[show abstract][hide abstract] ABSTRACT: Several algorithms are available for the dermoscopic diagnosis of pigmented skin lesions. The MC1R gene is a key determinant of pigmentation characteristics that are established host-related melanoma risk factors.
To investigate the association of dermoscopic features of sporadic cutaneous melanomas with clinical characteristics of patients and corresponding tumours and with genetic changes in the MC1R and BRAF genes.
A total of 64 dermoscopic images of 62 patients were scored by ABCD rule and modified pattern analysis. Detailed patients' and melanomas' characteristics were collected. Patients were screened for germline MC1R variants and related melanomas for somatic V600 BRAF mutations.
A lower total dermoscopic score (TDS) was observed in melanomas of patients with red hair (P = 0.019), due to reduced dermoscopic structures (P < 0.0001). Thicker melanomas showed higher TDS values (P = 0.021) due to sharper borders (P < 0.0001) and higher number of colors (P = 0.004). An atypical pigment network was prevalent in superficial spreading melanomas (P = 0.010), in individuals with dark skin (P = 0.043) and hair color (P = 0.001). An atypical vascular pattern was more frequent in nodular (P < 0.0001) and thick (P < 0.0001) melanomas, in individuals with skin type I-II (P = 0.037), blond or red hair color (P = 0.032) and blue or green eyes (P = 0.014). Melanomas of MC1R R carriers showed lower TDS value (P = 0.037), reduced dermoscopic structures (P = 0.001) and lower prevalence of atypical pigment network (P = 0.001). No differences were identified between BRAF-mutated or wild-type melanomas.
We suggest a phenotypic/MC1R profile for melanoma patients and their tumours. Melanomas of MC1R R carriers show a significant lower TDS value, with reduced dermoscopic structures, and a lower prevalence of an atypical pigment network. Non-carriers of MC1R R variants develop melanomas dermoscopically characterized by an atypical pigment network which is prevalent in superficial spreading melanomas, in patients with dark complexion and less frequent in red-haired individuals.
Journal of the European Academy of Dermatology and Venereology 03/2014; · 2.69 Impact Factor
[show abstract][hide abstract] ABSTRACT: Objective. Evaluate the ecological relationship between skin melanoma epidemiology and latitude in Italy. Methods. We used data from the Italian network of cancer registries (Airtum). In a Poisson model, we evaluated the effect on incidence, mortality, and survival of latitude, adjusting for some demographic, social, phenotypic, and behavioural variables. Results. Incidence increased in Italy by 17% for each degree of increase in latitude. The effect of latitude was statistically significantly present also adjusting for other variables (incidence rate ratio = 1.08). The effect of latitude on increasing mortality (mortality rate ratio = 1.27) and improving survival (relative excess risk of death = 0.93) was no longer present in the multivariate model. Conclusion. Melanoma incidence, mortality, and survival vary in Italy according to latitude. After adjustment for several confounders, incidence still grows with growing latitude. Presumably, latitude expresses other variables that might be related to individual susceptibility and/or local care.
[show abstract][hide abstract] ABSTRACT: The objective of this study was to evaluate the time trend of melanoma thickness in a population-based case series. All invasive (n=2862) and in-situ (n=605) cutaneous melanoma incident cases diagnosed in 1985-2004 were retrieved from the Tuscany Cancer Registry, central Italy. Standardized (European population) incidence rates were computed for four periods: 1985-1989, 1990-1994, 1995-1999, 2000-2004, and for Breslow thickness classes (< or =1, 1.01-2.00, >2 mm). The annual percent change (APC) of the standardized rates was computed. Thickness was evaluated on the basis of sex, age, morphology type, site and period of time. Median thickness was evaluated by means of a nonparametric K-sample test. The incidence rate of melanoma rose significantly for both invasive (APC=+5.1%) and in-situ lesions (APC=+11.1). The sex distribution of patients with invasive melanoma did not change over time (mean male/female ratio 0.95). The mean age at diagnosis did not change (57.2 years; SD=17.2 years). From 1985-1989 to 2000-2004 the median value of thickness decreased from 1.68 to 0.8 mm (P<0.001). Within the Breslow categories the median value of thickness decreased significantly for thin melanomas (< or =1 mm) but not for intermediate (1.01-2.00) or for thick melanomas (>2 mm). Among the most common melanoma types, the median thickness decreased for superficial spreading melanomas but not for nodular melanomas. Over time, the incidence of melanoma has increased notably and the median thickness has decreased. However, median thickness has decreased only among thin melanomas, whereas it has not changed for thick melanomas, most of which are of the nodular type.
