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Melanoma is a malignancy of the skin in which melanocytes (the cells which give the skin it's colour) become cancerous. Melanoma occurs most frequently in white people, and is rare in people with dark skin; it is usually found in adults, though occasionally melanoma may develop in children and adolescents. Over exposure to sunlight can cause skin changes which can lead to melanoma. Half of all melanomas are thought to arise in a benign (non-cancerous) pigmented nevus (a mole). Moles are very common and normally change only slightly over time; however in melanoma there may be a more rapid increase in size - symptoms include a darker or variable discoloration, itching, and possibly ulceration and bleeding

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Intraocular Melanoma
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  • PubMed search for publications about Melanoma - Limit search to: [Reviews]

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    MeSH term: Melanoma
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Latest Research Publications

This list of publications is regularly updated (Source: PubMed).

Valentini V, Zelli V, Gaggiano E, et al.
MiRNAs as Potential Prognostic Biomarkers for Metastasis in Thin and Thick Primary Cutaneous Melanomas.
Anticancer Res. 2019; 39(8):4085-4093 [PubMed] Related Publications
BACKGROUND/AIM: The identification of novel prognostic biomarkers for melanoma metastasis is essential to improve patient outcomes. To this aim, we characterized miRNA expression profiles in relation to metastasis in melanoma and correlated miRNAs expression with clinical-pathological factors.
MATERIALS AND METHODS: MiR-145-5p, miR-150-5p, miR-182-5p, miR-203-3p, miR-205-5p and miR-211-5p expression levels were analyzed in primary cutaneous melanomas, including thin and thick melanomas, and in melanoma metastases by quantitative Real-Time PCR.
RESULTS: A significantly lower miR-205-5p expression was found in metastases compared to primary melanomas. Furthermore, a progressive down-regulation of miR-205-5p expression was observed from loco-regional to distant metastasis. Significantly lower miR-145-5p and miR-203-3p expression levels were found in cases with Breslow thickness >1 mm, high Clark level, ulceration and mitotic rate ≥1/mm

Liu FX, Ou W, Diede SJ, Whitman ED
Real-world experience with pembrolizumab in patients with advanced melanoma: A large retrospective observational study.
Medicine (Baltimore). 2019; 98(30):e16542 [PubMed] Related Publications
Pembrolizumab has been approved in the United States for treating advanced melanoma for >4 years. We examined real-world pembrolizumab use and associated outcomes in US oncology clinical practices, including patients who would not be eligible for clinical trials.Flatiron Health longitudinal database was used to identify adult patients with advanced melanoma initiating ≥1 dose of pembrolizumab from September 4, 2014, through December 31, 2016, with follow-up through December 31, 2017. Patients in any clinical trial during the study period were excluded. Overall survival (OS) and time on treatment from pembrolizumab initiation were analyzed using the Kaplan-Meier (KM) method. Subgroup analyses were conducted to examine OS for several patient characteristics including Eastern Cooperative Oncology Group (ECOG) performance status >1, brain metastases, and corticosteroids before pembrolizumab initiation.Pembrolizumab was administered to 315 (59%), 152 (29%), and 65 (12%) patients as first-, second-, and third-line/later therapy. Median age at pembrolizumab initiation was 68 years (range, 18-84); most patients were male (66%) and white (94%). Of those with available data, 38% had BRAF-mutant melanoma, 21% had elevated lactate dehydrogenase (LDH) level, and 23% had ECOG >1. Overall, 18% had brain metastases, and 23% were prescribed corticosteroids <3 months before initiating pembrolizumab. Median study follow-up was 12.9 months (range, 0.03-39.6). Median OS was 21.8 months (95% confidence interval [CI] 16.8-29.1); KM 1-year and 2-year survival rates were 61% and 48%, respectively; and median time on pembrolizumab treatment was 4.9 months (95% CI 3.7-5.5). Median OS for first-line pembrolizumab was not reached, and for second-line and third-line/later was 13.9 and 12.5 months, respectively (log-rank P = .0095). Significantly better OS (all P ≤.0014, log-rank test) was evident for patients with ECOG performance status (PS) of 0 to 1 (vs >1), normal (vs elevated) LDH level, and no (vs yes) corticosteroid prescription <3 months before. No difference was recorded in OS by brain metastases (log-rank P = .22) or BRAF mutation status (log-rank P = .90).These findings support effectiveness of pembrolizumab in the real-world clinical setting and provide important insights into patient characteristics and outcomes associated with pembrolizumab therapy for a heterogeneous patient population with advanced melanoma, including patients who would not be eligible for clinical trials.

Pang Y, Yuan H, Ren A, et al.
Primary malignant melanoma of the female genital tract synchronously involving the vulva and uterine cervix: A case report.
Medicine (Baltimore). 2019; 98(30):e16366 [PubMed] Related Publications
RATIONALE: Primary melanomas of the female genital tract are rare and usually occur in the vulva and vagina. Involvement of the cervix, uterus, and ovary are extremely rare. Surgery and adjuvant therapy remain the mainstay of treatment. The majority of patients experience poor long-term survival. This report aimed at highlighting an extremely rare case of primary melanoma of the female genitalia, synchronously involving the vulva and uterine cervix.
PATIENT CONCERNS: A 58-year-old multiparous female presented with postmenopausal bleeding for 10 days.
DIAGNOSES: Speculum examination and histologic analysis of the surgical specimens revealed synchronous involvement of the vulva and uterine cervix by malignant melanoma. According to the American Joint Committee on Cancer stage grouping for melanoma, this tumor was at stage V.
INTERVENTIONS: The patient subsequently underwent radical surgery and postoperative chemotherapy.
OUTCOMES: She has been on regular follow-up, and is now free of disease for 50 months after the operation.
LESSONS: Primary melanomas of the female genital tract have biologically aggressive characteristics. Optimal management consists of individualized surgery and adjuvant therapy. However, early recognition and prompt intervention offer maximal benefit from treatment.

