Melanoma Skin Metastases Research Articles

Response and outcome of patients with melanoma skin metastases and immune checkpoint inhibition.

It is known, that different metastatic organ systems respond differently to immune checkpoint inhibitors (ICIs). In this study, we aimed to investigate the extent to which skin/subcutaneous metastases respond to ICI or targeted therapies (TTs) and whether the response rate differs from that of distant metastases in the same patient. Patients with melanoma diagnosed between January 2021 and September 2023 with at least one skin/subcutaneous metastasis who had received therapy with ICI or TT in an advanced setting were included in the analysis. Best overall response (BOR) was classified according to the revised response evaluation criteria in solid tumors (RECIST). The BOR of skin metastases and visceral metastases to ICI and TT was compared using the chi-square test. Skin metastases treated with ICI a first-line setting showed an overall response rate (ORR) of 44.1%. In contrast, visceral metastases had a higher ORR of 51.1%. However, the difference was not statistically significant (p = .77). Regarding TT, the ORR for skin metastases was 57.1%, compared to 38.5% for visceral metastases (p = .59). Interestingly, the ORR for skin/subcutaneous metastases was notably lower with ICI compared to visceral metastases, in contrast to patients who underwent TT. Skin metastases showed a poorer response to ICI than visceral metastases. Therefore, careful monitoring is recommended to detect non-response early in patients with skin metastases as skin metastases may have a worse response than TT. A larger cohort is needed for a comprehensive analysis and confirmation of our results.

Predictive Factors for Metastasis of Skin Melanoma of Varying Thickness According to Breslow to Sentinel Lymph Nodes

Purpose: To evaluate the prognostic factors in patients with Breslow skin melanoma of various thicknesses that affect the incidence of metastases in the signal lymph nodes (SLN).Material and methods: From November 2018 to November 2020, 324 patients with diagnosed melanoma of the skin of various localization and stages were examined and operated on. We used lymphotropic colloidal radiopharmaceutical (RPh) labeled with 99mTc. RPh with an activity of 150 MBq was administered one day before the operation intradermally around the scar of resected melanoma or peritumorally at 4 points in the case of a primary tumor. Lymphoscintigraphy was performed 1–3 hours after the RP injection on a Symbia E or Symbia E gamma camera (Siemens, Germany). Anteroposterior and lateral static polypositional scintigraphy was performed to determine the topography and mark the SLN. 324 planar studies were performed. In 259 cases, an additional study was performed SPECT (including SPECT / CT) on a Symbia T2 device (Siemens, Germany). Surgical intervention was performed the next day, taking into account the data of intraoperative radiometry using a domestic specialized hand-held gamma detector Radical (Amplituda, Russia).Results: The mean primary melanoma Breslow thickness was 2.77 ± 2.2 mm (range 0.2–13.0 mm). Localization of SLN: axillary (n = 161. 51 %), inguinal (n = 100. 31 %), cervical (n = 16. 5 %), submandibular (n = 9. 3 %), supraclavicular (n = 4. 1 %), more than one basin (n = 34. 9 %). In the group of melanomas <0.75 mm thick, no SLN metastases were found, among 0.75–1 mm melanomas, one positive lymph node with metastasis (SLN+) was found, in the largest group of melanomas of medium thickness (1–3.5 mm) — 25 (17 %). The largest percentage of metastases in SLN is determined in thick melanomas (>3.5 mm) — 17 (28 %), which is consistent with the data of foreign literature, while SLN is most often affected with a Breslow tumor thickness of more than 7 mm.In the group with negative sentinel lymph nodes (SLN–), the average tumor thickness according to Breslow was 2.6 ± 2.0 mm, in the SLN+ group — 4.0 ± 2.9 mm, the differences between the groups are statistically significant, which is confirmed by the result of one-way analysis of variance.The optimal threshold value of tumor thickness according to Breslow for the isolation of patients with a positive prognosis of metastasis in the SLN is 2.0 mm. It is characterized by the maximum levels of sensitivity (79 %) and specificity (59.1 %). An older age of patients (over 35 years old) is also associated with an increased incidence of metastases in the SLN, but this indicator is not statistically significant. Most often, SLN metastases were detected when the primary tumor was localized in the back (more often in men) and lower extremities (more often in women), while they are thicker (> 3.5 mm).Conclusion: 1. According to the ROC-analysis, the optimal threshold value of the tumor thickness according to Breslow for the isolation of patients with a positive prognosis of metastasis in the SLN is 2.0 mm. It is characterized by the maximum levels of sensitivity (79 %) and specificity (59.1 %). 2. Statistically significant prognostic factors of metastasis in SLN: localization of the primary tumor in the back (more often in men) and lower extremities (more often in women); Breslow thickness over 3.5 mm. 3. The absence of the influence of gender and age was noted, with a slight predominance of women in both groups.

