Outcome In Melanoma Research Articles

The Impact of Obesity on Surgically Treated Locoregional Melanoma.

The impact of obesity on early-stage melanoma is poorly understood. We examined the impact of overweight and obesity on clinical outcomes in locoregional melanoma. Adults who underwent surgery at Emory University Healthcare between 2010 and 2017 for clinically stage I-II cutaneous melanoma, with known stage, height, and weight at the time of presentation, were identified. The relationship between body mass index (BMI) and clinicopathologic characteristics was assessed. Of 1756 patients, 584 were obese (33.2%; BMI ≥ 30), 658 were overweight (37.5%; BMI ≥ 25 and < 30), and 514 were normal weight (29.3%; BMI < 25). Demographics associated with obesity included male sex (odds ratio [OR] 2.6, 95% confidence interval [CI] 2.1-3.3; p < 0.001) and lower income (OR 1.5, 95% CI 1.2-1.9; p = 0.003). Melanomas in obese patients were thicker (2.0 ± 0.2mm) than in overweight (1.7±0.1mm) or normal-weight patients (1.4±0.1mm; p=0.002). Ulceration, mitoses, BRAF status, and sentinel lymph node (SLN) status were not affected by obesity. In multivariable analysis, obesity independently predicted increased odds of pathologic stage II melanoma (vs. stage 0 or I; OR 1.9, 95% CI 1.4-2.7, p=0.001), but not pathologic stage III melanoma (p>0.05). At 33 months' median follow-up, obesity was not an independent predictor of stage-specific overall survival (p>0.05). Obese patients are nearly twice as likely as their normal-weight peers to present with thicker melanomas, but they have similar stage-specific overall survival and SLN positivity. Obesity may promote more aggressive growth of the primary tumor, and barriers to preventive care in obese patients may exacerbate later-stage presentation.

Analysis of malignant melanoma risk and outcomes in solid organ transplant recipients: Assessment of transplant candidacy and the potential role of checkpoint inhibitors.

Malignant melanoma (MM) causes tremendous morbidity and mortality in the solid organ transplant population and may arise in three different clinical scenarios: (1) pretransplant melanoma; (2) de novo melanoma post transplantation and (3) donor-derived melanoma. This manuscript primarily addresses the first two scenarios with respect to the evaluation and management of pretransplant MM, consideration of transplant candidacy and the occurrence and management of de novo MM post transplantation. The authors outline current evidence describing risks associated with pre-transplant melanoma to support recently established expert opinion for transplant candidacy.

Cutaneous Melanoma: Mutational Status and Potential Links to Tertiary Lymphoid Structure Formation.

Recent advances in immunotherapy have enabled rapid evolution of novel interventional approaches designed to reinvigorate and expand patient immune responses against cancer. An emerging approach in cancer immunology involves the conditional induction of tertiary lymphoid structures (TLS), which are non-encapsulated ectopic lymphoid structures forming at sites of chronic, pathologic inflammation. Cutaneous melanoma (CM), a highly-immunogenic form of solid cancer, continues to rise in both incidence and mortality rate, with recent reports supporting a positive correlation between the presence of TLS in melanoma and beneficial treatment outcomes amongst advanced-stage patients. In this context, TLS in CM are postulated to serve as dynamic centers for the initiation of robust anti-tumor responses within affected regions of active disease. Given their potential importance to patient outcome, significant effort has been recently devoted to gaining a better understanding of TLS neogenesis and the influence these lymphoid organs exert within the tumor microenvironment. Here, we briefly review TLS structure, function, and response to treatment in the setting of CM. To uncover potential tumor-intrinsic mechanisms that regulate TLS formation, we have taken the novel perspective of evaluating TLS induction in melanomas impacted by common driver mutations in BRAF, PTEN, NRAS, KIT, PRDM1, and MITF. Through analysis of The Cancer Genome Atlas (TCGA), we show expression of DNA repair proteins (DRPs) including BRCA1, PAXIP, ERCC1, ERCC2, ERCC3, MSH2, and PMS2 to be negatively correlated with expression of pro-TLS genes, suggesting DRP loss may favor TLS development in support of improved patient outcome and patient response to interventional immunotherapy.

