Background.
Subtypes of melanoma, such as mucosal, uveal, and acral, are believed to result in worse prognoses than nonacral cutaneous melanoma. After a diagnosis of distant metastatic disease, ...however, the overall survival of patients with mucosal, uveal, acral, nonacral cutaneous, and unknown primary melanoma has not been directly compared.
Materials and Methods.
We conducted a single‐center, retrospective analysis of 3,454 patients with melanoma diagnosed with distant metastases from 2000 to 2013, identified from a prospectively maintained database. We examined melanoma subtype, date of diagnosis of distant metastases, age at diagnosis of metastasis, gender, and site of melanoma metastases.
Results.
Of the 3,454 patients (237 with mucosal, 286 with uveal, 2,292 with nonacral cutaneous, 105 with acral cutaneous, and 534 with unknown primary melanoma), 2,594 died. The median follow‐up was 46.1 months. The median overall survival for those with mucosal, uveal, acral, nonacral cutaneous, and unknown primary melanoma was 9.1, 13.4, 11.4, 11.7, and 10.4 months, respectively. Patients with uveal melanoma, cutaneous melanoma (acral and nonacral), and unknown primary melanoma had similar survival, but patients with mucosal melanoma had worse survival. Patients diagnosed with metastatic melanoma in 2006–2010 and 2011–2013 had better overall survival than patients diagnosed in 2000–2005. In a multivariate model, patients with mucosal melanoma had inferior overall survival compared with patients with the other four subtypes.
Conclusion.
Additional research and advocacy are needed for patients with mucosal melanoma because of their shorter overall survival in the metastatic setting. Despite distinct tumor biology, the survival was similar for those with metastatic uveal melanoma, acral, nonacral cutaneous, and unknown primary melanoma.
Implications for Practice:
Uveal, acral, and mucosal melanoma are assumed to result in a worse prognosis than nonacral cutaneous melanoma or unknown primary melanoma. No studies, however, have been conducted assessing the overall survival of patients with these melanoma subtypes starting at the time of distant metastatic disease. The present study found that patients with uveal, acral, nonacral cutaneous, and unknown primary melanoma have similar overall survival after distant metastases have been diagnosed. These findings provide information for oncologists to reconsider previously held assumptions and appropriately counsel patients. Patients with mucosal melanoma have worse overall survival and are thus a group in need of specific research and advocacy.
The overall survival of patients with mucosal, uveal, acral, nonacral cutaneous, and unknown primary metastatic melanoma has not been directly compared. A retrospective analysis of 3,454 patients with melanoma and distant metastases was conducted. Patients with mucosal melanoma had inferior overall survival. Additional research and advocacy are needed for patients with mucosal melanoma because of their shorter overall survival in the metastatic setting.
Many patients with advanced cancers achieve dramatic responses to a panoply of therapeutics yet retain minimal residual disease (MRD), which ultimately results in relapse. To gain insights into the ...biology of MRD, we applied single-cell RNA sequencing to malignant cells isolated from BRAF mutant patient-derived xenograft melanoma cohorts exposed to concurrent RAF/MEK-inhibition. We identified distinct drug-tolerant transcriptional states, varying combinations of which co-occurred within MRDs from PDXs and biopsies of patients on treatment. One of these exhibited a neural crest stem cell (NCSC) transcriptional program largely driven by the nuclear receptor RXRG. An RXR antagonist mitigated accumulation of NCSCs in MRD and delayed the development of resistance. These data identify NCSCs as key drivers of resistance and illustrate the therapeutic potential of MRD-directed therapy. They also highlight how gene regulatory network architecture reprogramming may be therapeutically exploited to limit cellular heterogeneity, a key driver of disease progression and therapy resistance.
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•Minimal residual diseases in melanoma exhibit cellular and spatial heterogeneity•Cell-state transition contributes to co-emergence of distinct drug-tolerant states•RXR signaling drives emergence of a cell population conferring treatment resistance•Targeting RXR signaling is promising for delaying or obviating relapse in melanoma
Drug-tolerant cells that persist through treatment of melanoma exhibit multiple transcriptional states, one of which is a key driver that can be targeted therapeutically.
The head and neck cutaneous melanoma (HNCM) accounts for 20% of newly diagnosed melanoma. Research on prognostic models for their survival yet remains largely unexplored. This study employed a ...nomogram approach to develop and validate a predictive model for both overall survival (OS) and disease-specific survival (DSS) in patients with HNCM.
This study analyzed the HNCM patients diagnosed between 2004 and 2014 from Surveillance, Epidemiology, and End Results database. To identify independent prognostic factors for HNCM, we integrated results from univariate Cox regression analysis, random survival forests, and LASSO regression with cross-validation. A nomogram was designed and validated based on the identified characteristics to predict the 3-, 5-, and 8-year OS and DSS of patients with HNCM.
