Multiple endocrine neoplasia type 2: A review.

Multiple endocrine neoplasias are rare hereditary syndromes some of them with malignant potential. Multiple endocrine neoplasia type 2 (MEN 2) is an autosomal dominant hereditary cancer syndrome due to germline variants in the REarranged during Transfection (RET) proto-oncogene. There are two distinct clinical entities: MEN 2A and MEN 2B. MEN 2A is associated with medullary thyroid carcinoma (MTC), phaeochromocytoma, primary hyperparathyroidism, cutaneous lichen amyloidosis and Hirschprung's disease and MEN 2B with MTC, phaeochromocytoma, ganglioneuromatosis of the aerodigestive tract, musculoskeletal and ophthalmologic abnormalities. Germline RET variants causing MEN 2 result in gain-of-function; since the discovery of the genetic variants a thorough search for genotype-phenotype associations began in order to understand the high variability both between families and within family members. These studies have successfully led to improved risk classification of prognosis in relation to the genotype, thus improving the management of the patients by thorough genetic counseling. The present review summarizes the recent developments in the knowledge of these hereditary syndromes as well as the impact on clinical management, including genetic counseling, of both individual patients and families. It furthermore points to future directions of research for better clarification of timing of treatments of the various manifestations of the syndromes in order to improve survival and morbidity in these patients.

Trends in melanoma in the elderly in Denmark, 1980-2012.

BACKGROUND: The incidence of melanoma is rising in Denmark. In the present paper we describe incidence, mortality and survival in Denmark from 1980 to 2012 focusing on age, comparing persons aged 70 years or more with those aged less than 70 years. MATERIAL AND METHODS: Melanoma was defined as ICD-10 code C43. Data derived from the NORDCAN database with comparable data on incidence, mortality, survival in the Nordic countries, where the Danish data were delivered from the Danish Cancer Registry and the Danish Cause of Death Registry with follow-up until the end of 2013. RESULTS: In 1980, 21.4% of the patients diagnosed with melanoma were older than 70 years compared to 28.4% in 2012. In persons aged less than 70 years, the incidence rate was higher among women than in men, but men aged 70-89 years had an incidence rate almost twice that of women. Incidence rates were increasing, particularly among the elderly. In 1980, 32.6% of the patients who died from melanoma were older than 69 years compared to 56.2% in 2012. In 1980, the mortality rate was 121.4 per 100,000 person years, increasing to 353.1 in 2012. For the younger patients, the mortality rates are only slight increasing, but for the elder patients the mortality rates are increasing dramatically. In general the survival has increased for all age groups over the years. CONCLUSION: The incidence rates for all age groups are rising. The increase was mainly caused by a rising incidence among the elderly. Mortality among Danish patients with melanoma is increasing and especially the mortality in the elderly. This important knowledge must be kept in mind when future treatment strategies are planned.

The Danish metastatic melanoma database (DAMMED): A nation-wide platform for quality assurance and research in real-world data on medical therapy in Danish melanoma patients.

BACKGROUND: Clinical trials enroll patients with specific diseases based on certain pre-defined eligibility criteria. Disease registries are crucial to evaluate the efficacy and safety of new expensive oncology medicines in broad non-trial patient populations. METHODS: We provide detailed information on the structure, including variables, and the scientific results from a nation-wide Danish database covering advanced melanoma, illustrating the importance of continuous real-world data registration. Disease status and treatment-related information on all patients with American Joint Committee on Cancer (AJCC) 8th edition stage III or IV melanoma candidates to medical treatment in Denmark are prospectively registered in the Danish Metastatic Melanoma Database (DAMMED). RESULTS: By January 1st, 2021, DAMMED includes 4156 patients and 7420 treatment regimens. Response rates and survival data from published randomized clinical trial data are compared with real-world efficacy data from DAMMED and presented. Overall, nine independent manuscripts highlighting similarities and discrepancies between real-world and clinical trial results are already reported to date. CONCLUSION: Nation-wide disease registries take into consideration the complexity of daily clinical practice. We show a concrete example of how disease registries can complement clinical trials' information, improving clinical practice, and support health-related technology assessment.

The real-world impact of modern treatments on the survival of patients with metastatic melanoma.

Between 2010 and 2015, pivotal trials with strict enrolment criteria led to the approval of several new treatments for metastatic melanoma (MM). We sought to determine the impact of these treatments in the 'real world'. We took advantage of the Danish MM database (DAMMED), which contains data on the entire, unselected population diagnosed with MM within Denmark. All MM cases (excluding ocular MM, n = 837) diagnosed in three non-consecutive years marked by major changes in the first-line treatments (2012: interleukin-2 and BRAF inhibitors; 2014: anti-CTLA-4: Cytotoxic T-Lymphocyte Antigen 4 and 2016: anti-PD-1: programmed cell death protein 1 and MEK inhibitors) were retrieved. Patients were grouped into 'trial-like' and 'trial-excluded' based on the common trial eligibility criteria. In the 'trial-like' population (39% of all MM), the median overall survival (OS) was not reached in 2016 versus 18.8 months in 2014 (hazard ratio [HR] 0.52, 95% confidence interval [CI] 0.35-0.75; p = 0.0005) and 16.5 months in 2012 (HR 0.41, 95% CI 0.27-0.63; p < 0.0001). In the 'trial-excluded' population (61% of all MM), 75% had brain metastases and/or (performance status) PS ≥ 2. Here, the median OS improved to 6.9 months in 2016 versus 5.2 months in 2014 (HR 0.66, 95% CI 0.52-0.84; p = 0.0008) and 4.2 months in 2012 (HR 0.66, 95% CI 0.52-0.84; p = 0.0007). Subgroup analysis of the BRAF wild-type population showed an improved 1-year survival rate in 2016 versus 2014 (35.9% vs 18.8%, p = 0.0153). In conclusion, the introduction of modern treatments has led to an improved survival of real-world patients with MM, regardless of their eligibility to clinical trials and the BRAF status. These data support the application of modern treatments to patient populations which are not represented in pivotal trials.

