Cutaneous Melanoma Metastases Research Articles

1325P - Validation of a clinicopathological and gene expression profile (CP-GEP) model for sentinel lymph node metastasis in primary cutaneous melanoma

BackgroundAs primary cutaneous melanoma patients with a positive sentinel lymph node (SLN, stage III) are now considered candidates for adjuvant systemic therapy, a SLN biopsy (SLNB) is indicated in more patients. However, SLNB is an invasive procedure and is negative in approximately 80% of patients. Therefore, there is a need for a non-invasive test to accurately identify patients with primary cutaneous melanoma without nodal metastases. Here we describe the first independent validation of a recently developed CP-GEP model to predict nodal metastasis. This risk model combines Breslow thickness, age, and gene expression variables from the primary melanoma. MethodsThis study focused on all patients >18 years who underwent a SLNB at the Erasmus Medical Center (between January 2007 and December 2017), within 90 days after diagnosis of primary cutaneous melanoma. Total RNA was extracted from formalin-fixed paraffin-embedded (FFPE) primary cutaneous melanomas, reversed transcribed into cDNA and subsequently analyzed for the expression of 8 target genes involved in melanoma metastasis (ITGB3, PLAT, SERPINE2, GDF15, TGFBR1, LOXL4, IL8, MLANA) using an optimized qPCR protocol. ResultsFFPE tissue samples from 211 patients were analyzed using the CP-GEP model. At diagnosis, the median age was 55 years (interquartile range [IQR] 45-65), and the median Breslow thickness was 2.1mm (IQR 1.4-3.4). Most patients presented with a T2 or T3 melanoma, accounting for 94 and 70 patients, respectively. Overall, 27.5% of patients had a positive SLN. The CP-GEP model had a negative predictive value (NPV) of 89.4%. In patients with stage T1-T2 melanoma, the model was able to achieve an SLNB reduction rate of 40.1% with an NPV of 90.7%. ConclusionsThe CP-GEP model is a non-invasive and validated tool that is able to predict nodal metastasis in an independent Dutch population. Consequently, this risk model is able to accurately identify patients with primary cutaneous melanoma that can safely forego SLNB. Therefore, the CP-GEP model is a promising tool for patient care, preventing unnecessary surgery in the majority of patients. Legal entity responsible for the studyErasmus University Medical Center, Department of Dermatology. FundingSkylineDx. DisclosureJ.T. Dwarkasing: Shareholder / Stockholder / Stock options, Full / Part-time employment: SkylineDx BV. D. Tempel: Shareholder / Stockholder / Stock options, Full / Part-time employment: SkylineDx BV. L. Bosman: Shareholder / Stockholder / Stock options, Full / Part-time employment: SkylineDx. A.A.M. Van der Veldt: Advisory / Consultancy: BMS; Advisory / Consultancy: MSD; Advisory / Consultancy: Roche; Advisory / Consultancy: Novartis; Advisory / Consultancy: Pierre Fabre; Advisory / Consultancy: Pfizer; Advisory / Consultancy: Sanofi; Advisory / Consultancy: Ipsen. All other authors have declared no conflicts of interest.

No association between smoking and sentinel lymph node metastasis and survival in cutaneous melanoma.

There is little evidence that smoking is associated with metastasis in patients with cutaneous melanoma. Using a propensity score matching analysis, we assessed whether smoking was associated with a higher rate of sentinel lymph node (SLN) metastasis and worse survival in these patients. Retrospective cohort study at a referral hospital for melanoma. We studied 762 patients with known smoking status from the melanoma database of the Instituto Valenciano de Oncología who underwent SLN biopsy between 1 January 2000 and 31 December 2016. The patients were matched by smoking status. The matching procedure was implemented using three logistic regression models featuring never vs. former smokers, never vs. current smokers and former vs. current smokers. The study outcomes were disease-free survival (DFS), melanoma-specific survival (MSS), overall survival (OS) and SLN status. The following groups were formed based on the propensity matching scores: 114 pairs of smokers vs. never smokers, 113 pairs of smokers vs. former smokers and 174 pairs of never smokers vs. former smokers. Smoking status was not associated with SLN metastasis or with DFS, MSS or OS in any of the three groups. Smoking does not influence SLN metastasis or survival in patients with cutaneous melanoma.

