Clinical efficacy of 300IR 5-grass pollen sublingual tablet in a US study: the importance of allergen-specific serum IgE.

BACKGROUND: Previous trials have demonstrated the efficacy, safety, and optimal dosage of the 5-grass pollen sublingual tablet for adults and children with grass pollen-induced allergic rhinoconjunctivitis. OBJECTIVES: We sought to evaluate the efficacy and safety of 300 index of reactivity (IR) 5-grass pollen sublingual tablet in US adults. METHODS: Adults with grass pollen allergy and Rhinoconjunctivitis Total Symptom Scores of 12 or greater (scale, 0-18) during the previous grass pollen season were randomized in a double-blind, placebo-controlled study to receive 300IR 5-grass pollen sublingual tablet or placebo starting 4 months before and continuing through the pollen season. The primary efficacy end point was the daily Combined Score (CS; scale, 0-3), which integrates symptoms and rescue medication use. RESULTS: Four hundred seventy-three participants were randomized. The mean daily CS over the pollen period was significantly lower in the active treatment group versus the placebo group (least-squares mean difference: -0.13; 95% CI, -0.19 to -0.06; P = .0003; relative reduction: 28.2%; 95% CI, 13.0% to 43.4%). In placebo-treated participants, the daily CS least-squares mean was 0.32 in the subgroup with baseline timothy grass-specific serum IgE of less than 0.1 kU/L (n = 23) and 0.46 in those with baseline timothy grass-specific serum IgE of 0.1 kU/L or greater (n = 204). The most frequent reported adverse events were oral pruritus, throat irritation, and nasopharyngitis. There were no reports of anaphylaxis, and no actively treated participant received epinephrine. CONCLUSION: In US adults with grass pollen-induced allergic rhinoconjunctivitis, preseasonal and coseasonal treatment with 300IR 5-grass pollen sublingual tablet demonstrated clinically meaningful efficacy, especially in study subjects with measurable timothy grass-specific serum IgE. Use of 300IR 5-grass pollen sublingual tablet was safe and well tolerated. A requirement for a measurable level of allergen-specific serum IgE should be considered in future studies in this field.

The retinoblastoma protein/p16 INK4A pathway but not p53 is disrupted by human papillomavirus in penile squamous cell carcinoma.

AIMS: The pathogenesis of penile squamous cell carcinoma (PSCC) is not well understood. Human papillomavirus (HPV) may be involved in carcinogenesis, but few studies have compared cell-cycle protein expression in HPV positive and negative cancers. The aim was to determine the extent of HPV infection in different histological subtypes of PSCC and its impact on the expression of key cell-cycle proteins: p53, p21, p16(INK4A) and retinoblastoma (RB) protein. METHODS AND RESULTS: One hundred and forty-eight PSCC samples were examined immunohistochemically for RB, p16(INK4A) , p53 and p21 protein expression. One hundred and two cases were typed for HPV by PCR. HPV DNA was detected in 56% of tumours, with HPV16 present in 81%. Basaloid tumours were related strongly to HPV infection (10 of 13), while verrucous were not (three of 13). Fifty-nine per cent (38 of 64) of usual type SCCs had HPV infection. RB protein correlated negatively (P<0.0001) and p16(INK4A) (P<0.0001) and p21 (P=0.0002) correlated positively with HPV infection. p53 did not correlate with HPV infection. CONCLUSIONS: HPV infection is present in more than half of penile cancers and it is responsible for RB pathway disruption. However, no link between HPV and p53 immunodetection was found. Only basaloid and half of usual-type PSSCs correlate with HPV infection, confirming possible separate aetiologies for those tumours.

Immunohistochemistry for p16, but not Rb or p21, is an independent predictor of prognosis in conservatively treated, clinically localised prostate cancer.

