Effects of Interferons and Cytokines on Melanoma Cells

This review summarizes recent information on the effects of immunomodulatory cytokines on human melanoma cells. The action of interferon (IFN)-alpha, -beta, and -gamma has been extensively examined in melanoma and melanocyte cultures in vitro, and increasing information on the action of other cytokines is now available. All IFNs revealed a dose-dependent antiproliferative effect on melanoma cells with the highest growth inhibition caused by IFN-beta. Proliferation was also inhibited by interleukin (IL) 1-alpha and -beta, and tumor necrosis factor (TNF)-alpha. For IL-4, both growth-stimulatory and -inhibitory properties have been reported. Cellular differentiation in terms of melanin synthesis, formation of dendritelike structures, and antigenic changes was not affected by IFN-alpha or -beta. IFN-gamma, however, induced a more dedifferentiated and biologically more aggressive phenotype of melanoma cells. His-tocompatibility antigen (HLA) class I molecules were found upregulated by all IFNs and by TNF-alpha, associated with a marked increase of melanoma cell lysis by tumor infiltrating lymphocytes in vitro. HLA class II molecules were de novo expressed or enhanced by IFN-gamma and TNF-alpha. The adhesion molecules ICAM-1, LFA-3, and VLA-2 were up-regulated by IFN-gamma, TNF-alpha, and IL-1-beta, whereas melanoma-associated antigens were hardly affected by cytokines. It seems that both antiproliferative and immunomodulatory effects may contribute to the antitu-moral activity of cytokines in vivo. In vivo application of cytokines as well as combinations with cytotoxic drugs, therefore, may be promising for future treatment strategies. J Invest Dermatol 100:239S–244S, 199

Epidemiology of skin cancer

V zadnjih desetletjih je zelo narasla incidenca tako epitelijskih kožnih karcinomov kot malignega melanoma. To je tudi razlog za pospešeno preučevanje zlasti malignih melanomov, zaradi česar jih danes odkrivamo v zgodnejših stadijih. Med prognostičnimi dejavniki je treba pri malignem melanomu izpostaviti zlasti debelino po Breslowu, stopnjo invazije po Clarku, spol, anatomsko lokalizacijo, klinično histološki podtip in starost. Vpliv sončenja na razvoj melanoma je še vedno predmet študij, domnevajo pa, da so najbolj ogrožene osebe, ki so bile v otroštvu izpostavljene občasnemu sončnemu obsevanju. Množični presejalni testi v smislu prevencije problema malignega melanoma niso zmanjšali.The incidence of epithelial cutaneous carcinoma as well as of malignant melanoma has sharply increased in recent decades. For this reason, cutaneous tumors have been studied with more interest which resulted in an earlier recognition of such lesions. Among prognostic factors, the tumor width according to Breslow\u27s criteria, invasion level according to Clark, sex, anatomic localization, clinical-histological subtype and patient\u27s age are commonly cited. The effects of sun-bathing are still under investigation with special interest in an increased risk in people who were exposed to intermitent sun-bathing in their childhood. The importance of massive screenings in prevention has been overestimated

Non-AIDS Associated Kaposi's Sarcoma: Clinical Features and Treatment Outcome

Background: Kaposi’s sarcoma (KS) in HIV negative patients is rare and has to be distinguished from AIDS associated KS. Two groups are at risk to develop non-AIDS related KS: elderly men mainly of Mediterranean origin and persons with iatrogenic immunosuppression. Patients and Methods: In order to define risk-groups and major clinical features we retrospectively evaluated clinical data of all patients with non-AIDS associated KS presenting to the Department of Dermatology, University Hospital Tuebingen between 1987 and 2009. Data were extracted from the tumor registry of the Comprehensive Cancer Center Tuebingen and from patient records. Results: 20 patients with non-AIDS KS have been identified. The average age at KS onset was 66.6 years; the male-to-femaleratio was 3:1. Most of the patients were immigrants from Mediterranean or Eastern European countries (60%). 15 cases of classic KS versus 5 cases of iatrogenic KS were observed. In 95 % of the cases, KS was limited to the skin, without mucosal, lymph node or visceral manifestation. KS lesions were in all cases multiple and mostly bilateral, the most common localization was the skin of the lower extremities. Tumor control was achieved in nearly all cases by the use of local or systemic therapy. No patient died from KS. Conclusions: Unlike KS in AIDS patients, non-AIDS associated KS is a rather localized process which rarely involves lymph nodes or organs. It is mostly seen in elderly males from Mediterranean or Eastern European countries and in most cases responsive on local or systemic therapeutic strategies

