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The introduction of targeted therapies for the treatment of BRAF-mutated metastatic melanoma was associated with different cutaneous adverse events (AEs).To describe the type, frequency and severity of cutaneous AEs related to vemurafenib; to understand the association between AEs and vemurafenib efficacy in terms of median overall survival (OS) and median progression-free survival (PFS); to identify molecular characteristics of long-term responders.This observational, retrospective, monocentric study included all consecutive patients with unresectable stage III or stage IV melanoma and BRAF V600E mutation that started treatment with vemurafenib between May 2012 and May 2014.62 patients with a median age of 56 years (range 26-82) were enrolled and received vemurafenib for a median period of 7.9 months (range 0.8-63.7). Among them, 45 patients presented at least one skin AE, 12 reduced the dosage due to cutaneous toxicity, and only one firstly reduced and after stopped the therapy. No specific molecular biomarkers were detected in long-term survivors.Among long-term survivors, skin AEs seem to be less frequent and less severe. Results on multivariable analysis revealed that the presence of at least one G2 toxicity is a protective factor considering PFS, but not in terms of OS.

Background Amelanotic/hypomelanotic lentigo maligna and lentigo maligna melanoma (AHLM/LMM) may be very difficult to diagnose at an early stage. Objectives To quantify the predictive value of dermoscopic and reflectance confocal microscopy (RCM) features for AHLM/LMM. Methods Dermoscopic and RCM images of histopathologically diagnosed AHLM/LMM, amelanotic/hypomelanotic benign lesions (AHBL), and amelanotic/hypomelanotic basal and squamous cell carcinomas (AHBCC/AHSCC) of the head and neck from consecutive patients were retrospectively collected and blindly evaluated by three observers to assess presence or absence of dermoscopic and RCM criteria. Results Overall, 224 lesions in 216 patients including LM/LMM (n = 55, 24.6%), AHBL (n = 107, 47.8%) and AHBCC/AHSCC (n = 62, 27.7%) were analysed. Multivariable analysis showed that milky-red areas (OR = 5.46; 95% CI: 1.51-19.75), peripheral light brown structureless areas (OR = 19.10; 4.45-81.96), linear irregular vessels (OR = 5.44; 1.45-20.40), and asymmetric pigmented follicles (OR = 14.45; 2.77-75.44) at dermoscopy, and >= 3 atypical cells in five fields (OR = 10.12; 3.00-34.12) and focal follicular localization of atypical cells at dermo-epidermal junction (DEJ) (OR = 10.48; 1.10-99.81) at RCM were significantly independent diagnostic factors for AHLM/LMM vs. AHBL. In comparison with AHBCC/AHSCC, peripheral light brown structureless area (OR = 7.11; 1.53-32.96), pseudonetwork around hair follicles (OR = 16.69; 2.73-102.07), and annular granular structures (OR = 42.36; 3.51-511.16) at dermoscopy and large dendritic (OR = 6.86; 3.15-38.28) and round pagetoid cells (OR = 26.78; 3.15-227.98) at RCM led to a significantly increased risk of diagnosing AHLM/LMM. Conclusions Amelanotic/hypomelanotic lentigo maligna and lentigo maligna melanoma may have the same dermoscopic features of AHM on other body sites, such as milky red areas, peripheral light brown structureless areas and linear irregular vessels. These features, asymmetric pigmented follicles and at RCM >= 3 atypical cells in five fields and focal follicular extension of atypical cells at DEJ may help in recognizing AHLM/LMM even when LM conventional features (e.g., obliteration of hair follicles under dermoscopy and large pagetoid cells under RCM) are absent or present only in very small areas of the lesion.