CX-F9, a novel RSK2 inhibitor, suppresses cutaneous melanoma cells proliferation and metastasis through regulating autophagy

Approximately 60% of melanoma have BRAF mutation which leads to the abnormal activation of MAPK signaling pathway. Therefore, targeting these signaling pathways is particularly important for melanoma therapy. Ribosomal S6 Kinase 2 (RSK2) is a downstream target of ERK1/2 in MAPK/ERK pathway and inhibition of RSK2 suppresses the tumorigenesis and metastasis of neoplasm. We investigated whether CX-F9, a novel RSK2 inhibitor predicted by computer, inhibits the malignant phenotype of melanoma cells. In this study, we found knockdown of RSK2 expression in melanoma cells induces autophagy and inhibits its proliferation, migration and invasion. CX-F9 directly binds to RSK2 and inhibits the kinase activity. CX-F9 significantly suppressed cell proliferation, induced autophagy, apoptosis and cycle arrest, as well as inhibited migration and invasion in SK-MEL-5 and SK-MEL-28 cells. Western blotting revealed that CX-F9 declined the activation of p-CREB. Moreover, CX-F9 inhibited tumor formation and metastasis in vivo. Furthermore, CX-F9 suppressed cell proliferation, migration, invasion in BRAF inhibitor resistant melanoma cells. These findings reveal a new RSK2 inhibitor CX-F9 could significantly suppressed malignant phenotype of melanoma in vitro and in vivo, which provide a novel strategy for melanoma treatment in clinic.

Vitrectomie diagnostique dans les inflammations intraoculaires : étude d’une série rétrospective

To determine the diagnostic and functional yield of vitrectomy in patients with uveitis of unknown origin. A single-centered retrospective study was performed on patients who underwent a diagnostic vitrectomy for uveitis in the Department of Ophthalmology of the Nancy University Hospital from January 2011to December 2016. Vitreous samples were analyzed in the cytology laboratory by cytological and immunohistochemical techniques, and in the microbiological laboratory by culture and bacterial, fungal and viral PCR, depending on clinical findings. Preoperative and one- and six-month postoperative visual acuity were collected and compared. Thirty-four patients (39vitrectomies) were included. Vitreous testing led to a diagnosis in 14out of 39cases (36%): 10intraocular lymphoma, 2amyloidosis, 1CMV retinitis, and 1choroidal metastasis of cutaneous melanoma with vitreous dissemination. Vitrectomy was negative in 20patients. Visual acuity improved from 1.2±0.7logMAR preoperatively to 0.8±0.7logMAR at 1month (p<0.001) and 0.9±0.8logMAR at 6months (p=0.054). In our study, diagnostic vitrectomy and vitreous fluid analysis were useful to diagnose uveitis of unknown origin, most of which were found to be intraocular lymphomas. Visual acuity improved for the majority of patients. Diagnostic vitrectomy with appropriate vitreous analysis related to clinical examination must be considered in the evaluation of uveitis of unknown origin.

Soluble PD-L1 is a potential biomarker of cutaneous melanoma aggressiveness and metastasis in obstructive sleep apnoea patients.

Obstructive sleep apnoea (OSA) upregulates the programmed cell death-1 receptor and its ligand (PD-L1) pathway, potentially compromising immunosurveillance. We compared circulating levels of soluble PD-L1 (sPD-L1) in patients with cutaneous melanoma according to the presence and severity ofOSA, and evaluated relationships with tumour aggressiveness and invasiveness.In a multicentre observational study, 360 patients with cutaneous melanoma underwent sleep studies, and serum sPD-L1 levels were assayed using ELISA. Cutaneous melanoma aggressiveness indices included mitotic rate, Breslow index, tumour ulceration, Clark level and tumour stage, and sentinel lymph node (SLN) metastasis was recorded as a marker of invasiveness.sPD-L1 levels were higher in severe OSA compared to mild OSA or non-OSA patients. In OSA patients, sPD-L1 levels correlated with Breslow index and were higher in patients with tumour ulceration, advanced primary tumour stages or with locoregional disease. The incorporation of sPD-L1 to the classic risk factors to SLN metastasis led to net improvements in the classification of 27.3%.Thus, sPD-L1 levels are increased in melanoma patients with severe OSA, and, in addition, might serve as a potential biomarker of cutaneous melanoma aggressiveness and invasiveness in this group of subjects.

