NOP14 inhibits melanoma proliferation and metastasis by regulating Wnt/ß-catenin signaling pathway

Malignant melanoma is an aggressive skin cancer with a high mortality rate. Nucleolar protein 14 (NOP14) has been implicated in cancer development. However, the role of NOP14 in malignant melanoma progression remains largely unclear. In this study, we observed that malignant melanoma tissue showed NOP14 down-regulation compared to melanocytic nevi tissues. Moreover, we observed that NOP14 expression was significantly associated with melanoma tumor thickness and lymph node metastasis. NOP14 overexpression in melanoma cells suppressed proliferation, caused G1 phase arrest, promoted apoptosis, and inhibited melanoma cell migration and invasion. Further investigations revealed that NOP14 overexpression reduced the expression levels of Wnt3a, β-catenin, and GSK-3β of the Wnt/β-catenin pathway. In summary, we demonstrated that NOP14 inhibited melanoma cell proliferation and metastasis by regulating the Wnt/β-catenin signaling pathway.

Metastatic choroidal melanoma to the contralateral eye: a rare case / Melanoma de coróide metátastico para o olho contralateral: caso raro

ABSTRACT Uveal melanoma is the most common adult primary intraocular cancer. Although liver metastasis is common to the natural history of the disease, metastasis to the fellow eye is extremely rare. Here we report the case of a 59-year-old man with choroidal melanoma in his right eye who underwent enucleation at a different center. The patient was referred to our service 21 months postoperatively, complaining of decreased vision. He was found to have a new pigmented choroidal tumor in his left eye associated with liver disease. Ocular ultrasonography and liver biopsy with histopathological and immunohistochemical analysis were performed and confirmed the diagnosis. Few similar cases have been described in the literature. The differential diagnosis included primary bilateral choroidal melanoma and metastatic choroidal tumor from a primary skin melanoma.

RESUMO O melanoma uveal é o câncer intraocular primário mais frequente em adultos. Embora a metástase hepática seja comum à história natural da doença, a metástase para o outro olho é extremamente rara. Aqui relatamos o caso de um homem de 59 anos com melanoma de coroide em seu olho direito que foi submetido à enucleação em um centro diferente. O paciente foi encaminhado ao nosso serviço 21 meses após a cirurgia, com queixa de diminuição da visão. Foi encontrado um novo tumor de coróide pigmentado em seu olho esquerdo associado com doença hepática. Ultrassonografia ocular e biópsia hepática com exame histopatológico e imuno-histoquímico foram realizadas e confirmaram o diagnóstico. Poucos casos semelhantes foram descritos na literatura. O diagnóstico diferencial incluiu melanoma de coróide bilateral orimário e tumor coroidal metastático de um melanoma primário da pele.

Diphencyprone as a therapeutic option in cutaneous metastasis of melanoma. A single-institution experience

Abstract: Diphencyprone has been reported as a local immunotherapy for cutaneous melanoma metastases. We aim to report cases of melanoma patients treated with diphencyprone in a single Brazilian institution and highlight their outcomes. Since 2012, we have treated 16 melanoma patients with cutaneous metastases with topical diphencyprone. To date, we have had 37.5% of complete response, 25% of partial responses, and 31.25% patients without any response. Treatment was well tolerated and local toxicity was easily controlled. We believe topical diphencyprone is a feasible treatment that can be another option for treating melanoma patients, especially in cases of in-transit or extensive disease.