BACKGROUND Negative pigment network (NPN) is a dermoscopic structure observed more frequently among melanomas than naevi. Precise tissue correlates of NPN are still elusive. OBJECTIVE To describe the reflectance confocal microscopy (RCM) findings underlying NPN in melanocytic neoplasms. METHODS We retrospectively identified all melanocytic neoplasms displaying dermoscopic NPN that were imaged with RCM and subsequently biopsied between 2011 and 2015. Images from study lesions (n = 50) were evaluated for dermoscopic and RCM Criteria. Histopathological correlational study was performed in a subset of cases (n = 15). RESULTS The study data set consisted of 21 melanomas (42%) and 29 naevi (58%). Melanomas showed more frequently irregularly shaped globules than naevi (62% vs. 28%, P = 0.03); NPN also tended to be more asymmetrically located among melanomas (86%) than naevi (62%), albeit not significant (P = 0.06). Under RCM, we observed three patterns of dermal papillae (DP): (i) 'Dark DP' - whereby DP were devoid of nests and often surrounded by a junctional proliferation as thick-Rings - this pattern was less common among melanomas (n = 10, 48%) than naevi (n = 23, 79%, P = 0.02); (ii) 'Bulging DP' - whereby junctional nests of melanocytes protrude into the DP, often in association with junctional proliferation as Meshwork - with comparable frequency among melanomas (n = 12, 57%) and naevi (n = 23, 79%, P = 0.09) and (iii) 'Expanded DP' - whereby junctional and/or dermal nests filled and expanded the DP, often in association with dermal-epidermal junction (DEJ) Clod pattern - seen more commonly among melanomas (n = 15, 71%) than naevi (n = 6, 21%, P

Background Digital dermoscopy follow up (DDF) is useful in improving the recognition of melanoma, catching early changes over time, although benign nevi can also show changes. Reflectance confocal microscopy (RCM) improves accuracy in diagnosing melanoma and decreases the number of unnecessary resections. Objective To evaluate dynamic dermoscopic and RCM changes during follow up of equivocal melanocytic lesions and assess the impact of adjunctive RCM to DDF for melanoma diagnosis. Methods A retrospective, multicenter study of extrafacial atypical melanocytic lesions excised during follow up was performed. Morphologic changes were evaluated, comparing dermoscopy and RCM baseline and follow-up images. Results One hundred thirty-seven atypical melanocytic lesions were studied, including 14 melanomas and 123 benign nevi. Significantly greater changes in DDF of atypical network, regression, atypical streaks, and asymmetrical growth as well as in dynamic RCM of atypical cells and dermal-epidermal junction disarray were noted in melanomas. With adjunctive dynamic RCM and major changes at DDF, sensitivity reached 100%, with 40.6% specificity. Limitations Selected series of difficult to recognize lesions, with both DDF and dynamic RCM images. Conclusion Adjunctive dynamic RCM improves early melanoma recognition sensitivity.

Background: The ratio of benign moles excised for each malignant melanoma diagnosed (number-needed-to-excise (NNE)) is a metric used to express the efficiency of diagnostic accuracy of melanoma. The literature suggests a progressive effort to reduce the NNE, thus raising concerns about missing early melanoma because the NNE does not capture the most significant outcome for melanoma prognosis, which is linked to the Breslow thickness. A lower NNE could reduce health costs related to melanoma diagnosis only if doing so does not increase the proportion of thicker melanomas. Objectives: The diagnostic performance by two tertiary referral centres using the NNE and proportion of thick (Breslow thickness > 1 mm) versus thin (Breslow thickness ≤ 1 mm) excised melanoma (thick/thin ratio: TTR) was compared to determine if a lower NNE is associated with a greater proportion of thicker melanoma. Combining TTR with NNE allows a better estimate of the effectiveness in melanoma diagnosis, assessing both the overall cost for a given pool of excised melanomas and costs due to unnecessary nevi excision at a particular dermatology centre. Methods: Demographic data and Breslow thickness of excised melanoma were extracted from patient histologic records at two referral centres for melanoma (Parma Dermatology Unit and Ravenna and Meldola Skin Cancer Unit, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori. IRCCS (IRST)) on all skin tumours excised between 2002 and 2011 and diagnosed as melanoma or melanocytic nevus. NNE and TTR were calculated and compared among the considered variables. Logistic regression was used to assess the contribution of each variable in predicting a higher TTR. Results: Data from 16,738 excised lesions were analysed. The IRST Unit reported a mean NNE of 4.6, whereas the Parma Unit excised 10.6 nevi for each melanoma. No statistically significant differences existed in the mean (IRST Unit, 0.56 ± 0.89 mm; Parma Unit, 1.07 ± 2.2 mm) and median (range) Breslow thickness (IRST Unit, 0.4 (9) mm; Parma Unit 0.4 (30) mm). The TTR between centres was significantly different (Parma Unit, 24%; IRST Unit, 12%; p < 0.001). Based on logistic regression, the diagnosing centre was the most powerful factor in determining a thickness of >1 mm among diagnosed melanomas (OR = 1.8; 95% CI, 1.2–2.7; p < 0.01), with all other factors being equal. The NNE decreased at both centres from younger-to-older patients, whereas the TTR increased simultaneously; however, the increase in TTR was non-significantly related to NNE reduction after adjusting for confounders (age, gender, and localization). Conclusions: A better diagnostic performance is capable of reducing the NNE and TTR, i.e., unnecessary excisions of melanocytic nevi can be reduced without increasing the risk of overlooking melanomas. The TTR, in addition to the NNE, allows stakeholders to better estimate the effectiveness in melanoma diagnosis because both overall costs for a given pool of excised melanomas and costs due for unnecessary nevi excision at a particular dermatology centre can be compared.

