Treatment Of Melanoma Metastases Research Articles

Treatment of Melanoma Metastasis: Surgical, Chemotherapy, and Innovation

Treatment of Melanoma Metastasis: Surgical, Chemotherapy, and Innovation

Efficacy of Electrochemotherapy in the Treatment of Cutaneous Melanoma Metastases and Rare Non-melanoma Skin Cancer.

We aimed to verify the clinical efficacy and safety of the electrochemotherapy in melanoma metastases and in cases of rare non-melanoma tumors that were difficult to treat for the specific anatomical site or for patient comorbidities. We treated 68 patients (699 cutaneous nodules), 44 patients with metastatic melanomas and 24 patients with non-melanoma tumors, at the Melanoma & Skin Cancer Unit, Florence, Italy. We obtained an objective response of 89.7% (88.6% in melanomas and 91.7% in non-melanoma tumors), complete response 54.4% and partial response 35.3%. This study showed that electrochemotherapy is effective in the treatment of melanoma metastases and in rare types of non-melanoma tumors. In particular, we successfully treated rare tumors as angiosarcoma, pleomorphic sarcoma, myxofibrosarcoma, sarcoma di Kaposi, porocarcinoma, sebaceous carcinoma, Merkel cell carcinoma, malignant blue nevus, undifferentiated epitheliomorphic cell neoplasia and metastases from thyroid carcinoma. No serious adverse events were observed.

Combination therapy of PKC\u03b6 and COX-2 inhibitors synergistically suppress melanoma metastasis

BackgroundMetastatic malignant melanoma is one of the most aggressive malignancies and its treatment remains challenging. Recent studies demonstrate that the melanoma metastasis has correlations with the heightened activations of protein kinase C ζ (PKCζ) and cyclooxygenase-2 (COX-2) signaling pathways. Targeted inhibitions for PKCζ and COX-2 have been considered as the promising strategies for the treatment of melanoma metastasis. Thus, the PKCζ inhibitor J-4 and COX-2 inhibitor Celecoxib were combined to treat melanoma metastasis in this study.MethodsThe Transwell assay, Wound-healing assay and Adhesion assay were used to evaluate the inhibition of combined therapy of J-4 and Celecoxib on melanoma cells invasion, migration and adhesion in vitro, respectively. The impaired actin polymerization was observed by confocal microscope and inactivated signal pathways about PKCζ and COX-2 were confirmed by the Western blotting assay. The B16-F10/C57BL mouse melanoma model was used to test the inhibition of combined therapy of J-4 and Celecoxib on melanoma metastasis in vivo.ResultsThe in vitro results showed that the combination of J-4 and Celecoxib exerted synergistic inhibitory effects on the migration, invasion and adhesion of melanoma B16-F10 and A375 cells with combination index less than 1. The actin polymerization and phosphorylation of Cofilin required in cell migration were severely impaired, which is due to the inactivation of PKCζ related signal pathways and the decrease of COX-2. The combined inhibition of PKCζ and COX-2 induced Mesenchymal-Epithelial Transition (MET) in melanoma cells with the expression of E-Cadherin increasing and Vimentin decreasing. The secretion of MMP-2/MMP-9 also significantly decreased after the combination treatment. In C57BL/6 mice intravenously injected with B16-F10 cells (5 × 104 cells/mouse), co-treatment of J-4 and Celecoxib also severely suppressed melanoma lung metastasis. The body weight monitoring and HE staining results indicated the low toxicity of the combination therapy.ConclusionsThis study demonstrates that the combination therapy of PKCζ and COX-2 inhibitors can significantly inhibit melanoma metastasis in vitro and in vivo, which will be an efficient strategy for treatment of melanoma metastasis in clinics.

How important is multidisciplinary treatment of melanoma metastases?

How important is multidisciplinary treatment of melanoma metastases?

