| Abstract |
INTRODUCTION: Melanoma is the deadliest skin cancer, and its incidence is increasing rapidly every year around the world. Characteristics such as light skin and red hair are associated with more frequent melanoma development. Sun exposure habits are also a risk factor for developing melanoma. Finally, mutations in genetic factors can trigger both familial and sporadic melanoma. Exposure to ultraviolet radiation, however, is identified as the most important risk factor for developing melanoma.
The diagnosis of melanoma begins with the patient's history and skin examination. All pigmented lesions should be checked for asymmetry, irregular borders, color variety, diameter, and evolution over time. The golden rule for diagnosing melanoma is surgical resection biopsy.
We distinguish four types of melanoma: superficial, nodular, lentigo maligna and lenticular melanoma of the extremities. Each type has separate characteristics. Crucial pathological elements that are important for patient management and treatment decisions are: Breslow infiltration depth, primary tumor ulceration, Clark infiltration level, mitotic activity per mm2, tumor cell infiltration, lymphatic infiltration, perineural infiltration and regression. The infiltration or not of the regional lymph nodes, as well as the presence or absence of in-transit and/or satellite metastases, is also of significant prognostic value. The existence or not of systemic metastases has a decisive role for the prognosis of the disease.
Prevention of melanoma is important. The following treatments can be applied to the manifestation of the disease: Surgery, chemotherapy, photodynamic therapy, immunotherapy, targeted therapy, and a combination of these.
THE ROAD TO MELANOMA: Melanocytes are derived from cells of the neural crest. Their migration to the skin, their growth, survival, and differentiation are controlled by the microphthalmia-associated transcription factor (MITF) with multiple signaling pathways and multiple target genes. Any disturbance in the expression levels and regulation of MITF function can trigger the development of melanoma.
Metastasis is a complex multiphase process. Melanoma due to the origin of the cells from the neural crest is resistant to adverse conditions during metastasis. It metastasizes using plasticity mechanisms related to the alternation of malignant properties such as proliferation, filtration and oncogenesis. The main mediator of these rotations is the MITF.
RECURRENT MELANOMA OF THE LIMBS: Recurrent limb melanoma in the form of in-transit and/or satellite metastases is a therapeutic challenge due to the high resistance it presents in the various treatment protocols. Hyperthermic diffusion of chemotherapeutic and biological agents into a vascularly isolated organ (HILP) is a recognized method of regional chemotherapy with particularly good results. The use of tumor necrosis factor alpha (TNFα) leads to increased vascular permeability of the tumor causing high penetration of the chemotherapeutic agent (Melphalan) and hemorrhagic tumor necrosis.
PURPOSE: Modern studies include circulating melanoma cells (CMCs) in the most specialized biomarkers of the disease. Due to the mechanism of action of TNFα-Melphalan-HILP, we assumed that a significant number of melanoma cells are released into the patient's systemic circulation.
The aim of this study was to evaluate the effect of HILP on CMCs concentration and to investigate whether alteration of CMCs affects disease-specific survival, if it is associated with response to treatment, or whether it ultimately affects disease progression.
METHODS: The study included 20 patients who underwent TM-HILP for recurrent unresectable limb melanoma, stage IIIB-IIID. Peripheral blood CMCs were analyzed at five time points from the preoperative day to the seventh postoperative day using the following biomarkers: MITF, Tyrosinase mRNA, Melan-A and S100b by quantitative RT-PCR.
RESULTS: No CMCs were found or altered in any patients according to the Melan-A and Tyrosinase biomarkers. The Friedman test showed significant perioperative changes for the MITF biomarker (p<0.001) and for the S100b (p=0.001). Paired tests showed a significant increase in MITF levels on the seventh postoperative day compared to other time points (p<0.05). Paired tests for the S100b biomarker showed a significant difference between the intraoperative sample and the seventh postoperative day (p<0.0001). Patients with complete response to TM-HILP therapy (n=12) had higher mean MITF values and the difference was significant between the intraoperative sample (p=0.014) and the first postoperative day (p=0.046). There was no correlation between the changes in the MITF and the S100b with the four-year disease specific survival.
CONCLUSIONS: HILP surgery causes an increase in the number of CMCs in the patient's systemic circulation, especially on the seventh postoperative day according to the MITF biomarker. There was no correlation between increased CMCs and survival. Patients with a complete response had higher MITF values immediately postoperatively than patients with a non-complete response.
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