Melanoma research 10/2010; 20(5):422-6. · 2.06 Impact Factor
[show abstract][hide abstract] ABSTRACT: Imiquimod use in the treatment of basal cell carcinoma (BCC) has proven to be successful in a large percentage of cases, inducing tumor regression; however, the exact cellular mechanism has not been fully clarified.
To measure the morphological changes in the tumor microenvironment and the markers of apoptosis in skin biopsies from patients with BCC before and after imiquimod treatment.
In this open label study, skin biopsies obtained from 11 patients with BCC were evaluated before and after imiquimod treatment for: (i) morphological changes in the tumor microenvironment, with specific emphasis on the immunophenotype of inflammatory cells around the tumor; and (ii) markers of apoptosis, including expression of death receptors.
Imiquimod treatment induced a significant increase in the mononuclear inflammatory response. In the majority of cases, the cellular infiltrate was predominantly composed of CD3(+)/CD4(+) T cells, suggesting that the effector response is mediated by CD3(+)/CD4(+) lymphocytes, with a minor cytotoxic and natural killer (NK) component. An increase in the cytotoxic CD3(+)/CD8(+) T-cell population was also observed. Imiquimod treatment was associated with a marked increased in CD20(+) B cells, and a less pronounced enhancement in cells of monocyte-macrophage origin (CD68(+)) surrounding, or within, the tumor. This finding indicates either that macrophages play a minor role in the imiquimod-induced response, or the recruitment of these cells is related to time and dose. Imiquimod treatment decreased CD1A(+) Langerhans cells in the epidermis and increased the number of CD1A(+) dendritic cells within the tumor aggregates. Imiquimod reduced Bcl-2 expression, but no difference was found in Bax, Fas/FasL, and p53 expression in BCC cells.
Our results support the hypothesis that imiquimod activity in the treatment of BCC is partly a result of a pro-inflammatory action mediated by CD3(+)/CD4(+) lymphoid cells and of a pro-apoptotic activity associated with decreased Bcl-2 expression.
International journal of dermatology 04/2009; 48(3):312-21. · 1.18 Impact Factor
[show abstract][hide abstract] ABSTRACT: We have investigated the frequency and spectrum of CDKN2A/CDK4 mutations in 23 cutaneous melanoma families from Central Italy (Tuscany). Three distinct mutations were identified in five families. One mutation, p.G23S, was present in three families. Several lines of evidence indicate that p.G23S is a pathogenic mutation: it is located in the functionally important first ankyrinic domain of p16, it was not detected in a sample of 100 control individuals, and it was present in all tested affected individuals from the three families. Haplotype analysis showed a common ancestral origin of the p.G23S mutation. Our data show that the p.G23S mutation is an important cause of hereditary melanoma in Tuscany.
Melanoma Research 01/2008; 17(6):387-92. · 2.52 Impact Factor
[show abstract][hide abstract] ABSTRACT: UV Index information is currently recommended as a vehicle to raise public awareness about the risk of sun-exposure. It remains unknown to what extent this information can change personal sun-protective behavior. The aim of the study was to analyze the effects of UV-Index (UV-I) information provided by low cost, commercially available UV-I sensors on major indicators of sun-tanning behavior. A randomized-controlled trial was carried out on 94 healthy volunteers aged 21-23 years. After the exclusion of subjects with photosensitive disorders (n=3), 91 subjects were randomized in two arms after stratification based on phototype and sex. Both arms received a diary to be filled every day with a log of intentional sun-exposure during summer. Subjects in the intervention group also received a commercially available UV-I sensor. The UV-I sensors were switched on and the UV-value was recorded in 77% of days with sun-exposure. During days of sun-exposure, subjects randomized to the intervention group had longer average time of sun-exposure (227.7 vs 208.7 min per day, P=0.003), also between noon and 4 pm (P<0.001), and less frequently adopted sun protective measures than controls (hat [6.4%vs 10.2%, P=0.007], sunglasses [23.9%vs 30.8%, P=0.003], sunscreen [41.4%vs 47.2%, P=0.02]) and they experienced more frequent sunburns (27.8%vs 21.5%, P=0.004). The odd ratio of sunburns was 1.60 for subjects in the intervention group compared with controls (after adjustment for sex, sunscreen use and skin type). The mean UV-I value recorded by volunteers was lower (5.6 [SD+/-0.9]) than that (7.3 [SD+/-0.46]) recorded by a professional instrument in the same period at the same latitude. Poststudy laboratory tests showed that the sensor was able to detect only about 60% of the solar diffuse radiation. The use of UV-I sensors changed the sun protective behavior of sunbathers in the direction of less use of sun protective measures. One possible explanation is that the low cost UV-meters may have functioned incorrectly and under-reported UV exposure. This may have led to an underestimation of UV-I values, erroneously reassuring subjects and causing a less protective sunbathing behavior. Another hypothesis relies on a cognitive pitfall in the subjects' dealing with intermediate UV-I values, as they may have been discouraged in the use of sunscreen as they did not feel that they had yet been exposed to very harmful UV radiation.