Melanoma brain metastasis presentation, treatment, and outcomes in the age of targeted and immunotherapies.

Historically, the prognosis for patients who have melanoma brain metastasis (MBM) has been dismal. However, breakthroughs in targeted and immunotherapies have improved long-term survival in those with advanced melanoma. Therefore, MBM presentation, prognosis, and the use of multimodality central nervous system (CNS)-directed treatment were reassessed. In this retrospective study, the authors evaluated patients with MBM who received treatment at Memorial Sloan Kettering Cancer Center between 2010 and 2019. Kaplan-Meier methodology was used to describe overall survival (OS). Recursive partitioning analysis and time-dependent multivariable Cox modeling were used to assess prognostic variables and to associate CNS-directed treatments with OS. Four hundred twenty-five patients with 2488 brain metastases were included. The median OS after an MBM diagnosis was 8.9 months (95% CI, 7.9-11.3 months). Patients who were diagnosed with MBM between 2015 and 2019 experienced longer OS compared to those who were diagnosed between 2010 and 2014 (OS, 13.0 months [95% CI, 10.47-17.06 months] vs 7.0 months [95% CI, 6.1-8.3 months]; P = .0003). Prognostic multivariable modeling significantly associated shortened OS independently with leptomeningeal dissemination (P < .0001), increasing numbers of brain metastases at diagnosis (P < .0001), earlier MBM diagnosis year (P = .0008), higher serum levels of lactate dehydrogenase (P < .0001), receipt of immunotherapy before MBM diagnosis (P = .003), and the presence of extracranial disease (P = .02). The use of different CNS-directed treatment modalities was associated with presenting symptoms, diagnosis year, number and size of brain metastases, and the presence of extracranial disease. Multivariable analysis demonstrated improved survival for patients who underwent craniotomy (P = .01). The prognosis for patients with MBM has improved within the last 5 years, coinciding with the approval of PD-1 immune checkpoint blockade and combined BRAF/MEK targeting. Improving survival reflects and may influence the willingness to use aggressive multimodality treatment for MBM. Historically, melanoma brain metastases (MBM) have carried a poor survival prognosis of 4 to 6 months; however, the introduction of immunotherapy and targeted precision medicines has altered the survival curve for advanced melanoma. In this large, single-institution, contemporary cohort, the authors demonstrate a significant increase in survival of patients with MBM to 13 months within the last 5 years of the study. A worse prognosis for patients with MBM was significantly associated with the number of metastases at diagnosis, previous exposure to immunotherapy, spread of disease to the leptomeningeal compartment, serum lactate dehydrogenase elevation, and the presence of extracranial disease. The current age of systemic treatments has also been accompanied by shifts in the use of central nervous system-directed therapies.

Conjunctival Melanoma: Outcomes based on the American Joint Committee on Cancer Clinical Classification (8th Edition) of 425 Patients at a Single Ocular Oncology Center.

The aim of this study was to evaluate outcomes of conjunctiva melanoma based on the American Joint Committee on Cancer Classification (AJCC) 8th edition. Retrospective interventional case series. Outcomes analysis of 425 patients. In this analysis of 425 patients with conjunctival melanoma, there were 266 (63%) patients classified as T1, 75 (18%) as T2, 84 (20%) as T3, and 0 (0%) as T4. A comparison (T1 vs T2 vs T3) revealed that history of primary acquired melanosis was more common in T2 (81% vs 96% vs 81%; P = 0.01) and conjunctival nevus more common in T1 (20% vs 9% vs 11%; P = 0.03). Of 381 patients with follow-up (mean of 57.6 months), comparison revealed higher T category with increasing local recurrence/new tumor (30% vs 43% vs 49%; P = 0.004), increasing exenteration (3% vs 9% vs 28%; P < 0.001), increasing melanoma-related locoregional lymph node metastasis (2% vs 7% vs 12%; P = 0.001), increasing melanoma-related systemic metastasis (9% vs 25% vs 23%; P < 0.001), and increasing melanoma-related death (4% vs 12% vs 18%; P < 0.001). A comparison at 10 years revealed visual acuity loss of >3 lines (32% vs 42% vs 63%; P < 0.001), melanoma recurrence/new tumor (47% vs 70% vs 74%; P < 0.001), exenteration (4% vs 24% vs 46%; P < 0.001), melanoma-related locoregional lymph node metastasis (3% vs 13% vs 25%; P < 0.001), melanoma-related systemic metastasis (13% vs 45% vs 40%; P < 0.001), and melanoma-related death (8% vs 22% vs 37%; P < 0.001). Based on the AJCC 8th edition of conjunctival melanoma, the 10-year risk per T category significantly increased for visual acuity loss of >3 lines, recurrence/new tumor, exenteration, locoregional and systemic melanoma-related metastasis, and melanoma-related death.

