Development and Implementation of a Web-Based International Registry Dedicated to Atypical Pigmented Skin Lesions of the Face: Teledermatologic Investigation on Epidemiology and Risk Factors.

Background: Atypical pigmented facial lesions (aPFLs) often display clinical and dermoscopic equivocal and/or overlapping features, thus causing a challenging and delayed diagnosis and/or inappropriate excisions. No specific registry dedicated to aPFL paired with clinical data is available to date. Methods: The dataset is hosted on a specifically designed web platform. Each complete case was composed of the following data: (1) one dermoscopic picture; (2) one clinical picture; (3) two lesion data, that is, maximum diameter and facial location (e.g., orbital area/forehead/nose/cheek/chin/mouth); (4) patient's demographics: family history of melanoma, history of sunburns in childhood, phototype, pheomelanine, eyes/hair color, multiple nevi/dysplastic nevi on the body; and (5) acquisition device (videodermatoscope/camera-based/smartphone-based system). Results: A total of 11 dermatologic centers contributed to a final teledermoscopy database of 1,197 aPFL with a distribution of 353 lentigo maligna (LM), 146 lentigo maligna melanoma (LMM), 231 pigmented actinic keratoses, 266 solar lentigo, 125 atypical nevi, 48 seborrheic keratosis, and 28 seborrheic-lichenoid keratoses. The cheek site was involved in half of aPFL cases (50%). Compared with those with the other aPFL cases, patients with LM/LMM were predominantly men, older (69.32 ± 12.9 years on average vs. 62.69 ± 14.51), exhibited larger lesions (11.88 ± 7.74 mm average maximum diameter vs. 9.33 ± 6.46 mm), and reported a positive history of sunburn in childhood. Conclusions: The iDScore facial dataset currently represents a precious source of data suitable for the design of diagnostic support tools based on risk scoring classifiers to help dermatologists in recognizing LM/LMM among challenging aPFL in clinical practice.

A review of nevus-associated melanoma: What is the evidence?

Cutaneous melanoma may have an adjacent nevus remnant on histological examination in 30% of cases (nevus-associated melanoma, NAM), while it may appear de novo, without a precursor lesion, in the remaining 70% of cases. Nevus-associated melanoma and the concept of acquired melanocytic nevi serving as precursors of melanoma has long been considered as a controversial topic. This controversy is, in part, due to their overall low rate of transformation to melanoma and scarce data on the natural history of progression. Another matter of debate regarded the possibility that the reported differences in NAM vs. de novo melanoma were due to an underestimation of NAM in thicker lesions due to obliteration of the nevus component by the tumour. During the last few years, several evidence has accumulated in order to address these controversies. In this review, we present a comprehensive synthesis of the epidemiological, clinical, dermoscopic and genetic findings in NAM, including thin NAM, compared to de novo melanoma. Answering the questions on nevus-associated melanoma may provide further insight into the classification of these tumours and disentangle their biology and route of development from that of de novo melanoma.

Choroidal nevi in children: prevalence, age of onset, and progression.

PURPOSE: To determine the age of onset and prevalence of choroidal nevi in children. METHODS: In this cross-sectional study, the fundus photographs of a pooled sample of children 6 months to 18 years of age with 6-year longitudinal follow-up who participated in the Sydney Paediatric Eye Disease Study, Sydney Myopia Study, and the Sydney Adolescent Vascular Eye Disease Study were reviewed. Prevalence by age, clinical features, and longitudinal follow-up assessment was undertaken. RESULTS: Of 5,533 children (7,059 examinations), 48 children with a choroidal nevus were identified. Prevalence increased with age: <6 years, 0.47%; 6 years, 0.63%; 12 years, 1.06%; 18 years, 1.79%. Nevus was unilateral in all cases (100%), and the majority were melanotic (46, 96%). Most (36 [75%]) were irregular in shape, with ill-defined margins (45 [94%]). All identified nevi were posterior to the equator. All nevi were small, with the average largest basal diameter of 1.6 mm (range, 0.5-3.2) and were not associated with secondary changes (drusen, orange pigment, subretinal fluid). The majority (18/31 [58%]) of nevi remained stable, with 5 of 31 (16%) demonstrating subtle growth (minimum of 600 µm). Four new-onset nevi were documented. Malignant transformation was not observed in any of the nevi. CONCLUSIONS: In our study cohort, the prevalence of choroidal nevi increased with age up to 18 years. The distribution and prevalence of choroidal melanocytic lesions reported herein can be used for designing population-based studies in children that incorporate emerging imaging technologies.

