Riccardo Gattai

HEDGEHOG‐GLI Signaling Drives Self‐Renewal and Tumorigenicity of Human Melanoma‐Initiating Cells

The question of whether cancer stem/tumor‐initiating cells (CSC/TIC) exist in human melanomas has arisen in the last few years. Here, we have used nonadherent spheres and the aldehyde dehydrogenase (ALDH) enzymatic activity to enrich for CSC/TIC in a collection of human melanomas obtained from a broad spectrum of sites and stages. We find that melanomaspheres display extensive in vitro self‐renewal ability and sustain tumor growth in vivo, generating human melanoma xenografts that recapitulate the phenotypic composition of the parental tumor. Melanomaspheres express high levels of Hedgehog (HH) pathway components and of embryonic pluripotent stem cell factors SOX2, NANOG, OCT4, and KLF4. We show that human melanomas contain a subset of cells expressing high ALDH activity (ALDHhigh), which is endowed with higher self‐renewal and tumorigenic abilities than the ALDHlow population. A good correlation between the number of ALDHhigh cells and sphere formation efficiency was observed. Notably, both pharmacological inhibition of HH signaling by the SMOOTHENED (SMO) antagonist cyclopamine and GLI antagonist GANT61 and stable expression of shRNA targeting either SMO or GLI1 result in a significant decrease in melanoma stem cell self‐renewal in vitro and a reduction in the number of ALDHhigh melanoma stem cells. Finally, we show that interference with the HH‐GLI pathway through lentiviral‐mediated silencing of SMO and GLI1 drastically diminishes tumor initiation of ALDHhigh melanoma stem cells. In conclusion, our data indicate an essential role of the HH‐GLI1 signaling in controlling self‐renewal and tumor initiation of melanoma CSC/TIC. Targeting HH‐GLI1 is thus predicted to reduce the melanoma stem cell compartment. Stem Cells2012;30:1808–1818

Photodynamic Therapy for the Treatment of Endoanal Condylomata Acuminata

Lise E. Nigrovic, Richard Malley, Dewesh Agrawal, and Nathan Kuppermann, for the Pediatric Emergency Medicine Collaborative Research Committee of the American Academy of Pediatrics Divisions of Emergency Medicine and Infectious Diseases, Children’s Hospital Boston and Harvard Medical School, Boston, Massachusetts; Division of Emergency Medicine, Children’s National Medical Center and George Washington University School of Medicine, Washington, DC; and Departments of Emergency Medicine and Pediatrics, University of California, Davis, Medical Center and School of Medicine, Davis

Toxicity and morbility after isolated lower limb perfusion in 242 chemo-hyperthermal treatments for cutaneous melanoma: The experience of the Tuscan Reference Centre

BackgroundThe aim of this retrospective study was to assess the results concerning the regional and systemic toxicity and complications in 242 chemo-hyperthermal treatments (HILPs) for lower limb melanoma.Patients and methods60 HILPs (G-A) were performed with mild HT plus L-PAM (10 mg/lt) ± D-actimomycin; 74 HILPs (G-B) with true HT (40–41.8°C) plus L-PAM (10 mg/lt) ± D-act; 108 HILPs (G-C) with true HT plus L-PAM (10 mg/lt) ± D-act plus L-PAM (5 mg/lt) additional bolus.ResultsLimb toxicity was very low in G-A and in G-B; increasing toxicity (grade III = 37%) in G-C; no grade IV statistical difference was registered in all three groups, with percentage values among 1.6% and 2.7%. Systemic toxicity showed itself only in the haemopoietic parameters. No differences were registered in G-B vs G-A group. In G-C vs G-B a significative increase of systemic toxicity was seen in grade 3 (p < 0.05). Postoperative complications were acceptable. Local and systemic side-effects were transient; no permanent neurological limb deficit was registered. The postoperative mortality was recorded in 3/182 HILPs (1.6%) of the G-B and G-C groups.ConclusionThese data suggested that the technical implementations reduced the occurrence and the severity of the side effects and complications. The essential requirement for HILP is the quality assurance of the procedures. Although higher regional and systemic toxicity were observed in the G-C group caused by L-PAM additional bolus, the safeness of the procedures under the true hyperthermal regimen and the time increase of the high L-PAM concentration have assured the treatment reliability along with the increased clinical efficacy expectations of the treatments.

Results of isolated lower limb perfusion for loco-regional advanced/recurrent melanoma using borderline true hyperthermia plus additional bolus of melphalan. A critical analysis of homogeneous cases

This study was conducted to assess the safety and efficacy of our modified ILP treatment with borderline true hyperthermia and high melphalan concentration in stage III lower limb melanoma.

Photodynamic therapy with topical photosensitizers in mucosal and semimucosal areas: review from a dermatologic perspective

Photodynamic Therapy is a procedure based on the interaction between a Photosensitizer, a light source with a specific wavelength and oxygen. The aim of this review is to provide a brief and updated analysis of scientific reports on the use of PDT with topical PS in the management of oncological, infectious, and inflammatory disorders involving mucosal and semimucosal areas, with a specific focus on diseases of dermatologic interest.

Melanoma metastases occuring 40 years after primary melanoma

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Thick melanoma in Tuscany

BACKGROUND The epidemiologic trends of cutaneous melanoma are similar in several countries with a Western-type life style, where there is a progressive increasing incidence and a low but not decreasing mor- tality, or somewhere an increase too, especially in the older age groups. Also in Tuscany there is a steady rise in incidence with prevalence of in situ and invasive thin melanomas, with also an increase of thick melanomas. It is necessary to reduce the frequency of thick melanomas to reduce specific mortality. OBJECTIVE AND METHODS The objective of the current survey has been to compare, in the Tuscany population, by a case- case study, thin and thick melanoma cases, trying to find out those personal and tumour characteristics which may help to customize preventive interventions. RESULTS The results confirmed the age and the lower edu- cation level are associated with a later detection. The habit to perform skin self-examination is resulted protec- tive forward thick melanoma and also the diagnosis by a doctor. The elements emerging from the survey allow to hypothesize a group of subjects resulting at higher risk for a late diagnosis, aged over 50 and carrier of a fewer constitutional and environmental risk factors: few total and few atypical nevi, and lower sun exposure and burning. It is assumable that a part of people did not be reached from messages of prevention because does not recognize oneself in the categories of people at risk for skin cancers described in educational cam- paigns. CONCLUSIONS If we want to obtain better results on diagnosis of skin melanoma we have to think a new strategy. At least to think over the educational messages discriminating people more at risk of incidence of melanoma from people more at risk to die from melanoma, and to renewed active involvement of the Gen- eral Practitioners .

Upper G.I. hemorrhage from glass fragments’ ingestion in a patient with jejunal diverticula – Case report☆

Highlights • Bleeding may be due for foreign bodies ingestion.• Both foreign body ingestion and jejunal diverticula are rare causes of bleeding.• Surgeons should be aware that patients may fail to recognize and report the possible cause of bleeding.