Ji Y, Dai F, Yan S, et al.
Identification of Catechol-Type Diphenylbutadiene as a Tyrosinase-Activated Pro-oxidative Chemosensitizer against Melanoma A375 Cells via Glutathione
J Agric Food Chem. 2019; 67(32):9060-9069 [PubMed] Related Publications

Amrane K, Le Goupil D, Quere G, et al.
Prediction of response to immune checkpoint inhibitor therapy using 18F-FDG PET/CT in patients with melanoma.
Medicine (Baltimore). 2019; 98(29):e16417 [PubMed] Related Publications
We aimed to assess serial F-FDG PET/CT imaging according to morphological (RECIST1.1, iRECIST) and functional (PERCIST, PECRIT) criteria to predict clinical response to therapy in patients with advanced melanoma receiving immune checkpoint blocking agents.Retrospective data collection and analysis was done for 37 patients with unresectable metastatic cutaneous melanoma eligible for immunotherapy (cycles: 4 for ipilimumab and pembrolizumab/ 6 for nivolumab).F-FDG PET/CT imaging was performed prior to (F-FDG PET/CT 0) and 14 weeks after ICI onset (F-FDG PET/CT 1). Some cases during the follow-up required imaging (F-FDG PET/CT 2). Assessment of patient response to treatment was done according to RECIST1.1, iRECIST, PERCIST and PECRIT criteria.Among 37 assessed patients, 27 had 1 line of ICI, 8 had 2 lines of ICI and 2 patients had 3 lines of ICI: total of 49 PET/CTs. Mean time between initiation of ICI and F-FDG PET/CT (1 or 2) were respectively 13.82 ± 4.32 and 24.73 ± 9.53 weeks. Time between F-FDG PET/CT 1 and F-FDG PET/CT 2 was at mean +/- SD: 11.19w ± 5.59. Median PFS was 29.62 months (range 22.52-36.71) (P = .001: RECIST 1.1), (P < .0001: iRECIST), (P = .000: PERCIST), (P = .072: PECRIT). Median OS was 36.62 months (30.46-42.78) (P = .005: RECIST 1.1), (P < .0001: iRECIST), (P = .001: PERCIST), (P = .082 PECRIT).F-FDG PET/CT could detect eventual ICI-response in patients with metastatic melanoma undergoing ICI using iRECIST and PERCIST criteria.

Zhou J, Li J, Guleria I, et al.
Immunity to X-linked inhibitor of apoptosis protein (XIAP) in malignant melanoma and check-point blockade.
Cancer Immunol Immunother. 2019; 68(8):1331-1340 [PubMed] Article available free on PMC after 01/08/2020 Related Publications
Expression of inhibitors of apoptosis protein (IAP) family members is associated with poor prognosis in cancer patients. Immunity to ML-IAP (livin) and survivin has been well studied in patients with a variety of tumors. XIAP, the most potent inhibitor of apoptosis, is widely expressed in melanoma. To better define its potential role as an immunogenic target, cellular and humoral responses to XIAP were investigated in patients with advanced melanoma. An overlapping peptide library covering the full length of the XIAP protein was used to screen T cell responses of peripheral blood mononuclear cells (PBMC) from stage-IV melanoma patients treated with or without anti-CTLA4 (ipilimumab). The screen identified an array of peptides that predominantly induced CD4

Hsu KF, Chen CY, Chu TS, et al.
Scalp melanoma with rectus abdominis metastasis: A rare case report.
Medicine (Baltimore). 2019; 98(28):e16395 [PubMed] Article available free on PMC after 01/08/2020 Related Publications
RATIONALE: The main cause of death in melanoma patients is widespread metastases as it can metastasize to almost every organ. However, melanoma skeletal muscle metastases (MSMM) are exceptional, and only a few cases of MSMM to the rectus abdominis muscles have been previously described. And our case maybe the first reported case in Asia region.
PATIENT CONCERNS: A 45-year-old man with history of right scalp melanoma, pT3aN0M0, stage IIA status post wide excision with 2 cm safe margin and right neck lymph node dissection at 5 years before. He had an almost 5 years disease-free period but presented to our clinic due to intermittent abdominal sharp pain for 1 to 2 months, with a palpable soft tissue mass over his right abdomen. Metastatic melanoma to rectus abdominis muscles was highly suspected.
INTERVENTIONS: The patient subsequently underwent radical en-block extraperitoneal 15 cm segmental resection of the right rectus abdominis muscle including tumor mass. The resected tumor was a black-gray colored solid mass, and the final histologic study showed a metastasis of melanoma.
OUTCOMES: Postoperative course of the patient was uneventful, and the right abdominal pain was improved. The patient was referred for further target therapy, but passed away half a year later due to multiple metastasis.
LESSONS: Scalp melanoma with isolated rectus muscle metastasis is extremely rare especially for a young aged patient who had an almost 5-year disease-free period. Surgery is a potentially curative therapy for patients with isolated metastatic melanoma. The goal is negative resection margins, in order to avoid local recurrences. Radical compartmental surgery should be considered for selected stage IV melanoma patients with sole rectus abdominis MSMM, whose disease could be amenable to complete resection, in preliminary procedure to prolong disease-free survival time. For oligometastatic disease, surgical resection is sometimes useful in carefully selected patients after systemic therapy; also, it could be performed as symptomatic treatment.