Prevalence of nevi, atypical nevi, and lentigines in relation to tobacco smoking.

BACKGROUND: Melanocytic nevi have a complex evolution influenced by several endogenous and exogenous factors and are known risk factors for malignant melanoma. Interestingly, tobacco use seems to be inversely associated with melanoma risk. However, the association between tobacco use and nevi and lentigines has not yet been evaluated. METHODS: We investigated the prevalence of nevi, atypical nevi, and lentigines in relation to tobacco smoking in a cohort of 59 smokers and 60 age- and sex-matched nonsmokers, using a questionnaire and performing a total body skin examination by experts. RESULTS: No significant differences were detected between smokers and nonsmokers in the numbers of nevi, atypical nevi, and lentigines in sun-exposed areas (p = 0.966, 0.326, and 0.241, respectively) and in non-sun-exposed areas (p = 0.095, 0.351, and 0.546, respectively). CONCLUSION: Our results revealed no significant differences in the prevalence of nevi, atypical nevi, and lentigines between smokers and nonsmokers in sun-exposed and non-sun-exposed areas.

Dermatologic findings in individuals with genetically confirmed Proteus syndrome.

BACKGROUND/OBJECTIVE: Proteus syndrome, caused by a mosaic activating AKT1 variant, typically presents in toddlers with progressive, asymmetric overgrowth of the skin and bones. We aimed to define the spectrum of dermatologic disease in individuals with genetically confirmed Proteus syndrome. METHODS: We conducted a retrospective review of records from dermatologic examinations of individuals evaluated at the NIH with a molecular diagnosis of Proteus syndrome. The types, prevalence, and localization of dermatologic findings were assessed. RESULTS: Fifty-one individuals (29 males, 22 females, mean age: 9 years) with clinical features of Proteus syndrome had the mosaic c.49G>A, p.Glu17Lys AKT1 variant. Fifty (98%) had at least one cutaneous feature constituting current clinical diagnostic criteria, including vascular malformations in 42 (82%), epidermal nevus in 41 (80%), volar cerebriform connective tissue nevi in 34 (67%), and adipose dysregulation in 30 (59%). Forty-nine (96%) had at least one dermatologic finding not included within the diagnostic criteria, including confluent volar skin-colored to hypopigmented papules or nodules (n = 33, 65%), papules or nodules on the digits or face (n = 27, 53%), and nonlinear epidermal nevi (n = 15, 29%). Other frequently observed features include nail changes (n = 28, 55%), hyperpigmented macules (n = 27, 53%), patchy dermal hypoplasia (n = 18, 35%), gingival/oral mucosal overgrowth (n = 17, 33%), hypopigmented macules (n = 16, 31%), dental enamel changes (n = 9, 18%), acrochordons (n = 6, 12%), and lingual overgrowth (n = 4, 8%). CONCLUSIONS: The range of mucocutaneous features occurring in Proteus syndrome is broader than previously considered. These observations may assist in earlier diagnosis and management and provide novel insights regarding the pathogenesis of the condition.

The utility of PRAME staining in identifying malignant transformation of melanocytic nevi.

BACKGROUND: PReferentially expressed Antigen in MElanoma (PRAME) immunohistochemical (IHC) staining is used to aid melanoma diagnosis. PRAME expression in nevus-associated melanoma (NAM) has not been evaluated. METHODS: PRAME IHC was applied to cases of NAM; staining for each population of melanocytes (benign and malignant) was graded based on the percentage of labeled cells. No labeling was graded 0, 1% to 25% labeling was 1+, 26% to 50% was 2+, 51% to 75% was 3+, and >76% was 4+. RESULTS: Thirty-six cases were reviewed. Sixty-seven percent (24/36) of melanomas were PRAME positive (4+) while no (0/36) nevi showed 4+ positivity. Eighty-one percent (29/36) of nevi were completely PRAME negative compared to 17% (6/36) of melanomas. In 67% of cases (24/36) PRAME differentiated between benign and malignant melanocyte populations. CONCLUSIONS: We identified a high rate (67%) of differential PRAME staining in adjacent benign and malignant melanocyte populations in NAM. In PRAME positive (4+) melanomas, PRAME differentiates 100% (24/24) of benign and malignant melanocyte populations. When 4+ staining is used as the threshold for positivity, PRAME staining has a sensitivity of 67% (24/36) and a specificity of 100% (36/36). These results support PRAME IHC can assist in distinguishing melanocyte populations in melanoma arising within nevi.