Photochemistry and Photobiology 01/2008; 84(3):758-63. · 2.29 Impact Factor
[show abstract][hide abstract] ABSTRACT: Guidelines for optimized use of digital follow-up of melanocytic lesions are not yet available, and little is known about inclusion criteria adopted in clinical practice.
Our purpose was to describe the frequency of digital follow-up adoption in melanoma screening, the characteristics of patients and lesions selected, and the predictors of duration of the intervals of digital follow-up.
Baseline characteristics of patients and lesions selected for digital follow-up in 12 Italian pigmented lesion clinics were examined. Predictors of a short follow-up interval (<or=3 months) compared with a 6-month interval were investigated by means of logistic regression analysis.
Out of 2116 subjects consecutively examined, 409 were submitted to digital follow-up (19.3%), with 1.6 mean lesions found per patient (range, 1-9; median, 1). According to an a posteriori analysis, 15.2% of the lesions were diagnostically equivocal and 7.8% of lesions had a total dermoscopy score (TDS) suggestive of malignancy. However, large differences in the TDS were found among the participating centers. Determinants of a short follow-up interval, adopted in 40.8% of patients, were the personal history of melanoma (odds ratio [OR] 2.56, 95% confidence interval [CI] 1.09-5.99) and the presence of atypical nevi (at least one atypical nevus (OR 4.54, 95% CI 2.45-8.42). Unexpectedly, the dermoscopic atypia of the lesion (TDS >4.75) was associated only with a marginal effect on the scheduled duration of follow-up interval (OR 1.34, 95% CI 0.97-1.86). These findings were confirmed by a multivariate analysis.
The adoption of different digital dermoscopy systems in the participating centers may have limited the reliability of the TDS assigned by a central group to dermoscopy images.
Practicing dermatologists who use digital epiluminescence microscopy in screening for melanoma decided to submit at least one melanocytic lesion to digital follow-up for approximately 1 patient for every 5 examined. This implies costs and time spent that need to be evaluated together with the benefits of this procedure from a large-scale perspective. The lack of well-defined guidelines for inclusion and exclusion criteria may hamper optimized use of digital follow-up in daily practice.
Journal of the American Academy of Dermatology 08/2006; 55(2):256-62. · 4.91 Impact Factor
[show abstract][hide abstract] ABSTRACT: In clinical practice, decisions regarding management of a pigmented skin lesion are based on morphologic examination, as well as on anamnestic, emotional, and medicolegal aspects. In some cases, the "ugly duckling" sign may be an indication for excision of a morphologically featureless melanoma. Therefore, examination of pigmented skin lesions based on clinical and dermoscopic images, without contact with the patient, may be associated with a not negligible risk of incorrect lesion management.
In this study, we tried to assess to what extent lesion management based on purely morphologic examination diverges from optimal management based on in vivo examination with direct contact with the patient, lesion history, and clinical and dermoscopic evaluation.
The study included clinical and dermoscopic images of 100 diagnostically equivocal pigmented lesions, including 20 early melanomas and 5 pigmented basal cell carcinomas consecutively referred for surgery; the images were reviewed by six dermatologists who specialize in melanoma screening and were previously trained in dermoscopy.