Cowey CL, Liu FX, Boyd M, et al.
Real-world treatment patterns and clinical outcomes among patients with advanced melanoma: A retrospective, community oncology-based cohort study (A STROBE-compliant article).
Medicine (Baltimore). 2019; 98(28):e16328 [PubMed] Article available free on PMC after 01/08/2020 Related Publications
Recently, the effectiveness of novel immune checkpoint inhibitors and BRAF-directed therapies has been demonstrated in advanced melanoma trial populations. Limited research, however, has evaluated the impact of these therapies in a real-world setting. The aim of this study was to evaluate treatment patterns and clinical outcomes among advanced melanoma patients treated with modern therapies within community oncology clinics. Adult patients with advanced melanoma who initiated treatment within the US Oncology Network between 1/1/14 and 12/31/16 were included. Data were sourced from electronic healthcare records. Patients were followed through 12/31/17. Descriptive analyses were performed to assess patient and treatment characteristics and Kaplan-Meier methods were used for time-to-event outcomes. In total, 484 patients met eligibility criteria (32.0% with brain metastasis, 12.6% with Eastern Cooperative Oncology Group performance status ≥2). In the first-line (1L) setting during the study period, 37.0% received anti-PD1 monotherapies, 26.4% ipilimumab monotherapy, 19.8% BRAF/MEK combination therapy, 6.4% BRAF or MEK monotherapy, 4.1% ipilimumab/nivolumab combination therapy and 6.2% other regimens. Differences in baseline demographic and clinical characteristics were observed across treatment groups. For the overall study population, the median (95% confidence interval) estimates for overall survival, time to next treatment and progression-free survival were 20.7 (16.0, 26.8), 5.8 (5.3, 6.5), and 4.9 (4.2, 5.7) months, respectively. The results of this study provide real-world insight into advanced melanoma treatment trends and clinical outcomes, including high utilization of immunotherapies and BRAF/MEK combination therapy. Future research can explore underlying differences in patient subpopulations and the sequence of therapies across lines of therapy.

Utjés D, Malmstedt J, Teras J, et al.
2-cm versus 4-cm surgical excision margins for primary cutaneous melanoma thicker than 2 mm: long-term follow-up of a multicentre, randomised trial.
Lancet. 2019; 394(10197):471-477 [PubMed] Related Publications
BACKGROUND: The optimal surgical excision margins are uncertain for patients with thick (>2 mm) localised cutaneous melanomas. In our previous report of this multicentre, randomised controlled trial, with a median follow-up of 6·7 years, we showed that a narrow excision margin (2 cm vs 4 cm) did not affect melanoma-specific nor overall survival. Here, we present extended follow-up of this cohort.
METHODS: In this open-label, multicentre randomised controlled trial, we recruited patients from 53 hospitals in Sweden, Denmark, Estonia, and Norway. We enrolled clinically staged patients aged 75 years or younger diagnosed with localised cutaneous melanoma thicker than 2 mm, and with primary site on the trunk or upper or lower extremities. Patients were randomly allocated (1:1) to treatment either with a 2-cm or a 4-cm excision margin. A physician enrolled the patients after histological confirmation of a cutaneous melanoma thicker than 2 mm. Some patients were enrolled by a physician acting as responsible for clinical care and as a trial investigator (follow-up, data collection, and manuscript writing). In other cases physicians not involved in running the trial enrolled patients. Randomisation was done by telephone call to a randomisation office, by sealed envelope, or by computer generated lists using permuted blocks. Patients were stratified according to geographical region. No part of the trial was masked. The primary outcome in this extended follow-up study was overall survival and the co-primary outcome was melanoma-specific survival. All analyses were done on an intention-to-treat basis. The study is registered with ClinicalTrials.gov, number NCT03638492.
FINDINGS: Between Jan 22, 1992, and May 19, 2004, 936 clinically staged patients were recruited and randomly assigned to a 4-cm excision margin (n=465) or a 2-cm excision margin (n=471). At a median overall follow-up of 19·6 years (235 months, IQR 200-260), 621 deaths were reported-304 (49%) in the 2-cm group and 317 (51%) in the 4-cm group (unadjusted HR 0·98, 95% CI 0·83-1·14; p=0·75). 397 deaths were attributed to cutaneous melanoma-192 (48%) in the 2-cm excision margin group and 205 (52%) in the 4-cm excision margin group (unadjusted HR 0·95, 95% CI 0·78-1·16, p=0·61).
INTERPRETATION: A 2-cm excision margin was safe for patients with thick (>2 mm) localised cutaneous melanoma at a follow-up of median 19·6 years. These findings support the use of 2-cm excision margins in current clinical practice.
FUNDING: The Swedish Cancer Society, Stockholm Cancer Society, the Swedish Society for Medical Research, Radiumhemmet Research funds, Stockholm County Council, Wallström funds.