MODERN EFFECTIVE TREATMENT OF BRAIN METASTASES OF SKIN MELANOMA. THE EXAMPLE OF CLINICAL OBSERVATION

Introduction. Melanoma of the skin has the highest potential for metastasis to the brain, ranking 15th in the frequency of occurrence among all malignant tumors – it is in third place in the incidence of intracerebral metastases. Modern methods of treatment of metastases of skin melanoma to the brain include neurosurgical treatment, radiation therapy and radiosurgery, antitumor drug therapy, including targeted therapy, immunotherapy and chemotherapy. The article discusses the indications for different methods of treatment, provides data on patient survival when using these methods of treatment alone or in combination. Additionally, a clinical case of long-term survival of a patient with skin melanoma with progression in the form of extra- and intracranial metastasis is discussed.Purpose. Evaluation of the result of using modern methods of antitumor treatment in real clinical practice in a patient with skin melanoma metastases in the brain. Materials and methods. On a clinical example, a possible sequence of an individual approach to the treatment of a patient with extracranial and intracerebral metastases of skin melanoma based on modern methods of treatment and examination is considered.Results. The use of modern methods of anticancer therapy has increased the overall survival and disease-free survival of patients with metastases of skin melanoma to the brain and reduces the need for neurosurgical interventions. As a confirmation of this, the life expectancy of the patient after the progression of skin melanoma in the form of metastases to the brain against the background of all the antitumor treatment carried out to date was 5.5 years, while neurosurgical treatment was not carried out at the request of the patient, although it was shown, but were used the possibilities of modern anticancer therapy, including sequential radiation therapy, targeted therapy and immunotherapy.Conclusion. Modern methods of anticancer therapy can significantly increase the survival rate of patients with melanoma brain metastases and individualize the treatment plan.

Single-Cell Characterization of the Immune Microenvironment of Melanoma Brain and Leptomeningeal Metastases.

Melanoma brain metastases (MBM) and leptomeningeal melanoma metastases (LMM) are two different manifestations of melanoma CNS metastasis. Here, we used single-cell RNA sequencing (scRNA-seq) to define the immune landscape of MBM, LMM, and melanoma skin metastases. scRNA-seq was undertaken on 43 patient specimens, including 8 skin metastases, 14 MBM, and 19 serial LMM specimens. Detailed cell type curation was performed, the immune landscapes were mapped, and key results were validated by IHC and flow cytometry. Association analyses were undertaken to identify immune cell subsets correlated with overall survival. The LMM microenvironment was characterized by an immune-suppressed T-cell landscape distinct from that of brain and skin metastases. An LMM patient with long-term survival demonstrated an immune repertoire distinct from that of poor survivors and more similar to normal cerebrospinal fluid (CSF). Upon response to PD-1 therapy, this extreme responder showed increased levels of T cells and dendritic cells in their CSF, whereas poor survivors showed little improvement in their T-cell responses. In MBM patients, therapy led to increased immune infiltrate, with similar T-cell transcriptional diversity noted between skin metastases and MBM. A correlation analysis across the entire immune landscape identified the presence of a rare population of dendritic cells (DC3) that was associated with increased overall survival and positively regulated the immune environment through modulation of activated T cells and MHC expression. Our study provides the first atlas of two distinct sites of melanoma CNS metastases and defines the immune cell landscape that underlies the biology of this devastating disease.

Prognostic factors of metastasis of skin melanoma to sentinel lymph nodes

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Characteristics of Tertiary Lymphoid Structures in Melanoma Skin Metastases Predict Overall Survival

Characteristics of Tertiary Lymphoid Structures in Melanoma Skin Metastases Predict Overall Survival

The role of topical imiquimod in melanoma cutaneous metastases: A critical review of the literature.

