[Show abstract][Hide abstract] ABSTRACT: The capacity of cancer cells to undergo epithelial-to-mesenchymal transition (EMT) is now considered a hallmark of tumor progression, and it is known that interactions between cancer cells and mesenchymal stem cells (MSCs) of tumor microenvironment may promote this program. Herein, we demonstrate that MSC-conditioned medium (MSC-CM) is a potent inducer of EMT in melanoma cells. The EMT profile acquired by MSC-CM-exposed melanoma cells is characterized by an enhanced level of mesenchymal markers, including TGFβ/TGFβ-receptors system upregulation, by increased invasiveness and uPAR expression, and in vivo tumor growth. Silencing TGFβ in MSC is found to abrogate ability of MSC to promote EMT characteristics in melanoma cells, together with uPAR expression, and this finding is strengthened using an antagonist peptide of TGFβRIII, the so-called P17. Finally, we demonstrate that the uPAR antisense oligonucleotide (uPAR aODN) may inhibit EMT of melanoma cells either stimulated by exogenous TGFβ or MSC-CM. Thus, uPAR upregulation in melanoma cells exposed to MSC-medium drives TGFβ-mediated EMT. On the whole, TGFβ/uPAR dangerous liaison in cancer cell/MSC interactions may disclose a new strategy to abrogate melanoma progression.
Mesenchymal stem cell (MSC)-conditioned medium induces EMT-like profile in melanoma. MSC-derived TGFβ promotes uPAR and TGFβ/TGFβ-receptor upregulation in melanoma. TGFβ gene silencing in MSCs downregulates uPAR expression and EMT in melanoma. uPAR downregulation prevents MSC-induced EMT-like profile in melanoma cells. Inhibition of the dangerous TGFβ/uPAR relationship might abrogate melanoma progression.
Journal of Molecular Medicine 02/2015; · 4.77 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The body image (BI) is very important to take into account, especially in cancer patients. It's important an adequate psychological support is recalled as it has been widely demonstrated that problems connected to the body image interfere negatively with the quality of life of patients, especially in the oncology field. Such support has the aim of containing those aspects that can compromise our patients' equilibrium.
We administered the Body Image Scales, with a specifically created semi--structured questionnaire which includes items that investigate the level of awareness and the degree of acceptance of the disease of the patient7, was administered to patients giving their written informed consent to participate to the study.
The results show that our population sample got an average score of 17.25 showing precisely problems related to body image.
Giornale italiano di dermatologia e venereologia: organo ufficiale, Societa italiana di dermatologia e sifilografia 01/2015; · 0.86 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Psoriasis is traditionally defined as an inflammatory chronic--relapsing disease of the skin. It is also -- as widely demonstrated -- a disease associated with multiple comorbidities: arthropathy, inflammatory bowel disease, metabolic, cardiovascular, ocular and psychological disorders. The disease also has a significant impact on patients' quality of life, whose work ability decreases considerably with clear consequences for the social costs. Therefore, if we consider that in Tuscany, more than 100,000 people out of 3,672,202 suffer from psoriasis, it is of paramount importance focusing the attention on a rational model of clinical and therapeutic management of the disease.
All the leading experts in Tuscany have come together with the aim of ● defining regional universally accepted guidelines for the diagnosis, treatment, follow--up and management of psoriasis ● providing practical guidance / protocol on diagnosis, treatment, follow up and management of special cases of moderate--to--severe plaque psoriasis METHODS: ● working groups ● discussion on the main topics and approval by plenary vote RESULTS: The diagnosis includes a proper general health condition overview, a careful evaluation of skin and joints, the assessment and management of other comorbidities and the definition of disease severity. With regards to the therapy the best time to start a systemic treatment, the therapeutic goal, the most appropriate drug and blood tests to be performed in case of moderate severe--psoriasis have been taken into account. During the follow--up, proper monitoring of systemic therapy and its management in the long term have also been considered. Eventually, the experts have addressed the problem of how to manage the disease in special conditions such as during surgery, pregnancy, in children and in case of infections (HBV, HCV, HIV ) (TAB.1) CONCLUSIONS: The main aim of the CONSENSUS was to find out the criteria for the diagnosis, treatment and follow up of psoriasis, shared by all the Dermatology Therapeutic Units of Tuscany. The need to create an easier way for the patient to access to specialized dermatological outpatient services and to reduce the waiting list and the costs related to the management of such a disease has been highlighted. The most important fact that came out during the CONSENSUS was the shared opinion of all the participants on the central role of the patient and the need of a multidisciplinary management of the disease, among the various specialists and the regional centers, in order to build on the gained experiences.
