The incidence of second primary invasive melanoma in Queensland, 1982–2003

OBJECTIVE: To describe the incidence of second primary invasive melanoma. METHODS: Data describing 52,997 subjects with melanoma notified to The Queensland Cancer Registry between 1982 and 2003. We calculated incidence rates of second primary invasive melanoma (per 1,000 person-years) by sex, age, and characteristics of the first primary. RESULTS: The rate of second primary invasive melanoma was relatively constant over 20 years of follow-up at 6.01 per 1,000 person-years indicating a high, constant lifetime risk of second primary invasive melanoma. Rates were 62% higher in males than in females and increased with age at first diagnosis with the rate in older patients (80+ years) more than double the rate observed in younger patients (40-49 years). Rates in patients with melanomas thicker than 2 mm were over 50% higher than in patients with thinner melanomas. CONCLUSIONS: Melanoma patients are at high risk of a second primary invasive melanoma. This risk does not diminish with time and does not differ significantly between patients first diagnosed with lentigo maligna, in situ melanoma or invasive melanoma. These results indicate that all melanoma patients require lifetime surveillance. Current treatment guidelines should be modified to reflect this.     

Role of bacillus Calmette-Guérin in the treatment of advanced melanoma

Early trials of Bacillus Calmette-Guérin (BCG)-based immunotherapy for melanoma consistently show a trend toward improved clinical outcomes in patients treated with BCG compared with observation alone. As an extension of these findings, investigators have initiated the Malignant Melanoma Active Immunotherapy (MMAIT) trials in patients with stage III (MMAIT-III) and stage IV (MMAIT-IV) disease. The overall survival of the patients receiving BCG plus placebo was much better than expected in both studies, thus suggesting a potential for BCG as an adjuvant after the resection of advanced disease. The work contained herein will explore the clinical rationale for adjuvant BCG in future trials focused on the treatment of patients with advanced malignant melanoma.     

Advances in treatment of melanoma with immunotherapy北大核心CSCD

Immunotherapy, primarily headed by immune checkpoint inhibitors, has become a standard, first-line therapeutic methodin treatment for patients with melanoma. Combination immunotherapy, that is the combination of programmed cell death-1 (PD-1) inhibitor and cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) inhibitor, further enhanced the anti-tumor efficacy, improved the objective response rate, and extended both the overall and progressionfree survival of patients in the past years. Therefore, combination immunotherapy has also become a new direction for the treatment of melanoma. Meanwhile, the anti-tumor effects and clinical outcomes of combination immunotherapy in other types of tumors are also encouraging. Combination immunotherapy offers a new treatment option for patients, but there are still many issues that need to be further discussed. In order to maximize the benefit of patients, more large-scale clinical researches are needed to answer the questions which may strongly affect the clinical decisions, such as, how to optimize the regimens of combination therapy, how to identify the appropriate treatment population, and how to balance the risk-benefit ratio of patients. Copyright © 2017 by TUMOR All rights reserved.     

Ultraviolet exposure of melanoma cells induces fibroblast activation protein-α in fibroblasts: Implications for melanoma invasion

Fibroblast activation protein-α (FAP-α) promotes tumor growth and cell invasiveness through extracellular matrix degradation. How ultraviolet radiation (UVR), the major risk factor for malignant melanoma, influences the expression of FAP-α is unknown. We examined the effect of UVR on FAP-α expression in melanocytes, keratinocytes and fibroblasts from the skin and in melanoma cells. UVR induces upregulation of FAP-α in fibroblasts, melanocytes and primary melanoma cells (PM) whereas keratinocytes and metastatic melanoma cells remained FAP-α negative. UVA and UVB stimulated FAP-α-driven migration and invasion in fibroblasts, melanocytes and PM. In co-culture systems UVR of melanocytes, PM and cells from regional metastases upregulated FAP-α in fibroblasts but only supernatants from non-irradiated PM were able to induce FAP-α in fibroblasts. Further, UV-radiated melanocytes and PM significantly increased FAP-α expression in fibroblasts through secretory crosstalk via Wnt5a, PDGF-BB and TGF-β1. Moreover, UV radiated melanocytes and PM increased collagen I invasion and migration of fibroblasts. The FAP-α/DPPIV inhibitor Gly-ProP(OPh)2 significantly decreased this response implicating FAP-α/DPPIV as an important protein complex in cell migration and invasion. These experiments suggest a functional association between UVR and FAP-α expression in fibroblasts, melanocytes and melanoma cells implicating that UVR of malignant melanoma converts fibroblasts into FAP-α expressing and ECM degrading fibroblasts thus facilitating invasion and migration. The secretory crosstalk between melanoma and tumor surrounding fibroblasts is mediated via PDGF-BB, TGF-β1 and Wnt5a and these factors should be evaluated as targets to reduce FAP-α activity and prevent early melanoma dissemination.     