Despite of the emerging new systemic and local oncologic treatments (immunotherapy and checkpoint inhibitors, oncolytic viral treatments and injected immunostimulants) the management of skin melanoma metastasis can be still challenging. The main aim of this review was to assess the efficacy and the role of imiquimod in local metastatic melanoma disease. An extensive literature review was performed from September 2000 to March 2020 using PubMed, MEDLINE, Embase, and Cochrane Library databases. Selected articles regarded topical imiquimod, its mode of action as an antitumoral agent and its applications in melanoma metastases treatment. We analyzed a total of 18 published article of clinical cases and small case series and five studies: two retrospective large case series, two Phase I and II clinical trials and one cohort non randomized study. Generally, the treatment is safe and well tolerated. Imiquimod lead to an unstable locoregional control. The use of topical imiquimod for the treatment of MM cutaneous metastases should be considered in selected cases and in palliative settings.

Bcl6 Preserves the Suppressive Function of Regulatory T Cells During Tumorigenesis.

During tumorigenesis, tumor infiltrating regulatory T (Treg) cells restrict the function of effector T cells in tumor microenvironment and thereby promoting tumor growth. The anti-tumor activity of effector T cells can be therapeutically unleashed, and is now being exploited for the treatment of various types of human cancers. However, the immune suppressive function of Treg cells remains a major hurdle to broader effectiveness of tumor immunotherapy. In this article, we reported that the deletion of Bcl6 specifically in Treg cells led to stunted tumor growth, which was caused by impaired Treg cell responses. Notably, Bcl6 is essential in maintaining the lineage stability of Treg cells in tumor microenvironment. Meanwhile, we found that the absence of follicular regulatory T (Tfr) cells, which is a result of Bcl6 deletion in Foxp3+ cells, was dispensable for tumor control. Importantly, the increased Bcl6 expression in Treg cells is associated with poor prognosis of human colorectal cancer and lymph node metastasis of skin melanoma. Furthermore, Bcl6 deletion in Treg cells exhibits synergistic effects with immune checkpoint blockade therapy. Collectively, these results indicate that Bcl6 actively participates in regulating Treg cell immune responses during tumorigenesis and can be exploited as a therapeutic target of anti-tumor immunity.

FEATURES OF DEFEATS OF SENTINEL LYMPH NODES AT PRIMARY MELANOMA OF SKIN

Introduction. Each tenth tumor of skin is melanoma. Presence of tumor cells in sentinel lymph node influenced the medical tactics.The objective of the research was to study the metastasis of skin melanoma into the clinically negative regional lymph nodes.Material and methods. Histological, immunohistochemical, cytological and immunocytochemical methods were used to study biopsies of regional lymph nodes in 60 patients with skin melanoma.Results. 5 % of patients were diagnosed with melanoma in situ, 15 % – Т1, 28.3 % – Т2, 23.3 % – Т3, 28.3 % – Т4. At outflow of the lymph through 1 collector, the metastases in sentinel lymph node (SLN) was defined in 51 %, through 2 collectors – in 81.8 % of cases. Tumor cells damaged single lymph node in 35.3 % of cases, two and more lymph nodes in 64.7 % of cases. Metastases in SLN with formation of secondary tumor at the T1 melanoma were observed at 11.1 %, T2 – 5.9 %, T3 – 21.4 %, T4 – 47.1 % of studies. Clusters of cells or isolated cells of melanoma in SLN at Т1 were noted in 22.2 %, at Т2 – in 41.2 %, at Т3 – in 42.9 %, at Т4 – in 35.3 % of cases. At outflow of lymph through 1 collector, metastasises of melanoma in non-sentinel lymph nodes (NSLN) were revealed in 24 %, through 2 collectors – in 44.4 % of cases. Secondary changes of NSLN were noted in 16.7 % of cases of defeat of single SLN, in 31.8 % of cases of defeat of two and more SLN. Metastases of melanoma were revealed in 69.2 % of cases of formation of secondary tumor and in 4.8 % of cases of presence of clusters in SLN in removed NSLN.Conclusion. At increase of Тmelanoma of the skin, the quantity of sentinel lymph nodes with reactive changes decreased, and their number with metastases increased. Metastatic defeat of sentinel lymph nodes at outflow of lymph through 2 lymph collectors in two and more SLN and NSLN exceeded the defeat of SLN at outflow of lymph through 1 lymph collector in single lymph nodes. The use of immunocytochemical method of research allowed to expand pathomorphological verification of metastatic defeat of sentinel lymph nodes by 66.7%.