AIMS: Treatment decisions are difficult in clinically localised prostate cancer and further biomarkers of aggressive behaviour are required. We investigated the hypothesis that the tissue expression of three cell cycle markers, Rb, p21 and p16, would provide helpful prognostic information in a well characterised series of prostate cancers which were clinically localised and treated conservatively. METHODS: The immunohistochemical staining expression of these markers was assessed in tissue microarrays and correlated with 10 year prostate cancer survival and overall survival and then compared with pathological data including contemporary Gleason score, age, measures of tumour extent and initial serum prostate specific antigen (PSA) level. RESULTS: Rb overexpression did not show any significant association with Gleason score or prostate cancer survival. p21 protein expression showed a significant association with prostate cancer survival (p = 0.02) and overall survival (p = 0.01) in a univariate model but not in a multivariate model with pathological and serum PSA data. There was a significant association between p16 cytoplasmic expression and prostate cancer survival (HR = 2.52, 95%CI = 1.79-3.55, p < 0.001) and overall survival (HR = 1.54, 95% CI = 1.20-1.98, p = 0.001) in a univariate model. p16 expression remained an independent prognostic factor for prostate cancer survival (HR = 1.50, 95%CI = 1.05-2.14, p = 0.03). CONCLUSION: We conclude that p16 cytoplasmic expression can be used as a predictor of outcome in conservatively treated prostate cancer. Rb and p21 show no independent association with outcome and therefore further research is not warranted.

Performance of the Abbott RealTime high-risk HPV test in women with abnormal cervical cytology smears.

HPV DNA testing is known to be much more sensitive than cytology, but less specific. A range of HPV and related tests in 858 women referred for colposcopy because of an abnormal smear were evaluated to compare the performances of these tests. This article compared the Abbott test to other tests which had been previously evaluated. This test was a real true test for 14 high-risk HPV types. The Abbott test was found to be highly sensitive for cervical intraepithelial neoplasia grade 3 or worse (CIN3+) (98.9%) with a specificity of 31.5%. These numbers were comparable with the Qiagen HC2 test, the Roche Linear Array and Amplicor tests, and the Gen-Probe APTIMA test. Differences between these tests appeared to be related mostly to the choice of cutoff level. An added feature of the Abbott test was the provision of type specific results for HPV 16 and 18.

SOX9 elevation in the prostate promotes proliferation and cooperates with PTEN loss to drive tumor formation.

Dysregulation of tissue development pathways can contribute to cancer initiation and progression. In murine embryonic prostate epithelia, the transcription factor SOX9 is required for proper prostate development. In this study, we examined a role for SOX9 in prostate cancer in mouse and human. In Pten and Nkx3.1 mutant mice, cells with increased levels of SOX9 appeared within prostate epithelia at early stages of neoplasia, and higher expression correlated with progression at all stages of disease. In transgenic mice, SOX9 overexpression in prostate epithelia increased cell proliferation without inducing hyperplasia. In transgenic mice that were also heterozygous for mutant Pten, SOX9 overexpression quickened the induction of high-grade prostate intraepithelial neoplasia. In contrast, Sox9 attenuation led to a decrease proliferating prostate epithelia cells in normal and homozygous Pten mutant mice with prostate neoplasia. Analysis of a cohort of 880 human prostate cancer samples showed that SOX9 expression was associated with increasing Gleason grades and higher Ki67 staining. Our findings identify SOX9 as part of a developmental pathway that is reactivated in prostate neoplasia where it promotes tumor cell proliferation.

PRKC-ζ Expression Promotes the Aggressive Phenotype of Human Prostate Cancer Cells and Is a Novel Target for Therapeutic Intervention.

We show protein kinase C-zeta (PKC-ζ) to be a novel predictive biomarker for survival from prostate cancer (P < 0.001). We also confirm that transcription of the PRKC-ζ gene is crucial to the malignant phenotype of human prostate cancer. Following siRNA silencing of PRKC-ζ in PC3-M prostate cancer cells, stable transfectant cell line si-PRKC-ζ-PC3-M(T1-6) is phenotypically nonmalignant in vitro and in vivo. Genome-wide expression analysis identified 373 genes to be differentially expressed in the knockdown cells and 4 key gene networks to be significantly perturbed during phenotype modulation. Functional interconnection between some of the modulated genes is revealed, although these may be within different regulatory pathways, emphasizing the complexity of their mutual interdependence. Genes with altered expression following PRKC-ζ knockdown include HSPB1, RAD51, and ID1 that we have previously described to be critical in prostatic malignancy. Because expression of PRKC-ζ is functionally involved in promoting the malignant phenotype, we propose PKC-ζ as a novel and biologically relevant target for therapeutic intervention in prostate cancer.

Functional MC1R-gene variants are associated with increased risk for severe photoaging of facial skin.

