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AIM: To examine neuroretinal function by using the multifocal electroretinography (mfERG) test in patients with neurofibromatosis type 1 (NF1) without optic pathway gliomas (OPGs). METHODS: This study was conducted on 35 patients (35 eyes) with NF1 and 30 healthy subjects (30 eyes) for the control group. Each subject underwent a complete ophthalmological examination including spectral domain-optical coherence tomography (SD-OCT) and mfERG. The 1.5-Tesla magnetic resonance imaging (MRI) scan of the brain was performed in NF1 patients to assess the presence of OPGs. All participants were recruited having a best corrected visual acuity (BCVA) of no less than 20/20 in each eye. The amplitude and implicit time of the P1 wave (first-order Kernel component) were evaluated on mfERG. Data analysis was carried out in the two central degrees and in the four quadrants from two to 25 degrees of visual field. RESULTS: Statistically significant results were obtained for the P1 wave amplitudes in the 4 quadrants in NF1 patients compared to healthy controls, while the reduction was not significant in the 2 central degrees between the groups. A statistically significant difference was observed among the P1 wave amplitudes as recorded in the 4 quadrants within the NF1 group, with lower amplitudes detected in the nasal quadrants. No differences in the implicit times were recorded in the 2 central degrees and in the 4 quadrants as compared between NF1 patients and controls. CONCLUSION: Impaired neuroretinal function in NF1 patients is expressed in a decreased amplitude of the P1-wave between 2 and 25 central retinal degrees on mfERG. Altered intracellular signal transduction due to abnormal neurofibromin-mediated cyclic adenosine monophosphate (cAMP) generation, can be involved. The possible use of mfERG as subclinical retinal damage indicator has a potential utility in clinical practice for the follow-up of NF1 patients.

Background Neurofibromatosis Type I (NF1), also termed von Recklinghausen disease, is a rare genetic disorder that is transmitted by autosomal dominant inheritance, with complete penetrance and variable expressivity. It is caused by mutation in the NF1 gene on chromosome 17 encoding for neurofibromin, a protein with oncosuppressive activity, and it is 50% sporadic or inherited. The disease is characterized by a broad spectrum of clinical manifestations, mainly involving the nervous system, the eye and skin, and a predisposition to develop multiple benign and malignant neoplasms. Ocular diagnostic hallmarks of NF1 include optic gliomas, iris Lisch nodules, orbital and eyelid neurofibromas, eyelid café-au-lait spots. Choroidal nodules and microvascular abnormalities have recently been identified as additional NF1-related ocular manifestations. The present study was designed to describe the features and clinical significance of a new sign related to the visual apparatus in NF-1, represented by hyperpigmented spots (HSs) of the fundus oculi. Results HSs were detected in 60 (24.1%) out of 249 patients with NF1, with a positive predictive value of 100% and a negative predictive value of 44.2%. None of the healthy subjects (150 subjects) showed the presence of HSs. HSs were visible under indirect ophthalmoscopy, ultra-wide field (UWF) pseudocolor imaging and red-only laser image, near-infrared reflectance (NIR)-OCT, but they were not appreciable on UWF green reflectance. The location and features of pigmentary lesions matched with the already studied NF1-related choroidal nodules. No significant difference was found between the group of patients (n = 60) with ocular HSs and the group of patients (n = 189) without ocular pigmented spots in terms of age, gender or severity grading of the disease. A statistically significant association was demonstrated between the presence of HSs and neurofibromas (p = 0.047), and between the presence of HSs and NF1-related retinal microvascular abnormalities (p = 0.017). Conclusions We described a new ocular sign represented by HSs of the fundus in NF1. The presence of HSs was not a negative prognostic factor of the disease. Following multimodal imaging, we demonstrated that HSs and choroidal nodules were consistent with the same type of lesion, and simple indirect ophthalmoscopy allowed for screening of HSs in NF1.