Development of a New Model of Melanoma Brain Metastases

Metastatic spread of melanoma is associated with poor prognosis. The tumor microenvironment plays a key role in the formation and progression of melanoma metastases. We aimed to establish a melanoma brain metastases model, which represents the tumor-stroma interaction in the human brain. The non-melanotic mouse B16-melanoma clone F1 was examined in vivo using syngeneic C57BL/6 mouse model. Cancer cells were labeled with green fluorescence protein (GFP) to facilitate tumor identification. Melanoma cells were introduced via intracardiac injection under ultrasound guidance. Within 4–6 weeks after injection, 40% of the animals exhibited brain metastases. Metastases were evident in the brain parenchyma and leptomeninges. We compared the dynamics of immune reaction in our mouse model, with human pathological specimens excised from the brains of melanoma patients. Immunohistochemistry fluorescent analyses revealed that F4/80-positive macrophages/microglia were most abundant at the tumor front compared with the center of tumor. In the tumor core, F4/80-positive cells were abundant only around blood vessels (CD31+ cells). Similarly, CD3+ T-cells were found at the tumor front but not in the core. The most prominent T-cells around metastases were CD4-positive, compared with CD8+ cells (1:2 ratio, respectively; P < 0.001). In conclusion, our comparative study shows similarity between the tumor microenvironment in our mouse model and the human disease. This novel model should facilitate future studies of the regulating mechanism and treatment of melanoma metastasis.

Treatment of melanoma metastases in a limb by isolated limb perfusion and isolated limb infusion

In-transit melanoma metastases are often confined to a limb. In this circumstance, treatment by isolated limb perfusion or isolated limb infusion can be a remarkably effective regional treatment option.

Abstract 4476: The effect of electrochemotherapy on metastatic potential of human melanoma cells SK-Mel28

Abstract Electrochemotherapy is a local treatment, combining chemotherapy and application of electric pulses to the tumour. Electrochemotherapy with bleomycin or cisplatin has demonstrated its effectiveness in controlling local tumour growth in the treatment of malignant melanoma and is proposed as one of the treatment options for in-transit melanoma metastases in Europe. An important aspect of successful treatment is prevention of metastasis, however, it is known that metastasis can be induced by different treatment modalities. Alterations in tumour microenvironment caused by surgery or radiation therapy, can lead to increased formation of metastasis. Furthermore, formation of metastases can be directly linked to migratory potential of the cells. Although electrochemotherapy is now routinely used for treatment of various cancers in many cancer centres, the effect of electrochemotherapy on the metastatic potential of tumour cells is not known. Therefore, the aim of this study was to evaluate the effect of electrochemotherapy with bleomycin and cisplatin on the metastatic potential of human malignant melanoma cells. Human malignant melanoma cells SK-MEL 28 were treated by electrochemotherapy with a range of bleomycin concentrations from 0.01 nM to 1μM and cisplatin concentrations from 2 to 80 μg/mL. SK-MEL 28 cells that were viable 48 h after electrochemotherapy were tested for their metastatic potential by ability to migrate and invade through Matrigel coated porous membrane. In addition, cell adhesion and proliferation using MTS assay were also tested. Furthemore, RNA was isolated from the cells 16 h after each treatment and differentially expressed genes were investigated by microarray analysis to evaluate the effect of electrochemotherapy with bleomycin or cisplatin on expression of genes involved in the development of cancer. The Gene Ontology Tree Machine program was used for gene enrichment analysis. Migration and invasion of melanoma cells that survived 48h after electrochemotherapy with bleomycin or cisplatin were not changed compared to control untreated cells. Also, there were no changes observed in cell adhesion on Matrigel. Gene expression analysis demonstrated that a very low number of genes were differentially expressed after electrochemotherapy with either bleomycin or cisplatin. Specifically, the expression of metastasis promoting genes was not increased after electrochemotherapy. Our data suggest that electrochemotherapy with bleomycin or cisplatin does not increase metastatic behaviour of human melanoma cells, having important clinical implication for safe use in treatment of melanoma metastases. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4476. doi:10.1158/1538-7445.AM2011-4476

Antivascular effects of electrochemotherapy: implications in treatment of bleeding metastases

Solid tumors of various etiologies can be treated efficiently by electrochemotherapy (ECT), a combined use of electroporation (EP) and chemotherapeutic drugs, such as bleomycin and cisplatin. EP alone and ECT in particular, induce a profound reduction in tumor blood flow, which contributes to the antitumor effect. After EP and ECT, the time course of blood flow changes and follows the same two-phase pattern. The first rapid and short-lived vasoconstriction phase is followed by the second much longer-lived phase resulting from disrupted cytoskeletal structures and a compromised barrier function of the microvascular endothelium. In the case of ECT, however, tumor vascular endothelial cells are also affected by the chemotherapeutic drug, which leads to irrecoverable damage to tumor vessels and to a further decrease in tumor blood flow within hours after application of ECT. Tumor cells surviving the direct effects of ECT are consequently exposed to lack of oxygen and nutrients and are pushed into the secondary cascade of induced cell death. Clinically, the antitumor effectiveness of ECT has been proven extensively in the treatment of melanoma metastases, with 70–80% complete responses. The antivascular effects of ECT were also exploited for palliative treatment of bleeding melanoma metastases, with immediate cessation of bleeding and very good antitumor effectiveness. The antivascular effect of ECT is of utmost importance for translation of ECT into the treatment of deep-seated tumors, especially in well vascularized organs, such as the liver, where it prevents bleeding of the treated area.