Prognostic factors for metastasis in cutaneous melanoma

Abstract: Background: Melanoma is a malignant neoplasia that shows high mortality when diagnosed in advanced stages. Early identification of high-risk patients for the development of melanoma metastases is the main strategy to reduce mortality. Objective: To assess the influence of eight epidemiological and histopathologic features on the development of metastases in patients diagnosed with primary cutaneous melanoma. Methods: Our historical cohort comprised patients with invasive primary cutaneous melanoma seen between 1995 and 2012 at a public university hospital and a private oncologic surgery institution in Southeastern Brazil. The following variables were analyzed: gender, age, family history of melanoma, site of the primary tumor, clinical and histologic subtype, Breslow thickness, histologic ulceration and the mitotic index. Kaplan-Meier univariate test and multivariate Cox proportional hazard analysis were used to assess factors associated with disease-free survival. Results: Five hundred and fourteen patients were enrolled. The univariate analysis identified the following significant risk factors: gender, age, site of the tumor, clinical and histologic subtype, Breslow thickness, histologic ulceration and mitotic index. Multivariate analysis included 244 patients and detected four significant prognostic factors: male gender, nodular clinical and histologic subtype, Breslow thickness > 4mm, and histologic ulceration. The mitotic index was not included in this analysis. Study limitations: Small number of patients in multivariate analysis. Conclusions: The following prognostic factors to the development of melanoma metastasis were identified in the study: male gender, nodular histologic subtype, Breslow thickness > 4mm and ulceration.

Effects of nivolumab in peritoneal carcinamatosis of malign melanoma in mouse model

Abstract Purpose: To evaluate the efficacy of nivolumab and comparison with dacarbazine (DTIC) on peritoneal carcinomatosis of malignant melanoma in mouse model. Methods: Mouse skin melanoma cells was injected under the capsule of the peritoneal surface in the left side of the abdomen. On postoperative day ten, mouses randomised into three groups. Group 1: Control, Group 2: HIPEC (Hyperthermic intraperitoneal chemotherapy) with DTIC and Group 3: HIPEC with Nivolumab. After the sacrification on postoperative day fifteen, peritoneum evaluated macroscopically and histopathologically by using peritoneal regression grading score (PRGS). Results: In the 15th day exploration, all animals developed extensive intraperitoneal tumor growth in Group 1. In Group 2 and Group 3 median tumor size was 0.7±0.3cm and 0.3±0.2cm respectively (p: 0.023). Peritoneal carcinomatosis index (PCI) were significantly lower in Group 3 than other groups (p: 0.019). The lowest total tumor nodules in group 3 was 4 ± 2. The PGRS score was found significantly lower in Group 3 than other groups (p: 0.03). Lymphocytic response rate was found higher in the Group 3. Conclusions: It has been found that nivolumab significantly better than DTIC on peritoneal metastases of malign melanoma in mouse models. Nivolumab treatment gives promising results with pathological evidence in the treatment of metastatic disease of malignant melanoma.

Occult metastatic melanoma presenting as an acute coronary syndrome

Abstract Melanoma is a tumor that virtually involves any tissue and commonly metastasizes to the heart. It is usually not diagnosed because of the absent/nonspecific cardiac signs and symptoms. Herein, we present a case of a 41-year-old man without any cardiovascular risk factor, admitted to the emergency room with chest pain, diagnosed with a myocardial infarction. Due to the presence of a mass adjacent to the mitral valve on the cardiac ultrasound examination, causing mitral regurgitation, the patient was referred to surgery. Pathological analysis of the excised specimens diagnosed the melanoma. The chemotherapy was started and achieved a partial response. Cardiac metastases usually affect the myocardium, leaving the valves unaffected. In this case, the acute coronary syndrome was the first manifestation of the malignant melanoma. We highlight the high level of suspicion needed in these cases.

Malignant melanoma with synchronous thyroid metastases: case report and literature review

SUMMARY Thyroid metastases are rare in clinical practice. We describe the case of an 85-year-old woman who was referred to our department due to a multinodular goiter with compressive symptoms and subclinical hyperthyroidism. The patient was also undergoing evaluation for a polyp in her left nasal cavity, which was then diagnosed as a malignant melanoma of the nasal mucosa. A thoracoabdominal magnetic resonance imaging obtained for cancer staging revealed a > 50% tracheal obstruction caused by the goiter. The patient underwent simultaneous total thyroidectomy and melanoma excision. Histological analysis of the thyroid showed the presence of multiple metastatic foci from the melanoma. Due to the patient’s age, a decision was made to maintain her under surveillance and administer palliative treatment if necessary. Although metastases to the thyroid are rare, they should be considered in the differential diagnosis of thyroid lesions in patients with a known primary tumor. The thyroidectomy, performed in this patient’s case, allowed the diagnosis of the metastases and relief of compressive symptoms caused by the goiter.