Prognostic significance of β2-adrenergic receptor expression in malignant melanoma

Tumor Biology - Recent studies cite β2-adrenergic receptor (β2AR) antagonists as novel therapeutic agents for melanoma, as they may reduce the disease progression. The β2AR has shown...     

A Wnt-er Wonderland—The complexity of Wnt signaling in melanoma

Wnt signaling is a complex process that requires the interplay of several different proteins. In addition to a large cohort of Wnt ligands, and frizzled receptors, some Wnt pathways also require the presence of co-receptors. Wnt ligands may activate one of three pathways, the canonical pathway, involving β -catenin, the planar cell polarity pathway and the Wnt/ calcium pathway. All three pathways have different results for the cells in which they signal. Aberrant activation of these pathways can lead to the development and progression of several cancers. In this review we will discuss the different Wnt pathways, and their contribution to melanoma progression.     

Prospective evaluation of follow-up in melanoma patients in Germany – Results of a multicentre and longitudinal study

BackgroundPatient numbers requiring long-term melanoma surveillance are constantly rising. Surveillance is costly and guideline recommendations vary substantially.MethodsIn this German nationwide study, information on surveillance and treatment of patients diagnosed with melanoma and melanoma in situ (MMis) between April and June 2008 was prospectively collected over four years. Additionally, patient self-report questionnaires were evaluated to assess anxiety, depression, health-related quality of life, socio-demographic information and use of disease specific health information sources at year 4 after primary diagnosis.ResultsComplete data was available for 668 patients from 67 centres, of whom 96.0% were in regular melanoma surveillance. In year 3–4 of surveillance, only 55.6% of locoregionary metastases were detected during surveillance visits. Only 33.3% were self-detected by the patient even though 69.4% were documented as being clinically visible or palpable. Costs of 4 year surveillance of 550 patients without tumour recurrence (stage I–IIC and MMis) accumulated to 228,155.75 €. Guideline-adherence for follow-up frequency, lymph node ultrasound, S100 serum level tests and diagnostic imaging recommendations was approximately 60% in year 3–4 of surveillance. Multivariate regression analysis showed that certain patient/tumour characteristics and regional differences were significantly associated with guideline deviations. The percentage of patients who exceeded published cut-off scores indicating clinically relevant symptoms of anxiety and depression were significantly increased. Patients frequently reported lack of psychosocial support and education but ascribed great importance to these.ConclusionsWe recommend further reduction of melanoma follow-up in low-risk melanoma patients and improvement of psycho-social support and patient education for all melanoma patients.     

Role of bacillus Calmette–Guérin in the treatment of advanced melanoma

Early trials of Bacillus Calmette–Guérin (BCG)-based immunotherapy for melanoma consistently show a trend toward improved clinical outcomes in patients treated with BCG compared with observation alone. As an extension of these findings, investigators have initiated the Malignant Melanoma Active Immunotherapy (MMAIT) trials in patients with stage III (MMAIT–III) and stage IV (MMAIT–IV) disease. The overall survival of the patients receiving BCG plus placebo was much better than expected in both studies, thus suggesting a potential for BCG as an adjuvant after the resection of advanced disease. The work contained herein will explore the clinical rationale for adjuvant BCG in future trials focused on the treatment of patients with advanced malignant melanoma.     