Electrochemotherapy for the treatment of melanoma skin metastases in the era of new drugs

Electrochemotherapy for the treatment of melanoma skin metastases in the era of new drugs

Uveal melanoma clonogenic response to proton beam irradiation

PurposeThe goal of this study was to compare the cellular clonogenic response to proton beam and X‐ray irradiation of uveal melanoma cell line Mel270 and human melanoma cell line BLM.MethodsBLM line was derived from a skin melanoma metastasis to the lung, and Mel270 is a primary uveal melanoma cell line. Cells were irradiated with 1–5 Gy of X ray (300 kVp Phillips, 1 Gy/min) or proton beam (60 MeV) from Proteus C‐235. After irradiation cells were seeded for the clonogenic assay. Two weeks after seeding the number and type of clones were determined. Three types of clones were found: the largest in size holoclones (with the highest potential to proliferate), medium sized meroclones and the smallest paraclones (low potential to proliferate).ResultsThe total number of clones were similar for both cell lines and both types of irradiation. The RBE values calculated for 37% of survival fraction were 1.11 and 1.13 for Mel270 and BLM cells, respectively. Three types of clones seen in untreated cultures imply the heterogeneity of cellular populations. After irradiation the proportion between the three types of clones was changed: the number of holoclones was drastically lower, and the number of paraclones increased. The number of paraclones was lower after proton bean irradiation in comparison to X‐rays in both cell lines.ConclusionsProton beam and X‐ray irradiation differently modify the proliferation potential of melanoma cells.

Highlights of This Issue

The receptor tyrosine kinase Met and its ligand hepatocyte growth factor/scatter factor are major metastasis targets. In this study, Winter and colleagues developed small molecule antagonists for the interaction between those two proteins using a fragment-based approach. The authors were able to identify small lead compounds that inhibit cell migration and prevent tumor formation in cell-based assays. Developing inhibitors against protein–protein interactions using fragment-based approaches could be the key to unlocking previously thought “undruggable” protein–protein interactions to drug development campaigns, especially when no structural information of the target interface is available.Chemoresistance presents a major limitation to the efficacy of cancer treatment. The current study describes an original approach for sensitizing colorectal liver metastasis to conventional chemotherapy, using a signal-interfering DNA called DT01. DT01 inhibits DNA repair by inducing “false” DNA damage signals. DT01 has recently undergone a phase I clinical trial on melanoma skin metastases with promising results in association with radiotherapy. Here, Herath and colleagues investigated the therapeutic efficacy of associating DT01 with oxaliplatin and 5-fluorouracil in preclinical models. This work highlights that combining DT01 with chemotherapy may be a safe and effective therapeutic strategy in the treatment of colorectal liver metastases.ML264 is a third-generation small molecule compound developed with the goal of inhibiting the growth of colorectal cancer cells by targeting oncogenic Krüppel-like factor 5 (KLF5). Ruiz de Sabando and colleagues demonstrated that ML264 has multiple effects on colorectal cancer cell lines, such as cessation of mitotic figures through modification of the cell-cycle profile. ML264 can also inhibit the growth of colorectal tumors in an established xenograft mouse model, achieved by the reduction in proliferation and inhibition of KLF5 and EGR1, a transcriptional activator of KLF5. These findings suggest that ML264 may be a potential novel therapeutic agent for colorectal cancer.Conventional photodynamic therapy (PDT) using photosensitive dyes has unsolved problems due to systemic photosensitive adverse effect and lack of sufficient, as well as continuous, accumulation of photosensitizers in tumor tissues. Takehara and colleagues developed a conditionally replicating adenovirus-mediated delivery system for photosensitive cytotoxic fluorescent protein KillerRed as a novel PDT. This treatment demonstrated the antitumor effect not only for subcutaneous xenograft tumor but also for intraperitoneal lymph node metastasis of human cancer in mouse models. This adenovirus-mediated delivery system of KillerRed is a novel strategy to improve the anticancer potential of PDT.