Improving Melanoma Classification by Integrating Genetic and Morphologic Features

Boris Bastian and colleagues present a refined morphological classification of primary melanomas that can be used to improve existing melanoma classifications by defining genetically homogeneous subgroups

Study protocol for a prospective, non-controlled, multicentre clinical study to evaluate the diagnostic accuracy of a stepwise two-photon excited melanin fluorescence in pigmented lesions suspicious for melanoma (FLIMMA study)

Introduction: Non-invasive, nanosecond, stepwise two-photon laser excitation of skin tissue was shown to induce melanin fluorescence spectra that allow for the differentiation of melanocytic nevi from cutaneous melanoma. Methods and analysis: This prospective, non-controlled, multicentre clinical study is performed to evaluate the diagnostic performance of the stepwise two-photon excited melanin fluorescence in the detection of cutaneous melanoma. The comparator will be the histopathological diagnosis. A total of 620 pigmented skin lesions suspicious for melanoma and intended for excision will be enrolled. Ethics and dissemination: Ethics approval was provided by the local ethics committees of the medical faculties of the University of Tuebingen, Heidelberg and Berlin. Study registration: The FLIMMA study NCT02425475

Modifiable risk-factors for keratinocyte cancers in Australia: a case-control study

Keratinocyte cancer is the most common malignancy in Caucasians. The aim of this study was to investigate risk-factors responsible for development of keratinocyte cancer in Australia. A case-control study was conducted, including 112 cases of squamous cell carcinoma (SCC), 95 cases of basal cell carcinoma (BCC) and 122 controls. Freckling during adolescence (SCC: odds ratio (OR) 1.04, p < 0.01; BCC: OR 1.05, p < 0.01), propensity to sunburn (SCC: OR 2.75, p = 0.01, BCC: OR 2.68 p = 0.01) and high cumulative sun-exposure (SCC: OR 2.43, p = 0.04; BCC: OR 2.36 p = 0.04) were independent risk-factors for both SCC and BCC. This study provides further evidence that a sun-sensitive phenotype and excessive sun-exposure during adulthood contribute to the risk of developing keratinocyte cancer. Wearing a hat, long-sleeved shirts, and sunscreen did not significantly reduce the risk of keratinocyte cancer in this study

Inhibition of PI3K-AKT-mTOR Signaling Sensitizes Melanoma Cells to Cisplatin and Temozolomide

In melanoma, the PI3K-AKT-mTOR (AKT) and RAF-MEK-ERK (MAPK) signaling pathways are constitutively activated and appear to play a role in chemoresistance. Herein, we investigated the effects of pharmacological AKT and MAPK pathway inhibitors on chemosensitivity of melanoma cells to cisplatin and temozolomide. Chemosensitivity was tested by examining effects on growth, cell cycle, survival, expression of antiapoptotic proteins, and invasive tumor growth of melanoma cells in monolayer and organotypic culture, respectively. MAPK pathway inhibitors did not significantly increase chemosensitivity. AKT pathway inhibitors consistently enhanced chemosensitivity yielding an absolute increase of cell growth inhibition up to 60% (P<0.05, combination therapy vs monotherapy with inhibitors or chemotherapeutics). Cotreatment of melanoma cells with AKT pathway inhibitors and chemotherapeutics led to a 2- to 3-fold increase of apoptosis (P<0.05, combination therapy vs monotherapy) and completely suppressed invasive tumor growth in organotypic culture. These effects were associated with suppression of the antiapoptotic Bcl-2 family protein Mcl-1. These data suggest that inhibition of the PI3K-AKT-mTOR pathway potently increases sensitivity of melanoma cells to chemotherapy