Li J, Shi SZ, Wang JS, et al.
Efficacy of melanoma patients treated with PD-1 inhibitors: Protocol for an overview, and a network meta-analysis of randomized controlled trials.
Medicine (Baltimore). 2019; 98(27):e16342 [PubMed] Article available free on PMC after 01/08/2020 Related Publications
BACKGROUND: Melanoma is a malignant tumor of melanocytes that produces pigments and can occur in the whole body. It is characterized by strong invasiveness, high metastasis rate and poor prognosis, and brings heavy burden to patients and society. In order to find the most effective and safe treatment measures, in this study, a network meta-analysis (NMA) for randomized controlled trials (RCTs) of advanced melanoma treated with PD-1 inhibitors will be conducted based on the existing systematic reviews (SRs) of PD-1 inhibitor in the treatment of advanced melanoma.
METHODS: PubMed, EMBASE, Web of Science and the Cochrane Library were searched on December 18, 2018 to obtain systematic reviews of PD-1 inhibitor in the treatment of advanced melanoma. Assessing the Methodological Quality of Systematic Reviews (AMSTAR2) will be used to assess the methodological quality of systematic reviews, Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach will be applied to evaluate the evidence quality of outcome measures, and the Cochrane's risk of bias tool will be utilized to appraise risks of bias of each embedded RCTs. And the outcomes are overall survival (OS), progression-free survival (PFS) and objective response rate (ORR). Hazard ratio (HR) or odds ratio (OR) with their 95% confidence interval (CI) were used to synthesize dichotomous outcomes, while the mean difference (MD) for the continuous variables. R3.5.1 will be used to create a network evidence map for direct and indirect comparative analysis.
RESULTS: This study will provide a comprehensive summary of the current evidences related to the efficacy and safety of PD-1 inhibitor in advanced melanoma.
CONCLUSION: Our findings will be useful to assist clinicians make reasonable decisions to the treatment of advanced melanoma.
ETHICS AND COMMUNICATION: It is unnecessary for this NMA to acquire an ethical approval, because it is based on published researches.

Song Y, Bruce AN, Fraker DL, Karakousis GC
Isolated limb perfusion and infusion in the treatment of melanoma and soft tissue sarcoma in the era of modern systemic therapies.
J Surg Oncol. 2019; 120(3):540-549 [PubMed] Related Publications
BACKGROUND AND OBJECTIVES: Isolated limb perfusion (ILP) and infusion (ILI) are treatment modalities for unresectable melanoma in-transit metastases and extremity soft tissue sarcomas (STS). We sought to characterize the national trend in their utilization in the context of novel melanoma therapies introduced in 2011.
METHODS: Using the National Inpatient Sample (2005-2014), patients with a primary diagnosis of limb melanoma or STS who underwent ILP/ILI were identified by diagnosis and procedure codes. Annual percent change (APC) in ILP/ILI procedures was determined.
RESULTS: From 2005 through 2014, 670 and 130 ILP/ILI procedures were performed for melanoma and STS, respectively. Mean age was 64 (SD 15) years for melanoma and 59 (SD 18) years for STS. Over time, procedures for melanoma decreased with an APC of -17 (P = .019). Comparing 2005-2010 and 2011-2014, the mean number of procedures for melanoma decreased from 91 to 32 per year (P = .007). In contrast, there was no change for STS (APC 6.5, P = .39; mean 11 and 16 per year in 2005-2010 and 2011-2014, respectively, P = .46).
CONCLUSIONS: ILI/ILP utilization has decreased for melanoma, but not for STS. Whether trends for ILP and ILI differed could not be determined. ILP/ILI remains an important option to consider for regional disease control.

Zhou AY, Wang DY, McKee S, et al.
Correlates of response and outcomes with talimogene laherperpvec.
J Surg Oncol. 2019; 120(3):558-564 [PubMed] Related Publications
BACKGROUND AND OBJECTIVES: Patients with in-transit or limited cutaneous metastatic melanoma may benefit from intralesional injections with talimogene laherparepvec (TVEC), a modified oncolytic herpesvirus. However, its use in patients with adverse prognostic scores in a real-life clinical setting has not been studied.
METHODS: We performed a two-center retrospective analysis of 40 patients with metastatic melanoma treated with TVEC from 2015-2017. Demographics, overall response, and survival after therapy were noted.
RESULTS: Overall, there was a durable response rate of 40%; median progression-free survival (PFS) was 10.5 months and median overall survival (OS) was not reached. Bulky disease was associated with decreased OS (15.7 months vs not reached, P < .05) and mPFS (2.3 months vs not reached, P < .05), when compared with smaller tumors. Poor performance status (ECOG 2-3) was associated with worse OS (10.2 months vs not reached, P < .05) and PFS (2.1 months vs not reached, P < .05) compared to patients with ECOG 0-1. There was no difference in the outcomes with age greater than 75 or with prior therapies. Adverse events were relatively tolerable.
CONCLUSIONS: These findings demonstrate that TVEC is an effective and safe treatment for metastatic melanoma in a real-life clinical setting, and suggest parameters to aid in appropriate therapy selection for optimal response.

Marjanska A, Galazka P, Marjanski M, et al.
Efficacy and Toxicity of Pembrolizumab in Pediatric Metastatic Recurrent Melanoma.
Anticancer Res. 2019; 39(7):3945-3947 [PubMed] Related Publications
BACKGROUND/AIM: Malignant melanoma is a rare disease in the pediatric population and there are no recommendations regarding its management in children, while the current standard of care in metastatic or unresectable melanoma in adult patients includes immunotherapy (anti-CTLA-4 and anti-PD-1 antibodies). Advances in the management of adults with melanoma offer the prospect of promising therapeutic options for children.
CASE REPORT: We describe a case of a 7-year-old patient with recurrent metastatic melanoma, for whom pembrolizumab was used as an adjuvant therapy on compassionate use basis.
CONCLUSION: Due to adverse events, the treatment was discontinued after 5 months of pembrolizumab, but with 12-months of follow-up, patient remains in complete remission.

