Local interventions for actinic keratosis in organ transplant recipients: a systematic review.

BACKGROUND: Actinic keratosis (AK) in organ transplant recipients (OTRs) has a high risk of progressing to invasive squamous cell carcinoma of the skin. Thus, early and consequent treatment of AKs is warranted in OTRs. OBJECTIVES: To summarize the current evidence for nonsystemic treatments of AKs in OTRs. METHODS: We performed a systematic literature search in MEDLINE, Embase and the Cochrane Central Register of Controlled Trials (CENTRAL) and hand-searched pertinent trial registers up to 22 August 2018. Randomized controlled trials (RCTs) evaluating nonsystemic interventions for AKs in OTRs were included. The risk of bias was estimated using the Cochrane Risk of Bias Tool. RESULTS: Of 663 records initially identified, eight RCTs with 242 OTRs were included in a qualitative synthesis. Most studies evaluated methyl aminolaevulinate photodynamic therapy (MAL-PDT), followed by ablative fractional laser (AFXL) and diclofenac sodium 3% in hyaluronic acid, imiquimod 5% cream and 5-fluorouracil 5% cream (5-FU). MAL-PDT showed the highest rates of participant complete clearance (40-76·4%), followed by imiquimod (27·5-62·1%), diclofenac (41%) and 5-FU (11%). Similar results were observed for lesion-specific clearance rates. Treatment with AFXL alone revealed low lesion clearance (5-31%). Local skin reactions were most intense in participants treated with a combination of AFXL and daylight MAL-PDT. There were no therapy-related transplant rejections or worsening of graft function in any trial. The overall risk of bias was high. CONCLUSIONS: Limited evidence is available for the treatment of AKs in OTRs. MAL-PDT is currently the best-studied intervention. Lesion-specific regimens may not be sufficient to achieve disease control. Field-directed regimens are preferable in this high-risk population.

Sorafenib and pegylated interferon-α2b in advanced metastatic melanoma: a multicenter phase II DeCOG trial.

BACKGROUND: The combination of sorafenib, a multikinase inhibitor, and pegylated interferon-α2b (Peg-IFN-α2b) could potentially lead to an improved antitumoral response. Previously, combinations of interferon and sorafenib have been used in renal cell cancer. PATIENTS AND METHODS: Patients with stage IV metastatic melanoma and no previous systemic therapies apart from adjuvant immunotherapy received Peg-IFN-α2b 3 µg/kg once per week, and sorafenib 400-mg b.i.d. for a minimum of 8 weeks. The primary study end point was disease control rate (DCR). RESULTS: Between February 2008 and February 2009, 55 patients were enrolled with a median age of 64 years (20-85). At 8 weeks, 2 patients (3.6%) had a partial response (PR) and 14 patients a stable disease (25.5%), for a DCR of 29.1% in the intention-to-treat (ITT) population. The median progression-free survival in the ITT population was 2.47 months (95% confidence interval 1.22-3.72 months). The toxicity of sorafenib and Peg-IFN-α2b combination was characterized by mainly hematological side-effects, including one treatment-related bleeding complication with a fatal outcome. Other grade 3/4 toxic effects were fatigue and flu-like symptoms. CONCLUSION: The combination of sorafenib and Peg-IFN-α2b showed modest clinical activity and some serious side-effects including fatal bleeding complications.

Topical 3.0% diclofenac in 2.5% hyaluronic acid gel induces regression of cancerous transformation in actinic keratoses.

BACKGROUND: Actinic keratoses (AKs) are frequently diagnosed in dermatological patients. As they represent in situ carcinomas, effective treatment is required. OBJECTIVES: We investigated the effect of topical 3.0% diclofenac in 2.5% hyaluronic acid gel on AK. METHODS: Sixty-five patients with AKs were clinically evaluated before and after 3 months' treatment with topical 3.0% diclofenac in 2.5% hyaluronic gel. Biopsy specimens were taken and stained with haematoxylin-eosin and immunohistological markers. Specimens were evaluated for histological type of AKs using the AK classification scheme suggested by Röwert-Huber et al. [(early) in situ squamous cell carcinoma type AK Grade I-III], number of mitoses per high-power field and expression of immunohistological markers. RESULTS: Complete clinical resolution was observed in 11 patients (16.9%). A significant (P<0.001) downgrading of AK grade was observed. Complete histological resolution was achieved in 15 patients (23.1%). The number of mitoses per high-power field was reduced significantly (P<0.001). The expression of anti-p53-antibody decreased significantly (P=0.009), as did the expression of anti-MiB-1 antibody (P=0.021). CONCLUSIONS: 3.0% diclofenac in 2.5% hyaluronic acid gel causes regression of signs of cancerous transformation after 3 months' therapy.