Sun protection early in life is an essential issue for primary prevention of skin cancers. The Il Sole per Amico was an educational campaign among 66 Italian primary schools. A total of 12,188 questionnaires were completed at baseline. Overall, 9.4% children reported >1 sunburn during the last year and 44.7% parents a use of sunlamps. Independent factors associated with sunburns were: age, lower level of parents' education, light eye and skin color, freckles, nevi on arms, intense sun exposure during the last year, sporadic use of sunscreens, and parental use of sunlamps. A total of 7280 (59.7%) questionnaires were completed at the end of the educational intervention. No significant difference was documented about behavior between the pre- and post-intervention periods. A significant reduction was instead found in both prevalence of recent sunburns and total number of sunburn episodes after comparison with the data obtained by identical questionnaire in the same geographic areas in the "Sole Si Sole No" project in 2001.

Background: Cutaneous melanoma is one of the most frequent malignancies of the skin in Caucasian populations. Patients who develop cutaneous melanoma are at increased risk of developing a second primary melanoma. The estimated incidence of multiple primary melanoma (MPM) ranges from 1.2% to 8.2% of cases, with a high preponderance of melanomas occurring metachronously. Objectives: The aim of this study was to describe dermoscopic, microscopic, clinical, and molecular correlations between first and subsequent melanomas in patients with metachronous MPMs. Materials & methods: Twenty-four paired melanomas from 12 MPM patients were evaluated for architectural characteristics based on dermoscopy and confocal microscopy, as well as for mutations in BRAF and NRAS genes by Sanger-based sequencing analysis. Specific scores used for classifying features of dermoscopy (global pattern; 7-point check list; ABCD Stolz score) and confocal microscopy (Segura and Pellacani) were compared with genetic and histological data. Results: Consistency in dermoscopic patterns between the primary and subsequent cutaneous melanomas were observed in about two thirds of cases, whereas concordant features based on confocal microscopy were found in only about two fifths of cases. The majority of patients (7/12; 58%) presented consistent BRAF/NRAS mutation patterns between first and subsequent primary melanomas. A significant association between BRAF mutations and Pellacani score was evident. Conclusions: Similarities between the index melanoma and subsequent cutaneous melanomas were observed with regards to dermoscopic features and, to a much less extent, confocal microscopy findings. Our data further indicate that the Pellacani score may be used to predict BRAF mutations.

A conservative management of Spitz nevi (SN) in children is currently adopted by many pediatric dermatologists in case of flat to slightly palpable lesions, clinically and dermoscopically diagnosed as SN (1-5). The aim of the current study was to analyze the dermoscopic and reflectance confocal microscopy (RCM) in vivo changes observed over time, during the sequential follow up of a series of SN. This article is protected by copyright. All rights reserved.