Survey of 138 Conjunctival Tumors in the Dominican Republic.

PURPOSE: To report the frequency of conjunctival tumors in the Dominican Republic. METHODS: Retrospective noninterventional case series. One hundred thirty-eight consecutive patients with a conjunctival mass evaluated at two tertiary referral centers from 2010 to 2018. Main outcome measures were frequency of tumors by diagnosis and distribution of tumors relative to patients' age and gender. RESULTS: The mean age at presentation was 41.2 years (median, 42 years; range 10 days - 91 years). There were 83 male patients (60%) and 55 female patients (40%). The three most common specific diagnoses were junctional, compound, and subepithelial naevi (47 [34%]), squamous cell carcinoma (SCC) (26 [19%]) and conjunctival squamous intraepithelial neoplasia (CIN) (17 [12%]). The mean age at detection was 36.5 years for non-malignant tumors and 56.3 years for malignant tumors (p < .001), with a mean difference of 19.8 years at time of diagnosis (95% CI, 10.7-28.8). Benign tumors were more common in children and young adults; malignant and premalignant tumors were more common in mid and older adults (p = .009). Malignant tumors were more common in males (73%) than in females (27%) (p = .04). CONCLUSION: In the Dominican Republic, conjunctival tumors are benign (63%), premalignant (13%) and malignant (24%). Malignant tumors are more common in older adults and men.

Nevus-associated melanoma: An observational retrospective study of 22 patients evaluated with dermoscopy and reflectance confocal microscopy.

BACKGROUND: The frequency of nevus-associated melanoma (NAM) has been estimated to be 29% of diagnosed melanomas. MATERIALS AND METHODS: This is an observational retrospective study of 22 cases of NAM diagnosed in the Universitary Hospital Alcorcón between September 2011 and 2018. The main objective was to analyze dermoscopic and RCM features of NAM. We also studied if there was an association between any dermoscopic or RCM parameter and Breslow depth. RESULTS: The most frequent dermoscopic characteristics were multicomponent pattern (50%), multifocal pigmentation (45.5%), atypical network (59.1%), and blue-gray regression structures (77.3%). RCM evidenced pagetoid cells in 95.5% melanomas (abundant in 59.1%), non-edged dermal papillae in 86.4%, atypical cells at the dermal-epidermal junction in 90.9%, and atypical junctional nesting in 81.8%. Deeper Breslow index was associated with red color (mean Breslow 0.65 vs 0.37 in melanomas without red, P = 0.035), shiny white streaks (0.85 vs 0.38, P = 0.041), abundant pagetoid cells (0.68 vs 0.26, P = 0.017), and non-edged papillae (0.59 vs 0.00, P = 0.014). CONCLUSION: RCM is a valuable tool for diagnosing NAM. Even it is very difficult to differentiate NAM from DNM both with dermoscopy and RCM, RCM can help us to detect remnants of a preexisting nevus and estimate Breslow depth.

Cutaneous nevi and internal cancer risk: Results from two large prospective cohorts of US women.

Elevated cutaneous nevus number has been linked to longer telomeres. Recently, a large systematic Mendelian randomization study identified a significant positive association between telomere length and risk of cancer. Here, we hypothesized that higher nevus count, as a phenotypic marker of longer telomere, may be associated with increased risk of internal cancer, and prospectively examined the association between nevus count and total as well as site-specific cancer risk among participants in the Nurses' Health Study (NHS, 1986-2012) and the Nurses' Health Study 2 (NHS2, 1989-2013) using Cox proportional hazards models. During 3,900,264 person-years of follow-up, we documented a total of 23,004 internal cancer cases (15,484 in the NHS and 7,520 in the NHS2). Compared to participants who had no nevi, the multivariate hazard ratios of total cancer (excluding skin cancer) were 1.06 (95% confidence interval [CI], 1.03-1.09) for women with 1-5 nevi, 1.08 (95% CI, 1.03-1.15) for those who had 6-14 nevi and 1.19 (95% CI, 1.05-1.35) for those with 15 or more nevi (p trend <0.0001). Moreover, because nevus count has been associated with risk of breast cancer previously, we conducted a secondary analysis by excluding breast cancer from the outcomes of interest. The results were very similar to those of our primary analysis. For individual cancer, most of the associations with nevus count were positive but not statistically significant. In conclusion, we identified the number of cutaneous nevi as a phenotypic marker associated with internal cancer risk, which may be explained by telomere biology.