Antisense-Mediated Suppression of Heparanase Gene Inhibits Melanoma Cell Invasion

Cancer metastasis is a frequent manifestation of malignant melanoma progression. Successful invasion into distant organs by tumor cells must include attachment to microvessel endothelial cells, degradation of basement membranes and extracellular matrix (ECM). Heparan sulfate proteoglycans (HSPG) are essential and ubiquitous macromolecules associated with the cell surface and ECM of a wide range of cells and tissues. Heparanase (HPSE-1) is an ECM degradative enzyme, which degrades the heparan sulfate (HS) chains of HSPG at specific intrachain sites. To investigate effects of changes in heparanase gene expression in metastatic melanoma cells, we constructed adenoviral vectors containing the fulllength human HPSE-1 cDNA in both sense (Ad-S/hep) and antisense orientations (Ad-AS/hep). We found increased HPSE-1 expression and activity in melanoma cell lines following Ad-S/hep infection by Western blot analyses and specific HPSE-1 activity assay. Conversely, HPSE-1 content was significantly inhibited following infection with Ad-AS/Hep. Importantly, HPSE-1 modulation by these adenoviral constructs correlated with invasive cellular properties in vitro and in vivo. Our results suggest that HPSE-1 not only contributes to the invasive phenotype of melanoma cells, but also that the Ad-AS/hep-mediated inhibition of its enzymatic activity can be efficacious in the prevention and treatment of melanoma metastasis.

Current treatment of melanoma metastases of the brain

The appearance of brain metastases in patients with malignant melanoma predicts poor prognosis. During the last ten years important progress has been made in the treatment of brain metastases providing longer survival and better quality of life for these patients. In this review article the different treatment modalities, surgery, radiosurgery, radiation therapy and chemotherapy are described and the results published in the literature are briefly presented. Emphasis is made to show the effectiveness of a multimodality approach of this group of patients resulting in a better clinical outcome.

Cisplatin/epinephrine injectable gel for the intralesional treatment of melanoma metastases: Results of a multi-institutional trial

Cisplatin/epinephrine injectable gel for the intralesional treatment of melanoma metastases: Results of a multi-institutional trial

Treatment of melanoma metastases in the brain.

Melanoma is prone to spread to the brain and is the third most common source of intracranial metastasis. Patients usually present with signs and symptoms of increased intracranial pressure, a new focal neurologic deficit, or seizures. Contrasted magnetic resonance imaging (MRI) is the single most valuable imaging modality. Surgical therapy is the appropriate choice for single lesions that are accessible, especially if they are causing significant mass effect or are located in the posterior fossa. Patients with several intracranial metastases who undergo resection of all lesions may have a similar prognosis to those with single resected lesion. Stereotactic radiosurgery appears to provide good local control of small lesions. External beam radiotherapy may provide some benefit to patients, and is often used in conjunction with surgery or stereotactic radiosurgery. To date, chemotherapy has been limited because of chemo-resistance and drug delivery issues. Future directions for treatment may include local sustained delivery of either chemotherapy or immunoregulatory molecules.

Treatment of melanoma metastases in the brain

Melanoma is prone to spread to the brain and is the third most common source of intracranial metastasis. Patients usually present with signs and symptoms of increased intracranial pressure, a new focal neurologic deficit, or seizures. Contrasted magnetic resonance imaging (MRI) is the single most valuable imaging modality. Surgical therapy is the appropriate choice for single lesions that are accessible, especially if they are causing significant mass effect or are located in the posterior fossa. Patients with several intracranial metastases who undergo resection of all lesions may have a similar prognosis to those with a single resected lesion. Stereotactic radiosurgery appears to provide good local control of small lesions. External beam radiotherapy may provide some benefit to patients, and is often used in conjunction with surgery or stereotactic radiosurgery. To date, chemotherapy has been limited because of chemo-resistance and drug delivery issues. Future directions for treatment may include local sustained delivery of either chemotherapy or immunoregulatory molecules. © 1996 Wiley-Liss, Inc.

Malignant: The value of chromolymphography in the diagnosis and treatment of melanoma metastases to lymph nodes. (Polish)

Malignant: The value of chromolymphography in the diagnosis and treatment of melanoma metastases to lymph nodes. (Polish)