Melanoma skin metastasis

In order to evaluate the incidence, clinical features and prognosis of cutaneous tumor metastases, the records of adult patients with melanoma treated over a thirteen year period were examined. The diagnosis of Melanoma skin metastases was established in 221 (11,3%) of 1,948 patients. Each diagnosis was histologically confirmed by evaluation of both the primary tumor and the skin. Metastatic cutaneous melanoma presented with a wide variety of lesions: satellite, thrombophlebitis-like, inflammatory and nodular. In some cases the combination of satellite and nodular metastases was observed. Cancer patients with cutaneous metastases have a poor prognosis: the median survival of these patients is reduced by almost a half in comparison with cancer patients without cutaneous metastases.

Giant Centrifugal and Necrotizing Cutaneous Metastases of Melanoma

Melanoma is a neoplasm derived from melanocytes of the skin and other sites. In the natural history of melanoma, cutaneous metastases occur relatively frequently and can arise in early or late stages of the disease. Melanoma skin metastases have a variable appearance. Several clinical appearances are described in the literature. We describe an unusual clinical pattern of cutaneous melanoma metastasis, defined as giant, centrifugal, and necrotizing, and we provide a brief review of the literature.

Photodynamic therapy in patients with skin metastases of melanoma

Results of treating 114 skin metastases of melanoma in 21 patients are represented. Melanoma progression with cutaneous metastases after previous treatment was diagnosed in all patients. The method of prolonged photodynamic therapy developed by authors with fotosens administrated intravenously at dose of 0.4 mg/kg of body weight was used in the study. First session of tumor irradiation was performed 2 h after injection of photosensitizer. Patients underwent superfi cial or contact irradiation depending on topography and type of growth of metastatic foci. Course of treatment accounted for 7–10 sessions of photodynamic therapy with 24 h interval, light dose delivered to tumor for one session – 350 J/cm 2 . Signifi cant clinical effect (complete and partial tumor regression) was obtained in 89% of cases for developed method.

Electrochemotherapy for the management of melanoma skin metastasis: a review of the literature and possible combinations with immunotherapy

Despite surgical treatment of primary tumor, about 5-10 % of melanoma patients will eventually suffer from cutaneous or subcutaneous metastasis. The presence of skin metastases decreases patients' quality of life. Their management is a challenge and depends on several variables such as size and number of the lesions, their location, the presence or absence of visceral metastasis. When possible, radical surgical resection is the best approach; if surgery is not expected to provide a reasonable functional outcome, alternative treatments must be considered. Several local and loco-regional treatments, such as electrochemotherapy and regional chemotherapy, are available for the management of melanoma skin metastasis. Even if high response rates have been observed in several clinical trials, their impact on survival is not clear. Efforts are being made to improve their efficacy and minimize toxicity. The combination of such treatments with immunotherapy could be a strategy to induce durable responses and improve survival. In fact, regionally treated patients do not have the immune suppression associated with most systemic treatments, which could compromise the efficacy of immunotherapy, and recent findings suggest that the inflammatory reactions following loco-regional cytotoxic treatments, such as electrochemotherapy, may enhance the activity of immunotherapeutic agents. In this manuscript, we review recent studies on electrochemotherapy and melanoma skin metastasis, and we comment about the role that combinations with immunotherapy may have based on the data provided by clinical trials and translational research.

Chemovirotherapy of Malignant Melanoma with a Targeted and Armed Oncolytic Measles Virus

Effective treatment modalities for advanced melanoma are desperately needed. An innovative approach is virotherapy, in which viruses are engineered to infect cancer cells, resulting in tumor cell lysis and an amplification effect by viral replication and spread. Ideally, tumor selectivity of these oncolytic viruses is already determined during viral cell binding and entry, which has not been reported for melanoma. We engineered an oncolytic measles virus entering melanoma cells through the high molecular weight melanoma-associated antigen (HMWMAA) and proved highly specific infection and spread in melanoma cells. We further enhanced this oncolytic virus by inserting the FCU1 gene encoding the yeast-derived prodrug convertases cytosine deaminase and uracil phosphoribosyltransferase. Combination treatment with armed and retargeted MV-FCU1-αHMWMAA and the prodrug 5-fluorocytosine (5-FC) led to effective prodrug conversion to 5-fluorouracil, extensive cytotoxicity to melanoma cells, and excessive bystander killing of noninfected cells. Importantly, HMWMAA-retargeted MV showed antitumor activity in a human xenograft mouse model, which was further increased by the FCU1/5-FC prodrug activation system. Finally, we demonstrated susceptibility of melanoma skin metastasis biopsies to HMWMAA-retargeted MV. The highly selective, entry-targeted and armed oncolytic virus MV-FCU1-αHMWMAA may become a potent building block of future melanoma therapies.