Primary cutaneous melanoma: correlation between clinical and histologic aspects in a retrospective Italian study.

BACKGROUND: In Italy, the incidence of new cases of melanoma is roughly 10,000 cases per year, with an average rate of mortality of 5-6 per 100,000 population per year respectively. The objective of this retrospective study was to evaluate the epidemiological incidence of primitive melanoma, including the incidence of multiple melanomas occurring in the same patient. Furthermore, we studied all histological different types of melanoma focusing on the presence of an association nevus-melanoma. METHODS: A clinical epidemiologic retrospective study from January 2010 to March 2015 was recorded. For each lesion, mitotic rate, Breslow's index, ulceration, presence of regression, vascular and perineural invasion, lymphocytic infiltrate, microsatellitosis and presence of pre-existencing nevus were also studied. RESULTS: Five hundred eighty primitive cutaneous melanomas (CMs) were removed from 525 patients with an incidence of 18-20 new melanomas/100,000 habitants/year. Eighty percent of these were at stage T0-1. Among other melanomas, SSM was the predominant subtype (85% of cases). Only 18 cases had lymph node metastases and 13 (2%) lymph node and/or distant metastases (stage IV) at time of diagnosis. Mitotic figures were present in 25% of cases (143 cases out of 580) without significant gender differences. CONCLUSIONS: The incidence of new melanomas founded is close to the CM's incidence in US population in 2016 with a high percentage of superficial melanomas highlighting the importance of prevention campaigns. The presence of melanoma on a preexisting nevus in only 16% of cases allow to conclude that this association is overestimated in literature. On the contrary the high incidence of a second melanoma in the 7% of cases in a relatively short period of survey leads to the conclusion that this data is underestimated.

Is Endurance Exercise Safe? The Myth of Pheidippides.

With the increase in participation in endurance events in the general population, patient concern may arise as to whether endurance exercise is safe. Acute but not chronic increases in blood urea nitrogen, creatinine, and urine albumin occur in endurance exercise. Iron-deficiency anemia may be observed in female athletes. Upper respiratory illness is increased in elite athletes but decreased in intense recreational athletes. No convincing evidence of developing osteoarthritis exists. Common gastrointestinal symptoms occur and isolated reports of gastrointestinal bleeding exist. Nevi are increased and the minimal erythematous dose is decreased. Exercising in the presence of air pollution has negative pulmonary effects, but overall, benefit exists. Numerous reports pertain to the cardiovascular system. The risk of cardiac arrest increases during exercise, troponin is elevated after exercise, and a predisposition for atrial fibrillation exists. Ventricular myocardial scar formation as assessed by gadolinium enhancement on magnetic resonance imaging is inconsistently observed, and increased coronary plaque of a more stable variety is reported. Left ventricular compliance is chronically increased and no decrease in longevity is found. Although some concerns exist, endurance exercise is safe.

Nevus depigmentosus: review of a mark of distinction.

Nevus depigmentosus (ND), also known as nevus achromicus or achromic nevus, is an uncommon congenital hypomelanosis of the skin that is often characterized as being nonprogressive and having serrated borders. It needs to be distinguished from other hypopigmented skin conditions such as nevus anemicus, hypomelanosis of Ito, Fitzpatrick patches (ash leaf spots) of tuberous sclerosis, vitiligo, indeterminate leprosy, and pigment demarcation lines. Treatment may be desired for aesthetic and possible psychosocial considerations. We review and update knowledge about ND and its simulants.

Association of sunbed use with skin cancer risk factors in Europe: an investigation within the Euromelanoma skin cancer prevention campaign.

