Recurrent Melanoma Research Articles

Intraoperative Immunohistochemistry During Mohs Micrographic Surgery and Staged Excision Decreases Local Recurrence Rates for Invasive Cutaneous Melanoma: A Systematic Review and Meta-Analysis.

Mohs micrographic surgery (MMS) is increasingly used to treat cutaneous melanoma. However, it is unclear whether intraoperative immunohistochemistry (IHC) improves surgical outcomes. To determine whether intraoperative IHC during MMS and staged excision is associated with a decreased risk of poor surgical outcomes. Search of 6 databases identified comparative and noncomparative studies that reported local recurrence after MMS or staged excision with or without IHC for melanoma. Random-effects meta-analysis was used to estimate pooled local recurrence rates, nodal recurrence, distant recurrence, and disease-specific mortality. Overall, 57 studies representing 12,043 patients with cutaneous melanoma and 12,590 tumors met inclusion criteria. Combined MMS and staged excision with IHC was associated with decreased local recurrence in patients with invasive melanoma (0.3%, 95% CI: 0-0.6) versus hematoxylin and eosin alone (1.8%, 95% CI: 0.8%-2.8%) [ p < .001]. Secondary outcomes including nodal recurrence, distant recurrence, and disease-specific mortality were not significantly different between these 2 groups. Study heterogeneity was moderately-high. Local recurrence of invasive melanoma is significantly lower after MMS and staged excision with IHC as opposed to without IHC. These findings suggest that the use of intraoperative IHC during MMS or staged excision should strongly be considered, particularly for invasive melanoma.Trial Registration PROSPERO Identifier: CRD42023435630.

Transcriptomics analysis of LINC02202/XBP1 axis in melanoma: Implications for drug targeting and PD-1 monoclonal antibody efficacy.

Malignant melanoma (MM) is a highly aggressive and deadly form of skin cancer, primarily caused by recurrence and metastasis. Therefore, it is crucial to investigate the regulatory mechanisms underlying melanoma recurrence and metastasis. Our study has identified a potential targeted regulatory relationship between LINC02202, miR-526b-3p and XBP1 in malignant melanoma. Through the regulation of the miR-526b-3p/XBP1 signalling pathway, LINC02202 may play a role in tumour progression and immune infiltration and inhibiting the expression of LINC02202 can increase the efficacy of immunotherapy for melanoma. Our findings shed light on the impact of LINC02202/XBP1 on the phenotype and function of malignant melanoma cells. Furthermore, this study provides a theoretical foundation for the development of novel immunotherapy strategies for malignant melanoma.

Abstract 4399: HMGA1 is an epigenetic regulator and plays a critical role in melanoma recurrence

Abstract Among various genetic mutation in melanoma, BRAFV600E is one of the key drivers of melanoma initiation and progression and has become the frontline target in clinical trials. Although BRAF/MEK inhibitors show very promising therapeutic outcomes, recurrence or relapse is still a major challenge and its underlying mechanisms are still poorly understood. We hypothesized that survival of recurrent tumors is BRAF independent and relies on epigenetic reprogramming. To test our hypothesis, we used either pharmacological inhibition of BRAF/MEK or CRISPR/Cas9 mediated knockout of BRAF to create cell/tumor models of BRAF-independent survival. Cut&amp;Run sequencing was then used to identify epigenetic alterations regulated by H3K4me3 or H3K27Ac in a genome scale and capture the landscape of epigenetic alterations of BRAF-independent cell survival. Combining regular bulk RNAseq, we narrowed down our top candidates and focused on one of the functionally validated candidates, HMGA1. Interestingly, CRISPR/Cas9 mediated HMGA1 knockout cells show significantly slower growth in both in vitro colony formation assays and in vivo xenografts assay in BRAF/MEK resistant Patient-Derived-Xenograft (PDX) tumor models resembling melanoma recurrence. Furthermore, we selected CRISPR/Cas9 single knockout cells of HMGA1, which is a pure genetic depletion model, and confirmed the phenotype of impaired tumor growth of HMGA1 knockout cells. We then performed RNAseq and ChIPseq, and identified downstream targets of HMGA1 and elucidated mechanisms by which HMGA1 reprograms epigenetics of recurrence. Utilizing the single knockout cell, we re-introduced HMGA1 in the pure knockout cells, and anticipated that restoration of HMGA1 in pure HMGA1 knockout cells rescues impaired tumor growth and confer cells resistance to BRAF/MEK inhibition. Finally, we subcutaneously injected the HMGA1 single knockout cells into humanized mice and tested whether epigenetic alterations perturb the immune microenvironment and sensitize cells to immunotherapy. In conclusion, this study sheds new lights on how melanoma cells reprogram the epigenome to develop mechanisms of recurrence. Identification of HMGA1 and its upstream or downstream targets provides potential druggable targets of overcoming relapse after BRAF/MEK inhibitor therapy. Citation Format: Haiwei Mou, Kristen DeRosa, Veronika Yakovishina, Yeqing Chen, Abdiel Mandella Reynolds, Min Xiao, Monzy Thomas, Meenhard Herlyn. HMGA1 is an epigenetic regulator and plays a critical role in melanoma recurrence [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4399.