Combined targeting of MAPK and AKT signalling pathways is a promising strategy for melanoma treatment.

BACKGROUND: In melanoma, several signalling pathways are constitutively activated. Among them, the RAS/RAF/MEK/ERK (MAPK) and PI3K/AKT (AKT) signalling pathways are activated through multiple mechanisms and appear to play a major role in melanoma development and progression. OBJECTIVES: In this study, we examined whether targeting the MAPK and/or AKT signalling pathways would have therapeutic effects against melanoma. METHODS: Using a panel of pharmacological inhibitors (BAY 43-9006, PD98059, U0126, wortmannin, LY294002) we inhibited the MAPK and AKT signalling pathways at different levels and evaluated the effects on growth, survival and invasion of melanoma cells in monolayer and organotypic skin culture. RESULTS: Antiproliferative and proapoptotic effects of inhibitors alone in monolayer culture were disappointing and varied among the different cell lines. In contrast, combined targeting of the MAPK and AKT signalling pathways significantly inhibited growth and enhanced apoptosis in monolayer culture. To verify our data in a more physiological context we incorporated melanoma cells into regenerated human skin mimicking the microenvironment of human melanoma. Combinations of MAPK and AKT inhibitors completely suppressed invasive tumour growth of melanoma cells in regenerated human skin. CONCLUSIONS: Combined targeting of MAPK and AKT signalling pathways is a promising strategy for melanoma treatment and should encourage further in-depth investigations.

Prognostic impact of the type of anaesthesia used during the excision of primary cutaneous melanoma.

The prognostic value of the type of anaesthesia used for the excision of malignant tumours has been a subject of controversy. Cell-mediated as well as humoral immune responses can be compromised after general anaesthesia, and recurrences may therefore occur more frequently. On the other hand, excision of primary tumours under local anaesthesia might also influence the prognosis unfavourably. The aim of the present study was to determine the prognostic impact of general and local anaesthesia for the primary excision of cutaneous melanoma. Follow-up data of 4329 patients on the Central Melanoma Registry of the German Dermatological Society were analysed. Cox proportional hazards analysis was performed to evaluate the independent significance of the prognostic factors, and survival probabilities were calculated for matched pairs using Kaplan-Meier estimates. Statistical analysis revealed an independent significant effect on survival for tumour thickness, ulceration, level of invasion, anatomical site and gender. General anaesthesia for primary excision of melanoma was associated with a decrease in the survival rate (relative risk 1.46, P<0.0001). This study revealed a slight but significantly increased risk of death for patients treated with general anaesthesia for the primary excision of melanoma. Therefore local anaesthesia should be preferred for the treatment of primary melanoma.

12-O-tetradecanoylphorbol-13-acetate not only modulates proliferation rates, but also alters antigen expression and LAK-cell susceptibility of normal human melanocytes in vitro.

For serial cultivation of normal human melanocytes media supplemented with the tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA) are largely employed. By using a culture medium that permits cultivation of melanocytes without TPA, the effects of TPA on melanocyte proliferation, phenotype, and susceptibility to lymphokine-activated killer cells were studied. Addition of 50 ng/ml TPA to the medium induced rapid dendrite formation and increased the cell proliferation rate by 16-63% in mitogen-rich media (four of seven cultures, p < 0.01), and by 237% in mitogen-reduced media (p < 0.001). Furthermore, several phenotypic changes indicating early stages of melanocyte transformation were induced by 50 ng/ml TPA. These included increased expression of melanoma progression-associated antigens such as A.1.43 and A.10.33, upregulation of nerve-growth factor receptor as well as of the melanocyte-activation marker HMB-45 and of histocompatibility class I antigens. In contrast, the expression of the differentiation marker K.1.2 and of intercellular adhesion molecule-1 was decreased in TPA-treated cultures. Most of these changes persisted even after removal of TPA from the culture medium (> or = 2 weeks). Staurosporine, a protein kinase C inhibitor, modulated melanocyte-antigen expression similar to TPA, suggesting that protein kinase C downmodulation rather than activation by TPA is involved. In addition to the antigenic alterations, the susceptibility of TPA-treated melanocytes to lymphokine-activated killer cell cytotoxicity decreased by 40% (p < 0.01), possibly due to their altered surface antigen expression. The presented data reveal that the tumor promoter TPA hitherto used as a supplement of melanocyte culture media induces profound phenotypic and functional changes of the cultured cells, indicating incipient transformation of normal human melanocytes in vitro.