Impact of COVID-19 on melanoma diagnosis.

Impact of COVID-19 on melanoma diagnosis.

Innate RIG-I signaling restores antigen presentation in tumors and overcomes T cell resistance.

In recent years, therapy with immune modulating antibodies, termed immune checkpoint blockade (ICB), has revolutionized the treatment of advanced metastatic melanoma, yielding long-lasting clinical responses in a subgroup of patients. But despite this remarkable progress, resistance to therapy represents a major clinical challenge. ICB efficacy is critically dependent on cytotoxic CD8+ T cells targeting tumor cells in an HLA class I (HLA-I) antigen-dependent manner. Transcriptional suppression of the HLA-I antigen processing and presentation machinery (HLA-I APM) in melanoma cells leads to HLA-I-low/-negative tumor cell phenotypes escaping CD8+ T cell recognition and contributing to ICB resistance. In general, HLA-I-low/-negative tumor cells can be re-sensitized to T cells by interferons (IFN), augmenting HLA-I APM expression. However, this mechanism fails when melanoma cells acquire resistance to IFN, which recently turned out as a key resistance mechanism in ICB, besides HLA-I APM suppression. Seeking for a strategy to overcome these barriers, we identified a novel mechanism that restores HLA-I antigen presentation in tumor cells independent of IFN (Such et al. (2020) J Clin Invest, doi: 10.1172/JCI131572). We demonstrated that tumor cell-intrinsic activation of the cytosolic innate immunoreceptor RIG-I by its synthetic ligand 3pRNA overcomes transcriptional HLA-I APM suppression in patient-derived IFN-resistant melanoma cells. De novo HLA-I APM expression is IRF1/IRF3-dependent and re-sensitizes melanoma cells to autologous cytotoxic CD8+ T cells. Notably, synthetic RIG-I ligands and ICB synergize in T cell activation, suggesting combinational therapy could be an efficient strategy to improve patient outcomes in melanoma.

Gender-specific associations between polymorphisms of the circadian gene RORA and cutaneous melanoma susceptibility

BackgroundMelanoma is the deadliest of skin cancers and has an increasing annual incidence worldwide. It is a multi-factorial disease most likely arising from both genetic predisposition and environmental exposure to ultraviolet light. Genetic variability of the components of the biological circadian clock is recognized to be a risk factor for different type of cancers. Moreover, two variants of a clock gene, RORA, have been associated with melanoma patient’s prognosis. Our aim is to test the hypothesis that specific single nucleotide polymorphisms (SNPs) of the circadian clock genes may significantly influence the predisposition to develop cutaneous melanoma or the outcome of melanoma patients.MethodsWe genotyped 1239 subjects, 629 cases of melanoma and 610 healthy controls in 14 known SNPs of seven selected clock genes: AANAT, CLOCK, NPAS2, PER1, PER2, RORA, and TIMELESS. Genotyping was conducted by q-PCR. Multivariate logistic regression was employed for susceptibility of melanoma assessment, modeled additively. Subgroup analysis was performed by gender. For the female subgroup, a further discrimination was performed by age. For prognosis of melanoma assessment, multivariate Cox proportional hazard regression was employed. The Benjamini–Hochberg method was utilized as adjustment for multiple comparisons.ResultsWe identified two RORA SNPs statistically significant with respect to the association with melanoma susceptibility. Considering the putative role of RORA as a nuclear steroid hormone receptor, we conducted a subgroup analysis by gender. Interestingly, the RORA rs339972 C allele was associated with a decreased predisposition to develop melanoma only in the female subgroup (OR 0.67; 95% CI 0.51–0.88; P = 0.003) while RORA rs10519097 T allele was associated with a decreased predisposition to develop melanoma only in the male subgroup (OR 0.62; 95% CI 0.44–0.87; P = 0.005). Moreover, the RORA rs339972 C allele had a decreased susceptibility to develop melanoma only in females aged over 50 years old (OR 0.67; 95% CI 0.54–0.83; P = 0.0002). None of the studied SNPs were significantly associated with the prognosis.ConclusionsOverall, we cannot ascertain that circadian pathway genetic variation is involved in melanoma susceptibility or prognosis. Nevertheless, we identified an interesting relationship between melanoma susceptibility and RORA polymorphisms acting in sex-specific manner and which is worth further future investigation.