INTRODUCTION: Sunbed use has been significantly associated with increased risk of melanoma and non-melanoma skin cancer (NMSC), but its relationship with melanoma's risk factors such as high nevus count, atypical nevi and lentigines is poorly studied. Euromelanoma is a skin cancer prevention campaign conducted all over Europe. It offers a once-a-year screening during which participants' data, including sunbed use and phenotype, are collected via questionnaires. OBJECTIVES: To investigate the association of sunbed use with nevus count, atypical nevi, lentigines and suspicion of skin cancer. METHODS: To ensure reliability of the data, we defined inclusion and exclusion criteria for countries' eligibility for the risk analysis. Multivariate logistic regression models (including age, gender, education, skin type, family history of melanoma, personal history of skin cancer, any sun exposure and any sunscreen use) were used to calculate summary odds ratios (SORs) of each clinical endpoint for ever sunbed use. RESULTS: Overall, 227 888 individuals from 30 countries completed the Euromelanoma questionnaire. After the data quality check, 16 countries were eligible for the multivariate analysis, for a total of 145 980 participants (64.8% females; median age 43 years; 62.3% highly educated; 28.5% skin type I-II; 11.0% ever sunbed use). Ever sunbed use was independently associated with nevus count >50 [SOR = 1.05 (1.01-1.10)], atypical nevi [SOR = 1.04 (1.00-1.09)], lentigines [SOR = 1.16 (1.04-1.29)] and suspicion of melanoma [SOR = 1.13 (1.00-1.27)]. Conversely, no significant association was found between ever sunbed use and suspicion of NMSC [SOR = 1.00 (0.91-1.10)]. CONCLUSIONS: Indoor tanning is significantly associated with well-recognized risk factors for melanoma (including high nevus count, presence of atypical nevi and lentigines) as well as suspicion of melanoma within the Euromelanoma screenees. In order to reduce the prevalence of melanoma risk factors, avoidance/discontinuation of sunbed use should always be encouraged, especially but not exclusively for individuals with high-risk phenotypes.

Cutaneous nevi and risk of melanoma death in women and men: A prospective study.

BACKGROUND: It was unclear whether an increased number of common nevi (moles) predicts melanoma death. OBJECTIVE: We prospectively examined the association between number of common nevi and risk of melanoma death. METHODS: Our study used data from the Nurses' Health Study (n = 77,288 women) and Health Professionals Follow-up Study (n = 32,455 men). In 1986, participants were asked about the number of moles they had with a ≥3-mm diameter on the upper extremity, and we stratified their answers into 3 categories (none, 1-2, or ≥3) on the basis of data distribution. RESULTS: During follow-up (1986-2012), 2452 melanoma cases were pathologically confirmed; among these, we identified 196 deaths due to melanoma. Increased number of nevi was associated with melanoma death; the hazard ratio (HR) for ≥3 nevi compared with no nevi was 2.49 (95% confidence interval [CI] 1.50-4.12) for women and 3.97 (95% CI 2.54-6.22) for men. Among melanoma cases, increased number of nevi was associated with melanoma death in men (≥3 nevi, HR 1.89, 95% CI 1.17-3.05) but not in women. Similarly, the number of nevi was positively associated with Breslow thickness in men only (Ptrend = .01). LIMITATIONS: This is an epidemiologic study without examination into mechanisms. CONCLUSION: Increased number of cutaneous nevi was significantly associated with melanoma death. High nevus count might serve as an independent prognostic factor to predict the risk of melanoma death particularly among male melanoma patients.

Prevalence of Histopathologically Diagnosed Ophthalmic Neoplastic Lesion Among Ophthalmic Biopsies in a Pathology Laboratory of Tertiary Hospital of Nepal.

INTRODUCTION: Many vision threatening or life threatening neoplastic conditions often mimic less aggressive neoplastic or non-neoplastic inflammatory variants. This study aims to comprehensively analyze the histopathological spectrum of ophthalmic neoplastic lesions tumors in a pathology laboratory in a tertiary care hospital. METHODS: A descriptive cross-sectional study was conducted in the Department of Pathology at Birat Medical College and Teaching Hospital, Morang, Nepal over a period from November 2016 to October 2018. Ethical clearance was taken from Institutional Review Committee of Birat Medical College. Sample size was calculated and convenience sampling was done. Data was collected in excel and analyzed in Statistical Package for Social Sciences version 16. Point estimate at 95% Confidence Interval was calculated and frequency and percentage was calculated for binary data. Subgroup analysis was done based on age, sex, nature of lesions and site of lesions. RESULTS: Prevalence of ophthalmic neoplastic lesion was 139 (55.37%), of which 74 (53.24%) were benign and 65 (46.76%) were malignant. Benign was mostly seen in females and of second decade and malignant was common in males and seventh decade of life respectively. Nevus in 18 (24.3%) and squamous cell carcinoma in 30 (17.6%) was found to be the most common benign and malignant lesions among the specimens. Conjunctiva and cornea in 52 (37.41%) was the most common location for those neoplastic lesions. CONCLUSIONS: The most common ophthalmic neoplastic lesion was benign. Nevus is common in females and second decade and squamous cell carcinoma is common in males and seventh decade of life.