Diffuse cutaneous melanosis: rare complication of metastatic melanoma

Abstract Diffuse cutaneous melanosis is a rare complication of metastatic melanoma related to a worse prognosis. There are few cases reported in the literature. Its pathogenesis has not been completely elucidated, although studies have suggested certain mechanisms for its occurrence. It is clinically manifested as a blue-gray discoloration of the skin and mucous membranes in a cephalo caudal progression and usually associated with melanuria. Skin and mucosa histopathology reveals only the presence of melanophages in the dermis, mainly perivascular, and free interstitial melanin. We report the case of a 68-year-old male with metastatic melanoma, diffuse hyperpigmentation of the skin and melanuria.

Proton NMR characterization of intact primary and metastatic melanoma cells in 2D & 3D cultures

OBJECTIVE: To characterize the differences between the primary and metastatic melanoma cell lines grown in 2D cultures and 3D cultures. METHODS: Primary melanoma cells (WM115) and metastatic melanoma cells (WM266) extracted from a single donor was cultured in 2D as well as 3D cultures. These cells were characterized using proton NMR spectrometry, and the qualitative chemical shifts markers were identified and discussed. RESULTS: In monolayer culture (2D), we observed one qualitative chemical shift marker for primary melanoma cells. In spheroid cultures (3D), we observed nine significant chemical shifts, of which eight markers were specific for primary melanoma spheroids, whereas the other one marker was specific to metastatic melanoma spheroids. This study suggests that the glucose accumulation and phospholipid composition vary significantly between the primary and metastatic cells lines that are obtained from a single donor and also with the cell culturing methods. 14 qualitative chemical shift markers were obtained in the comparison between monolayer culture and spheroids cultures irrespective of the differences in the cell lines. Among which 4 were unique to monolayer cultures whereas 10 chemical shifts were unique to the spheroid cultures. This study also shows that the method of cell culture would drastically affect the phospholipid composition of the cells and also depicts that the cells in spheroid culture closely resembles the cells in vivo. CONCLUSION: This study shows the high specificity of proton NMR spectrometry in characterizing cancer cell lines and also shows the variations in the glucose accumulation and phospholipid composition between the primary and metastatic melanoma cell lines from the same donor. Differences in the cell culture method does plays an important role in phospholipid composition of the cells.

Entendiendo las terapias actuales en melanoma metastásico / Understanding current therapies in metastatic melanoma

Cutaneous melanoma is a highly aggressive tumor developing from melanocytes, its incidence is increasing, and prognosis in advanced stages is daunting. New therapies have been approved during the recent years with unprecedented results, including inhibitors of MAPK/ERK pathway and immune checkpoint blockade (anti-cytotoxic T lymphocyte antigen-4 (CTLA-4) as ipilimumab, anti-programmed cell death protein 1 (PD-L1) as pembrolizumab and anti-programmed cell death protein 1 ligand (PD-L1), among many others). The aim of this paper is to review currently available metastatic melanoma therapies focusing mainly on new therapies that have demonstrated effectiveness, after several decades of little progress in the treatment of this disease.

Multiple cutaneous melanomas associated with gastric and brain metastases

Abstract The occurrence of multiple primary melanomas in a single individual is rare. Most commonly, malignant melanocytic lesions subsequent to the initial diagnosis of melanoma are secondary cutaneous metastases. We report a patient with gastrointestinal bleeding from gastric metastasis of cutaneous melanoma. During clinical evaluation and staging, we discovered a brain metastasis associated with 3 synchronous primary cutaneous melanomas. We suggest the research on the mutation in the cyclin-dependent kinase inhibitor 2A (CDKN2A) (INK4a) in such cases. We also emphasize the importance of clinical examination and dermoscopy of the entire tegument, even after a malignant melanocytic lesion is identified.