Cutaneous immune-related adverse events in patients with melanoma treated with checkpoint inhibitors.

Checkpoint inhibitor (CPI) therapy has vastly improved long-term outcomes in metastatic malignant melanoma (MMM). Therapy takes the form of monoclonal antibody infusions that target immune cell checkpoint proteins, such as cytotoxic T-lymphocyte-associated protein 4 (CTLA4) and programmed death 1/programmed death ligand 1 (PD1/PDL1). Cutaneous immune-related adverse effects (IrAEs) are frequent in patients with MMM treated with CPIs. Our aim was to review the clinical presentations of cutaneous IrAEs associated with CPI therapy in adult patients with MMM. We carried out a literature review of clinical trials, case series and case reports of patients with melanoma and those with other cancers treated with anti-CTLA4, anti-PD1/PDL1, or a combination of these therapies. Diverse clinical presentations of cutaneous IrAEs are recognized. Anti-CTLA4 therapy has a higher associated rate of cutaneous IrAEs than anti-PD1/PDL1 therapies. Low-grade cutaneous IrAEs are common and are usually managed supportively while continuing CPI therapy. Delayed presentations arising after established use of CPIs can make therapy-associated cutaneous IrAEs difficult to distinguish from coincidental dermatological disease. Vitiligo-like depigmentation is a good prognostic indicator of outcome in patients with melanoma. Life-threatening adverse events including toxic epidermal necrolysis are rare. The identification of predictive biomarkers that highlight patients at risk of life-threatening IrAEs remains an unmet need. The involvement of dermatologists in the multidisciplinary assessment of cutaneous IrAEs is increasingly pertinent in the management and care of CPI-treated patients with melanoma.

Myosteatosis is prognostic in metastatic melanoma treated with nivolumab.

While immunotherapy agents have improved outcomes in metastatic melanoma (MM), predictive biomarkers in these patients are lacking. Parameters identified from body composition analysis, such as low SMD (also termed myosteatosis), may prognosticate MM patients on immunotherapy. In this retrospective study, 44MM patients received nivolumab, either as monotherapy or in combination with ipilimumab. Pre-treatment computed tomography (CT) scans were analyzed to determine skeletal muscle density (SMD) in Hounsfield units (HU) and muscle surface area (MSA) in cm2 at L3. MSA was used to determine nivolumab dosing in mg/cm2. Low SMD was associated with worse overall survival (OS) by log rank test (median 12.03 vs. 34.96 months, p=0.001) and in multivariate analysis when accounting for age, sex, performance status, and number of prior lines of therapy (HR 4.40, 95% CI 1.44-13.42, p=0.009). Lower nivolumab dosing by MSA was significantly associated with improved OS (median 42.9 vs. 12.3 months, p<0.001). This association remained significant in multivariate analysis with age, sex, performance status, and number of prior lines of therapy (HR 0.05, 95% CI 0.01-0.30, p=0.001). Neither SMD nor higher nivolumab dose per MSA were associated with increased incidence of treatment toxicity. Low SMD is prognostic in MM treated with nivolumab immunotherapy. Presence of myosteatosis or higher nivolumab dose based on body composition did not predict treatment toxicity.