Real-World Impact of Immune Checkpoint Inhibitors in Metastatic Uveal Melanoma.

Uveal melanoma (UM) is the most common intraocular malignancy in adults and shows a high rate of metastatic spread. As randomized clinical trials with immune checkpoint inhibitors (ICI) have not been performed in patients with metastatic UM, we analyzed the real-world outcomes in a nationwide population-based study. Clinical data of patients with UM were extracted from the Danish Metastatic Melanoma database, a nationwide database containing unselected records of patients diagnosed with metastatic melanoma in Denmark. Survival before (pre-ICI, n = 32) and after (post-ICI, n = 94) the approval of first-line treatment with ICI was analyzed. A partial response to first-line treatment was observed in 7% of patients treated with anti-programmed cell death protein (PD)-1 monotherapy and in 21% with combined anti-cytotoxic T lymphocyte antigen (CTLA)-4 plus anti-PD-1 therapy. Median progression-free survival was 2.5 months for patients treated in the pre-ICI era compared to 3.5 months in the post-ICI era (hazard ratio (HR) 0.43; 95% confidence interval (CI) 0.28-0.67; p < 0.001). The estimated one-year overall survival rate increased from 25.0% to 41.9% and the median overall survival improved from 7.8 months to 10.0 months, respectively (HR 0.52; 95% CI 0.34-0.79; p = 0.003). Thus, the introduction of ICI as first-line treatment appears to have significantly improved the real-world survival of patients with metastatic UM, despite relatively low response rates compared to cutaneous melanoma. With the lack of therapies proven effective in randomized trials, these data support the current treatment with ICI in patients with metastatic UM.

Low incidence of minor BRAF V600 mutation-positive subclones in primary and metastatic melanoma determined by sensitive and quantitative real-time PCR.

BRAF V600 mutation is an important biological marker for therapeutic guidance in melanoma, where mutation-positive cases are candidates for therapy targeting mutant B-Raf. Recent studies showing intratumor variation in BRAF mutation status have caused concern that sensitive mutation analysis can lead to mutation-positive results in patients with melanomas with small subsets of mutation-positive cells who may not benefit from therapy targeting mutant B-Raf. Mutation analysis with high analytical sensitivity is generally preferred, to reduce the risk of false-negative results. In this study, sensitive and quantitative BRAF V600E and V600K mutation-specific real-time quantitative PCR was used to study the occurrence of small subsets of mutation-positive cells in primary melanomas and melanoma metastases. The BRAF V600E mutation was detected in 39 of 82 melanoma patients. We observed a highly dichotomous pattern, with most samples either testing mutation positive in a high fraction of alleles (median, 51%) or negative with a high sensitivity (median, 0.06%). This finding demonstrates that the occurrence of small subsets of mutation-positive cells was rare in our study population and indicates that sensitive mutation analysis can generally be expected to produce clinically relevant results in melanoma patients.

Interleukin-6 and melanoma.

Interleukin-6 (IL-6) is a pleiotropic immunomodulatory cytokine produced by various types of cells, including melanoma cells. IL-6 plays a major role in the pathogenesis and development of malignancies. It promotes tumour growth by inhibition of apoptosis and induces tumour angiogenesis. IL-6 is deregulated in many types of cancers, and increased serum concentration of IL-6 has been correlated with a worse prognosis in patients with different cancers, including melanoma. Several serum cytokines including IL-6 play an important role in the development and progression of melanoma; however, the specific biological functions of IL-6 in progression of melanoma are unknown. In this review, we present studies on cell cultures and mouse models and summarize published clinical studies on IL-6 and melanoma.

Serum interleukin-6 as a prognostic biomarker in patients with metastatic melanoma.

Interleukin-6 (IL-6) is an immunomodulatory cytokine produced by both normal cells and tumor cells, including melanoma cells. The specific biological function of IL-6 in melanoma is unknown. The present study examined whether the serum concentration of IL-6 can predict prognosis in patients with metastatic melanoma. IL-6 was measured by ELISA in serum samples from 103 patients with metastatic melanoma obtained before IL-2-based immunotherapy. Patients with metastatic melanoma had higher serum IL-6 than healthy individuals (median 3.4 ng/l, range 0.3-93 ng/l vs. median 1.4 ng/l, range 0.25-22.5 ng/l, P<0.0001). Pretreatment serum IL-6 was elevated in 43% of the patients. Patients with elevated pretreatment serum IL-6 had shorter overall survival (OS) compared with patients with normal serum IL-6 (P<0.0002). The median OS was 10.8 months [95% confidence interval (CI): 8.86-13.46] in patients with normal serum IL-6 compared with 4.5 months (95% CI: 3.04-7.39) in patients with elevated serum IL-6. Multivariate Cox analysis showed that serum IL-6 [hazard ratio (HR)=1.82, 95% CI: 1.19-2.78, P=0.006] and serum lactate dehydrogenase (HR=2.02, 95% CI: 1.31-3.11, P=0.001) were independent prognostic biomarkers of OS. A combination variable of elevated serum IL-6 and elevated serum lactate dehydrogenase almost quadrupled the risk of early death (HR=3.67, 95% CI: 2.17-6.20, P<0.0001) compared with patients with normal serum levels of these two biomarkers. Elevated serum IL-6 is an independent prognostic biomarker of short OS in patients with metastatic melanoma. A larger retrospective study is ongoing to confirm the findings. To validate serum IL-6 further as a prognostic biomarker, a prospective study is required.