Giornale italiano di dermatologia e venereologia: organo ufficiale, Societa italiana di dermatologia e sifilografia 01/2015; · 0.86 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Unilesional mycosis fungoides (UMF) was firstly described in 1981 as solitary lesion with clinical and histological features of MF. Although over 100 cases have been reported in the literature, there is a lack of clear-cut criteria characterising UMF. Only 10 cases featured by follicolotropism of the neoplastic T-cells have been reported: the so-called unilesional folliculotropic MF (UFMF). This paper questions whether or not UFMF should be considered as a true rarity in MF clinico-pathological spectrum.
We retrieved 28 folliculotropic MF cases in the database of the Dermatological Divisions of Bologna (12 patients) and Florence University (16 patients). Four of them were UFMF patients (2 males and 2 females, mean age 45 years; median age: 39 years).
All patients achieved after therapy disease complete remission. Notably, only one patient was treated with radiotherapy, that seems the most recommended strategy in UMF. For the remaining patients, we choose different managements in order to achieve both clinical efficacy and the best aesthetical outcome.
No definitive conclusions can be drawn whether or not UFMF has the same indolent clinical course of UMF. Recently, Kempf et al. reported 2 UFMF patients with progression to tumour stage and large-cell transformation, respectively. UFMF in our database is 14.3% of the 28 FMF cases. Our data suggest that UFMF can be regarded as a true rarity in MF clinico-pathological spectrum.
Giornale italiano di dermatologia e venereologia: organo ufficiale, Societa italiana di dermatologia e sifilografia 12/2014; 149(6):639-42. · 0.86 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Rhinophyma is a benign, disfiguring disorder, commonly reffered to as the end stage of severe rosacea and characterized by a progressive thickening and hypertrophy of the nasal skin and soft tissues..
Giornale italiano di dermatologia e venereologia: organo ufficiale, Societa italiana di dermatologia e sifilografia 09/2014; · 0.86 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The most frequent site for melanoma is the back in men and the lower limbs in women, where intermittent sun exposure has been reported to be an environmental agent, although studies on age-specific incidence have suggested that melanoma in chronically sun-exposed areas, such as the face, increases with age. To identify the preferential development of melanoma in chronically or intermittently sun-exposed areas and the relationship between body site distribution and parameters such as sex, age, distribution of melanocytic naevi, atypical naevi and actinic keratoses, a prospective epidemiological multicentre study was carried out on all the consecutive melanoma cases diagnosed in a 2-year period from 27 Italian GIPMe centres (GIPMe: the Italian Multidisciplinary Group on Melanoma). Both the relative density of melanoma (RDM), defined as the ratio between observed and expected melanoma for a specific body site, and the average nevi density were identified. The most common melanoma site was the back, a factor that was not affected by either age or sex, even if men had higher density values. Statistically significant higher RDM values were observed in women aged more than 50 years for leg lesions and in the anterior thighs for young women (<50 years), whereas the lowest values were observed in the posterior thighs in women of any age. Facial RDM was statistically significantly higher than expected in both male and female patients more than 50 years of age. Melanoma was associated with a significantly higher atypical naevi density only for the back, chest and thighs. Indeed, facial melanoma was related to the presence of more than four actinic keratoses and not naevi density. To the best of our knowledge, the RDM method was applied for the first time together with naevus density calculation to obtain these data, which strongly substantiate the 'divergent pathway' hypothesis for the development of melanoma, but not find a direct correlation between melanoma and nevi for each anatomical site.