Impact of the time interval between primary melanoma excision and sentinel node biopsy: A systematic review and meta-analysis

Obtaining a sentinel lymph node biopsy (SLNB) specimen is a standard staging procedure in the management of cutaneous melanoma. However, there is no consensus on the safe time interval between the primary melanoma biopsy procedure and the SLNB procedure. We evaluated the association between time from biopsy to SLNB and patients' outcomes for melanoma. We performed this systematic review and meta-analysis based on the recommendations of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Six retrospective studies were included. Nine thousand seven hundred five patients were identified, of which 4383 underwent a SNLB procedure at a time interval defined as early and 4574 at an interval defined as late. A combined hazard ratio of 1.25 (95% confidence interval [CI] 0.92-1.68) was determined, and there was high heterogeneity (I2=83%; P=.002) of the SLNB time interval on melanoma-specific survival. The combined HR for disease-free survival was 1.05 (95% CI 0.95-1.15), with low heterogeneity (I2=9%; P=.36). Regarding overall survival, a combined HR of 1.25 (95% CI 0.92-1.70) was found, with low heterogeneity (I2=37%; P=.2). There is heterogeneity between some studies. There are no significant differences in patient outcome between a short interval versus a long interval between the primary biopsy procedure and obtaining a SNLB specimen.

Risk factors for thick melanoma among veterans: A cross-sectional study

Risk factors for thick melanoma among veterans: A cross-sectional study

Clinical profile and outcomes of malignant melanoma in patients from an Indian institute: A retrospective analysis

Background: The profile of patients with malignant melanoma in Asian countries is distinctly disparate from that of those in Western countries. Malignant melanoma is a rare malignancy with scarce literature from India.Objectives: We aimed to describe the clinical profiles and outcomes of Indian patients with advanced malignant melanoma.Materials and Methods: We retrospectively analyzed the data of consecutive patients with malignant melanoma who presented to the bone and soft tissue sarcoma clinic at the All India Institute of Medical Sciences, New Delhi, between January 2016 and March 2019. Our primary endpoint was to evaluate the clinical profile of the patients and the patterns of treatment. The secondary endpoints were response rate, progression-free survival (PFS), and overall survival (OS). Results: We included 93 patients in the cohort, with a median age of 53 years (range, 25–85). The majority of patients were men (61.3%); almost half had an Eastern Cooperative Oncology Group performance status of 2 or greater. Most (89.2%) patients had metastases at presentation. The most common primary sites were anorectal (24.7%), acral (24.7%), ocular (17.2%), head and neck (15.1%), and thigh (9.7%). The median number of metastatic sites at presentation was 2, with the most common sites of metastases being the lymph nodes (57%), lung (48.3%), liver (35.5%), and bone (25.8%). BRAF V600E mutation was present in three out of four tested patients, while c-KIT mutation was present in two out of seven tested patients. At a median follow-up of 18 months, the median PFS was 2 months (95% confidence interval, 1.2–2.7 months) and median OS was 7 months.Conclusion: Acral/mucosal melanoma is the most common melanoma among Indians and has poor outcomes. Limited access of patients with melanoma to standard-of-care therapeutic options remains an important issue in a resource-constrained country like India.

Microfluidic technologies for immunotherapy studies on solid tumours.

Immunotherapy is a powerful and targeted cancer treatment that exploits the body's immune system to attack and eliminate cancerous cells. This form of therapy presents the possibility of long-term control and prevention of recurrence due to the memory capabilities of the immune system. Various immunotherapies are successful in treating haematological malignancies and have dramatically improved outcomes in melanoma. However, tackling other solid tumours is more challenging, mostly because of the immunosuppressive tumour microenvironment (TME). Current in vitro models based on traditional 2D cell monolayers and animal models, such as patient-derived xenografts, have limitations in their ability to mimic the complexity of the human TME. As a result, they have inadequate translational value and can be poorly predictive of clinical outcome. Thus, there is a need for robust in vitro preclinical tools that more faithfully recapitulate human solid tumours to test novel immunotherapies. Microfluidics and lab-on-a-chip technologies offer opportunities, especially when performing mechanistic studies, to understand the role of the TME in immunotherapy, and to expand the experimental throughput when using patient-derived tissue through its miniaturization capabilities. This review first introduces the basic concepts of immunotherapy, presents the current preclinical approaches used in immuno-oncology for solid tumours and then discusses the underlying challenges. We provide a rationale for using microfluidic-based approaches, highlighting the most recent microfluidic technologies and methodologies that have been used for studying cancer–immune cell interactions and testing the efficacy of immunotherapies in solid tumours. Ultimately, we discuss achievements and limitations of the technology, commenting on potential directions for incorporating microfluidic technologies in future immunotherapy studies.