Caini, Saverio Boniol, Mathieu Tosti, Giulio Magi, Serena Medri, Matelda Stanganelli, Ignazio Palli, Domenico Assedi, Melania Marmol, Veronique Del Gandini, Sara eng Meta-Analysis Research Support, Non-U.S. Gov't Review England 2014/08/05 06:00 Eur J Cancer. 2014 Oct;50(15):2649-58. doi: 10.1016/j.ejca.2014.06.024. Epub 2014 Jul 30.; International audience; Vitamin D is formed mainly in the skin upon exposure to sunlight and can as well be taken orally with food or through supplements. While sun exposure is a known risk factor for skin cancer development, vitamin D exerts anti-proliferative and pro-apoptotic effects on melanocytes and keratinocytes in vitro. To clarify the role of vitamin D in skin carcinogenesis, we performed a review of the literature and meta-analysis to evaluate the association of vitamin D serum levels and dietary intake with cutaneous melanoma (CM) and non-melanoma skin cancer (NMSC) risk and melanoma prognostic factors. Twenty papers were included for an overall 1420 CM and 2317 NMSC. The summary relative risks (SRRs) from random effects models for the association of highest versus lowest vitamin D serum levels was 1.46 (95% confidence interval (CI) 0.60-3.53) and 1.64 (95% CI 1.02-2.65) for CM and NMSC, respectively. The SRR for the highest versus lowest quintile of vitamin D intake was 0.86 (95% CI 0.63-1.13) for CM and 1.03 (95% CI 0.95-1.13) for NMSC. Data were suggestive of an inverse association between vitamin D blood levels and CM thickness at diagnosis. Further research is needed to investigate the effect of vitamin D on skin cancer risk in populations with different exposure to sunlight and dietary habits, and to evaluate whether vitamin D supplementation is effective in improving CM survival.

This study aimed to evaluate the prevalence of sunbed use among teenagers and the association between familial behavior and the adoption of UV-protective practices in this age group. We also assessed the impact of an educational program on students’ knowledge about the potential risks of sunbed use. The educational intervention focused on: (i) skin effects of UV radiation, (ii) photoaging and photocarcinogenesis, (iii) risk factors for skin cancer, (iv) indoor sun tanning and misleading concepts such as possible protective effect of sunbed use on skin cancer risk, (v) sun protection and relation with skin phototype, and (vi) early diagnosis of melanoma using the ABCDE check list and the ugly duckling sign. We carried out a survey of 3098 students and found a strong association between parental sunbed use and students’ use of the same (P

Summary Background Successful treatment of melanoma depends on early diagnosis, but its varied clinical presentation means that no single noninvasive method or criterion can provide reliable detection in all cases. Objectives To determine whether combining sequential dermoscopy imaging with reflectance confocal microscopy (RCM) can improve melanoma detection and reduce the burden of unnecessary excisions. Methods We conducted a retrospective study with median follow-up of 25 months. We included equivocal pigmented lesions that lacked clear dermoscopy criteria for melanoma at baseline but were excised subsequently because of changes during digital monitoring. RCM imaging was performed before excision. Main melanoma dermoscopy features, seven-point checklist score at baseline, and changes in structure and/or colour, and development of new melanoma-specific criteria at follow-up (scored as major, moderate or minor) were considered. Main melanoma RCM criteria were evaluated and diagnosis was made. Histopathological diagnosis was the reference standard for defining parameter frequency and diagnostic accuracy. Results Seventy lesions were included. Major changes were more frequently correlated with melanoma diagnosis, although one-third (four of 12) of melanomas showed moderate or minor changes. Cytological atypia and architectural disarrangement on RCM were correlated with melanoma diagnosis. A correct melanoma diagnosis was achieved with RCM in almost all cases (11 of 12, 92%). Referring for excision only those lesions with RCM-positive features and/or presenting major changes at digital dermoscopy follow-up, theoretically 27 of 58 naevi could be saved from surgery. Conclusions Integration of RCM in the clinical and instrumental strategy for managing difficult pigmented lesions provided additional diagnostic information useful in the decision-making process.

Background: There is now much data that suggest a relationship between angiogenesis and breast cancer prognosis. Angiogenesis is a multistep process resulting from an ordered set of events and regulated by positive and negative modulators of microvessels growth and by the expression of various proteolytic enzymes. Materials and methods: We prospectively evaluated VEGF and microvessels density on tumor specimen and cytosolic levels of uPA and PAI-1. Results: We enrolled 81 primary breast cancer patients. The median follow-up was 38 months. Using the median value as cutoff for the statistical analysis, we found significant correlation between cytosolic levels of uPA and PAI-1(r=0.61;p

