Background Thin melanomas cause a high death toll despite excellent prognosis. Objective We examined melanoma mortality burden and prognosis by categories of thickness within Surveillance, ...Epidemiology, and End Results (SEER) 13 Registry 1992-2013. Methods We divided 49,319 stage I and II melanoma cases diagnosed between 1992 and 2003 into T1 through T4 and then subdivided T1 into 0.01-0.25 mm, 0.26-0.50 mm, 0.51-0.75 mm, and 0.76-1.00 mm categories. We determined the number and proportion of deaths due to melanoma within 10 years of diagnosis for each thickness category and proportions within T1 subcategories with ulceration. Results We confirmed prognosis worsened as melanoma thickened from T1 to T4; however, most deaths resulted from melanomas that were diagnosed at the T1 stage. The smallest number of deaths within T1 resulted from 0.01-0.25 mm–thick melanomas; however, the risk for death within 10 years was greater for those diagnosed with melanoma when tumor depth was 0.01-0.25 mm than for those diagnosed when tumor depth was 0.26-0.50 mm. Prognosis worsened with depths starting at 0.51 mm. The pattern within T1 was not explained by ulceration. Limitations We did not evaluate melanoma subtype, mitotic rate, or other associated features. Conclusion Thin melanomas are a substantial public health burden. Efforts should be made to diagnose melanoma at the in situ stage.
Melanoma is the deadliest form of skin cancer. In the early stages, melanoma can be treated successfully with surgery alone and survival rates are high, but after metastasis survival rates drop ...significantly. Therefore, early and correct diagnosis is key for ensuring patients have the best possible prognosis. Melanoma misdiagnosis accounts for more pathology and dermatology malpractice claims than any cancer other than breast cancer, as an early misdiagnosis can significantly reduce a patient's chances of survival. As far as treatment for metastatic melanoma goes, there have been several new drugs developed over the last 10 years that have greatly improved the prognosis of patients with metastatic melanoma, however, a majority of patients do not show a lasting response to these treatments. Thus, new biomarkers and drug targets are needed to improve the accuracy of melanoma diagnosis and treatment. This article will discuss the major advancements of melanoma diagnosis and treatment from antiquity to the present day.
•Melanogenesis stimulates expression of HIF-1α and downstream regulators of metabolism.•Melanogenesis affects expression of stress related genes.•Advanced melanomas show increased expression of ...HIF-1α protein.•Advanced melanomas show increased expression of membrane-bound GLUT-1.
To study the effect of melanogenesis on HIF-1α expression and attendant pathways, we used stable human and hamster melanoma cell lines in which the amelanotic vs. melanotic phenotypes are dependent upon the concentration of melanogenesis precursors in the culture media. The induction of melanin pigmentation led to significant up-regulation of HIF-1α, but not HIF-2α, protein in melanized cells for both lines. Similar upregulation of nuclear HIF-1α was observed in excisions of advanced melanotic vs. amelanotic melanomas. In cultured cells, melanogenesis also significantly stimulated expression of classical HIF-1-dependent target genes involved in angiogenesis and cellular metabolism, including glucose metabolism and stimulation of activity of key enzymes in the glycolytic pathway. Several other stress related genes containing putative HRE consensus sites were also upregulated by melanogenesis, concurrently with modulation of expression of HIF-1-independent genes encoding for steroidogenic enzymes, cytokines and growth factors. Immunohistochemical studies using a large panel of pigmented lesions revealed that higher levels of HIF-1α and GLUT-1 were detected in advanced melanomas in comparison to melanocytic nevi or thin melanomas localized to the skin. However, the effects on overall or disease free survival in melanoma patients were modest or absent for GLUT-1 or for HIF-1α, respectively. In conclusion, induction of the melanogenic pathway leads to robust upregulation of HIF-1-dependent and independent pathways in cultured melanoma cells, suggesting a key role for melanogenesis in regulation of cellular metabolism.