SLC25A38 as a Novel Biomarker for Metastasis and Clinical Outcome in Uveal Melanoma

SLC25A38 as a Novel Biomarker for Metastasis and Clinical Outcome in Uveal Melanoma

Surgical Excision of Perirectal Melanoma in the Horse. 3 Cases

Equine melanoma is one of the most common skin neoplasms encountered in equine practice. Surgical excision of melanocytic tumors is a viable treatment option and is considered to be locally curative. In the literature, information regarding surgical removal and long-term outcome of perirectal melanomas is limited. A total of three cases were included in this report, all presented with large perirectal melanomas, infiltrating the retroperitoneal musculature, leading to extra-luminal obstruction of the rectum. Horses were showing signs of dyschezia and tenesmus, secondary to rectal fecal impaction. Rectal palpation and transrectal ultrasonography aided in assessing the depth and size of the masses, as well as tumor invasion into the rectal wall. Tumor biopsy by fine needle aspiration was used to confirm the diagnosis. All horses underwent surgical excision of the masses to permanently alleviate clinical signs. In one horse, complete incision and reconstruction of the rectal wall was necessary in order to excise the whole tumor. Although surgery was successful in all three horses, one of them had to be euthanized 5 days after surgery, as clinical signs persisted. The aim of this report was to extensively describe the surgical approach, pre-operative considerations and postsurgical complications associated with surgical excision of perirectal melanoma in the horse.

Immunoaffinity-Based Isolation of Melanoma Cell-Derived and T Cell-Derived Exosomes from Plasma of Melanoma Patients.

Tumor-derived exosomes (TEX), a subset of small extracellular vesicles (EVs) which originate from the endocytic compartment of tumor cells, are emerging as key players in cancer progression. TEX circulate freely in patients' body fluids and transfer bioactive cargos from tumor to various recipient cells. The molecular cargo of melanoma cell-derived exosomes (MTEX) mimics that of the tumor, and MTEX serve as a liquid biopsy that provides potentially useful information for cancer diagnosis, prognosis, or responses to therapy. Plasma of melanoma patients contains a mix of MTEX and exosomes produced by nonmalignant cells (NMTEX). Isolation of these exosome subtypes from the bulk of plasma exosomes is necessary to evaluate contributions of each as potential biomarkers of melanoma progression and outcome. Here, methods for separation of MTEX from T cell-derived exosomes from a single small volume of plasma and their subsequent molecular and functional characterization are described. Following size exclusion chromatography (SEC) to isolate total plasma exosomes, immune affinity-based capture of MTEX with anti-CSPG4 antibody and then of exosomes produced by T cells with anti-CD3 antibody is used to sequentially isolate the two subsets. This immune capture method enables the recovery of MTEX and CD3+ exosomes in quantities sufficient both for molecular profiling by flow cytometry or western blotting and for functional analyses.

Immunotherapy toxicities in metastatic vulvar and vaginal melanomas: a retrospective cohort study

This retrospective cohort study examined the factors for patients with metastatic vulvar and vaginal melanomas on immune checkpoint inhibitors. The study included all patients over the age of 18 who received either anti-cytotoxic T-lymphocyte-4 (anti-CTLA-4) therapy or anti-programmed cell death protein-1 (anti-PD-1) therapy at the Sunnybrook Hospital from June 2012 to December 2018. There were 11 patients with vulvar or vaginal melanoma on immune checkpoint inhibitor therapy. The main sites of metastasis included the lungs, lymph nodes, soft tissues, and liver. The majority of patients received prior radiation therapy (7/11) and prior surgical therapy (9/11). There were no differences in overall survival for vulvar or vaginal melanomas on anti-PD-1 vs. anti-CTLA-4 therapy (p &gt; 0.05). There were no significant differences in overall survival for vulvar and vaginal vs. cutaneous melanoma (p &gt; 0.5). There were no significant differences in overall survival in patients with vulvar and vaginal melanoma in the presence vs. absence of immune-related adverse events (p &gt; 0.05), yet there was a significant difference in patients with cutaneous melanoma in the presence vs. absence of immune-related adverse events (p &lt; 0.05). Knowledge of the presentation and outcome of vulvar and vaginal melanomas is important for clinical practice in gynecology.