Manaster Y, Shipony Z, Hutzler A, et al.
Reduced CTL motility and activity in avascular tumor areas.
Cancer Immunol Immunother. 2019; 68(8):1287-1301 [PubMed] Related Publications
Patchy infiltration of tumors by cytotoxic T cells (CTLs) predicts poorer prognosis for cancer patients. The factors limiting intratumoral CTL dissemination, though, are poorly understood. To study CTL dissemination in tumors, we histologically examined human melanoma samples and used mice to image B16-OVA tumors infiltrated by OT-I CTLs using intravital two-photon microscopy. In patients, most CTLs concentrated around peripheral blood vessels, especially in poorly infiltrated tumors. In mice, OT-I CTLs had to cluster around tumor cells to efficiently kill them in a contact-and perforin-dependent manner and cytotoxicity was strictly antigen-specific. OT-I CTLs as well as non-specific CTLs concentrated around peripheral vessels, and cleared the tumor cells around them. This was also the case when CTLs were injected directly into the tumors. CTLs crawled rapidly only in areas within 50 µm of flowing blood vessels and transient occlusion of vessels immediately, though reversibly, stopped their migration. In vitro, oxygen depletion and blockade of oxidative phosphorylation also reduced CTL motility. Taken together, these results suggest that hypoxia limits CTL migration away from blood vessels, providing immune-privileged niches for tumor cells to survive. Normalizing intratumoral vasculature may thus synergize with tumor immunotherapy.

Ao W, Wang J, Mao G, et al.
Primary hepatic melanoma: A case report of computed tomography and magnetic resonance imaging findings.
Medicine (Baltimore). 2019; 98(25):e16165 [PubMed] Article available free on PMC after 01/08/2020 Related Publications
RATIONALE: Malignant melanoma predominantly develops in middle-aged and older adults, most commonly occurring on the skin and rarely on internal organs. Malignant melanoma originating in the liver is extremely rare. Imaging findings of primary hepatic melanoma (PHM) are scarce in relevant literature.
PATIENT CONCERNS: The patient was a 69-year-old woman from Zhejiang, China, who was admitted to the hospital because of upper abdominal pain that persisted for >10 days.
DIAGNOSES: Computed tomography (CT) findings indicated the presence of a circular low-density shadow of approximately 7.5 × 8.0 cm in the hepatic hilar region. Magnetic resonance imaging (MRI) indicated a heterogeneous solid cystic mass in the hepatic hilar region. The mass exhibited heterogeneous low-signal intensity on a T1-weighted image (T1WI) and slightly higher signal intensity on a T2-weighted image (T2WI). The tumor appeared as multiple irregular strips with high-signal intensity on T1WI and low-signal intensity on T2WI. The diffusion-weighted image revealed increased signal intensity. The tumor continued to be enhanced after enhancement. Clinical data suggested that the tumor was a malignant liver tumor.
INTERVENTIONS: The patient underwent a CT guide puncture hepatic biopsy. The tumor was located in the hepatic hilar region adjacent to the large blood vessels and invaded the portal vein. Because a resection was highly risky, conservative treatment was conducted.
OUTCOMES: Postoperative pathology and clinical examination confirmed that the tumor was malignant PHM. The patient has been followed up for 6 months. The patient underwent CT reexamination 2 months after conservative treatment, the results of which revealed that the tumor progressed. Multiple lesions were identified; moreover, the tumor size had increased and the tumor had invaded the portal vein and intrahepatic bile duct. The patient was reexamined by CT in another hospital 6 months after conservative treatment. The results revealed peritoneal, omental metastases and multi bone metastases.
LESSONS: To our best knowledge, this is the first reported case of a PHM with complete imaging data, including preoperative CT and MRI examinations and a follow-up CT examination. From compiling the CT and MRI findings of this patient and those of relevant studies, this study can serve as a reference for the preoperative diagnosis and differential diagnosis of PHM.

Koumantou D, Barnea E, Martin-Esteban A, et al.
Editing the immunopeptidome of melanoma cells using a potent inhibitor of endoplasmic reticulum aminopeptidase 1 (ERAP1).
Cancer Immunol Immunother. 2019; 68(8):1245-1261 [PubMed] Article available free on PMC after 01/08/2020 Related Publications
The efficacy of cancer immunotherapy, including treatment with immune-checkpoint inhibitors, often is limited by ineffective presentation of antigenic peptides that elicit T-cell-mediated anti-tumor cytotoxic responses. Manipulation of antigen presentation pathways is an emerging approach for enhancing the immunogenicity of tumors in immunotherapy settings. ER aminopeptidase 1 (ERAP1) is an intracellular enzyme that trims peptides as part of the system that generates peptides for binding to MHC class I molecules (MHC-I). We hypothesized that pharmacological inhibition of ERAP1 in cells could regulate the cellular immunopeptidome. To test this hypothesis, we treated A375 melanoma cells with a recently developed potent ERAP1 inhibitor and analyzed the presented MHC-I peptide repertoire by isolating MHC-I, eluting bound peptides, and identifying them using capillary chromatography and tandem mass spectrometry (LC-MS/MS). Although the inhibitor did not reduce cell-surface MHC-I expression, it induced qualitative and quantitative changes in the presented peptidomes. Specifically, inhibitor treatment altered presentation of about half of the total 3204 identified peptides, including about one third of the peptides predicted to bind tightly to MHC-I. Inhibitor treatment altered the length distribution of eluted peptides without change in the basic binding motifs. Surprisingly, inhibitor treatment enhanced the average predicted MHC-I binding affinity, by reducing presentation of sub-optimal long peptides and increasing presentation of many high-affinity 9-12mers, suggesting that baseline ERAP1 activity in this cell line is destructive for many potential epitopes. Our results suggest that chemical inhibition of ERAP1 may be a viable approach for manipulating the immunopeptidome of cancer.