Melanoma patterns of distant relapse: a study of 108 cases from a South Brazilian center

Abstract Background: The incidence of cutaneous melanoma has increased over the last decades. Recurrences occur most frequently within the first 2-3 years after diagnosis but patients carry a lifelong risk of relapse. Nevertheless, there is no consensus in the literature on what screening tests patients should undergo. Objectives: To evaluate the most common melanoma metastasis sites among a South Brazilian population from a city with one of the highest melanoma rates, and establish the best screening method for these patients. Methods: A cross-sectional retrospective study of 108 consecutive melanoma patients followed up at a center from 2009 to 2013. Data were collected on demographic and tumoral characteristics, as well as the site of the first diagnosed metastasis. Results: Patients were divided into 3 groups for analytical purposes: Non-visceral metastases (48% of patients), visceral metastasis (39%) and brain metastasis (13%). We tried to correlate age, gender, mean Breslow thickness, mitosis and death rates with the aforementioned groups but none showed any statistically significant association. Conclusion: Melanoma patients must be monitored to detect early relapse and subsequent effective treatment but the best follow-up strategy remains to be established.

Reporte de dos casos clínicos de melanoma con metástasis cardíacas: ("dos caras de una misma moneda") / Melanoma with cardiac metastasis: report of two cases

A 39 year old man presented with signs of an ischemic in-farct in the territory of the medial cerebral artery. A large mobile mass was present in the left atrium and a biopsy showed tissue heavily infiltrated with fat and resection was not possible. A small lesion located at the dorsum allowed a histologic confirmation of a melanoma. The patient died 4 months after surgery. The second patient, a 34 year old woman being treated with chemotherapy for an ovarian melanoma was found to have a right atrial mass. After successful resection of the mass a metastasis of the original melanoma was confirmed and the patient remains in good condition at mid term follow up.

Vemurafenib and cutaneous adverse events - report of five cases

Vemurafenib is a selective inhibitor of V600E-mutant BRAF protein used to treat metastatic and unresectable melanoma. Clinical trials have shown increased overall survival and progression-free survival in patients treated with Vemurafenib. However, cutaneous adverse events are common during treatment. We report fi ve cases of metastatic melanoma with BRAF V600E positivity, treated with Vemurafenib and its cutaneous adverse events. Dermatologists and oncologists need to be aware of possible skin changes caused by this medication, which is increasingly employed in melanoma treatment. Monitoring of patients during therapy is important for early treatment of adverse cutaneous cutaneous adverse events, improvement in quality of life and adherence to treatment.

Melanoma inhibitory activity in Brazilian patients with cutaneous melanoma

Abstract BACKGROUND: Melanoma inhibitory activity is a protein secreted by melanoma cells and has been used as a tumor marker. Increased Melanoma inhibitory activity serum levels are related to metastatic disease or tumor recurrence. Currently there are no studies on Melanoma inhibitory activity and cutaneous melanoma involving Brazilian patients. OBJECTIVE: To evaluate the performance and feasibility of measuring Melanoma inhibitory activity levels in Brazilian patients with cutaneous melanoma. METHODS: Blood was obtained from ten patients with proved metastatic cutaneous melanoma (Group 1), 15 patients resected for cutaneous melanoma without metastasis (Group 2) and 5 healthy donors (Group 3). Melanoma inhibitory activity was measured using a commercially available ELISA kit. RESULTS: There was a statistically significant difference of Melanoma inhibitory activity levels between patients with and without metastasis (p=0.002), and between patients with metastasis and healthy donors (p=0.002). There was no difference between patients without metastasis and healthy donors (p=0.443). CONCLUSION: Melanoma inhibitory activity is a tumor marker for cutaneous melanoma and the Melanoma inhibitory activity-ELISA test can be easily performed. Patients with metastasis have increased Melanoma inhibitory activity serum levels when compared to patients without metastasis and healthy donors. .