The incidence of cutaneous malignant melanoma (CMM) is on the rise in many parts of the world. However, there is limited knowledge on the epidemiology of CMM in Canada.
To conduct a comprehensive ...population-based study of CMM in Canada.
We examined patient clinical and pathologic characteristics as well as the incidence and mortality trends of CMM in Canada using 3 independent population-based registries.
In total, 72,565 Canadian patients were given CMM diagnoses during 1992-2010; 47.5% were women. Average age at the time of diagnosis was 56.5 years for women and 60.4 years for men. We report a steady increase in CMM incidence and mortality rates in both sexes. The overall incidence rate of CMM in Canada was 12.29 cases/100,000 person-years. We also report important differences in the incidence and mortality rates between Canadian provinces and territories; the highest incidence of this cancer was documented in Nova Scotia and Prince Edward Island.
Data on race, clinical disease stage, and Breslow depth of CMM was not available.
This study, for the first time, defines the disease burden of CMM in Canada and highlights important longitudinal, geographic, and spatial differences in the distribution of CMM in this country.
In less than 10 years, melanoma treatment has been revolutionized with the approval of tyrosine kinase inhibitors and immune checkpoint inhibitors, which have been shown to have a significant impact ...on the prognosis of patients with melanoma. The early steps of this transformation have taken place in research laboratories. The mitogen‑activated protein kinase (MAPK) pathway, phosphoinositol‑3‑kinase (PI3K) pathway promote the development of melanoma through numerous genomic alterations on different components of these pathways. Moreover, melanoma cells deeply interact with the tumor microenvironment and the immune system. This knowledge has led to the identification of novel therapeutic targets and treatment strategies. In this review, the epidemiological features of cutaneous melanoma along with the biological mechanisms involved in its development and progression are summarized. The current state‑of‑the‑art of advanced stage melanoma treatment strategies and the currently available evidence of the use of predictive and prognostic biomarkers are also discussed.
Abstract Background After appropriate initial therapy for patients with stage II-III melanoma, there is no consensus regarding surveillance, thus follow up is highly variable among institutions and ...individual providers. The NCCN recommends routine clinical exam and consideration of imaging for stage IIB-IIIC every 3-12 months with no distinction between stages. Detection of recurrence is important as novel systemic therapies and surgical resection of recurrence may provide survival benefits. Methods We retrospectively reviewed 369 patients with Stage II and III melanoma treated at Ohio State University from 2009-2015 who underwent surgery as primary therapy. Two hundred forty-seven patients who were followed for a minimum of 6 months after surgical resection to achieve no evidence of disease status (NED) were included in this analysis. One hundred twenty-two were lost to follow up after surgery and were excluded. Results The rate of recurrence for stage IIA/IIB patients was 11% (14/125). Eleven of the 14 (79%) recurrences were detected by clinical symptoms or physical exam. Thirty-nine percent (49/125) of stage IIA or IIB patients were followed by clinical exam only while 61% (76/125) were followed with at least 2 serial chest x-rays. The median time to first chest x-ray after NED status was 4.7 months (n=76), median time to second chest x-ray after NED status was 12.7 months (n=76), and 66% (50/76) continued to have additional serial chest x-rays. At median follow-up of 35 months for the 125 patients with stage IIA/IIB, there was no difference in survival between those followed clinically (95% (95% CI: 0.88-.99)) versus those followed with at least 2 serial x-rays (96% (95% CI: 0.89-0.98). For stage IIC/IIIA-C patients, recurrence was detected in 23% (28/122) at median follow-up 31.2 months. Fifty percent of recurrences were detected by imaging in asymptomatic patients while 50% (14/28) had recurrence detected on imaging associated clinical findings. Eighty seven percent (106/122) of stage IIC/IIIA-C patients were followed with at least 2 serial whole body PET/CT scans or whole body CT scans plus brain MRI; median time between NED status and second scan was 10.3 months. Of stage IIC/IIIA-C patients with recurrence, 57% (16/28) went on to surgical resection of the recurrence while 11 (39%) patients received B-RAF inhibitor therapy, immune blockade therapy, or combination therapy. Conclusion For stage IIA and IIB melanoma, surveillance chest x-rays did not improve survival compared to physical exam alone. However, for stage IIC and IIIA-C melanoma, where the recurrence rates are higher, routine whole body imaging detected 50% of recurrences leading to additional surgery and/or treatment with novel systemic therapies for the majority of patients. Detection of melanoma recurrence is important and specific sub stage should be used to stratify risk and define appropriate follow up.