Abstract 6411: The gut microbiome is associated with recurrence free survival in patients with resected Stage III or Stage IV melanoma treated with immune checkpoint inhibitors

Abstract The gut microbiome (GMB) plays a crucial role in immune checkpoint blockade (ICB) therapy outcomes for metastatic melanoma patients, yet there remains a lack of consensus regarding the specific microbiota associated with clinical outcomes, particularly across different geographic regions. Furthermore, investigations into the relationship between GMB and melanoma outcomes in the adjuvant setting are notably absent. This highlights the pressing need for a comprehensive, large-scale study spanning diverse geographic locations within a well-controlled clinical trial environment. In this study, we conducted shotgun sequencing on pre-treatment stool samples collected from 674 melanoma patients participating in an international, randomized, double-blind, phase III adjuvant trial evaluating clinical outcomes following adjuvant nivolumab plus ipilimumab versus nivolumab. Our recruitment encompassed three continents and five geographically distinct regions. Given the significant influence of geographic region on GMB composition, we employed three analytical approaches: (a) region-specific analyses, (b) combined meta-analyses across regions, and (c) sub-set paired analyses involving subjects closely matched for overall GMB. Additionally, we assessed GMB stability by examining samples collected serially prior to therapy and at weeks 7 and 29 of ICB treatment. Through region-specific and meta-analyses, we identified ten pre-treatment gut bacterial markers, including Eubacterium, Ruminococcus, Clostridium, and Firmicutes, which exhibited associations with melanoma recurrence in the adjuvant setting. The predictive capacity of these microbial markers was directly proportion to GMB similarity (Spearman correlation = 0.86, p&amp;lt;0.001 for AUC vs. beta-diversity). Notably, for closely matched patients in terms of their GMB composition, the prediction of recurrence using the recurrence-associated markers, in conjunction with clinical characteristics, yielded an AUC of 0.917 (95% CI: 0.825-1.00). Furthermore, GMB remained largely stable across serial samples collected before and after treatment (PERMANOVA R2 = 0.867, p-val&amp;lt;0.001, at baseline, week 7, and week 29). This study underscores the remarkable stability of GMB during adjuvant ICB therapy for melanoma and identifies specific bacterial biomarkers that hold promise for predicting melanoma recurrence within the adjuvant treatment setting. The gut microbiome emerges as a potential source of microbial biomarkers for individualized prediction of melanoma recurrence in clinical practice. Citation Format: Mykhaylo Usyk, Richard B. Hayes, Rob Knight, Antonio Gonzalez, Huilin Li, Iman Osman, Jeffrey S. Weber, Jiyoung Ahn. The gut microbiome is associated with recurrence free survival in patients with resected Stage III or Stage IV melanoma treated with immune checkpoint inhibitors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6411.