Melanoma is the most deadly form of skin cancer and its incidence is increasing worldwide. In 2009, the International Agency for Research on Cancer classified the entire UV spectrum as carcinogenic. In many countries, including Italy, the use of tanning equipment by minors and individuals with high risk phenotypes has been banned. This study assessed tan-seeking behaviour in a Mediterranean population with a relatively high melanoma incidence, where a considerable time is spent tanning outdoors. Subjects spending the most time in the sun were typically young single men, who use significantly less sunscreen and sunglasses. The overall prevalence of sunbed use was 22% in youth (≤35 years old) and 18% of them used sunbeds throughout the year. Sunbed use in youth was greater for phenotypes at risk. In Italy, 3.8% of melanoma cases are attributable to sunbed use, more in women (4.2% vs 3.1%, for women and men respectively) and much more in the young (17%). Of 8013 new melanoma cases in 2008 in Italy, 293 were attributable to sunbed use, with a high proportion of these in women (168) and 1045 were attributable to sun exposure. Among youth, 172 cases were attributable to sunbed use and 140 exclusively to sunbed use. This analysis reveals that a large number of cancers each year in Italy could be avoided by changing cultural attitudes to tanning. Sun avoidance and protection is generally inadequate in adults, especially young men. These results have important implications for the primary prevention of melanoma.

Background: Alterations in key-regulator genes of disease pathogenesis (BRAF, cKIT, CyclinD1) have been evaluated in patients with multiple primary melanoma (MPM). Methods: One hundred twelve MPM patients (96 cases with two primary melanomas, 15 with three, and 1 with four) were included into the study. Paired synchronous/asynchronous MPM tissues (N = 229) were analyzed for BRAF mutations and cKIT/CyclynD1 gene amplifications. Results: BRAF mutations were identified in 109/229 (48%) primary melanomas, whereas cKIT and CyclinD1 amplifications were observed in 10/216 (5%) and 29/214 (14%) tumor tissues, respectively. While frequency rates of BRAF mutations were quite identical across the different MPM lesions, a significant increase of cKIT (p < 0.001) and CyclinD1 (p = 0.002) amplification rates was observed between first and subsequent primary melanomas. Among the 107 patients with paired melanoma samples, 53 (49.5%) presented consistent alteration patterns between first and subsequent primary tumors. About one third (40/122; 32.8%) of subsequent melanomas presented a discrepant pattern of BRAF mutations as compared to incident primary tumors. Conclusions: The low consistency in somatic mutation patterns among MPM lesions from same patients provides further evidence that melanomagenesis is heterogeneous and different cell types may be involved. This may have implications in clinical practice due to the difficulties in molecularly classifying patients with discrepant primary melanomas.

Background The World Health Organization classified the entire ultraviolet (UV) spectrum and artificial UV tanning devices as carcinogenic to humans. Italian law has prohibited the use of tanning equipment by children under 18 years of age and by high-risk populations. Objectives The present large survey aimed to determine the prevalence of current sunbed use in Italy and to identify user characteristics. This study identifies starting points for future national interventions to reduce the health risks of exposure to artificial UV radiation. Methods In 2011 we conducted a survey of 4703 people in an area on the sunny Mediterranean coast in Italy. Through multivariate logistic models we investigated the associations of sunbed use with phenotypical factors. Results Overall prevalence of sunbed use was 20%, higher among women (22% vs. 16%; P < 0·0001), and young (22% vs. 17% for age < 35 years; P < 0·0001) and highly educated people (22% vs. 14%; P < 0·0001). Subjects at high risk of melanoma used sunbeds significantly more; i.e. people with freckles (25% vs. 18%; P < 0·0001), red hair (30% vs. 19%; P = 0·01) or fair eyes (22% vs. 19%; P = 0·006). Associations were confirmed in multivariate models. Conclusions More skin cancer monitoring is needed at tanning centres, and educational campaigns should be promoted, especially for young women and subjects at high risk of melanoma.

Summary Background Scanty information is available on the prevalence of congenital melanocytic naevi (CMN) and congenital naevus-like naevi (CNLN), particularly the small ones. Objectives To estimate the prevalence of CMN/CNLN in Italian schoolchildren, and to assess variations according to potential risk factors for melanoma. Methods We conducted a survey in 13 Italian areas on 3406 schoolchildren aged 12–17 years. Children were examined by dermatologists who assessed pigmentary traits and made a count of small (6–15 mm in diameter) and medium/large (> 15 mm) CMN/CNLN on 19 anatomical areas. Results Overall, 592 children (17·4%) had one or more CMN/CNLN. Prevalence of small CMN/CNLN was 16·1%, and that of medium/large CMN/CNLN was 1·8%. There was no difference between age groups and sexes. CMN/CNLN were more frequent in children with a higher number of common melanocytic naevi (multivariate odds ratio, OR = 7·1 for the highest vs. the lowest quartile), consistent in small (OR = 7·2) and medium/large CMN/CNLN (OR = 6·0). Family history of malignant melanoma (OR = 1·4) and personal history of diabetes (OR = 4·4) appeared to be directly, and sun exposure inversely associated with CMN/CNLN. No relation was evident between CMN/CNLN and pigmentary traits, anthropometric characteristics, dietary habits, freckles, sunburns, sunscreen use or history of selected diseases. Conclusions The association with family history of melanoma, the strong association with acquired melanocytic naevi, and the lack of association with pigmentary traits and sunburns suggest that CMN/CNLN may act as an independent risk marker for subjects at increased risk for cutaneous melanoma later in life.