Nevus epidérmicos y síndromes relacionados. Parte 1: nevus queratinocíticos / Epidermal Nevi and Related Syndromes - Part 1: Keratinocytic Nevi

Los nevus epidérmicos son hamartomas originados en la epidermis y/o en las estructuras anexiales de la piel que se han clasificado clásicamente partiendo de la morfología. En los últimos años se han descrito variantes nuevas y se han producido avances en el campo de la genética que han permitido caracterizar mejor estas lesiones y comprender su relación con algunas de las manifestaciones extracutáneas a las que se han asociado. En esta primera parte revisaremos los nevus derivados de la epidermis y los síndromes que se han descrito asociados a ellos

Epidermal nevi are hamartomatous lesions derived from the epidermis and/or adnexal structures of the skin; they have traditionally been classified according to their morphology. New variants have been described in recent years and advances in genetics have contributed to better characterization of these lesions and an improved understanding of their relationship with certain extracutaneous manifestations. In the first part of this review article, we will look at nevi derived specifically from the epidermis and associated syndromes

Nevus epidérmicos y síndromes relacionados. Parte 2: Nevus derivados de estructuras anexiales / Epidermal Nevi and Related Syndromes - Part 2: Nevi Derived from Adnexal Structures

Los nevus epidérmicos son hamartomas originados en la epidermis y/o en las estructuras anexiales de la piel que se han clasificado clásicamente partiendo de la morfología. En los últimos años se han descrito variantes nuevas y se han producido avances en el campo de la genética que han permitido caracterizar mejor estas lesiones y comprender su relación con algunas de las manifestaciones extracutáneas a las que se han asociado. En esta segunda parte revisaremos los nevus derivados de estructuras anexiales de la piel y los síndromes que se asocian

Epidermal nevi are hamartomatous lesions derived from the epidermis and/or adnexal structures of the skin; they have traditionally been classified according to their morphology. New variants have been described in recent years and advances in genetics have contributed to better characterization of these lesions and an improved understanding of their relationship with certain extracutaneous manifestations. In the second part of this review article, we will look at nevi derived from the adnexal structures of the skin and associated syndromes

Combining common genetic variants and non-genetic risk factors to predict risk of cutaneous melanoma.

Melanoma heritability is among the highest for cancer and single nucleotide polymorphisms (SNPs) contribute to it. To date, only SNPs that reached statistical significance in genome-wide association studies or few candidate SNPs have been included in melanoma risk prediction models. We compared four approaches for building polygenic risk scores (PRS) using 12 874 melanoma cases and 23 203 controls from Melanoma Meta-Analysis Consortium as a training set, and newly genotyped 3102 cases and 2301 controls from the MelaNostrum consortium for validation. We estimated adjusted odds ratios (ORs) for melanoma risk using traditional melanoma risk factors and the PRS with the largest area under the receiver operator characteristics curve (AUC). We estimated absolute risks combining the PRS and other risk factors, with age- and sex-specific melanoma incidence and competing mortality rates from Italy as an example. The best PRS, including 204 SNPs (AUC = 64.4%; 95% confidence interval (CI) = 63-65.8%), developed using winner's curse estimate corrections, had a per-quintile OR = 1.35 (95% CI = 1.30-1.41), corresponding to a 3.33-fold increase comparing the 5th to the 1st PRS quintile. The AUC improvement by adding the PRS was up to 7%, depending on adjusted factors and country. The 20-year absolute risk estimates based on the PRS, nevus count and pigmentation characteristics for a 60-year-old Italian man ranged from 0.5 to 11.8% (relative risk  = 26.34), indicating good separation.