Background: Basal cell carcinoma can simulate melanoma and specific dermoscopic criteria have not yet been defined in a large cohort. Objective: To identify dermoscopic “trump” characteristics for differential diagnosis, identify cluster groups and assess the clinical impact of this study's findings. Methods: Retrospective, multicentric comparative study of atypical, non-facial basal cell carcinoma (≥1seven-point checklist criteria) and melanoma (with at least one BCC criteria) at dermoscopy. Observed dermoscopic features were used to develop a proposed score. Lesion clusters were defined with hierarchical analysis. Clinical impact was assessed with a blinded reader study following this study's results. Results: A total of 146 basal cell carcinoma and 76melanoma were included. Atypical vascular pattern was common to most lesions (74.5%). Twelve trump features were included in the proposed score (sensitivity 94.1% and specificity 79.5%). Cluster analysis identified 3 basal cell carcinoma and 3melanoma clusters. Findings improved overall diagnostic accuracy and confidence (26.8% and 13.8%, respectively; p&nbsp

Antonietta Moramarco,1,* Ludovico Alisi,1,* Alessandro Lambiase,1 Sandra Giustini,2 Luca Lucchino,1 Emanuele Miraglia,2 Vincenzo Roberti,2 Marcella Nebbioso1 1Department of Sense Organs, Faculty of Medicine and Odontology, Sapienza University of Rome, Rome, 00161, Italy; 2Department of Dermatology, Sapienza University of Rome, Rome, 00185, Italy*These authors contributed equally to this workCorrespondence: Alessandro LambiaseDepartment of Sense Organs, Sapienza University of Rome, Viale del Policlinico 155, Rome, 00161, ItalyTel +39 06 49975357Fax +39 06 49975425Email alessandro.lambiase@uniroma1.itIntroduction: Gorlin-Goltz syndrome (GGS) also known as nevoid basal cell carcinoma syndrome (NBCCS) is a complex rare genetic disorder characterized by a wide range of clinical and radiological manifestations. Ophthalmological alterations have always been reported, but no study on the eventual pattern visual evoked potentials (pVEPs) abnormalities has yet been published.Purpose: The purpose of the study was to evaluate the functionality of the optic pathways in a group of NBCCS patients through pattern reversal VEPs, after a thorough exclusion of subjects with preexisting ocular and optic pathways pathologies.Methods: Nineteen NBCCS patients (31 eyes) and 20 healthy controls (40 eyes) have been recruited for this study. All subjects underwent an evaluation of the functionality of the optic pathways through pVEPs with small (120ʹ), medium (60ʹ), and large (15ʹ) check size stimulation.Results: NBCCS patients showed a statistically significant alteration in the transmission of the macular pathway function when compared to controls. PVEPs analysis confirmed a reduced amplitude and an increased latency of the P100 component, suggesting an involvement of the visual pathway even in the absence of ocular clinical manifestations.Conclusion: Visual pathways may have been affected both by a subclinical myelination deficit, determined directly by the genetic alteration, as well as by neurological abnormalities typical of this syndrome. Further studies are warranted.Keywords: Gorlin-Goltz syndrome, nevoid basal cell carcinoma syndrome, pattern visual evoked potentials, rare diseases, electrophysiology, visual pathway, genodermatosis, PATCH1

Background Gorlin-Goltz syndrome, also known as nevoid basal cell carcinoma syndrome, is a rare genetic disorder that is transmitted in an autosomal dominant manner with complete penetrance and variable expressivity. It is caused in 85% of the cases with a known etiology by pathogenic variants in the PTCH1 gene, and is characterized by a wide range of developmental abnormalities and a predisposition to multiple neoplasms. The manifestations are multiple and systemic and consist of basal cell carcinomas in various regions, odontogenic keratocistic tumors and skeletal anomalies, to name the most frequent. Despite the scarce medical literature on the topic, ocular involvement in this syndrome is frequent and at the level of various ocular structures. Our study focuses on the visual apparatus and its annexes in subjects with this syndrome, in order to better understand how this syndrome affects the ocular system, and to evaluate with greater accuracy and precision the nature of these manifestations in this group of patients. Results Our study confirms the presence of the commonly cited ocular findings in the general literature regarding the syndrome [hypertelorism (45.5%), congenital cataract (18%), nystagmus (9%), colobomas (9%)] and highlights strabismus (63% of the patients), epiretinal membranes (36%) and myelinated optic nerve fiber layers (36%) as the most frequent ophthalmological findings in this group of patients. Conclusions The presence of characteristic and frequent ocular signs in the Gorlin- Goltz syndrome could help with the diagnostic process in subjects suspected of having the syndrome who do not yet have a diagnosis. The ophthalmologist has a role as part of a multidisciplinary team in managing these patients. The ophthalmological follow-up that these patients require, can allow, if necessary, a timely therapy that could improve the visual prognosis of such patients.