The objective of this study was to assess the association between melanocortin-1 receptor (MC1R) variants and the severity of facial skin photoaging. The study population comprised 530 middle-aged French women. A trained dermatologist graded the severity of facial skin photoaging from photographs using a global scale. Logistic regressions were performed to assess the influence of MC1R polymorphisms on severe photoaging with adjustment for possible confounders (demographic and phenotypic data and sun exposure intensity). Among the fifteen MC1R variants identified, the nine most common were V60L, V92M, R151C, R160W, R163Q, R142H, D294H, D84E, and I155T. One hundred and eighty-five individuals (35%) were WT homozygotes, 261 (49%) had one common variant, 78 (15%) had two common variants, and six (1%) had at least one rare variant. After adjustment for possible confounders, the presence of two common variants was already a risk factor for severe photoaging (AOR (95% confidence interval): 2.33 (1.17-4.63)). This risk reached 5.61 (1.43-21.96) when two major diminished-function variants were present. Surprisingly, the minor variant, V92M, was associated with increased risk of photoaging (2.57 (1.23-5.35)). Our results suggest that genetic variations of MC1R are important determinants for severe photoaging.

MC1R gene polymorphism affects skin color and phenotypic features related to sun sensitivity in a population of French adult women.

The melanocortin-1 receptor (MC1R) gene is known to play a major role in skin and hair pigmentation and to be highly polymorphic in Caucasians. This study was performed to investigate the relationships between MC1R gene polymorphisms and skin color in a large sample of French middle-aged Caucasian women. The codons 60 to 265 and the codon 294 of the MC1R gene were sequenced in 488 women. The skin color was measured on the inner side of the forearm using a spectrophotometric instrument. Fifteen variants were identified: Arg151Cys, Arg160Trp, Arg142His, Asp294His, Ile155Thr, Asp84Glu, Val60Leu, Val92Met, Arg163Gln, Ser83Pro, Thr95Met, Pro256Ser, Val265Ile, Ala166Ala and Gln233Gln. Women carrying Arg151Cys, Asp294His, Arg160Trp and Asp84Glu variants had a significantly higher reflectance in the red region, which indicates a lower level of functional melanin. This association was the most pronounced for women carrying Asp84Glu. In contrast, no significant difference was observed for other variants. Moreover, associations between MC1R polymorphisms and the risks of experiencing sunburn and of having freckles were found independently of skin color. Our findings support the hypothesis that MC1R polymorphisms do not necessarily alter the skin color but should sensitize the skin to UV-induced DNA damage.

HPV infection and immunochemical detection of cell-cycle markers in verrucous carcinoma of the penis.

Penile verrucous carcinoma is a rare disease and little is known of its aetiology or pathogenesis. In this study we examined cell-cycle proteins expression and correlation with human papillomavirus infection in a series of 15 pure penile verrucous carcinomas from a single centre. Of 148 penile tumours, 15 (10%) were diagnosed as pure verrucous carcinomas. The expression of the cell-cycle-associated proteins p53, p21, RB, p16(INK4A) and Ki67 were examined by immunohistochemistry. Human papillomavirus infection was determined by polymerase chain reaction to identify a wide range of virus types. The expression of p16(INK4A) and Ki67 was significantly lower in verrucous carcinoma than in usual type squamous cell carcinoma, whereas the expression of p53, p21 and RB was not significantly different. p53 showed basal expression in contrast to usual type squamous cell carcinoma. Human papillomavirus infection was present in only 3 out of 13 verrucous carcinomas. Unique low-risk, high-risk and mixed viral infections were observed in each of the three cases. In conclusion, lower levels of p16(INK4A) and Ki67 expressions differentiate penile verrucous carcinoma from usual type squamous cell carcinoma. The low Ki67 index reflects the slow-growing nature of verrucous tumours. The low level of p16(INK4A) expression and human papillomavirus detection suggests that penile verrucous carcinoma pathogenesis is unrelated to human papillomavirus infection and the oncogenes and tumour suppressor genes classically altered by virus infection.

p53 immunochemistry is an independent prognostic marker for outcome in conservatively treated prostate cancer.