Arozarena I, Wellbrock C
Phenotype plasticity as enabler of melanoma progression and therapy resistance.
Nat Rev Cancer. 2019; 19(7):377-391 [PubMed] Related Publications
Malignant melanoma is notorious for its inter- and intratumour heterogeneity, based on transcriptionally distinct melanoma cell phenotypes. It is thought that these distinct phenotypes are plastic in nature and that their transcriptional reprogramming enables heterogeneous tumours both to undergo different stages of melanoma progression and to adjust to drug exposure during treatment. Recent advances in genomic technologies and the rapidly expanding availability of large gene expression datasets have allowed for a refined definition of the gene signatures that characterize these phenotypes and have revealed that phenotype plasticity plays a major role in the resistance to both targeted therapy and immunotherapy. In this Review we discuss the definition of melanoma phenotypes through particular transcriptional states and reveal the prognostic relevance of the related gene expression signatures. We review how the establishment of phenotypes is controlled and which roles phenotype plasticity plays in melanoma development and therapy. Because phenotype plasticity in melanoma bears a great resemblance to epithelial-mesenchymal transition, the lessons learned from melanoma will also benefit our understanding of other cancer types.

Su FF, Chen JL
Expression and clinical significance of p16 and Ki-67 in malignant melanoma of the conjunctiva.
J Biol Regul Homeost Agents. 2019 May-Jun; 33(3):821-825 [PubMed] Related Publications

Yang J, Pan Z, Zhao F, et al.
A nomogram for predicting survival in patients with nodular melanoma: A population-based study.
Medicine (Baltimore). 2019; 98(24):e16059 [PubMed] Article available free on PMC after 01/08/2020 Related Publications
The use of traditional American Joint Committee on Cancer (AJCC) staging alone has limitations in predicting patient survival with nodular melanoma (NM). We aimed to establish a comprehensive prognostic nomogram and compare its prognostic value with the AJCC staging system.A nomogram was constructed to predict the 3-year and 5-year survival rates of NM patients by Cox regression. Several common model-validation parameters were used to evaluate the performance of our survival model.The multivariate analyses demonstrated that the age at diagnosis; being divorced, separated, or widowed; AJCC stages II, III, and IV; a regional SEER stage and the lymph-node density (LND) were risk factors for survival. The concordance index, the area under the time-dependent receiver operating characteristic curve, and calibration plots indicated that the nomogram performed well, while the net reclassification improvement and the integrated discrimination improvement showed that the nomogram performed better than the AJCC staging system. Finally, the decision curve analyses curves of the nomogram yielded net benefits that were higher than when using AJCC staging system with either the training or the validation cohort.The prognostic value of the nomogram is better than that of the AJCC staging system alone. In addition, we found that LND is an important risk factor for the survival of NM patients. The nomogram developed in this study may be a valuable tool for clinical practice when advising patients about their survival risk over the next 3 to 5 years.

Zhang Q, Xiong M, Liu J, et al.
Targeted nanoparticle-mediated LHPP for melanoma treatment.
Int J Nanomedicine. 2019; 14:3455-3468 [PubMed] Article available free on PMC after 01/08/2020 Related Publications

Bruner P, Bashline B
Skin Cancer: Precancers.
FP Essent. 2019; 481:23-27 [PubMed] Related Publications
Actinic keratoses (AKs) are common skin lesions caused by cumulative sun exposure. Rates of lesion progression to squamous cell carcinoma (SCC) have been reported to be between 0.025% and 16%, some lesions may regress. Atypical moles are melanocytic nevi that indicate a higher risk of melanoma and, on rare occasions, transform into malignant melanoma, particularly in patients with dysplastic nevus syndrome or familial atypical multiple mole-melanoma syndrome. Precancerous lesions can be identified by physical examination; diagnostic accuracy is enhanced by dermatoscopy. Biopsy is indicated when definitive diagnosis is deemed necessary for suspicious lesions. AKs can be managed with surgical methods, topical chemotherapeutic drugs, or photodynamic therapy. Complications of AKs include itching, pain, cosmetic concerns, and progression to SCC. Management of dysplastic nevi depends on the degree of atypia present. Lesions may be observed in cases of mild atypia with positive histologic margins but negative clinical margins. Dysplastic nevi with a high degree of atypia should be surgically excised or the patient should be referred to a dermatology subspecialist. Complications of atypical nevi include cosmetic concerns, recurrence, and rare progression to melanoma. Surveillance of precancerous lesions should include patient self-examination and regular follow-up skin examinations performed by the physician.

