availability, career decisions, and retirement of US dermatology physicians are not well delineated. The current study evaluates whether growth in the dermatology workforce will keep pace with population expansion in the United States. A dermatologist supply model was projected to 2030 drawing on data from the American Academy of Dermatology, American Medical Association, Bureau of Labor Statistics, American Association of Medical Colleges, and other associations. The clinically active dermatologist workforce in 2015 was 36 per capita (1,000,000); entry following postgraduate training was age 30 with career separation at age 65 on average. Added to the provider model are physician assistants and nurse practitioners in dermatology practices. A linear regression micro simulation model based on age cohorts produced a per capita supply of dermatology providers of 61 (±3) per 1,000,000 by 2030, up from 47 in 2016. The dermatology workforce is growing faster than population expansion. Workforce estimates could be affected by changing trends in retirement and training of dermatology providers. Investments in training of nurse practitioners and physician assistants, in addition to training more doctors, may be an effective strategy for increasing access to care in populations with low dermatologist density.

Anecdotal reports of children experiencing eczema flares during winter and summer months along with global variation in eczema prevalence has fueled speculation that climate may modulate disease activity. The aim of this study was to determine whether long-term weather patterns affect the severity and persistence of eczema symptoms in children. We performed a prospective cohort study of US children (N=5,595) enrolled in PEER (Pediatric Eczema Elective Registry) between 2004 and 2012 to evaluate the effect of climate (daily temperature, daily sun exposure, daily humidity) on the severity of eczema symptoms. Odds ratios (ORs) were calculated for the patient-evaluated outcome of disease control. Multivariate logistic regression modeling adjusting for gender, race, income, and topical medication use demonstrated that higher temperature (OR=0.90, 95% confidence interval (CI): 0.87–0.93, P

Connexins (Cx) are structural proteins that form gap junctions, which are vital to cell-cell communication and help to regulate cell division. The purpose of this study was to evaluate if there are diagnostically important differences in immunostaining for connexins 43 (Cx43) and 26 (Cx26) in melanoma compared with nevi. Formalin-fixed paraffin-embedded sections of 34 histologically well-characterized melanocytic lesions, 17 primary malignant melanomas (MM), and 17 nevi were stained with a polyclonal antibody to Cx43 and a polyclonal antibody to Cx26. Immunoreactivity in tumor cells was evaluated semiquantitatively based on extent (1%-100%) and intensity (0-3) of reactivity. A score of 0-300 was generated by the product of the extent and intensity readings in each case. Significantly higher Cx43 immunoreactivity was detected in MM (mean intensity score = 253.5; 95% confidence interval, 227.9-279.2; P = 0.002) compared with nevi (mean intensity score = 152.4; 95% confidence interval, 104.9-199.8). In contrast, Cx26 immunoreactivity was less than 5% or entirely absent in all melanocytic tumors (n = 34). The significantly higher Cx43 staining in MM when compared with nevi suggests an oncogenic role for this protein in melanocytic tumor progression. Consequently, the evaluation of immunohistochemical staining for Cx43 in conjunction with other ancillary stains and tumor histology may be helpful in distinguishing MM from nevi, although positive Cx26 reactivity suggests that a cutaneous neoplasm is of nonmelanocytic origin.

The purpose of this study was to identify the presence or absence of geographic variation in Medicare spending and mortality rates for diabetic patients with foot ulcers (DFU) and lower extremity amputations (LEA).Diabetic beneficiaries with foot ulcers (n=682,887) and lower extremity amputations (n=151,752) were enrolled in Medicare Parts A and B during the calendar year 2007. We used ordinary least squares (OLS) regression to explain geographic variation in per capita Medicare spending and one-year mortality rates.Health care spending and mortality rates varied considerably across the nation for our two patient cohorts. However, higher spending was not associated with a statistically significant reduction in one-year patient mortality (P=.12 for DFU, P=.20 for LEA). Macrovascular complications for amputees were more common in parts of the country with higher mortality rates (P.001), but this association was not observed for our foot ulcer cohort (P=.12). In contrast, macrovascular complications were associated with increased per capita spending for beneficiaries with foot ulcers (P=.01). Rates of hospital admission were also associated with higher per capita spending and increased mortality rates for individuals with foot ulcers (P.001 for health spending and mortality) and lower extremity amputations (P.001 for health spending, P=.01 for mortality).Geographic variation in Medicare spending and mortality rates for diabetic patients with foot ulcers and amputations is associated with regional differences in the utilization of inpatient services and the prevalence of macrovascular complications.