[Show abstract][Hide abstract] ABSTRACT: Cutaneous melanoma incidence is increasing. Most new cases are thin (≤ 1 mm) with favorable prognoses, but survival is nonetheless variable. Our aim was to investigate new prognostic factors and construct a nomogram for predicting survival in individual patients.
Journal of Clinical Oncology 07/2014; · 17.88 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The aim of followup programs for patients diagnosed with melanoma is early detection of local, regional and distant metastasis, as well as early recognition of eventual subsequent primary tumors. Currently, no universally accepted recommendations exist for monitoring patients with cutaneous melanoma. The present recommendations have been developed on the basis of the experience of a group of clinicians affiliated to referral centers dealing with melanoma diagnosis and management in Italy. Clinical evaluation is mandatory at any stage and is intended to be lifelong, with time frequencies of followup visits depending on the specific stage of disease. Sonography of regional lymph nodes has been demonstrated to have the highest accuracy and highest diagnostic validity to detect early regional relapse, and can be considered once per year starting from stage I melanoma. Total body CT scan should be considered in the follow up of patients with higher risk of developing distant metastasis. In stage II and III it should be performed once per year, alternated with abdomen and lymph node ultrasonography. Our aim is to provide a simplified schedule for the routine follow up of melanoma patients. These recommendations are intended as an initial guideline that must be tailored on the individual patient needs.
Giornale italiano di dermatologia e venereologia: organo ufficiale, Societa italiana di dermatologia e sifilografia 06/2014; · 0.86 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The CD63 tetraspanin is highly expressed in the early stages of melanoma and decreases in advanced lesions, suggesting it as a possible suppressor of tumor progression. We employed loss- and gain-of-gene function approaches to investigate CD63 role in melanoma progression and acquisition of the epithelial-to-mesenchymal transition (EMT) program. We used two human melanoma cell lines derived from primary tumors and one primary human melanoma cell line isolated from a cutaneous metastasis, differing by levels of CD63 expression. CD63 silenced melanoma cells showed enhanced motility and invasiveness with down-regulation of E-cadherin and up-regulation of N-cadherin and Snail. In parallel experiments, transient and stable ectopic expression of CD63 resulted in a robust reduction of cell motility, invasiveness and protease activities, which was proportional to the increase of CD63 protein level. Transfected cells overexpressing the highest level of CD63 when transplanted into immunodeficient mice showed a reduced incidence and rate of tumor growth. Moreover, these cells showed a reduction of N-cadherin, Vimentin, Zeb1 and a-SMA, and a significant resistance to undergo an EMT program both in basal condition and following stimulation with TGFβ. Thus, our results establish a previously unreported mechanistic link between the tetraspanin CD63 and EMT abrogation in melanoma.Journal of Investigative Dermatology accepted article preview online, 18 June 2014; doi:10.1038/jid.2014.258.
Journal of Investigative Dermatology 06/2014; · 6.37 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The receptor for the urokinase-type plasminogen activator (uPAR) accounts for many features of cancer progression, and is therefore considered a target for anti-tumoral therapy. Only full length uPAR mediates tumor progression. Matrix-metallo-proteinase-12 (MMP12)-dependent uPAR cleavage results into the loss of invasion properties and angiogenesis. MMP12 can be employed in the field of “targeted therapies” as a biological drug to be delivered directly in patient’s tumor mass. Endothelial Progenitor Cells (EPCs) are selectively recruited within the tumor and could be used as cellular vehicles for delivering anti-cancer molecules. The aim of our study is to inhibit cancer progression by engeneering ECFCs, a subset of EPC, with a lentivirus encoding the anti-tumor uPAR-degrading enzyme MMP12. Ex vivo manipulated ECFCs lost the capacity to perform capillary morphogenesis and acquired the anti-tumor and anti-angiogenetic activity. In vivo MMP12-engineered ECFCs cleaved uPAR within the tumor mass and strongly inhibited tumor growth, tumor angiogenesis and development of lung metastasis.