Electrochemotherapy as an adjunct to the surgical management of metastatic melanoma: experience of the inspECT group (2008 to 2018)

Background. Electrochemotherapy is a treatment for tumours in the skin, both primary and metastatic. The international Network for sharing practices on Electrochemotherapy (InspECT) group gathers information on treatment outcomes in a common database with defined, outcome parameters in order to improve and guide the use of Electrochemotherapy (ECT). Over a period of 10 years we have investigated the effectiveness of ECT in cutaneous melanoma metastasis and identified factors which affect the outcome.

Remission of In-Transit Melanoma following Combination BRAF and MEK Inhibition Therapy: A Case Report

Satellite and in-transit melanoma represent the metastasis of cutaneous melanoma along lymphatics between the primary lesion and the regional lymph nodes. In-transit melanoma often presents as a reoccurrence of previously resected melanoma, and as such is associated with a poorer prognosis than primary melanoma. Response rate to therapy is often suboptimal, with 5-year survival rates of 24-54% at 5 years.

Positive margins after surgical excision of locoregional cutaneous melanoma metastasis and their impact on patient outcome.

For melanoma patients, surgery is a standard treatment for locoregional skin metastasis (LSM). To assess the frequency and risk factors for positive margins after excision of LSM and their impact on patient overall survival (OS) and progression-free survival (PFS). A monocentric, retrospective observational study was performed including 87 patients with LSM who had undergone surgical excision. Positive margins were found in 45% of patients after excision. After additional excision, 28% of patients still had positive margins. Interestingly, there was no difference in PFS or OS for clear margins after the first or additional excision or for margins that remained positive without additional excision. LSM size was the only identified predictive factor for positive margins. This is the first reported study investigating the frequency of, and risk factors for positive margins of cutaneous LSM, which raises the question of whether additional excision should be performed following positive margin excision.

Metastaza kutanog melanoma u žučnu kesu - prikaz slučaja

Melanoma is an aggressive malignant tumor that originates from melanocytes and most commonly occurs on the skin. Dominantly metastasize to regional lymph nodes, in the brain and lungs and rarely in the gastrointestinal (GI) system. The aim of this report is to present a rare case of metastasis of cutaneous malignant melanoma in the gallbladder, discovered 10 months after excision of the primary melanoma of the skin. A45-year-old patient was hospitalized in our hospital due to abdominal pain in right upper quadrant and nausea lasting for 7 days. An intraluminal substrate was found in the gallbladder with computed tomography and later a CT guied biopsy was performed on it, thus proving a metastatic deposit of primary malignant melanoma. Metastatic deposits in the gallbladder are extremely rare finding, and 238 cases have been described in the literature.

Mechanism underlying the inhibitory effect of overexpression of tumor suppressor gene DKK3 on migration and invasion of human cutaneous malignant melanoma cells