The percentage of melanomas correctly classified was less than 50% both for naked eye and combined examination. Regarding lesion management, only about 70% of malignancies (melanomas and basal cell carcinomas) are correctly referred for surgery by observers. Similar results have been obtained focusing on melanoma (72.5%).
Facing difficulties in diagnosing pigmented skin tumors, lesion management based on the morphology of the lesion, even including dermoscopic images, but without direct contact with the patient, diverges greatly from the gold standard management established by face-to-face examination and comports a not negligible risk of leaving a melanoma unexcised.
Dermatologic Surgery 03/2005; 31(2):169-72. · 1.87 Impact Factor
[show abstract][hide abstract] ABSTRACT: We sought to assess the difference in lesion management between combined examination (naked-eye and dermoscopy) and conventional naked-eye examination in evaluations for melanoma; and to assess the impact on patient treatment of facilities for digital follow-up of diagnostically equivocal lesions.
We conducted a randomized, controlled trial at a pigmented lesion clinic in a university hospital. A total of 938 consecutive subjects presenting between November 1, 2001, and March 31, 2002, were eligible and 25 were excluded because they were younger than 12 years of age; hence 913 subjects were enrolled. Participants were randomized to combined examination with mandatory excision of equivocal lesion (arm B) and with possibility of digital follow-up according to the clinician's decision (arm C), or to conventional naked-eye examination (mandatory excision of equivocal lesion) (arm A). The same pigmented lesion clinic staff examined all subjects.
Combined examination determined a significant reduction in the percentage of patients referred for operation (9.0% vs 15.6%) (P =.013). When facilities for digital follow-up of equivocal lesions were available, the percentage of patients classified as harboring lesions difficult to diagnose increased (group C, 35.8%; group B, 17.8%; P <.01). About half of them were immediately referred for operation whereas the remainder submitted to second examination (digital follow-up). Two melanomas (1 in situ and 1 invasive, 0.40-mm thick) were diagnosed after second examination performed 6 months later. The number of melanomas eventually excised within the study were similar among the 3 allocation groups (3, 2, and 3, respectively).
the addition of dermoscopy to conventional naked-eye examination is associated with a significant reduction of number of pigmented skin lesions excised for diagnostic verification. The possibility of digital follow-up of equivocal lesions is associated with a not negligible occurrence of initial melanomas left unexcised until the second consultation.
Journal of the American Academy of Dermatology 05/2004; 50(5):683-9. · 4.91 Impact Factor
[show abstract][hide abstract] ABSTRACT: Pigmented Bowen's disease (BD) (squamous cell carcinoma in situ) has been rarely described among white patients.
We report the case of a 48-year-old white male presenting a lesion of pigmented BD on his left thigh, clinically mimicking a superficial spreading melanoma.
Naked-eye physical examination revealed a single 1.8 x 1.5 cm, hyperpigmented plaque with a rough surface, which appeared irregularly shaped and sharply demarcated. The assessment of this uncommon tumor by means of dermoscopy, never reported in literature before, was performed. According to standardized terminology, none among the well-established dermoscopic criteria useful to discriminate between melanocytic and nonmelanocytic origin was detected within the lesion. A reticular pigmentation simulated remnants of atypical pigment network, being of uncertain diagnostic value in the preoperative classification of the lesion. Other recognized patterns were irregular, brown globular structures and wide regression-like areas. None of the features diagnostic for pigmented basal cell carcinoma was found as well.
The correct classification of nonmelanocytic origin of the lesion was therefore achieved only at histologic examination, after the complete surgical excision. In spite of its rarity, pigmented BD should be included among those lesions, which may simulate cutaneous melanoma. According to criteria validated by literature, dermoscopy failed to improve a preoperative classification of this peculiar skin tumor.