Pérez LL, Bashline B
Skin Cancer: Melanoma.
FP Essent. 2019; 481:11-16 [PubMed] Related Publications
Melanoma is associated with the highest mortality rate among commonly diagnosed skin cancers. Intense intermittent exposure to UV radiation via sunlight is the most significant risk factor. A history of sunburns is another major factor. Patients with suspicious lesions or nevi typically ask about them during primary care visits, so it is imperative that primary care clinicians learn to recognize them. Clinicians and patients can apply the ABCDE (Asymmetry, irregular Borders, Color variation, Diameter greater than 6 mm, Evolution over time) criteria to monitor suspicious lesions. Dermatoscopy can aid clinicians in assessment. If melanoma is suspected, excisional biopsy is preferred over incisional biopsy. After a diagnosis of melanoma is confirmed, a multidisciplinary approach to management is needed, with involvement of a dermatology subspecialist and possibly an oncology subspecialist. Surgical excision is performed for early stage melanoma, and surgical excision with wide margins and possible sentinel lymph node biopsy for stages IB or II. For patients with metastatic disease, a combination of targeted therapy and immunotherapy is recommended. After initial treatment, patients should undergo follow-up examinations on a regular schedule. All patients diagnosed with stage IA to IV melanoma should undergo skin examinations at least annually for their lifetime.

Angela Y, Haferkamp S, Weishaupt C, et al.
Combination of denosumab and immune checkpoint inhibition: experience in 29 patients with metastatic melanoma and bone metastases.
Cancer Immunol Immunother. 2019; 68(7):1187-1194 [PubMed] Related Publications
BACKGROUND: PD-1 inhibition (PD-1i) is the standard of care in melanoma and other malignancies. In patients with bone metastases of solid tumors, the monoclonal antibody denosumab directed against RANKL is approved for the prevention of skeletal-related events. However, RANKL is not only relevant in osteoclastogenesis, but also has immunological effects. Hence, we aimed at investigating, whether the combination of PD-1i and denosumab produces synergistic effects in metastatic melanoma treatment.
METHODS: We retrospectively collected and analyzed clinical data of metastatic melanoma patients with bone metastases, who received PD-1i and denosumab therapy.
RESULTS: 29 patients were identified with a median age of 60.7 years: 20 were male and 9 were female. 20 patients (69%) were in stage IV M1c and 9 (31%) in stage IV M1d; 52% had an increased serum LDH. 24 patients (83%) received PD-1i as first-line therapy and five patients (17%) as second- or third-line therapy. 13 patients received the triple combination nivolumab, ipilimumab and denosumab (N + I+D), 16 patients received PD-1i and denosumab (PD-1i + D). Within a median follow-up time of 19.8 months, 17 patients progressed with a median time to progression of 6 months. The objective response rate was 54% in the N + I + D group and 50% in the PD-1i + D group. Recalcification of bone metastases was radiologically observed in 18 (62%) patients. No unexpected treatment-related adverse events emerged.
CONCLUSIONS: The combination therapy of metastatic melanoma with PD-1i and denosumab was feasible without unexpected safety issues and showed a promising efficacy signal. Further investigation in prospective studies is needed.

Kwon J, Kim YA, Lee C, et al.
Clinical Outcomes of Isolated Regional Lymph Node Recurrence in Patients With Malignant Cutaneous Melanoma.
Anticancer Res. 2019; 39(6):3147-3157 [PubMed] Related Publications
BACKGROUND/AIM: Regional lymph node recurrence (RLNR) is the most common pattern of recurrence within 2 years from the diagnosis of patients with non-metastatic malignant cutaneous melanoma. However, isolated RLNR without distant metastasis has been rarely studied.
PATIENTS AND METHODS: Forty patients with isolated RLNR as a first recurrence were analyzed retrospectively. The clinical outcomes and prognostic impact of clinicopathologic parameters were analyzed. Immunostaining for FOXP3, VEGF, pAKT, and pS6 was also performed.
RESULTS: The median disease-free interval from first diagnosis to isolated RLNR and post-recurrence recurrence-free survival (pRFS) were 12 months and 7.2 months, respectively. Distant failure was the most common pattern of failure after isolated RLNR (67.5%). The number of initially harvested lymph nodes (LN) >7 and LN ratio >22.2% at the time of recurrence were prognosticators for pRFS in multivariate analysis. None of the tested biomarkers were significantly related to prognosis. The 5-year post-recurrence overall survival rate was 84.9%.
CONCLUSION: Most patients with isolated RLNR will experience a second failure within months, especially distantly. The number of initially harvested LNs and LN ratio at the time of recurrence could predict pRFS.

Rossi E, Pagliara MM, Orteschi D, et al.
Pembrolizumab as first-line treatment for metastatic uveal melanoma.
Cancer Immunol Immunother. 2019; 68(7):1179-1185 [PubMed] Article available free on PMC after 01/08/2020 Related Publications
BACKGROUND: No standard treatment has been defined for metastatic uveal melanoma (mUM). Although clinical trials testing Nivolumab/Pembrolizumab for cutaneous melanoma did not include mUM, anti PD-1 agents are commonly used for this disease.
PATIENTS AND METHODS: In this prospective observational cohort single arm study, we investigated efficacy and safety of Pembrolizumab as first-line therapy for mUM. The efficacy was evaluated in terms of progression-free survival (PFS), response rate and overall survival (OS). Toxicity was also assessed.
RESULTS: Seventeen patients were enrolled. A median of 8 cycles were administered (range 2-28). Two patients achieved partial response (11.7%), 6 a disease stabilization (35.3%), whereas 9 (53%) had a progression. No complete response was observed. PFS of the overall population was 3.8 months. PFS was 9.7 months for patients with an interval higher than 5 years from diagnosis of primary tumor to metastatic disease and 2.6 months for patients with an interval lower than 5 years [p = 0.039, HR 0.2865 (95% CI 0.0869-0.9443)]. Median OS was not reached. The two responding patients were still on treatment with Pembrolizumab at the time of data analysis. Survival was 12.8 months for patients with clinical benefit, while OS for progressive patients was 3.1 months. PD-L1 expression and genomic abnormalities predictive of relapse after diagnosis of primary tumor were not associated with PFS. Toxicity was mild, without grade 3-4 side effects.
CONCLUSIONS: The efficacy of Pembrolizumab does not seem particularly different when compared to other agents for mUM, but responding patients had a remarkable disease control.