OBJECTIVE To determine whether p53 is an independent biomarker of prostate cancer outcome against currently used biomarkers in a cohort of conservatively treated prostate cancers with long-term follow-up available. PATIENTS AND METHODS We examined p53 expression by immunohistochemistry in a cohort of 705 patients with clinically localized prostate cancer, who were treated conservatively. Patients were selected through UK Cancer Registries. End-points included prostate cancer death and overall death rates. Standard biological variables, including diagnostic serum PSA, contemporary Gleason scoring, clinical staging and cancer extent were available. p53 expression was measured semi-quantitatively on microscopic examination and compared with current clinical biomarkers. RESULTS p53 over expression was a significant predictor of cause-specific survival (hazard ratio [HR] 2.95, 95% CI 2.05-4.25, P < 0.001) and overall survival (HR 2.37, 95% CI 1.84-3.05, P < 0.001). In multivariate analysis including competing biological variables p53 expression was still significantly linked to prostate cancer survival (HR 1.51, 95% CI 1.04-2.19, P = 0.03) and overall survival (HR 1.57, 95% CI 1.21-2.05, P = 0.001). CONCLUSIONS We conclude that p53 may have a role in the future assessment of newly diagnosed prostate cancer, as it significantly adds to the current prognostic model.

Comparison of predictors for high-grade cervical intraepithelial neoplasia in women with abnormal smears.

BACKGROUND: The detection of high-risk human papillomavirus (HPV) DNA provides higher sensitivity but lower specificity than cytology for the identification of high-grade cervical intraepithelial neoplasia (CIN). This study compared the sensitivity and specificity of several adjunctive tests for the detection of high-grade CIN in a population referred to colposcopy because of abnormal cytology. METHODS: 953 women participated in the study. Up to seven tests were carried out on a liquid PreservCyt sample: Hybrid Capture II (Digene), Amplicor (Roche), PreTect HPV-Proofer (NorChip), APTIMA HPV assay (Gen-Probe), Linear Array (Roche), Clinical-Arrays (Genomica), and CINtec p16INK4a Cytology (mtm Laboratories) immunocytochemistry. Sensitivity, specificity, and positive predictive value (PPV) were based on the worst histology seen on either the biopsy or the treatment specimen after central review. RESULTS: 273 (28.6%) women had high-grade disease (CIN2+) on worst histology, with 193 (20.2%) having CIN3+. For the detection of CIN2+, Hybrid Capture II had a sensitivity of 99.6%, specificity of 28.4%, and PPV of 36.1%. Amplicor had a sensitivity of 98.9%, specificity of 21.7%, and PPV of 33.5%. PreTect HPV-Proofer had a sensitivity of 73.6%, specificity of 73.1%, and PPV of 52.0%. APTIMA had a sensitivity of 95.2%, specificity of 42.2%, and PPV of 39.9%. CINtec p16INK4a Cytology had a sensitivity of 83.0%, specificity of 68.7%, and PPV of 52.3%. Linear Array had a sensitivity of 98.2%, specificity of 32.8%, and PPV of 37.7%. Clinical-Arrays had a sensitivity of 80.9%, specificity of 37.1%, and PPV of 33.0%.

Effects of anastrozole on cognitive performance in postmenopausal women: a randomised, double-blind chemoprevention trial (IBIS II).

BACKGROUND: Mild cognitive impairments have been recorded in cross-sectional studies of women with breast cancer receiving endocrine treatment. More comprehensive studies were warranted because aromatase inhibitors are being used increasingly in both chemoprevention and adjuvant settings. We report findings from the cognitive subprotocol of the International Breast Intervention Study (IBIS II), a double-blind placebo-controlled trial of anastrozole in postmenopausal women at high risk of developing breast cancer. We aimed to study and compare the effect of anastrozole versus placebo on memory and attention in these women. METHODS: Between Jan 3, 2003, and Dec 21, 2005, participants were recruited into the cognitive subprotocol from five UK centres. Cognitive assessments were done before randomisation, at 6 months, and at 24 months. 227 of 249 women approached completed a comprehensive set of standardised cognitive tasks at baseline and were randomly assigned to receive anastrozole (1 mg/day for 5 years) or placebo. Psychological morbidity, endocrine symptoms, and self-reported cognitive complaints were also measured. The main outcomes were cognitive task scores at baseline, 6 months, and 24 months. Analyses were done by intention to treat. This study is registered as an International Standard Randomised Controlled Trial, number ISRCTN31488319. FINDINGS: 111 women were assigned to anastrozole and 116 women to placebo. At 6 months, ten women in each group were excluded from analysis, leaving a total of 207 of 227 (91%) women available for further assessments. At 24 months, 24 women were excluded from the anastrozole group and 32 from the placebo group, leaving 151 of 227 (67%) women. We did not note any significant differences between the groups for any of the cognitive tasks. By 6 months, 13 women in both groups reported changes to their memory and this had decreased to five women in the placebo group and three women in the anastrozole group by the 24-month assessment. Significantly more women in the anastrozole group complained of hot flushes at 24 months (23 of 76 [30%] vs 11 of 73 [15%], p=0.032, not corrected for multiple comparison), but this was the only difference in reported endocrine symptoms. INTERPRETATION: These findings show little or no impairment of cognitive performance with the use of anastrozole compared with placebo in postmenopausal women at high risk of developing breast cancer who were able to tolerate endocrine-related side-effects. Future studies assessing cognition should be done within randomised trials with baseline assessments to ascertain the true extent of the putative effects that treatments for breast cancer might have on memory and attention. FUNDING: Cancer Research UK, London, UK (grant numbers C6280/A3162 and C6280/A6764).