Dermatologic Surgery 05/2004; 30(4 Pt 1):541-4. · 1.87 Impact Factor
[show abstract][hide abstract] ABSTRACT: The predictive value of melanoma diagnosis made by visual examination during pigmented lesion screening is low. This creates the problem of false-positive diagnoses, which lead to unnecessary treatment and scarring. The purpose of this study was to evaluate the impact of dermoscopy (epiluminescence microscopy, dermatoscopy) on the false-positive rate in the routine melanoma screening activity of a pigmented lesion clinic (PLC). In a series of 133 subjects consecutively referred to the PLC, lesions defined as suspicious or equivocal on visual examination were examined by dermoscopy. Only lesions also defined as suspicious on dermoscopy were excised; other lesions were observed at follow-up examinations. Among the 2542 pigmented lesions observed, clinical examination led to identification of 43 suspicious lesions, 13 of which were also suspicious on dermoscopy and were subsequently excised. Histopathological examination revealed three malignant melanomas. Compared with visual examination alone, the addition of dermoscopy to the subgroup of clinically equivocal lesions resulted in an increase in specificity from 98.4% to 99.6% and in positive predictive value from 6.9% to 23%. The specificity of the visit outcome 'subject to be referred for surgical excision' increased from 69.2% to 92.3%. No false-negative melanoma diagnoses on dermoscopy were observed during a follow-up period of 4 years. The addition of dermoscopy to routine PLC activity as a second-level examination led to a reduction in the number of false-positive diagnoses, thus producing an overall increase in the specificity and positive predictive value of melanoma diagnosis.
Melanoma Research 05/2003; 13(2):179-82. · 2.52 Impact Factor
[show abstract][hide abstract] ABSTRACT: Dermoscopy is able to correctly classify a higher number of melanomas than naked-eye examination. Little is known however about factors which may influence the diagnostic performance during practice. The aim of the study was to analyze the effect of size of the lesion on diagnostic performance of dermoscopy in melanoma detection.
Eight dermatologists examined clinical and, separately, clinical and dermoscopic (combined examination) images of 200 melanocytic lesions previously excised [64 melanomas, 24 in situ and 40 invasive (median thickness 0.30 mm) and 136 melanocytic nevi]. After examination, diagnostic performance was analyzed in accordance with the major diameter of the lesions divided into 3 groups, i.e. small (less than 6 mm), intermediate (between 6 and 9 mm) and large (10 mm or more) lesions. These groups were shown to be highly comparable concerning the microstaging of melanomas (median thickness value 0.30, 0.22 and 0.32 mm, respectively).
Dermoscopy increased the diagnostic performance of naked-eye examination of both intermediate and large lesions [sensitivity value: +19.3 (p = 0.002) and +10.3 (p = 0.007); diagnostic accuracy value: +7.4 (p = 0.004) and +6.1 (p = 0.07)]. On the contrary, no statistically significant increase was found dealing with small lesions (sensitivity +3.7, p = 0.66; diagnostic accuracy -1.7, p = 0.55).
The diagnostic improvement associated with the addition of dermoscopy to naked-eye examination is influenced by the size of the lesion, i.e. it is lacking with lesions up to 6 mm in diameter. The optimized use of dermoscopy in melanoma detection is obtained dealing with melanocytic lesions 6 mm in diameter or larger.
[show abstract][hide abstract] ABSTRACT: To investigate the impact of a surveillance program aimed at early diagnosis of melanoma in a cohort of subjects classified at risk on the basis of their number of nevi. To compare the number of observed cases of melanoma in the cohort to that expected number in the general population of the same area.
Two hundred and eighteen subjects with no personal or family history of melanoma residing in the Florence district who showed more than 30 common acquired nevi and 3 or more atypical nevi (high-risk) have been followed for an average period of 3.4 years (range 1-6.5); an additional intermediate-risk group with 237 subjects was also enrolled.
Four incident melanomas were detected in 218 high-risk subjects followed for a total of 741.7 person-years; no melanoma was detected in the lower risk group. All the 4 detected melanomas were in situ (Clark level I), with an average interval since enrollment of 4.6 years (range 1.4-6.5). In accordance with age-and sex-specific incidence rates of melanoma (including in situ forms) in the general population of the area, the standardized incidence ratio (SIR) in the cohort was 44.1 (95% CI 16.5-117.5).
Subjects with more than 30 common nevi and 3 or more atypical nevi show about a 40-fold increased risk of developing melanoma. Even allowing for some degree of diagnostic anticipation due to periodic controls the risk appears higher than in the intermediate risk population. As a consequence of active follow up of individuals, all the detected tumors were at favourable prognosis. Periodic examination of these subjects should therefore be recommended as part of a prevention program for cutaneous melanoma in southern European populations.