Author(s): Shi, Lucy L; Sargen, Michael R; Chen, Suephy C; Arbiser, Jack L; Pollack, Brian P | Abstract: Background: Botulinum toxin type A (BTX-A) injections are an effective treatment for controlling hyperhidrosis at sites of amputation. Hyperesthesia associated with amputated limbs is a major barrier to performing this procedure under local anesthesia.Objective: To present a novel method for improving local anesthesia with BTX-A injections.Methods a Results: A 29-year-old military veteran with a below-the-knee amputation of his right leg was suffering from amputation site hyperhidrosis, which was impeding his ability to comfortably wear a prosthesis. Prior to presenting to our clinic, the patient received one treatment of BTX-A injections to his amputation stump while under general anesthesia for surgical repair of trauma-related injuries. In our dermatology clinic, we repeated the procedure using topical lidocaine-prilocaine (30 gm total) for local anesthesia. This provided effective relief of hyperhidrosis for 6 months, but the procedure was very painful (9/10 intensity). We repeated the same procedure 6 months later, using ice in addition to topical lidocaine-prilocaine (30 gm) for local anesthesia; this resulted in reduced pain (3/10 intensity) for the patient.Conclusions: We suggest using ice in combination with a topical anesthetic as an effective method for pain control that avoids general anesthesia in treating amputation-associated hyperhidrosis.

Purpose: Male breast cancer has been linked extensively to mutations of BRCA2 and, to a lesser extent, BRCA1. The aim of this study was to perform a comprehensive analysis of point mutations and genomic rearrangements in the BRCA1 and BRCA2 genes in 41 men with breast cancer. Patients and Methods: Deleterious point mutations were identified in 15 men (37%): 4 (10%) and 11 (27%) in BRCA1 and BRCA2, respectively. In the remaining 26 men, we screened for large genomic rearrangements in BRCA1 and BRCA2 using multiplex ligation-dependent probe amplification. Results: We did not detect any large genomic rearrangements. Men with BRCA1 or BRCA2 mutations were more likely to have a family history of prostate cancer (P = 0.025). Three of 4 male breast tumors with BRCA1 mutations (75%) were estrogen receptor positive. Whereas some studies have reported an 8%-0 rate of large BRCA2 genomic rearrangement in familial male breast cancer cases, we did not detect any such genomic rearrangements in BRCA1 or BRCA2 for our cohort. Conclusion: Despite this negative finding, our study, to the best of our knowledge, is one of the first to comprehensively screen for mutations, including large genomic rearrangement mutations, in BRCA1 and BRCA2 in men with breast cancer in the United States.

Prescription rates for diabetic drugs vary considerably across the United States for Medicare beneficiaries. The goal of this study was to determine if non-clinical factors (patient race, ethnicity, gender, income) are associated with regional variation in pharmacotherapy decisions for diabetic patients enrolled in Medicare.We performed a spatially-weighted, linear regression analysis of the entire diabetic population enrolled in Medicare Parts A, B, and D for the years 2006 through 2009. Our outcomes of interest were the percentage of diabetic patients being treated with metformin, a sulfonylurea, a thiazolidinedione, or insulin within a hospital referral region (HRR).Prescription rates for metformin, sulfonylureas, thiazolidinediones, and insulin varied more than two-fold between hospital referral region. Metformin prescription rates were increased in western states while prescription rates for sulfonylureas and insulins were highest in the South and Midwest. In contrast with these other diabetic drug classes, members of the thiazolidinedione drug class were prescribed more frequently in the Central United States (Great Plains, Colorado Rockies, Northern Texas, Oklahoma). Prescription rates for each drug class were increased in hospital referral regions with a lower household income. Referral regions with larger African American populations were associated with higher prescription rates for insulin (p0.001) and lower prescription rates for metformin (p0.001). Gender and Hispanic ethnicity were not associated with regional variation in prescription rates for the four major diabetic drug classes.Geographic differences exist in the management of type 2 diabetes for Medicare enrollees. Prescription patterns were associated with household income and African American race. Further studies are necessary to identify local, unidentified factors that might be influencing provider management styles.