The Immunocytokine L19–IL2 Eradicates Cancer When Used in Combination with CTLA-4 Blockade or with L19-TNF

Systemic high-dose IL2 promotes long-term survival in a subset of metastatic melanoma patients, but this treatment is accompanied by severe toxicities. The immunocytokine L19-IL2, in which IL2 is fused to the human L19 antibody capable of selective accumulation on tumor neovasculature, has recently shown encouraging clinical activity in patients with metastatic melanoma. In this study, we have investigated the therapeutic performance of L19-IL2, administered systemically in combination with a murine anti-CTLA-4 antibody or with a second clinical-stage immunocytokine (L19-TNF) in two syngeneic immunocompetent mouse models of cancer. We observed complete tumor eradications when L19-IL2 was used in combination with CTLA-4 blockade. Interestingly, mice cured from F9 tumors developed new lesions when rechallenged with tumor cells after therapy, whereas mice cured from CT26 tumors were resistant to tumor rechallenge. Similarly, L19-IL2 induced complete remissions when administered in a single intratumoral injection in combination with L19-TNF, whereas the two components did not lead to cures when administered as single agents. These findings provide a rationale for combination trials in melanoma, as the individual therapeutic agents have been extensively studied in clinical trials, and the antigen recognized by the L19 antibody has an identical sequence in mouse and man.

A case of disseminated melanoma with esophageal metastasis in a dog.

Abstract. Melanoma is a tumor commonly diagnosed in dogs, in which the hereditary component is believed to play a significant role in the occurrence and prognostics. Although the metastasis’ localizations in melanoma are difficult to predict because of the complex factors that determine tumors` cells implantation in tissues, in dogs melanocytic metastases were observed in most of the organs. In this study we described, from our knowledge for the first time in dogs, a case of skin pleomorphic melanoma with multiple esophageal metastases. Keywords : dog malignant melanoma, esophageal melanoma, disseminated melanoma Introduction. Oesophageal metastasis of skin melanoma is rarely reported in human medicine (Eng, 1989; Naomoto 1998) and, from our knowledge, never observed in animals’ medical literature. Here, we present a case of metastatic skin malignant melanoma in a 7 years old, male Rottweiler with thoraco-abdominal visceral metastases, including the cervical and abdominal areas of oesophagus.

Electrochemotherapy for Non-Melanoma Head and Neck Cancers

To evaluate and confirm the efficacy and safety of electrochemotherapy (ECT) using bleomicyn in a large series of non-melanoma head and neck cancers. ECT combines chemotherapy and electroporation to increase drug uptake into cancer cells. ECT has proven to be effective in the treatment of tumor nodules of cutaneous and subcutaneous localization. Up to now, this therapy has been mainly used as a local control of melanoma skin metastasis. Few studies have focused on its role in the treatment of head and neck cutaneous and subcutaneous cancers. Twenty-five patients underwent ECT for the treatment of non-melanoma head and neck cancers. All tumors were classified by histological type (confirmed by biopsy), size, and TNM Classification of Malignant Tumors (TNM). Treatments were performed using a bolus of bleomicyn and a pulse generator under local or general anesthesia after the ESOPE (European Standard Operating Procedures of Electrochemotherapy) standard operating procedures. An objective response was achieved in 100% of treated patients (n = 25) at 6 weeks after the initial treatment. The complete response rate according to the WHO criteria was 72% (n = 18); the partial response rate was 28% (n = 7). None of the lesions that achieved a complete response relapsed after a median follow-up period of 18 months. Partial responders showed stable disease for the duration of the follow-up. In accordance with the clinical results shown, we encourage further investigation to establish ECT's use as first line treatment especially in basocellular carcinomas of the head and neck area and for squamocellular carcinomas of the lip with no detectable cervical lymphoadenopathy.