Age, Stage, Ulceration, Thickness, Chemotherapy, lymph node metastasis, and Radiation were identified as independent prognostic factors. The nomogram achieved a satisfactory performance with C-indices of 0.824(DSS) and 0.757(OS) in the training cohort and 0.827(DSS) and 0.749(OS) in the validation cohort, respectively. The area under the curves for the OS at 3, 5, and 8 years were 0.789, 0.788, and 0.794 for the training cohort, and 0.778, 0.776, and 0.795 for the validation cohort, respectively. For DSS, the area under the curves at 3, 5, and 8 years were 0.859, 0.842, and 0.828 in the training cohort, and 0.864, 0.844, and 0.834 in the validation cohort, respectively. The calibration curve showed that there was a strong correlation between the observed outcomes and the predicted survival probability.
This study established and validated predictive nomograms for HNCM patients with robust predictive performance.
The recurrence of cutaneous melanoma is one of the main reasons for surveillance after primary tumor treatment, and there is still little data on melanoma recurrence related to the Brazilian ...population.
We sought to evaluate the profile of patients with cutaneous melanoma recurrence within five years of (early) and five years after (late) initial diagnosis.
Patients diagnosed between 2006 and 2014 in a private reference service in Belo Horizonte, Brazil, were included. Demographic, clinical, histopathological, and disease evolution variables were collected and analyzed using the R version 4.0.0 program. A
-value less than 0.05 was considered significant.
The sample was composed of 331 patients with melanoma, and the 43 patients with recurrence presented with higher mean age (
=0.049), male predominance (
=0.030), a lower proportion of Breslow thickness under 0.8mm (
<0.001), and a more significant presence of mitosis (
=0.007). The 29 patients (8.8%) with early recurrence presented with tumors with ulceration (
<0.018). Late recurrence occurred in 14 patients (4.2%). Five patients relapsed after 10 years; most of them had tumors up to 1mm thick, without ulceration, regression, or satellitosis, but with the presence of mitosis.
The possibility of cutaneous melanoma recurrence after five, and even 10, years, although rare, might indicate the need for longer medical follow-up. Multicenter studies may better characterize Brazilian patient profiles of those with early and late recurrence of melanoma.
A substantial number of patients who relapse and die from cutaneous melanoma (CM) are categorized as being at low risk by traditional staging factors. The 31-gene expression profile (31-GEP) test ...independently stratifies metastatic risk of patients with CM as low (Class 1, with 1A indicating lowest risk) or high (Class 2,with 2B indicating highest risk).
To assess risk prediction by the 31-GEP test within 3 low-risk (according to the American Joint Committee on Cancer) populations of patients with CM: those who are sentinel lymph node (SLN) negative, those with stage I to IIA tumors, and those with thin (≤1 mm T1) tumors.
A total of 3 previous validation studies provided a nonoverlapping cohort of 690 patients with 31-GEP results, staging information, and survival outcomes. Kaplan-Meier and Cox regression analysis were performed.
The results included the identification of 70% of SLN-negative patients who experienced metastasis as Class 2, the discovery of reduced recurrence-free survival for patients with thin tumors and Class 2B biology compared with that of those with Class 1A biology (P < .0001); and determination of the 31-GEP test as an independent predictor of risk compared with traditional staging factors in patients with stage I to IIA tumors.
Diagnoses spanned multiple versions of pathologic staging criteria.
The 31-GEP test identifies high-risk patients who are likely to experience recurrence or die of melanoma within low-risk groups of subpopulations of patients with CM who have SLN-negative disease, stage I to IIA tumors, and thin tumors.
Cutaneous melanoma is the most common skin cancer with an incidence that has been rapidly increasing in the past decades. Melanomas are among the most immunogenic tumors and, as such, have the ...greatest potential to respond favorably to immunotherapy. However, like many cancers, melanomas acquire various suppressive mechanisms, which generally act in concert, to escape innate and adaptive immune detection and destruction. Intense research into the cellular and molecular events associated with melanomagenesis, which ultimately lead to immune suppression, has resulted in the discovery of new therapeutic targets and synergistic combinations of immunotherapy, targeted therapy and chemotherapy. Tremendous effort to determine efficacy of single and combination therapies in pre-clinical and clinical phase I-III trials has led to FDA-approval of several immunotherapeutic agents that could potentially be beneficial for aggressive, highly refractory, advanced and metastatic melanomas. The increasing availability of approved combination therapies for melanoma and more rapid assessment of patient tumors has increased the feasibility of personalized treatment to overcome patient and tumor heterogeneity and to achieve greater clinical benefit. Here, we review the evolution of the immune system during melanomagenesis, mechanisms exploited by melanoma to suppress anti-tumor immunity and methods that have been developed to restore immunity. We emphasize that an effective therapeutic strategy will require coordinate activation of tumor-specific immunity as well as increased recognition and accessibility of melanoma cells in primary tumors and distal metastases. This review integrates available knowledge on melanoma-specific immunity, molecular signaling pathways and molecular targeting strategies that could be utilized to envision therapeutics with broader application and greater efficacy for early stage and advanced metastatic melanoma.
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