Characteristics and outcomes of patients with psoriasis treated with apremilast in the real-world in Austria - results the APPRECIATE study.

Background: Apremilast, an oral phosphodiesterase 4 inhibitor, is approved in the European Union for the treatment of moderate-to-severe chronic plaque psoriasis in adult patients refractory or contraindicated to or intolerant of other systemic therapies. Objectives: The APPRECIATE study assessed apremilast use in real-world practice and its clinical value to physicians and patients. APPRECIATE was a multinational, observational, retrospective, cross-sectional study. Methods: Apremilast effectiveness at 6 (±1) months was assessed on the basis of psoriasis severity and health-related quality-of-life scores and treatment satisfaction using physician/patient-reported outcomes, respectively. We report the Austrian cohort of 72 patients. Results: At 6 (±1) months, three-quarters of patients remained on apremilast, while physicians and patients reported treatment benefits across all psoriasis symptoms and manifestations. Of patients, the majority were satisfied with their treatment and achieved treatment goals considered most relevant. Patients' and physicians' perceptions of treatment effectiveness were aligned, and health-related quality-of-life scores indicated an improvement in the majority of patients. Apremilast tolerability was consistent with the known safety profile. Conclusions: Among psoriasis patients receiving apremilast in Austria, improvement in clinical outcomes were observed and satisfaction with apremilast treatment among patients and physicians was high. Registration: ClinicalTrials.gov NCT02740218.

Fotemustine chemoembolization of hepatic metastases from uveal melanoma: a retrospective single-center analysis.

OBJECTIVE: The purpose of the current study was to retrospectively evaluate response and survival in patients with hepatic metastasis from uveal melanoma treated by palliative transarterial chemoembolization (TACE) with fotemustine. MATERIALS AND METHODS: During the study period, 21 patients with hepatic metastases from uveal melanoma were treated by TACE. A series of TACE interventions (mean number per patient, 3.29 interventions; range, 1-6 interventions) was performed on each patient with an emulsion of fotemustine dissolved in 10 mL of saline mixed with 10 mL of an oily contrast agent. Tumor response based on the Response Evaluation Criteria in Solid Tumors was evaluated using contrast-enhanced CT scans obtained 6-10 weeks after embolization. RESULTS: CT showed partial regression after TACE in three patients (14%). Six patients (29%) presented with stable disease but no significant change in tumor size after TACE, and 12 patients (57%) presented with progressive disease after TACE treatment. The overall response rate was 43%. The mean survival after diagnosis of hepatic metastasis was 28.7 months. CONCLUSION: TACE of hepatic metastasis from uveal melanoma with fotemustine is well tolerated, and the survival rates in this study (mean, 28.7 months) are among the longest reported.

Erlotinib and bevacizumab have synergistic activity against melanoma.

PURPOSE: Melanoma is one of the most aggressive types of cancer with currently no chance of cure once the disease has spread to distant sites. Therapeutic options for advanced stage III and IV are very limited, mainly palliative, and show response in only approximately 20% of all cases. The presented preclinical study was done to investigate the influence of a combined treatment of the epidermal growth factor receptor inhibitor erlotinib and the vascular endothelial growth factor monoclonal antibody bevacizumab in melanoma. EXPERIMENTAL DESIGN AND RESULTS: The epidermal growth factor receptor was expressed in all cell lines tested, and treatment with erlotinib did inhibit the activation of the MEK/extracellular signal-regulated kinase and AKT signaling pathways. Whereas in vitro no influence on tumor cell proliferation was seen with erlotinib or bevacizumab monotherapy, a decreased invasive potential on erlotinib treatment in a three-dimensional Matrigel assay was observed. Furthermore, both drugs inhibited proliferation and sprouting of endothelial cells. In vivo, in a severe combined immunodeficient mouse xenotransplantation model, reduction in tumor volume under combined treatment with erlotinib and bevacizumab was superior to the additive effect of both single agents. This was associated with reduced cell proliferation, increased apoptosis, and a reduction in tumor angiogenesis compared with control or single treatment groups. Likewise, the reduction in the extent of lymph node and lung metastasis was most pronounced in animals treated with both drugs. CONCLUSION: The presented data strongly support the use of a combination of erlotinib and bevacizumab as a novel treatment regimen for metastatic melanoma.

The interplay of CDK4 and CDK6 in melanoma.

The cyclin-dependent kinases CDK4 and CDK6 promote progression through the cell cycle, where their functions are considered to be redundant. Recent studies have identified an additional role for CDK6 in the transcriptional regulation of cancer-relevant genes such as VEGF-A and EGR1 in hematopoietic malignancies. We show that the CDK4/6 inhibitor PD0332991 causes a significant decrease in tumor growth in a xenotransplantation mouse model of human melanoma. shRNA knockdown of either CDK4 or CDK6 significantly reduces cell proliferation and impedes their migratory capacity in vitro, which translates into a strong inhibition of tumor growth in xenotransplantation experiments. CDK4/6 inhibition results not only in the pronounced reduction of cell proliferation but also in an impaired tumor angiogenesis. CDK6 knockdown in melanoma cell lines impairs VEGF-A expression and reduces the potential stimulation of endothelial cell growth. The knockdown of CDK4 ends in similar results. The effect is caused by changes of CDK6 localization, less CDK6 is detected on the VEGF-A promoter. Bioinformatic analysis of human melanoma patient data verifies the key role of CDK6 in tumor angiogenesis in melanoma. The results highlight the importance of the delicate balance between CDK4 and CDK6 in regulating the cell cycle and transcription.