Objective To investigate the expression of DKK3 in human cutaneous malignant melanoma cells and tissues, and to evaluate the effect of transfection with DKK3 gene on migration and invasion of a malignant melanoma cell line A375. Methods Western blot analysis was performed to measure the relative expression of DKK3 in human cutaneous melanoma cell lines HM, A375, WM451, SK-MEL-1, Hs-695T, MDA-MB-435s and WM35, as well as pigmented nevus tissues. Real-time fluorescence-based quantitative PCR (RT-PCR) was conducted to determine the mRNA expression of DKK3 in 58 melanoma tissues (including primary melanoma and metastatic melanoma) and 30 pigmented nevus tissues from Chongqing Traditional Chinese Medicine Hospital between August 2014 and June 2017. The pcDNA3.1 (+) -Flag-Vector (control group) and pcDNA3.1 (+) -Flag-DKK3 (transfection group) were transfected into A375 melanoma cells separately. RT-PCR and Western blot analysis were performed to verify the overexpression of DKK3, and to evaluate the effect of DKK3 overexpression on the expression of molecules related to the migration and invasion of melanoma cells. Cell scratch assay, Transwell migration and invasion assay were conducted to assess the effect of DKK3 on the migration and invasion of A375 cells. Statistical analysis was done by a two-sample t-test for comparisons between two groups, one-way analysis of variance (ANOVA) for intergroup comparison, and least significant difference (LSD) -t test for multiple comparisons with the SPSS 13.0 software. Results DKK3 protein was absent or lowly expressed in the human melanoma cell lines, but highly expressed in the pigmented nevus tissues. There were significant differences in the mRNA expression of DKK3 among the primary melanoma tissues (2-ΔΔCt:[0.325 ± 0.150] × 10-3) , metastatic melanoma tissues ([0.142 ± 0.210] × 10-3) and pigmented nevus tissues ([0.634 ± 0.120] × 10-3, F = 46.57, P < 0.05) . In addition, the mRNA expression of DKK3 was significantly lower in the metastatic melanoma tissues than in the primary melanoma tissues and pigmented nevus tissues (LSD-t = 2.48, 3.12, both P < 0.05) . After transfection with DKK3, cell scratch assay showed that the migration rate was significantly lower in the transfection group (22.11% ± 5.11%) than in the control group (54.36% ± 23.22%, t = 2.36, P < 0.001) . Transwell migration and invasion assay revealed that the number of A375 cells crossing the Transwell chamber was significantly lower in the transfection group (265 ± 33, 76 ± 18 respectively) than in the control group (429 ± 41, 135 ± 21 respectively; t = 1.24, 1.35 respectively, both P < 0.001) . After overexpression of DKK3 in the A375 cells in the transfection group, the mRNA and protein expression of E-cadherin were up-regulated, while the mRNA and protein expression of N-cadherin, vimentin, matrix metalloproteinase 2 (MMP2) , MMP7 and MMP11 were down-regulated compared with the control group. Conclusions The expression of DKK3 is down-regulated in the melanoma cell lines and tissues, and the migration and invasion of A375 cells are markedly inhibited by overexpression of DKK3. DKK3 may be a target for inhibiting the metastasis of cutaneous malignant melanoma. Key words: Melanoma; Genes, tumor suppressor; Cell movement; Invasion; Dickkopf-related protein 3; A375 cells

Predictive genetic profiles for regional lymph node metastasis in primary cutaneous melanoma: a case-matched pilot study.

Melanoma confers an estimated lifetime risk of one in 50 for 2016. Clinicopathologic staging and sentinel lymph node biopsy (SLNB) have been the standard of care for T2 and T3 lesions. Molecular biomarkers identified in the primary lesion suggestive of metastatic potential may offer a more conclusive prognosis of these lesions. Our purpose was to investigate molecular mutations in primary melanoma that were predictive for micrometastasis as defined by a positive sentinel lymph node (SLN) in a case-controlled manner: nine patients with negative SLN and nine with positive SLN. The two cohorts were statistically identical as shown by a t-test for age (P=0.17), race (P=0.18), Breslow depth (P=0.14), Clark level (P=0.33), host response (P=0.17), ulceration (P=0.50), satellite nodules (P=0.17), lymphovascular invasion (P=0.50), and mitotic activity (P=0.09). While no single gene was significantly associated with SLN status, multivariate analysis using classification and regression tree assessment revealed two unique gene profiles that completely represented regional metastases in our cohort as defined by a positive SLN: PIK3CA (+) NRAS (-) and PIK3CA (-) ERBB4 (-) TP53 (+) SMAD4 (-). These profiles were identified in 89% of the patients with positive SLN; none of these profiles were identified in the SLN-negative cohort. We identified two unique gene profiles associated with positive SLN that do not overlap other studies and highlight the genetic complexity that portends the metastatic phenotype in cutaneous melanoma.