Relevance of body mass index as a predictor of systemic therapy outcomes in metastatic melanoma: analysis of the MelBase French cohort data☆

The 'obesity paradox' suggests that higher body mass index (BMI) is associated with better survival values in metastatic melanoma patients, especially those receiving targeted and immune checkpoint inhibitor therapy. Higher BMI is also associated with higher incidences of treatment-related adverse events (TRAEs). This study assesses whether BMI is associated with survival outcomes and adverse events in metastatic melanoma patients with systemic therapy. This multicentric retrospective study, conducted from 1 March 2013 to 29 April 2019, enrolled adults with unresectable stage III or IV melanoma from the French multicentric prospective cohort-MelBase (NCT02828202). Patients with first-line chemotherapy and targeted and immune therapy were included. Underweight people and those with metastatic mucosal or ocular melanoma were excluded. BMI was categorized using the World Health Organization criteria. Co-primary outcomes included the association between BMI and progression-free survival and overall survival, stratified by treatment type, sex, and age. Secondary endpoints were the association of BMI with overall response and TRAEs. Multivariate analyses were carried out. A total of 1214 patients were analyzed. Their median age was 66.0 years (range, 53-75). Male predominance was observed [n= 738 (61%)]. Most patients received immune checkpoint inhibitor therapy (63%), followed by targeted therapy (32%), and had stage M1c disease (60.5%). Obese patients represented 22% of the cohort. The median follow-up duration was 13.5 months (range, 6.0-27.5). In the pooled analysis, no positive or negative association between BMI and progression-free survival (P= 0.88)/overall survival (P= 0.25) was observed, regardless of treatment type, sex, and age. These results were nonsignificant in the univariate and multivariate analyses. The objective response rate, according to BMI category, did not differ significantly regardless of age. TRAEs were not associated with BMI. The observed lack of an association between BMI and survival demonstrates that BMI is not a valuable marker of systemic treatment-related outcomes in metastatic melanoma. Future approaches might focus on the whole-body distribution.

Recent advances in molecular targeted therapy for unresectable and metastatic BRAF-mutated melanoma.

The clinical outcome of BRAF-mutated advanced melanoma has been improved by both molecular targeted therapies and immune checkpoint inhibitors. Long-term follow-up data reveal durable clinical responses in patients receiving first-line combinations of BRAF inhibitors plus MEK inhibitors, particularly those showing a complete response. Clinical outcomes are also associated with the lactate dehydrogenase levels and the number of metastatic organs. Although brain metastasis is frequently difficult to control, systemic therapy is preferred in cases with small and asymptomatic brain metastases associated with progressive extra-cranial disease. Control of intra-cranial disease with BRAF inhibitors plus MEK inhibitors is comparable with that of immune checkpoint inhibitors, although immune checkpoint inhibitors are superior to targeted therapies with respect to survival. The BRAF inhibitors plus MEK inhibitors regimen is well-tolerated, and toxicities are usually manageable and reversible, but differ according to the specific regimen used. Guidelines in the United States, Europe, and Japan recommend targeted therapy for patients who need early tumor responses. A meta-analysis of retrospective data shows that the baseline lactate dehydrogenase level is significantly higher in patients treated with BRAF inhibitors plus MEK inhibitors than in those treated with immune checkpoint inhibitors, suggesting that clinicians tend to use BRAF inhibitors plus MEK inhibitors for more advanced disease. Since there is insufficient efficacy and safety data on the use of targeted therapies for acral and mucosal melanoma, a retrospective analysis may be useful. The combination of molecular targeted therapy plus immune checkpoint inhibitors is expected to elicit further improvement. The results of several trials using combination or sequential therapies will be available in the next few years.