European journal of dermatology: EJD 01/2003; 13(5):482-6. · 1.76 Impact Factor
[show abstract][hide abstract] ABSTRACT: It is mandatory that a new diagnostic method be validated by comparison with a well-established reference procedure before being introduced for use in clinical practice. In the field of pigmented skin lesions (PSL), clinical examination should be considered the reference procedure for new diagnostic methods, such as dermoscopy. However, it has not yet been established which is the best photographic procedure for obtaining the most informative clinical images to be used in a formal diagnostic setting.
In this study we investigated the diagnostic information provided by the two most popular methods currently used for clinical photographing of PSL: "contact" images obtained with a Dermaphot (Heine Ltd) at original x 10 magnification without oil application and "distant" images obtained with a macro objective from a distance of 10 cm.
Two experienced dermatologists observed clinical images of a series of 57 PSL (11 melanomas, 31 melanocytic nevi, 10 pigmented basal cell carcinomas, and four other diagnoses). The degree of concordance between the diagnoses based on "contact" and "distant" images (melanoma/non-melanoma) was very good (k = 0.819). Regarding histology, the degree of concordance was better when the diagnosis was based on "contact" images (k = 0.54) than "distant" images (k = 0.47). In particular, "contact" images were superior to "distant" images for diagnosis of non-melanoma lesions (specificity of melanoma diagnosis 87.7% vs. 83.6%), but we found no difference in melanoma detection (73% of sensitivity for both methods).
Although the two photographic procedures appear to provide similar levels of diagnostic information, the "contact" method seems to provide a higher specificity for melanoma diagnosis.
Skin Research and Technology 12/2002; 8(4):255-9. · 1.41 Impact Factor
[show abstract][hide abstract] ABSTRACT: A subset of about 3-5% of melanoma patients present a second primary melanoma.
We describe two cases of primary multiple synchronous melanomas consecutively observed in the last 6 months in our department in two male patients presenting multiple atypical nevi. In both patients, the second melanoma was diagnosed by the clinician who had identified the first one, but at the time of the first follow-up consultation, 3 months later. The delayed discovery of the second melanoma required another referral for surgery with additional discomfort for the patients. Concern about the first lesion (the thickest in both cases) probably rendered the second one less evident to both patients and clinician, until the first follow-up examination after excision of the first lesion.
We stress the need for careful and thorough examination of the whole body surface at the time of detection of a cutaneous melanoma in subjects with multiple atypical moles because the finding of synchronous multiple melanomas is not uncommon.
International Journal of Dermatology 10/2002; 41(9):583-5. · 1.34 Impact Factor
[show abstract][hide abstract] ABSTRACT: the aims of Tuscany Regional project were: to study the sun protection attitude of outdoor workers; to measure solar ultraviolet (UV) exposure in work environment; to describe the frequency of photoaging, precancerous lesions, and skin cancers in outdoor workers; to collect information on solar ultraviolet radiation exposure from incident cases of Non-Melanoma Skin Cancer (NMSC) recruited from Tuscany Cancer Registry.
outdoor workers completed a questionnaire devoted to collect information on sun protection attitudes during a typical summer working week. Environmental and personal measurements were carried out. Expert dermatologists examined outdoor workers to assess the frequency of photoaging, precancerous lesions, and skin cancer. A structured questionnaire was mailed to incident cases of NMSC. Information were collected on personal habits and working history, focusing on solar ultraviolet radiation exposure.
agriculture, construction, quarrying and fishing activities were considered: 292 employees responded to questions about the type of clothing used in the morning and in the afternoon,while working outdoors; 637 outdoor workers underwent skin examination. We contacted 743 cases of NMSC occurred in 2004; 498 subjects accepted to participate in this study.
the clothing worn by surveyed subjects was often inadequate compared to the high level of exposure to UV. The skin examination of 637 outdoor workers highlighted 2 melanomas, 7 epitheliomas and 35 actinic keratoses.Among the 498 cases of NMSC, 135 (27%) were diagnosed in outdoor workers. Most represented economic activity sectors were: agriculture, construction, transport, sports.
the characterization of outside workers revealed unsatisfactory sun protection behaviours. Moreover, previously undetected skin cancers were diagnosed. The study on MNSC confirms the complexity of studying the exposure to UV radiation.The Tuscany Regional project provided useful information on the risk of solar ultraviolet radiation in outdoor workers. Prevention programs are needed.
Epidemiologia e prevenzione 37(1):51-9. · 0.92 Impact Factor