Background The dermoscopic diagnosis of cutaneous melanoma (CM) may be difficult because some CM lack specific dermoscopic features for melanoma diagnosis. Objective To evaluate whether a diagnosis of CM could be achieved using the classic dermoscopic melanoma-specific criteria, we conducted a retrospective multicenter study of 508 CM samples. Methods All the dermoscopic images were analyzed to identify the dermoscopic criteria found in dermoscopically difficult melanomas (DDM) and to examine the possible relation of dermoscopic diagnosis with respect to the difficulty of the dermoscopic diagnosis and the melanoma thickness. Results A significant percentage of melanomas, 89 of 508 (17.5%), were DDM. The criteria leading to a significant increased risk of DDM were presence of streaks [odds ratio (OR), 2.26; 95% confidence interval (CI), 1.15-4.47), absence or presence of regular pigmentation (OR, 3.41; 95% CI, 1.70-6.85), absence of a blue-whitish veil (OR, 4.04; 95% CI, 2.33-6.99), absence of regression structures (OR, 4.31; 95% CI, 2.42-7.66), and the presence of hypopigmentation (OR, 2.61; 95% CI, 1.49-4.58). Conclusions A significant number of melanomas defy even dermoscopic diagnosis. Only a meticulous comparative and interactive process based on an assessment of all the individual's other nevi ("ugly ducking" sign) and a knowledge about recent changes can lead to the recognition of DDM.

The clinical diagnosis of melanoma could be difficult for a general practitioner and, in some cases, for dermatologists. To enhance and support the clinical evaluation of pigmented skin lesions a computer-aided diagnosis has been introduced.Images of melanocytic lesions (477 total, 42 melanomas and 435 melanocytic nevi) evaluated in epiluminescence microscopy and recorded with x16 magnification were selected. A training set of 22 melanomas and 218 nevi was randomized from the dataset. The test set was formed by the complement (the remaining 20 melanomas and 217 nevi). Furthermore, a set of images consisting of 31 melanomas and 103 nevi was selected to compare the discrimination capacity of three general practitioners and three dermatologists with experience in dermoscopy (2 years), and with the automatic data analysis for the melanoma early detection system (ADAM). Sensitivity and specificity were estimated for observer assessments and computer diagnosis.The entire dataset used to test the implementation of the diagnostic algorithms ADAM showed a good sensitivity and specificity performance. Compared with the physicians, the ADAM system showed a slightly higher diagnostic performance in terms of sensitivity and a lower one in terms of specificity. Dermatologists showed higher levels of specificity, but lower levels in terms of sensitivity, when compared with the general practitioners.Image analysis has the potential to distinguish nevi and melanomas and to support the clinical diagnosis of melanocytic lesions by the general practitioner.

There is now much data that suggest a relationship between angiogenesis and breast cancer prognosis. Angiogenesis is a multistep process resulting from an ordered set of events and regulated by positive and negative modulators of microvessels growth and by the expression of various proteolytic enzymes.We prospectively evaluated VEGF and microvessels density on tumor specimen and cytosolic levels of uPA and PAI-1.We enrolled 81 primary breast cancer patients. The median follow-up was 38 months. Using the median value as cutoff for the statistical analysis, we found significant correlation between cytosolic levels of uPA and PAI-1 (r = 0.61; p.0001), between VEGF and steroid hormone receptor status (p = .01), between PAI-1 and tumor grading (p = .009), and between uPA and tumor size greater than 1 cm (p = .04). With respect to the prognosis, we observed a significant correlation between low uPA levels and RFS and an unforeseen, direct correlation between high VEGF values and better RFS.Our preliminary results indicate that the cytosolic level of uPA at diagnosis may be predictive of early relapse in primary breast cancer.