The possibility to exploit tumor homing and activity of autologous MMP12-engineered ECFCs represents a novel way to combat melanoma by a “personalized therapy”, without rejection risk.
The i.v. injection of radiolabelled MMP12-ECFCs can thus provide a new theranostic approach to control melanoma progression and metastasis.
[Show abstract][Hide abstract] ABSTRACT: In order to promote widespread adoption of appropriate clinical practice, the Italian Society of Hematology (SIE), and the affiliate societies SIES (Italian Society of Experimental Hematology) and GITMO (Italian Group for Bone Marrow Transplantation) established to produce guidelines in the most relevant hematological areas. Here we report the recommendations for management of T/NK-cell lymphomas, excluding mature T-cell leukemias.
By using the GRADE (Grades of Recommendations, Assessment, Development, and Evaluation) system we produced evidence-based recommendations for the key clinical questions that needed to be addressed by a critical appraisal of evidence. The consensus methodology was applied to evidence-orphan issues.
Six courses of CHOP or CHOEP chemotherapy were recommended for first-line therapy of patients with nodal, intestinal or hepatosplenic T-cell lymphomas (evidence: low; recommendation: do, weak). Except for ALK+ anaplastic large cell lymphoma and elderly unfit patients, consolidation with high-dose chemotherapy was recommended (evidence: low; recommendation: do, weak). 50 Gy radiotherapy was the recommended first-line therapy for localized extranodal T/NK-cell lymphoma nasal type (evidence: low; recommendation: do, strong), while L-asparaginase containing chemotherapy regimens were recommended for patients with systemic disease (evidence: very low; recommendation: do, strong).
In adult T/NK-cell lymphomas, GRADE methodology was applicable to a limited number of key therapeutic issues. For the remaining key issues, due to lack of appraisable evidence, recommendations was based on consensus methodology.
[Show abstract][Hide abstract] ABSTRACT: We report dermatologists' opinions and clinical practice patterns about clinical factors driving decision making in the management of actinic keratosis (AK) in Italy.
We carried out a cross-sectional survey among 33 Italian dermatologists. Physicians were asked to report their management choices in consecutive patients with AK seen at their practice within 2 weeks since study initiation. We collected patients' clinical and socio-demographic characteristics with a standardized data collection form and assessed physicians' opinions on AK management with a self-reported questionnaire.
Six hundred fifty-seven patients with new, single AK lesions without evidence of photo-damaged skin in the surrounding areas, were predominantly treated with lesion-directed therapies (primarily cryotherapy). In contrast, physicians preferentially prescribed field-directed therapies to patients with multiple lesions and evidence of photo-damaged skin in AK surrounding areas. However we observed a wide variation in treatment choices and physicians' opinions on AK management. Dermatologists underlined the importance of fostering patients' adherence and minimize therapy side effects.
Overall, our results show that current guidelines regarding management of AK are only partially integrated in dermatology practice. The active dissemination of up-to-date national guidelines might help harmonize clinical decision making in this complex and fast growing therapeutic area.