The non-receptor-associated tyrosine kinase Syk is a regulator of metastatic behavior in human melanoma cells.

Melanoma is one of the most aggressive neoplastic transformations and characterized by a high metastatic potential. The current study was performed to assess the impact of "spleen tyrosine kinase" (Syk), a non-receptor-associated tyrosine kinase, on growth and metastatic behavior of melanoma cells in vitro and in a severe combined immunodeficient (SCID)-mouse/human-melanoma xenotransplantation model in vivo. Syk was expressed in melanocytes but was found to be downregulated in melanoma cells. Vector-driven expression of Syk in two different melanoma cell lines did not influence growth speed, but significantly reduced the invasive growth potential of both cell lines in a Matrigel assay in vitro. In a SCID-mouse/human melanoma xenotransplantation model, Syk expressing Mel-Juso cells exhibited delayed and reduced tumor growth. After intravenous as well as subcutaneous injection of tumor cells, Syk-transfected cells formed significantly fewer metastatic tumor lesions than control cells. The presented data define Syk as a novel regulator of metastatic behavior of melanoma cells.

A rare case of primary rhabdoid melanoma of the urinary bladder treated with ipilimumab, an anti-CTLA 4 monoclonal antibody.

Primary melanoma of the urinary bladder is a rare subentity of melanoma. The same applies for melanoma of the rhabdoid histopathologic phenotype. A female patient was initially diagnosed with melanoma of unknown origin caused by macroscopic lymph node metastasis in the left inguinal and parailiacal regions. Because of the extent of the disease, radical surgery could not be performed. The patient underwent systemic chemotherapy with dacarbazine, followed by the experimental compound tasisulam. Upon sudden macrohematuria, cystoscopy showed a large infiltrating tumorous structure located on the left side of the urinary bladder. Clinically, the amelanotic tumor showed endophytic growth into the lumen; on the histopathological specimen, the growth pattern was partially undermining the urothelium, which is commonly observed in primary melanoma of the urinary bladder. Cytologically, the tumor cells were classified as rhabdoid melanoma, a very rare variant of melanoma, which is commonly amelanotic and expresses S100, vimentin and Ncam. Mutational analysis showed positive results for BRAF V600E. After detecting the primary melanoma, the patient received anti-CTLA4 antibody treatment with 3 mg/kg ipilimumab, through which a partial response was achieved. Past computed tomography scans should be re-evaluated for suspicious lesions, and cystoscopy should be included in the clinical workup if the pattern of metastasis is congruent with the drainage sites of the urinary bladder.

Proteome analysis identified the PPARγ ligand 15d-PGJ2 as a novel drug inhibiting melanoma progression and interfering with tumor-stroma interaction.

Peroxisome proliferator-activated receptors (PPARs) have been originally thought to be restricted to lipid metabolism or glucose homeostasis. Recently, evidence is growing that PPARγ ligands have inhibitory effects on tumor growth. To shed light on the potential therapeutic effects on melanoma we tested a panel of PPAR agonists on their ability to block tumor proliferation in vitro. Whereas ciglitazone, troglitazone and WY14643 showed moderate effects on proliferation, 15d-PGJ2 displayed profound anti-tumor activity on four different melanoma cell lines tested. Additionally, 15d-PGJ2 inhibited proliferation of tumor-associated fibroblasts and tube formation of endothelial cells. 15d-PGJ2 induced the tumor suppressor gene p21, a G(2)/M arrest and inhibited tumor cell migration. Shot gun proteome analysis in addition to 2D-gel electrophoresis and immunoprecipitation of A375 melanoma cells suggested that 15d-PGJ2 might exert its effects via modification and/or downregulation of Hsp-90 (heat shock protein 90) and several chaperones. Applying the recently established CPL/MUW database with a panel of defined classification signatures, we demonstrated a regulation of proteins involved in metastasis, transport or protein synthesis including paxillin, angio-associated migratory cell protein or matrix metalloproteinase-2 as confirmed by zymography. Our data revealed for the first time a profound effect of the single compound 15d-PGJ2 on melanoma cells in addition to the tumor-associated microenvironment suggesting synergistic therapeutic efficiency.

3,3',4,4',5,5'-hexahydroxystilbene impairs melanoma progression in a metastatic mouse model.

Stilbenes comprise a group of polyphenolic compounds, which exert inhibitory effects on various malignancies. The aim of this study was to evaluate the antitumor effects of a previously unreported stilbene derivative-3,3',4,4',5,5'-hexahydroxystilbene, termed M8-on human melanoma cells. Cell-cycle analysis of the metastatic melanoma cell line M24met showed that M8 treatment induces G(2)/M arrest accompanied with a dose- and time-dependent upregulation of p21 and downregulation of CDK-2 and leads to apoptosis. M8 induces the expression of phosphorylated p53, proteins involved in the mismatch repair machinery (MSH6, MSH2, and MLH1) and a robust tail moment in a comet assay. In addition, M8 inhibited cell migration in Matrigel assays. Shotgun proteomics and western analysis showed the regulation among others of paxillin, integrin-linked protein kinase, p21-activated kinase, and ROCK-1 indicating that M8 inhibits mesenchymal and amoeboid cell migration. These in vitro data were confirmed in vivo in a metastatic human melanoma severe combined immunodeficient (SCID) mouse model. We showed that M8 significantly impairs tumor growth. M8 also interfered with the metastatic process, as M8 treatment prevented the metastatic spread of melanoma cells to distant lymph nodes in vivo. In summary, M8 exerts strong antitumor effects with the potential to become a new drug for the treatment of metastatic melanoma.