Background Insulin-like growth factor (IGF) binding protein (IGFBP)-3 is the main carrier of circulating IGFs and the main modulator of their activity. IGFBP-3 controls cellular availability of IGFs, which cannot exert their pro-proliferative activity while bound to IGFBP-3. Proteolysis of IGFBP-3 is one mechanism to control IGF release. A reduction of serum IGFBP-3 levels and the associated increased availability of IGFs may represent a strategy whereby melanoma increases its metastatic potential. Objective The aim of our study was to evaluate the correlation between the IGFBP-3 serum level and melanoma stage. Methods The study included 41 patients, 24 male and 17 female, with median age of 60 years (range 24-80), affected by cutaneous melanoma. Blood samples were taken from each patient and IGFBP-3 serum levels were measured using Western blot analysis with commercial antibodies. Values were normalized using commercial IGFBP-3. Results The statistical analysis showed that full-size, glycosylated IGFBP-3 concentrations were significantly lower in the sera of patients with stage IV melanoma. Low serum levels of IGFBP-3 correlated with both disease progression and presence of disease at the time of sample collection. In patients who underwent follow-up visits with further collections of blood samples, the concentrations of glycosylated IGFBP-3 decreased only in those who showed progression of disease. Limitations Our study shows only preliminary results on a limited number of patients. Conclusion We demonstrate that there is a significant inverse correlation between the serum concentration of full-size, glycosylated IGFBP-3 and disease progression in patients with melanoma.

We describe a 79-year-old female with a chronic venous ulceration infected by Staphylococcus aureus and Enterococcus faecalis and not responsive to conventional treatments. The patient was treated with Methyl-Aminolaevulinate Photodynamic Therapy (MAL-PDT). After four weeks the cutaneous swabs become negative and we observed a significant clinical improvement. Therefore we suppose that MAL-PDT could represent a valid therapeutic option in the treatment of infected chronic ulcers.

Insulin-like-factor-binding-protein 3 (IGFBP-3) is known to modulate the activity of insulin-like growth factors (IGFs) besides having a number of IGF-independent effects on cell growth and survival. IGFBP-3 has been reported to decrease significantly in the blood serum of patients affected by certain cancers. In the present work, we have evaluated the levels of IGFBP-3 in the blood serum and tissues of patients affected by cutaneous melanoma, showing that loss of IGFBP-3 from both is strongly correlated with disease progression and reduced survival. In vitro treatment with IGFBP-3 of human and murine metastatic melanoma cell lines specifically inhibited the cells' migratory and invasive behaviour, inducing up-regulation of melanocytic differentiation markers such as tyrosinase activity and melanin content. A molecular analysis of the cellular pathways transducing the effect of IGFBP-3 implicated the Akt-GSK3β axis. Moreover, administration of IGFBP-3 in vivo to SCID mice inoculated with human metastatic melanoma cells strongly reduced or completely inhibited tumor growth. In summary, IGFBP-3 appears to exert a specific inhibitory effect on melanoma growth and dissemination, suggesting that it may qualify as a useful therapeutic agent in melanomas and perhaps other cancers, at the least as a valid adjuvant therapy during treatment with conventional anti-tumoral drugs.

Background: Seborrheic keratosis (SK) is a frequent benign epithelial skin tumor. Generally its diagnosis is clinical, however SK can sometimes clinically simulate a melanocytic lesion; therefore we need dermoscopy to reach a correct diagnosis. Milia-like cysts and comedo-like openings are the common dermoscopic features of SK, but it is not a rare finding that SK can display one or more dermoscopic patterns suggestive of a melanocytic origin. Objectives: We describe a case series of SKs with a blue globular pattern simulating a melanocytic lesion. Methods: We retrospectively evaluated 224 SKs seen during 2011 at the Dermatoscopy Unit of the Department of Dermatology, University of Rome ‘Sapienza'. Results: Five SKs showed a blue globular pattern, without the SK main features generally seen in dermoscopy; globules were multiple, round or oval, well-demarcated, small and medium-sized, blue-colored and equally distributed within the lesion. Histopathologic examination was consistent with acanthotic SK. Conclusions: Identification of the blue globular pattern can be helpful for the dermoscopic diagnosis of SK, especially when its common dermoscopic features are absent.