Conditional survival of malignant melanoma in The Netherlands: 1994–2008

BackgroundCutaneous malignant melanoma causes the majority of skin cancer related deaths and features increasing incidence and mortality rates in the Netherlands. Conditional survival analysis is performed on patients who survived the preceding year(s).MethodsPatients with invasive melanoma, as recorded in the population-based Netherlands Cancer Registry, were included. To assess prognosis of melanoma survivors according to gender and Breslow thickness, conditional five-year relative survival was calculated for lymph node negative melanoma patients and conditional one-year relative survival was analysed for melanoma patients with and without nodal involvement.FindingsBetween 1994 and 2008, 40,050 patients developed a melanoma (stage I–III, of whom 6% with nodal involvement). Six to 8 years after diagnosis, survival of patients with a 1–2 mm (T2) thick melanoma equalised the general population. Conditional five-year relative survival for patients with >4 mm thick (T4) melanomas increased from about 60% at diagnosis to 90% at 7 years after diagnosis. Largest improvements were found in patients with thick melanomas and female patients with nodal involvement.InterpretationThe prognosis for melanoma survivors improved with each additional year of survival after diagnosis, except for patients with a ⩽1 mm thick melanoma, who never had any excess mortality during follow-up. Conditional survival of melanoma was better amongst females, amongst those with lower Breslow thickness and nodal stage.     

Significance of serum protein S100 levels in screening for melanoma metastasis: does protein S100 enable early detection of melanoma recurrence?

A number of recent reports suggest serum protein S100 as a prognostic parameter in patients with metastatic melanoma. In the present study, serum protein S100 was investigated as a tumour marker for screening for melanoma metastasis in patients attending regular follow-up examinations. During the period from September 1997 to December 1998, serum protein S100 levels were measured by an immunoluminometric assay in 411 consecutive high risk melanoma patients (666 samples) and in 120 control subjects. Melanoma patients with resected primary tumours with a tumour thickness of 1.5 mm or more with resected metastasis were included in the study. Overall, 41 of the 411 patients developed metastasis during the period of observation. According to the distribution of protein S100 levels, the following different cut-off values were examined: 0.08 microg/l (95 percentile of the control group) and 0.13 microg/l (95 percentile of the group of melanoma patients without metastasis). The test efficiency for protein S100 as a diagnostic test for the detection of metastasis was highest for the cut-off value of 0.13 microg/l. In eight of the 41 patients (19.5%), elevation of protein S100 was the first sign of recurrence. Of the 41 patients with metastatic disease, 13 had elevated protein S100, giving a sensitivity of 0.32. The specificity for the detection of metastasis was 0.96. In eight of the 14 patients (57%) who developed distant metastasis, elevated S100 values were the first sign of tumour progression. In conclusion, determination of serum protein S100 levels enables earlier detection of distant metastasis in patients at high risk for metastasis. The impact on survival time needs to be investigated in follow-up studies.     

A pivotal role for ERK in the oncogenic behaviour of malignant melanoma?

During the process of oncogenic transformation, melanoma cells escape from normal growth-control mechanisms and acquire the ability to invade surrounding tissues and organs. The Ras/Raf/MEK/ERK pathway is a major pathway involved in the control of growth signals, cell survival and invasion. Melanomas are known to harbour activating mutations of both Ras and BRAF, suggesting that the downstream effector ERK may be playing a major role in the oncogenic behaviour of these tumours. The past few years have seen a growth in the understanding of the role of ERK and the MAP kinase pathway in melanoma. The aim of the current review is to assess the role of ERK in melanoma behaviour and to determine whether modulation of these kinases could offer new therapeutic opportunities.     

Inhibition of CXCR4–CXCL12 chemotaxis in melanoma by AMD11070

Background:

Despite intensive research and novel adjuvant therapies, there is currently no cure for metastatic melanoma. The chemokine receptor CXCR4 controls metastasis to sites such as the liver; however, the therapeutic blockade with the existing agents has proven difficult.

Methods:

{"type":"entrez-protein","attrs":{"text":"AMD11070","term_id":"985559755"}}AMD11070, a novel orally bioavailable inhibitor of CXCR4, was tested for its ability to inhibit the migration of melanoma cells compared with the commonly described antagonist AMD3100.

Results:

{"type":"entrez-protein","attrs":{"text":"AMD11070","term_id":"985559755"}}AMD11070 abrogated melanoma cell migration and was significantly more effective than AMD3100. Importantly for the clinical context, the expression of B-RAF-V600E did not the affect the sensitivity of {"type":"entrez-protein","attrs":{"text":"AMD11070","term_id":"985559755"}}AMD11070.

Conclusion:

Liver-resident myofibroblasts excrete CXCL12, which is able to promote the migration of CXCR4-expressing tumour cells from the blood into the liver. Blockade of this axis by {"type":"entrez-protein","attrs":{"text":"AMD11070","term_id":"985559755"}}AMD11070 thus represents a novel therapeutic strategy for both B-RAF wild-type and mutated melanomas.