Background Based on the goals of health care reform, growth in the demand for health care will continue to increase the demand for physicians and, as physician shortages widen, advanced practice nurses (APNs) and physician assistants (PAs) will play larger roles. Together with physicians they constitute a workforce of "advanced clinicians." The objective of this study was to assess the capacity of this combined workforce to meet the future demand for clinical services. Study Design Projections were constructed to the year 2025 for the supply of physicians, APNs, and PAs, and these were compared with projections of the demand for advanced clinical services, based on federal estimates of future spending and historic relationships between spending and the health care labor force. Results If training programs for APNs and PAs grow as currently projected but physician residency programs are not further expanded, the aggregate per capita supply of advanced clinicians will remain close to its current level, which will be 20% less than the demand in 2025. Increasing the numbers of entry-level (PGY1) residents by 500 annually will narrow the gap, but it will remain >15%. Conclusions The nation faces a substantial shortfall in its combined supply of physicians, APNs, and PAs, even under aggressive training scenarios, and deeper shortages if these scenarios are not achieved. Efforts must be made to expand the output of clinicians in all 3 disciplines, while also strengthening the infrastructure of clinical practice and facilitating the delegation of tasks to a broadened spectrum of caregivers in new models of care.

Background Recent studies have shown that breast cancer detected by screening has a more favorable prognosis than interval breast cancer. To further understand the biologic significance of this finding, we investigated the association of disease recurrence, local and distant, with the method of detection of the primary breast cancer in a cohort of 1686 women treated with breast conservation. Patients and Methods The charts of 1686 women with primarily stage I or II invasive breast cancer treated by breast conservation between 1977 and 2002 were reviewed. The median length of follow-up was 6 years. Univariate and multivariate analyses using binary logistic regression were performed for 2 subgroups: (1) those with local recurrence versus those without; and (2) those with distant metastasis versus those without distant metastasis. Results Our data confirmed several of the well-known risk factors for local and distant recurrence. In addition, we found that individuals with breast cancer detected on physical examination alone have a significantly higher risk for local recurrence compared with patients with cancer detected on mammogram alone, independent of tumor size (odds ratio [OR], 2.369; 95% CI, 1.235-4.547; P = .01). We also found a similar correlation for risk of distant metastasis in these 2 groups of women (OR, 2.201; 95% CI, 1.211-3.998; P = .01). Conclusion Breast cancers that are palpable might represent an aggressive biologic subtype with an increased risk of local and distant recurrence. Risk stratification might need to include this clinical feature in addition to conventional prognostic factors.

10512 Introduction: Prophylactic mastectomy (PM) reduces breast cancer risk by >90% in women who are carriers of deleterious BRCA1 or BRCA2 mutations. Genetic testing prior to breast cancer surgery has been reported to affect PM decision in high-risk patients. The ideal timing of genetic testing as well as the clinical characteristics of affected mutation carriers electing PM remain unclear. This is a pilot study to identify significant clinical characteristics associated with affected carriers who had undergone PM. Methods: Retrospective chart review was performed on 103 breast cancer affected BRCA1 or BRCA2 mutation carriers that were seen at our high risk clinic who had undergone genetic testing between 1995 and 2005. Clinical characteristic, initial surgery treatment modalities, and dates of genetic testing and prophylactic mastectomy were collected and analyzed using the chi-square or Fisher exact tests. Results: Of the 103 affected mutation carriers, 30 (29%) underwent prophylactic mastectomy (PM) where as 73 (71%) did not (no PM). Ethnicity, age of diagnosis, tumor size, nodal status, family history and initial breast cancer surgery types (BCT vs. mastectomy) were not significantly different between the two groups. Of the 30 women who underwent PM, 19 (63%) vs. 9 (30%) underwent PM before and after their genetic testing respectively. Of the 19 women who had PM before their genetic testing, 4 (21%) had BCT as initial treatment whereas 15 (78.9%) had mastectomy as initial treatment and 9 of 15 (60%) had synchronous contralateral prophylactic mastectomy. For the 9 women who had PM after their genetic testing, 5 (56%) had BCT vs. 4 (44%) had mastectomy as their initial surgical treatment (p < 0.001). Conclusion: In this study, we found a significant correlation between the initial breast cancer surgical modality of mastectomy with women undergoing prophylactic mastectomy. The impact of family history of breast cancer does not appear to be significant. Physician recommendations or patient preference are unknown. Our data suggest that high risk women who elect mastectomy as their initial surgical management to treat their breast cancer are more likely to undergo prophylactic mastectomy regardless of knowledge of their mutation status. No significant financial relationships to disclose.