Background: The last melanoma staging system of the 2009 American Joint Committee on Cancer takes into account, for stage IV disease, the serum levels of lactate dehydrogenase (LDH) and the site of distant metastases. Objective: Our aim was to compare the significance of metastatic volume, as evaluated at the time of stage IV melanoma diagnosis, with other clinical predictors of prognosis. Methods: We conducted a retrospective multicentric study. To establish which variables were statistically correlated both with death and survival time, contingency tables were evaluated. The overall survival curves were compared using the Kaplan-Meier method. Results: Metastatic volume and number of affected organs were statistically related to death. In detail, patients with a metastatic volume >15 cm3 had a worse prognosis than those with a volume lower than this value (survival probability at 60 months: 6.8 vs. 40.9%, respectively). The Kaplan-Meier method confirmed that survival time was significantly related to the site(s) of metastases, to elevated LDH serum levels and to melanoma stage according to the latest system. Conclusion: Our results suggest that metastatic volume may be considered as a useful prognostic factor for survival among melanoma patients.

BACKGROUND Sentinel lymph node biopsy (SLNB) represents a useful tool for staging melanoma patients. However false-negative SLNB are reported in the literature. OBJECTIVE The aim of our study is to identify predictive factors for false-negative SLNB in melanoma patients. MATERIALS AND METHODS We conducted a retrospective analysis on 316 melanoma patients who underwent SLNB and were followed up at the Department of Dermatology and Plastic Surgery of University of Rome “Sapienza” from March 1994 to June 2008. RESULTS In our patients, SLNB was positive in 35 cases (11.07%) whereas it was negative in 281 cases (88.93%); 12/316 patients (3.8%) had positive SLNB and positive therapeutic lymph node dissection (TLND); 23/316 (7.28%) patients had positive SLNB and negative TLND; 266/316 (84.18%) patients had negative SLNB but without subsequent metastases in the SLN site; 15/316 (4.74%) patients had negative SLNB, but with subsequent metastases in the same SLN site (false-negative patients). Among the different prognostic factors, only ulceration was the main predictive factor for false-negative SLNB, according to statistical analysis (p=.0420). CONCLUSION Our data confirm that SLNB is a useful technique for staging melanoma patients. However, in patients with negative SLNB, a closer follow-up is recommended when ulceration is present. The authors have indicated no significant interest with commercial supporters.

Background Different dermatoscopic algorithms have been developed to evaluate pigmented lesions of the skin, with pattern analysis being the most commonly used. We sought to develop and evaluate a diagnostic scoring system, the reticular point of view, to distinguish common melanocytic nevus from dysplastic nevus and from melanoma. Methods We analyzed 1543 pigmented lesions, most of which contained a pigment network, and assessed the presence of linear extensions, thickened or hyperpigmented lines, areas of abrupt cut off, and areas with large "holes." We then conducted statistical analyses on these parameters to verify which of these exerted the most influence on the dermatologist's decision to surgically excise the lesion and to verify which feature was most linked to histopathologic signs of dysplasia or malignancy. Results Among the lesions excised, histopathologic examination revealed 33 (10.28%) melanomas. Among these, 25 (75.75%) showed an asymmetric distribution of the pigment network, whereas 20 (60.6%) showed a linear extension of it. The analysis of our data showed that all the evaluated criteria were statistically significant and played an important role in the dermatologist's decision to perform surgical excision of the lesion. Regarding the diagnosis of melanoma, only the presence of large holes, areas of abrupt cut off, and linear extensions revealed statistical significance. Limitations Reticular point of view may be useful only in lesions with a large pigment network. It is not applicable in nodular, thick, and amelanotic melanomas that are usually lacking in pigment network. Conclusion Although pattern analysis represents the most effective analytical method in dermatoscopy, our scoring system may be useful to distinguish between benign lesions, which need only clinical follow-up, and malignant lesions, which need surgical excision.

Author(s): Devirgiliis, Valeria; Panasiti, Vincenzo; Curzio, Michela; Gobbi, Silvia; Rossi, Mariarita; Roberti, Vincenzo; Calvieri, Stefano