Influence of skin colour on the detection of cutaneous erythema and tanning phenomena using reflectance spectrophotometry.

BACKGROUND/PURPOSE: This research aims at assessing the influence of baseline skin colour on the ability of reflectance spectrophotometry to detect cutaneous erythema induced by a low concentration of methyl nicotinate (2.5 mM) (first objective), and to detect tanning induced by ultraviolet rays (UVA+UVB) at infra-erythemal doses (second objective). METHODS: Two independent studies were conducted to reach their respective objectives, on 27 women for the first study and on 12 women for the second study. Skin colour measurements were expressed in two different ways: percentages of reflected light at increasing wavelengths lambda (400 nm or =40 degrees. The assumption is that in the darkest skins, the emitted light is mainly absorbed by the melanin in the epidermis. Otherwise, after UV irradiation, the tanning was detectable only for individuals with fair to dark skin defined by ITA <50 degrees. This can be explained by the fact that UV stimulation of the fairest skin subjects, known to be melano-compromised individuals, can only produce a weak tanning that our study did not succeed in detecting.

Relationships between visual and tactile features and biophysical parameters in human facial skin.

BACKGROUND/PURPOSE: Skin properties, such as colour, hydration and texture, can be studied on a qualitative basis by a clinical assessment or on a quantitative basis using techniques that measure biophysical properties of the skin. The aim of this study was to explore the links between facial skin features and a range of skin biophysical parameters using multivariate methods. METHODS: A study was conducted on 256 female volunteers from Ile-de-France with apparent healthy skin, aged between 20 and 50, under controlled environmental conditions (mean+/-standard deviation: room temperature 22.9+/-0.3 degrees C; relative humidity 48.5+/-2.3%). The study included a medical questionnaire and a clinical examination of the skin performed by a dermatologist, and a biophysical evaluation of the skin properties. Seventy visual and tactile skin features were assessed on the forehead and the cheek using ordinal variables illustrated by photographic scales. Twenty-eight biophysical measurements were taken in the same areas using the following equipment: Chromameter, Evaporimeter, Corneometer, Skicon, Sebumeter, Sebutape, skin thermometer, skin pH-meter and Silflo. In order to group the variables illustrating a same unimodal phenomenon, a typology of the skin features and a typology of the biophysical parameters were carried out using a clustering method. Then, the relationships between each group of clinical features and each group of biophysical parameters were studied using a series of partial least squares (PLS) regressions. RESULTS: From eight groups of clinical features and three groups of biophysical parameters that were identified, 12 significant PLS regression models were built. Our findings suggest that differences in chromametric measurements express not only differences in skin colour but also differences in skin surface properties, such as skin vascularity status, thickness, and existence of wrinkles, and also demonstrate that the level of sebum excretion can affect other aspects of the skin surface. CONCLUSION: Some skin features assessed clinically do not appear to be linked to any biophysical parameter. This finding confirms that certain phenomena evaluated on the basis of visual or tactile skin features are not assessed on the basis of the biophysical properties of the skin measured by our bioengineering techniques. Indeed, visual skin features mainly appreciate the skin surface aspect, contrary to some biophysical surrogate markers known to provide information on underlying epidermal structures. Therefore, both clinical and biophysical assessments must be associated to supply a relevant and accurate approach for skin aspect characterisation.

Effect of hormonal replacement therapy on skin biophysical properties of menopausal women.