Effects of Ischemic Postconditioning on the Hemodynamic Parameters and Heart Nitric Oxide Levels of Hypothyroid Rats / Efeito do Pós-Condicionamento Isquêmico na Hemodinâmica e nos Níveis Cardíacos de Óxido Nítrico em Ratos com Hipotireoidismo

Background: Ischemic postconditioning (IPost) is a method of protecting the heart against ischemia-reperfusion (IR) injury. However, the effectiveness of IPost in cases of ischemic heart disease accompanied by co-morbidities such as hypothyroidism remains unclear. Objective: The aim of this study was to determine the effect of IPost on myocardial IR injury in hypothyroid male rats. Methods: Propylthiouracil in drinking water (500 mg/L) was administered to male rats for 21 days to induce hypothyroidism. The hearts from control and hypothyroid rats were perfused in a Langendorff apparatus and exposed to 30 min of global ischemia, followed by 120 min of reperfusion. IPost was induced immediately following ischemia. Results: Hypothyroidism and IPost significantly improved the left ventricular developed pressure (LVDP) and peak rates of positive and negative changes in left ventricular pressure (±dp/dt) during reperfusion in control rats (p < 0.05). However, IPost had no add-on effect on the recovery of LVDP and ±dp/dt in hypothyroid rats. Furthermore, hypothyroidism significantly decreased the basal NO metabolite (NOx) levels of the serum (72.5 ± 4.2 vs. 102.8 ± 3.7 μmol/L; p < 0.05) and heart (7.9 ± 1.6 vs. 18.8 ± 3.2 μmol/L; p < 0.05). Heart NOx concentration in the hypothyroid groups did not change after IR and IPost, whereas these were significantly (p < 0.05) higher and lower after IR and IPost, respectively, in the control groups. Conclusion: Hypothyroidism protects the heart from IR injury, which may be due to a decrease in basal nitric oxide (NO) levels in the serum and heart and a decrease in NO after IR. IPost did not decrease the NO level and did not provide further cardioprotection in the hypothyroid group. .

Fundamento: O pós-condicionamento isquêmico (PCI) é um método potente utilizado para proteger o coração contra a lesão de isquemia-reperfusão (I/R). Não está claro se o PCI é eficaz quando a doença cardíaca isquêmica é acompanhada de comorbidades, tais como hipotireoidismo. Objetivo: O objetivo deste estudo foi determinar o efeito do PCI sobre a lesão de I/R do miocárdio em ratos machos com hipotireoidismo. Métodos: O hipotireoidismo foi induzido pela administração de propiltiouracila em água potável na concentração de 500 mg/L durante 21 dias. Os corações de ratos controle e com hipotireoidismo foram perfundidos utilizando o aparelho de Langendorff e expostos a isquemia global por 30 minutos, seguido de reperfusão por 120 minutos. O PCI foi iniciado imediatamente após a isquemia. Resultados: O hipotireoidismo e PCI aumentaram significativamente a pressão ventricular esquerda desenvolvida (PVED) e as taxas máximas de variação positiva (+dp/dt) e negativa (–dp/dt) da pressão ventricular esquerda durante a reperfusão em ratos controle (p < 0,05). No entanto, o PCI não teve efeito aditivo no restabelecimento da PVED e das ±dp/dt em ratos com hipotireoidismo. Além disso, o hipotireoidismo diminuiu significativamente os níveis basais séricos (72,5 ± 4,2 vs. 102,8 ± 3,7 μmol/L; p < 0,05) e cardíacos (7,9 ± 1,6 vs. 18,8 ± 3,2 μmol/L; p < 0,05) de NOx. Os níveis cardíacos de NOx não se alteraram no grupo com hipotireoidismo após I/R e PCI mas foram significativamente maiores e menores (p < 0,05) nos grupos controle após I/R e PCI, respectivamente. Conclusão: O hipotireoidismo protegeu o coração da lesão de I/R, o que pode ser devido à diminuição dos níveis séricos e cardíacos basais de óxido nítrico (NO) e à diminuição dos níveis de NO após I/R. No entanto, o PCI não diminuiu os níveis de NO e não conferiu proteção adicional ao grupo com hipotireoidismo. .