Giornale Italiano di Dermatologia e Venereologia 04/2014; 149(2):185-92. · 0.49 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background
In primary cutaneous B-cell lymphomas (PCBCL), radiotherapy – or surgery in a minority of cases – is the first-line treatment in follicle center lymphoma (PCFCL) and marginal zone B-cell lymphoma (PCMZL). Conversely, patients with multifocal skin involvement or relapsed/refractory disease deserve a systemic chemotherapy. In diffuse large B-cell lymphoma, leg type (PCLBCL-LT), due its poorer outcome, CHOP-like regimens are the most commonly used frontline, although hard to propose in elderly patients. In this regard, the association of rituximab (R) and pegylated liposomal doxorubicin (PLD) can be considered a promising, alternative approach.AimsBased on the favourable results reported with R and PLD in several recent trials, we decided to test efficacy and safety of this combination.Methods
Twelve patients with PCBCL were treated with R plus PLD, 7 had relapsed disease. Treatment plan consisted of 2 monthly cycles of R 375mg/m2 and PLD 20mg/m2 day 1;15, followed (in responders) by 2 cycles given only at day 1. All patients received prophylactic pyridoxine to prevent Palmar-Plantar Erythrodysesthesia (PPE).ResultsTen out of 12 patients had a response (8 complete; 2 partial), remarkably 2/3 with primary cutaneous diffuse large B-cell lymphoma, leg type. Two patients did not respond (1 progressive disease, PD, and 1 stable disease). Three patients died after a median follow-up of 56 months, 2 patients due to PD and 1 due to a second neoplasm. Two out of 10 responders relapsed after 31 and 32 months, respectively. Haematological toxicity was negligible (1 case of grade 2 neutropenia), as well as extra-haematological toxicity (2 cases of grade 2 PPE).Conclusions
These preliminary data suggest that R-PLD is effective and well tolerated in all subsets of PCBCL and may be offered front-line in indolent cases unsuitable for radiotherapy or surgery as well as in more aggressive cases with contraindications to CHOP-like regimens.This article is protected by copyright. All rights reserved.
European Journal Of Haematology 03/2014; · 2.41 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Two different optical fiber probes for combined Raman and fluorescence spectroscopic measurements were designed, developed and used for tissue diagnostics. Two visible laser diodes were used for fluorescence spectroscopy, whereas a laser diode emitting in the NIR was used for Raman spectroscopy. The two probes were based on fiber bundles with a central multimode optical fiber, used for delivering light to the tissue, and 24 surrounding optical fibers for signal collection. Both fluorescence and Raman spectra were acquired using the same detection unit, based on a cooled CCD camera, connected to a spectrograph. The two probes were successfully employed for diagnosing melanocytic lesions in a good agreement with common routine histology. The obtained results demonstrated that the multimodal approach is crucial for improving diagnostic capabilities. Further investigations were performed on colon and brain tissue samples in order to have a benchmark for diagnosing a broader range of tissue lesions and malignancies. The system presented here can improve diagnostic capabilities on a broad range of tissues and has the potential of being used for endoscopic inspections in the near future.
[Show abstract][Hide abstract] ABSTRACT: Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare disease of controversial origin recently recognized as a neoplasm deriving from plasmacytoid dendritic cells (pDCs). Nevertheless, it remains an orphan tumor with obscure biology and dismal prognosis. To better understand the pathobiology of BPDCN and discover new targets for effective therapies, the gene expression profile (GEP) of 25 BPDCN samples was analyzed and compared with that of pDCs, their postulated normal counterpart. Validation was performed by immunohistochemistry (IHC), while functional experiments were carried out ex vivo. For the first time at the molecular level, we definitely recognized the cellular derivation of BPDCN, which proved to originate from the myeloid lineage and in particular from resting pDCs. Furthermore, thanks to an integrated bio-informatic approach we discovered aberrant activation of the NF-kB pathway and suggested it as a novel therapeutic target. We tested the efficacy of anti-NF-kB-treatment on the BPDCN cell line CAL-1, and successfully demonstrated by GEP and IHC the molecular shut-off of the NF-kB pathway. In conclusion, we identified a molecular signature representative of the transcriptional abnormalities of BPDCN and developed a cellular model proposing a novel therapeutic approach in the setting of this otherwise incurable disease.Leukemia accepted article preview online, 7 February 2014; doi:10.1038/leu.2014.64.
Leukemia: official journal of the Leukemia Society of America, Leukemia Research Fund, U.K 02/2014; · 10.16 Impact Factor