An unusual presentation of metastatic malignant melanoma causing jejuno-jejunal intussusception: a case report

BackgroundSmall bowel intussusception in adults is rarely encountered. In most cases small bowel intussusception is caused by benign neoplastic lesions, but metastasis of cutaneous malignant melanoma causing small bowel intussusception is rare. We present such a case of jejuno-jejunal intussusception with an intraluminal metastatic lesion acting as a lead point.Case presentationWe present a case of a 71-year-old Caucasian man who presented with small bowel obstruction. His medical history revealed that he had had a cutaneous malignant melanoma excised 7 years earlier and underwent total laryngectomy due to a metastasis 6 years later. The disease was classified as stage IV and he was receiving immunotherapy. An emergency abdominal computed tomography scan demonstrated small bowel obstruction, most probably caused by an intraluminal lesion. An emergency laparotomy revealed an intraluminal metastatic lesion causing jejuno-jejunal intussusception. Metastasectomy of the lesion was performed and 13 days later he was discharged.ConclusionsJejuno-jejunal intussusception with a malignant melanoma metastasis acting as a lead point is very rare. With the gastrointestinal tract being a common location of distal metastases, a medical history of malignant melanoma treatment in cases of small bowel obstruction should raise a suspicion of possible metastatic disease. A computed tomography scan is the diagnostic modality of choice and surgery still remains the standard of care.

Time to Procedure, Nuclear Imaging and Clinicopathological Characteristics as Predictive Factors for Sentinel Lymph Node Metastasis in Cutaneous Melanoma: A Single-Center Analysis.

Sentinel lymph node (SLN) biopsy is a widely accepted staging procedure for cutaneous melanoma patients who are at risk of clinically occult nodal metastases. Numerous predictive factors for regional lymph node metastases have been identified; however, few have been found to be reproducibly significant. Also, the role of blue dye in identification was questioned in recent trials. Time to procedure was also found to be predictive of SLN positivity, but this was not confirmed in other studies. In our study, predictive factors for metastatic involvement of SLN were analyzed, together with the role of addition blue dye in imaging on detection rate and false-negative SLN rate. An impact of time interval to procedure on the rate of SLN positivity was also explored. Data analysis was done in 362 cutaneous melanoma patients who underwent lymphoscintigraphy and SLN biopsy at our institution from 2010 to 2016, with a median follow-up of 29 months (1-98 months). To delineate the relation of each variable (demographical, time to procedure, and clinical and pathological variables, as well as the presence of in-transit nodes, the number of draining basins, and SLN localization on scintigraphy) with positive SLN status, we used univariate logistic regression with odds ratios representing effect size. Metastatic involvement SLN was found in 67 (18.8%) of 356 patients. Detection rate was similar with or without further intraoperative SLN identification with blue dye (98.8% vs 98.17%, P > 0.05). Time to procedure was not associated with higher SLN positivity rate (P > 0.05). In univariate analysis, Breslow thickness (P < 0.001), primary ulceration lesion (P = 0.001), and lymphovascular invasion (P = 0.006) were strongly correlated with SLN positivity, as well as the site of primary tumor (P = 0.024), tumor-infiltrating lymphocytes (TILs) (P = 0.021), and sex (P = 0.026). In multivariate analysis, Breslow thickness and TILs were found to be significant independent predictors of SLN status (P < 0.05). Addition of blue dye did not improve SLN detection rate; time to procedure was not found to be associated with higher SLN biopsy positivity rates. Breslow thickness and TILs, as a marker of immune response to tumor, were consistently found to be significant independent predictors of SLN status.