Interferon-associated retinopathy in a patient with metastatic melanoma / Retinopatia relacionada ao interferon em paciente com melanoma metastático

We present the unusual case of a 35 year-old woman with stage IV melanoma and widespread metastases, who was undergoing treatment with interferon alpha-2b and who presented with interferon-associated retinopathy. The patient, who had been taking interferon treatment for three months, complained of a sudden loss of visual acuity in the left eye. An ocular examination revealed multiple cotton wool spots along the retina and macular involvement. Interferon treatment was suspended. Although rare, retinopathy represents a potentially serious adverse effect of interferon treatment. Although normally patients are asymptomatic, complications derived of its use may arise, which can lead to significant visual impairment. We therefore suggest that before initiating treatment with this drug, patients should be informed of its potential ocular risks, and that regular eye examinations are conducted along with the treatment.

Apresentamos o caso de uma mulher de 35 anos com melanoma em estágio IV e metástases generalizadas tratados com interferon alpha-2b, que proporcionou uma retinopatia associada ao interferon. Mulher de 35 anos de idade tratados com interferon durante os últimos três meses apresentou uma perda súbita da acuidade visual no olho esquerdo. Exame ocular revelou vários pontos de algodão ao longo da retina e mácula. Tratamento com interferon foi parado. Retinopatia associada ao uso de interferon está entre os possíveis efeitos colaterais, embora rara, não deve ser subestimada. Embora geralmente assintomática, complicações decorrentes de seu uso podem levar à perda visual significativa. Consideramos, portanto, que antes de iniciar o tratamento com este medicamento, os pacientes devem ser informados sobre os riscos potenciais e os exames oftalmológicos são recomendados durante cada tratamento.

Sentinel lymph node biopsy in rats. Comparison between paraffin and frozen section analysis

PURPOSE: To simulate a lymph node metastasis in an animal model using activated carbon, assess their identification in frozen section analysis and compare with histopathological examination in paraffin. METHODS: Thirty two adult female rats were used. They received the carbon injection on its hind legs. Half of the rats was sacrificed on day one, and the other half after 21 days. Thus, 64 lymph nodes were dissected and split longitudinally. One half of the lymph node was sent immediately to frozen section analysis. The other half was fixed in 10% formaldehyde to be cut in paraffin. Slides were divided into quadrants and classified by the presence of carbon in these four quadrants_ They were also classified by the carbon staining intensity. RESULTS: Comparing the slides obtained in the first day and 21 days, there was a tendency of carbon to spread over time, but without statistical significance. The intensity did not alter over time. CONCLUSION: There was no concordance between the two methods of pathological analysis, however the actived carbon was seen in all lymph nodes. .

Breast Metastases from Extramammary Malignancies: Typical and Atypical Ultrasound Features

Breast metastases from extramammary malignancies are uncommon. The most common sources are lymphomas/leukemias and melanomas. Some of the less common sources include carcinomas of the lung, ovary, and stomach, and infrequently, carcinoid tumors, hypernephromas, carcinomas of the liver, tonsil, pleura, pancreas, cervix, perineum, endometrium and bladder. Breast metastases from extramammary malignancies have both hematogenous and lymphatic routes. According to their routes, there are common radiological features of metastatic diseases of the breast, but the features are not specific for metastases. Typical ultrasound (US) features of hematogenous metastases include single or multiple, round to oval shaped, well-circumscribed hypoechoic masses without spiculations, calcifications, or architectural distortion; these masses are commonly located superficially in subcutaneous tissue or immediately adjacent to the breast parenchyma that is relatively rich in blood supply. Typical US features of lymphatic breast metastases include diffusely and heterogeneously increased echogenicities in subcutaneous fat and glandular tissue and a thick trabecular pattern with secondary skin thickening, lymphedema, and lymph node enlargement. However, lesions show variable US features in some cases, and differentiation of these lesions from primary breast cancer or from benign lesions is difficult. In this review, we demonstrate various US appearances of breast metastases from extramammary malignancies as typical and atypical features, based on the results of US and other imaging studies performed at our institution. Awareness of the typical and atypical imaging features of these lesions may be helpful to diagnose metastatic lesions of the breast.