BACKGROUND/PURPOSE: Hormonal replacement therapy (HRT) has been shown in the past to influence well being as well as several somatic features in menopausal women. The aim of this analysis was to study the effect of HRT on various biophysical properties of the skin of menopausal women. Two sub-samples were built to test the effect (1) of 'short-term' HRT in recently menopausal women (n=15), and (2) the effect of 'medium- and long-term' HRT in menopausal women (n=78). METHODS: The analysis was performed on data from a study of 106 menopausal Caucasian women with apparent healthy skin. Self-report data on the menopausal status, the duration of the menopause, whether or not HRT has been taken and the duration of the HRT were collected. A series of biophysical measurements on the cheek, the forehead and the inner forearm were performed under controlled environmental conditions. Twenty women were menopausal for less than 5 years (eight with HRT for at least 1 year and seven who had never taken HRT) and 86 women for at least 5 years (35 with HRT for at least 5 years and 43 who had never taken HRT). Analyses of covariance with adjustment for age were performed. RESULTS: With regard to skin colour, the measurements in women treated for at least 1 year were significantly higher for red intensity (a*) and lower for brightness (L*) on the forearm as compared with the non-treated women. Furthermore, yellow intensity (b*) mean values were higher on the forehead and the forearm in women treated for at least 5 years compared with the non-treated women. Concerning sebum casual level, the mean values were significantly higher on the forehead and the cheek in women treated for at least 5 years. Regarding skin surface parameters reflecting hydration, the mean values for capacitance on the forehead and the cheek were significantly higher in women treated for at least 5 years. Finally, as regards with skin relief, parameters mean values for amplitude and roughness on the forehead were significantly higher in women treated for at least 5 years. CONCLUSION: The skin colour parameters showed a higher red intensity value in menopausal women who had been treated for at least 1 year. In menopausal women who had been treated for at least 5 years, the biophysical measurements were significantly higher for the parameters reflecting hydration and sebum secretion, which generally decrease after the menopause. These features were associated with higher values for the yellow intensity parameter and the skin relief parameters on the forehead. Our results support the subjective impression and the clinical evaluation concerning the impact of HRT on the development and the evolution of some skin properties after menopause.

Sun-reactive Skin Type in 4912 French adults participating in the SU.VI.MAX study.

Phototype classifications were initially developed in an attempt to predict the skin reactions of patients to phototherapy and are now widely used to advise individuals with regard to sun protection. A transversal study was conducted on the SU.VI.MAX cohort to estimate the frequency of sun-reactive skin features in a large, general adult population-based sample, and to describe the associations between these features. The data were collected 3 years after the beginning of the SU.VI.MAX nutritional intervention study on 4912 volunteers (2868 women aged 35-60 years and 2044 men aged 45-60 years). A multiple correspondence analysis was performed to study the associations between the features. The results showed that these features correspond to a one-dimensional phenomenon, which allowed us to establish a score to summarize skin sensitivity to sun exposure. Furthermore, we found a link between gender and phototype using the Césarini classification (phototype > or = IV: 37% of women, 47% of men). The analysis of the relationship with sun-reactive skin features and the score revealed the same trend. Phenotypic evaluation appears to be a good estimator of skin sensitivity to sun exposure for clinical screening or for use in research, and is easy to collect at a lower cost. Moreover, the sun sensitivity difference between gender should be considered in education about photoprotection.

Relative contribution of intrinsic vs extrinsic factors to skin aging as determined by a validated skin age score.

OBJECTIVE: To assess the relative contribution of intrinsic aging vs lifestyle factors to facial skin age. DESIGN: Prospective analysis of a cohort. SETTING: Skin research institute. STUDY SUBJECTS: A cohort of 361 white women (age range, 18-80 years) with apparently healthy skin. MEASUREMENTS: Visual and tactile assessment of facial skin features. RESULTS: Twenty-four skin characteristics were used to build a skin age score (SAS). The relationship between the SAS and chronological age followed a linear model with 2 plateaus--1 before age 30 years and 1 after age 71 years. An analysis was performed to determine whether certain lifestyle habits known to have effects on skin aging were related to the discrepancies between chronological age and the SAS. Significant effects were identified for phototype, body mass index, menopausal status, degree of lifetime sun exposure, and number of years of cigarette smoking. However, these factors accounted for only 10% of the discrepancies. Moreover, most skin characteristics used reflected changes understood to represent intrinsic aging rather than photodamage or other extrinsic factors. CONCLUSIONS: An SAS can be generated from multiple discrete signs evaluated on facial skin and is an informative tool for quantifying skin aging. The SAS is influenced by factors already recognized to affect the aging phenotypes; however, factors related to the rate of intrinsic aging, presumably genetic in character, seem to play a larger role than previously suspected.