Moya-Plana A, Herrera Gómez RG, Rossoni C, et al.
Evaluation of the efficacy of immunotherapy for non-resectable mucosal melanoma.
Cancer Immunol Immunother. 2019; 68(7):1171-1178 [PubMed] Related Publications
BACKGROUND: Immune checkpoint inhibitors are now standard-of-care treatments for metastatic cutaneous melanoma. However, for rare sub-groups, such as mucosal melanomas, few published data are available, and with no established therapeutic guidelines. Our objective was to assess the response to anti-CTLA4 and anti-PD1 immunotherapy in patients with mucosal melanomas.
METHODS: We performed a single-center, prospective cohort analysis of patients with non-surgical locally advanced and/or metastatic mucosal melanoma receiving anti-CTLA4 and/or anti-PD1 immunotherapy from 2010 to 2016.
RESULTS: Forty-four patients were enrolled, including 18 (40.9%) with head and neck, 12 (27.3%) with vulvo-vaginal and 14 (31.8%) with ano-rectal primary tumours. Eleven (25%) patients had stage 3 disease, and 11 (25%) had distant metastases. The first-line immunotherapy was ipilimumab in 24 patients and pembrolizumab in 20. The objective response rate (ORR) was 8.2% (one complete response) for ipilimumab and 35% (four complete responses) for pembrolizumab. No significant difference was observed for primary tumour location. The median follow-up was 24 months (range 4-73). The median progression-free survival (PFS) in the first-line ipilimumab and pembrolizumab groups was 3 months [95% confidence interval (CI) 2.5-4.6] and 5 months (95% CI 2.6-33.1), respectively (p = 0.0147).
CONCLUSION: In the patients with unresectable and/or metastatic mucosal melanoma, we found ORR and PFS rates comparable to those in patients with cutaneous melanoma, with no significant differences in the types of mucosal surfaces involved. Anti-PD1 therapy has a more favorable benefit-risk ratio than ipilimumab and should be used preferentially.

Ribas A, Lawrence D, Atkinson V, et al.
Combined BRAF and MEK inhibition with PD-1 blockade immunotherapy in BRAF-mutant melanoma.
Nat Med. 2019; 25(6):936-940 [PubMed] Related Publications
Oncogene-targeted therapy with B-Raf proto-oncogene (BRAF) and mitogen-activated protein kinase kinase (MEK) inhibitors induces a high initial response rate in patients with BRAF

Ascierto PA, Ferrucci PF, Fisher R, et al.
Dabrafenib, trametinib and pembrolizumab or placebo in BRAF-mutant melanoma.
Nat Med. 2019; 25(6):941-946 [PubMed] Related Publications
Blocking programmed death 1 (PD-1) may enhance the durability of anti-tumor responses that are induced by the combined inhibition of BRAF and MEK

Sullivan RJ, Hamid O, Gonzalez R, et al.
Atezolizumab plus cobimetinib and vemurafenib in BRAF-mutated melanoma patients.
Nat Med. 2019; 25(6):929-935 [PubMed] Related Publications
Melanoma treatment has progressed in the past decade with the development and approval of immune checkpoint inhibitors targeting programmed death 1 (PD-1) or its ligand (PD-L1) and cytotoxic T lymphocyte-associated antigen 4, as well as small molecule inhibitors of BRAF and/or MEK for the subgroup of patients with BRAF

Robert C, Grob JJ, Stroyakovskiy D, et al.
Five-Year Outcomes with Dabrafenib plus Trametinib in Metastatic Melanoma.
N Engl J Med. 2019; 381(7):626-636 [PubMed] Related Publications
BACKGROUND: Patients who have unresectable or metastatic melanoma with a
METHODS: We analyzed pooled extended-survival data from two trials involving previously untreated patients who had received BRAF inhibitor dabrafenib (at a dose of 150 mg twice daily) plus MEK inhibitor trametinib (2 mg once daily) in the COMBI-d and COMBI-v trials. The median duration of follow-up was 22 months (range, 0 to 76). The primary end points in the COMBI-d and COMBI-v trials were progression-free survival and overall survival, respectively.
RESULTS: A total of 563 patients were randomly assigned to receive dabrafenib plus trametinib (211 in the COMBI-d trial and 352 in the COMBI-v trial). The progression-free survival rates were 21% (95% confidence interval [CI], 17 to 24) at 4 years and 19% (95% CI, 15 to 22) at 5 years. The overall survival rates were 37% (95% CI, 33 to 42) at 4 years and 34% (95% CI, 30 to 38) at 5 years. In multivariate analysis, several baseline factors (e.g., performance status, age, sex, number of organ sites with metastasis, and lactate dehydrogenase level) were significantly associated with both progression-free survival and overall survival. A complete response occurred in 109 patients (19%) and was associated with an improved long-term outcome, with an overall survival rate of 71% (95% CI, 62 to 79) at 5 years.
CONCLUSIONS: First-line treatment with dabrafenib plus trametinib led to long-term benefit in approximately one third of the patients who had unresectable or metastatic melanoma with a

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