Melanoma Schadendorf, Dirk; van Akkooi, Alexander C J; Berking, Carola ...
The Lancet (British edition),
09/2018, Letnik:
392, Številka:
10151
Journal Article
Recenzirano
Cutaneous melanoma causes 55 500 deaths annually. The incidence and mortality rates of the disease differ widely across the globe depending on access to early detection and primary care. Once ...melanoma has spread, this type of cancer rapidly becomes life-threatening. For more than 40 years, few treatment options were available, and clinical trials during that time were all unsuccessful. Over the past 10 years, increased biological understanding and access to innovative therapeutic substances have transformed advanced melanoma into a new oncological model for treating solid cancers. Treatments that target B-Raf proto-oncogene serine/threonine-kinase (BRAF)V600 (Val600) mutations using selected BRAF inhibitors combined with mitogen-activated protein kinase inhibitors have significantly improved response and overall survival. Furthermore, advanced cutaneous melanoma has developed into a prototype for testing checkpoint-modulating agents, which has increased hope for long-term tumour containment and a potential cure. These expectations have been sustained by clinical success with targeted agents and antibodies that block programmed cell-death protein 1 in locoregional disease, which induces prolongation of relapse-free, distant-metastasis-free, and overall survival times.
Combination therapy with the BRAF inhibitor dabrafenib plus the MEK inhibitor trametinib improved survival in patients with advanced melanoma with BRAF V600 mutations. We sought to determine whether ...adjuvant dabrafenib plus trametinib would improve outcomes in patients with resected, stage III melanoma with BRAF V600 mutations.
In this double-blind, placebo-controlled, phase 3 trial, we randomly assigned 870 patients with completely resected, stage III melanoma with BRAF V600E or V600K mutations to receive oral dabrafenib at a dose of 150 mg twice daily plus trametinib at a dose of 2 mg once daily (combination therapy, 438 patients) or two matched placebo tablets (432 patients) for 12 months. The primary end point was relapse-free survival. Secondary end points included overall survival, distant metastasis-free survival, freedom from relapse, and safety.
At a median follow-up of 2.8 years, the estimated 3-year rate of relapse-free survival was 58% in the combination-therapy group and 39% in the placebo group (hazard ratio for relapse or death, 0.47; 95% confidence interval CI, 0.39 to 0.58; P<0.001). The 3-year overall survival rate was 86% in the combination-therapy group and 77% in the placebo group (hazard ratio for death, 0.57; 95% CI, 0.42 to 0.79; P=0.0006), but this level of improvement did not cross the prespecified interim analysis boundary of P=0.000019. Rates of distant metastasis-free survival and freedom from relapse were also higher in the combination-therapy group than in the placebo group. The safety profile of dabrafenib plus trametinib was consistent with that observed with the combination in patients with metastatic melanoma.
Adjuvant use of combination therapy with dabrafenib plus trametinib resulted in a significantly lower risk of recurrence in patients with stage III melanoma with BRAF V600E or V600K mutations than the adjuvant use of placebo and was not associated with new toxic effects. (Funded by GlaxoSmithKline and Novartis; COMBI-AD ClinicalTrials.gov, NCT01682083 ; EudraCT number, 2012-001266-15 .).
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