CHECKPOINT INHIBITOR IMMUNE THERAPY

To review immune checkpoint inhibitor indications and ophthalmic side effects. A literature review was performed using a PubMed search for publications between 1990 and 2017. Immune checkpoint inhibitors are designed to treat system malignancies by targeting one of three ligands, leading to T-cell activation for attack against malignant cells. These ligands (and targeted drug) include cytotoxic T-lymphocyte antigen-4 (CTLA-4, ipilimumab), programmed death protein 1 (PD-1, pembrolizumab, nivolumab), and programmed death ligand-1 (PD-L1, atezolizumab, avelumab, durvalumab). These medications upregulate the immune system and cause autoimmune-like side effects. Ophthalmic side effects most frequently manifest as uveitis (1%) and dry eye (1-24%). Other side effects include myasthenia gravis (n = 19 reports), inflammatory orbitopathy (n = 11), keratitis (n = 3), cranial nerve palsy (n = 3), optic neuropathy (n = 2), serous retinal detachment (n = 2), extraocular muscle myopathy (n = 1), atypical chorioretinal lesions (n = 1), immune retinopathy (n = 1), and neuroretinitis (n = 1). Most inflammatory side effects are managed with topical or periocular corticosteroids, but advanced cases require systemic corticosteroids and cessation of checkpoint inhibitor therapy. Checkpoint inhibitors enhance the immune system by releasing inhibition on T cells, with risk of autoimmune-like side effects. Ophthalmologists should include immune-related adverse events in their differential when examining cancer patients with new ocular symptoms.

A 3D Organotypic Melanoma Spheroid Skin Model.

Malignant transformation of melanocytes, the pigment cells of human skin, causes formation of melanoma, a highly aggressive cancer with increased metastatic potential. Recently, mono-chemotherapies continue to improve by melanoma specific combination therapies with targeted kinase inhibitors. Still, metastatic melanoma remains a life-threatening disease because tumors exhibit primary resistance or develop resistance to novel therapies, thereby regaining tumorigenic capacity. In order to improve the therapeutic success of malignant melanoma, the determination of molecular mechanisms conferring resistance against conventional treatment approaches is necessary; however, it requires innovative cellular in vitro models. Here, we introduce an in vitro three-dimensional (3D) organotypic melanoma spheroid model that can portray the in vivo architecture of malignant melanoma and may warrant new insights into intra-tumoral as well as tumor-host interactions. The model incorporates defined numbers of mature and differentiated melanoma spheroids in a 3D human full skin reconstruction model consisting of primary skin cells. The cellular composition and differentiation status of the embedded melanoma spheroids is similar to the one of cutaneous melanoma metastasis in vivo. Using this organotypic melanoma spheroid model as a drug screening platform may support the identification of responders to selected combination therapies, while sparing the unnecessary treatment burden for non-responders, thereby increasing the benefit of therapeutic interventions.

490 Samcyprone (diphenylcyclopropenone ointment) for the treatment of common warts

Diphenylcyclopropenone (DPCP) is a potent topical immunotherapy agent that has been used in a compounded form since the late 1970s by physicians for the treatment of common warts, alopecia areata, and cutaneous metastases of melanoma. Although not approved by the FDA or EMA, physicians continue to use compounded DPCP because of its proven effects in these dermatologic conditions. The use of the drug as reported in the literature is not standardized and widely varying strengths have been suggested for the sensitization and challenge treatments with DPCP, resulting in inconsistent results from a safety and efficacy viewpoint. RXi Pharmaceuticals has developed a proprietary ointment formulation of DPCP called Samcyprone that consists of a low sensitization (0.4% DPCP) dose followed by a standardized weekly treatment dose (0.04% DPCP) regimen. Cutaneous warts are benign epidermal tumors caused by human papillomaviruses (HPVs). A phase 2a clinical study was conducted evaluating Samcyprone (DPCP Sensitization and Treatment Ointments) for the treatment of common warts. The study was a multi-center, multi-dose trial conducted in subjects with at least one cutaneous, plantar or periungual wart present for at least four weeks. In this trial, subjects were first treated with a sensitization dose on the inner arm and on one or more preselected wart lesions. Once the sensitization response was confirmed, subjects continued with weekly treatments for 10 weeks. Wart clearance was evaluated based on the Investigators Global Assessment Score (IGAS) and wart measurements over time during the treatment period. Immunotherapeutic Skin Response Scores were also collected as a safety assessment of local reactions to be expected from a topical immunomodulator. Results show that while a sensitization reaction is a prerequisite for therapeutic response, the level of the reaction is not necessarily predicting the impact on wart clearance.