The price of tumor control

Ipilimumab, a cytotoxic T-lymphocyte antigen-4 (CTLA-4) blocking antibody, has been approved for the treatment of metastatic melanoma and induces adverse events (AE) in up to 64% of patients. Treatment algorithms for the management of common ipilimumab-induced AEs have lead to a reduction of morbidity, e.g. due to bowel perforations. However, the spectrum of less common AEs is expanding as ipilimumab is increasingly applied. Stringent recognition and management of AEs will reduce drug-induced morbidity and costs, and thus, positively impact the cost-benefit ratio of the drug. To facilitate timely identification and adequate management data on rare AEs were analyzed at 19 skin cancer centers. Patient files (n = 752) were screened for rare ipilimumab-associated AEs. A total of 120 AEs, some of which were life-threatening or even fatal, were reported and summarized by organ system describing the most instructive cases in detail. Previously unreported AEs like drug rash with eosinophilia and systemic symptoms (DRESS), granulomatous inflammation of the central nervous system, and aseptic meningitis, were documented. Obstacles included patientś delay in reporting symptoms and the differentiation of steroid-induced from ipilimumab-induced AEs under steroid treatment. Importantly, response rate was high in this patient population with tumor regression in 30.9% and a tumor control rate of 61.8% in stage IV melanoma patients despite the fact that some patients received only two of four recommended ipilimumab infusions. This suggests that ipilimumab-induced antitumor responses can have an early onset and that severe autoimmune reactions may reflect overtreatment. The wide spectrum of ipilimumab-induced AEs demands doctor and patient awareness to reduce morbidity and treatment costs and true ipilimumab success is dictated by both objective tumor responses and controlling severe side effects

The Great Debate at \u27Immunotherapy Bridge\u27, Naples, December 5, 2019.

As part of the 2019 Immunotherapy Bridge congress (December 4-5, Naples, Italy), the Great Debate session featured counterpoint views from leading experts on six topical issues in immunotherapy today. These were the use of chimeric antigen receptor T cell therapy in solid tumors, whether the Immunoscore should be more widely used in clinical practice, whether antibody-dependent cellular cytotoxicity is important in the mode of action of anticytotoxic T-lymphocyte-associated protein 4 antibodies, whether the brain is immunologically unique or just another organ, the role of microbiome versus nutrition in affecting responses to immunotherapy, and whether chemotherapy is immunostimulatory or immunosuppressive. Discussion of these important topics are summarized in this report

Open-label, multicenter, single-arm phase II DeCOG-study of ipilimumab in pretreated patients with different subtypes of metastatic melanoma

Background: Ipilimumab is an approved immunotherapy that has shown an overall survival benefit in patients with cutaneous metastatic melanoma in two phase III trials. As results of registrational trials might not answer all questions regarding safety and efficacy of ipilimumab in patients with advanced melanoma seen in daily clinical practice, the Dermatologic Cooperative Oncology Group conducted a phase II study to assess the efficacy and safety of ipilimumab in patients with different subtypes of metastatic melanoma. Patients and methods: We undertook a multicenter phase II study in melanoma patients irrespective of location of the primary melanoma. Here we present data on patients with pretreated metastatic cutaneous, mucosal and occult melanoma who received up to four cycles of ipilimumab administered at a dose of 3 mg/kg in 3 week intervals. Tumor assessments were conducted at baseline, weeks 12, 24, 36 and 48 according to RECIST 1.1 criteria. Adverse events (AEs),including immune-related AEs were graded according to National Cancer Institute Common Toxicity Criteria (CTC) v.4.0. Primary endpoint was the OS rate at 12 months. Results: 103 pretreated patients received at least one dose of ipilimumab, including 83 cutaneous, seven mucosal and 13 occult melanomas. 1-year OS rates for cutaneous, mucosal and occult melanoma were 38 %,14 % and 27 %,respectively. Median OS was 6.8 months (95 % CI 5.3-9.9) for cutaneous, 9.6 months (95 % CI 1.6-11.1) for mucosal, and 9.9 months (lower 95 % CI 2.3, upper 95 % CI non-existent) for occult melanoma. Overall response rates for cutaneous, mucosal and occult melanoma were 16 %,17 % and 11 %,respectively. Eleven patients had partial response (16 %) and ten patients experienced stable disease (14 %),none achieved a complete response. Treatment-related AEs were observed in 71 patients (69 %),including 20 grade 3-4 events (19 %). No new and unexpected safety findings were noted. Conclusions: Ipilimumab is a treatment option for pretreated patients with advanced cutaneous melanoma seen in daily routine. Toxicity was manageable when treated as per protocol-specific guidelines