Laser-Assisted Delivery Of Cold Atmospheric Plasma In Unresectable Cutaneous Metastasis In Melanoma Patients

According to the World Health Organization, the incidence of melanoma is increasing faster than that of any other major cancer in the world. Melanoma is the fifth most common cancer in the United States, posing a substantial health and economic burden. Treatment of early and multiple cutaneous unresectable metastasis in melanoma patients is a major therapeutic problem. Cold atmospheric plasma (CAP) contains electrons, charged particles, radicals, various excited molecules, UV photons, and transient electric fields. These various compositional elements have the potential either to enhance cellular activity, or to disrupt it. In particular, based on this unique composition, CAP could offer a minimally-invasive surgical approach allowing for specific cancer cell or tumor tissue removal without influencing healthy cells. Topical application of treatment agents is a basic principle of dermatological therapy. However, the effective barrier function of the skin significantly impairs the bioavailability of most topical drugs. Fractional ablative lasers represent an innovative strategy to overcome the epidermal barrier in a standardized, contact-free manner. The bioavailability of topical agents can be significantly enhanced using laser-assisted delivery. Ablative fractional laser resurfacing creates vertical channels that might assist the delivery of topically applied cold plasma into cutaneous melanoma metastasis. For lesions refractory to elective treatments, the laser-assisted drug delivery technique combined with cold atmospheric plasma may present a new potential option. We report on a pilot study showing a proof of concept for enhancing topical cold atmospheric plasma permeation into depth by ablative fractional laser technique.

Prognostic factors for metastasis in cutaneous melanoma

BackgroundMelanoma 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.ObjectiveTo assess the influence of eight epidemiological and histopathologic features on the development of metastases in patients diagnosed with primary cutaneous melanoma.MethodsOur 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.ResultsFive 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 limitationsSmall number of patients in multivariate analysis.ConclusionsThe following prognostic factors to the development of melanoma metastasis were identified in the study: male gender, nodular histologic subtype, Breslow thickness > 4mm and ulceration.

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

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.

A multigene support vector machine predictor for metastasis of cutaneous melanoma.

Gene expression profiles of cutaneous melanoma were analyzed to identify critical genes associated with metastasis. Two gene expression datasets were downloaded from Gene Expression Omnibus (GEO) and another dataset was obtained from The Cancer Genome Atlas (TCGA). Differentially expression genes (DEGs) between metastatic and non-metastatic melanoma were identified by meta-analysis. A protein-protein interaction (PPI) network was constructed for the DEGs using information from BioGRID, HPRD and DIP. Betweenness centrality (BC) was calculated for each node in the network and the top feature genes ranked by BC were selected to construct the support vector machine (SVM) classifier using the training set. The SVM classifier was then validated in another independent dataset. Pathway enrichment analysis was performed for the feature genes using Fisher's exact test. A total of 798 DEGs were identified and a PPI network including 337 nodes and 466 edges was then constructed. Top 110 feature genes ranked by BC were included in the SVM classifier. The prediction accuracies for the three datasets were 96.8, 100 and 94.4%, respectively. A total of 11 KEGG pathways and 13 GO biological pathways were significantly over-represented in the 110 feature genes, including endometrial cancer, regulation of actin cytoskeleton, focal adhesion, ubiquitin mediated proteolysis, regulation of apoptosis and regulation of cell proliferation. A SVM classifier of high prediction accuracy was acquired. Several critical genes implicated in melanoms metastasis were also revealed. These results may advance understanding of the molecular mechanisms underlying metastasis, and also provide potential therapeutic targets.