Abstract 1225: Novel cellular barcoding to dissect melanoma heterogeneity and drug resistance

Abstract Melanoma is the most common cause of death in skin cancer. While the development of targeted therapies (MAPK pathway inhibitors) led to a substantial improvement in overall survival of patients with melanoma harboring the BRAFV600E mutation, approximately 40% of treated patients acquire resistance and experience tumor recurrence after one year. Melanoma drug resistance is mediated by drug-tolerant persister (DTP) cell subpopulations present in tumors. DTP cells are either intrinsically rare sub-populations pre-existing prior to therapies, or adaptive sub-populations that acquire genetic and epigenetic alterations during treatments. Our lab has established six PDX models that responded to the treatment of BRAF/MEK inhibitor combination then relapsed in six to 40 weeks. We combined cell lineage barcoding and single-cell transcriptomics to trace the emergence of DTP cells in melanoma recurrence. The recent development of cellular barcoding facilitates the labelling of tens to millions of cancer clones and enables the identification of the complex mechanisms associated with clonal fate in response to therapy and in different microenvironments. We have constructed a library of approximately 15 million barcodes into a lentiviral vector. Melanoma cells were infected with the barcode library to ensure each cell carried a unique barcode. Labelled melanoma cells were injected into NSG mice, which were then treated with BRAF/MEK inhibitors, and they developed drug resistance with prolonged treatments. Treated tumors were harvested at different timepoints until relapse. The barcodes are localized close to the polyA tail of the expressed mRNA, the 3’ end sequence of which could be retrieved simultaneously through single-cell RNA sequencing (scRNAseq). Thus, we can trace the clonal information from the relapsed tumor back to earlier timepoints such as the treatment naive tumor and minimal residual disease (MRD) stage. Our data showed that the diversity of barcodes in MRD stage had no significance compared to treatment naive tumor, while the diversity of barcodes in the relapsed tumor decreased around 10-fold from the MRD stage. The most dominant sub-populations in MRD arose from minor sub-populations in the treatment naive tumor, while most of the dominant sub-populations in the relapsed tumor were daughter cells from minor sub-populations in MRD stage. The top three sub-populations dominated 25% of the relapsed tumor. The three dominant drug-resistant sub-populations shared a similar phenotype shown by scRNAseq clusters. The data indicate that the heterogeneity of melanoma is maintained in the early treatment stage but is lost in acquired resistance. And the lineages of DTP cells change continuously under prolonged BRAF/MEKi drug pressure. Citation Format: Haiyin Li, Yeqing Chen, Jessica Kaster, Nazifa Promi, Meenhard Herlyn. Novel cellular barcoding to dissect melanoma heterogeneity and drug resistance [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1225.

Abstract 6896: Biomimetic hydrogels at physiological stiffness reprogram patient derived melanoma cells

Abstract Melanoma is a uniquely difficult cancer to treat due to complex tumor heterogeneity and resistance, where upon dissemination, survival drops to less than 17%. Drug resistance has arisen for the current standard of care and combinatorial therapies, expediting the need for new efficacious agents. The lack of physiologically relevant preclinical models has impeded the development of these therapeutics. Potential melanoma drugs are typically assayed using cell lines on tissue culture plastic, then tested for in vivo efficacy and side effects in animals. This paradigm is inherently unsuitable for the generation of effective therapies as typical cell culture platforms fail to replicate the complex microenvironments known to play critical roles in tumor pathology and rodent models are prohibitively expensive for optimizing novel and combination therapies. Thus, our goal is to synthesize tissue-engineered melanoma models using biomimetic polymers that recapitulate patient tumor characteristics to assess combination and novel therapies that attenuate resistance and disrupt metastatic processes. In this study, patient melanoma cells, which were unable to recapitulate drug responses on traditional cell culture platforms, were cultured in a controlled spatial and temporal manner on polyacrylamide hydrogels. The hydrogel scaffolds feature stiffnesses spanning that of physiological tissue, with microcontact printed human fibronectin for biomimetic protein presentation to create a microtumor array. Cells cultured on the hydrogel showed a 2.5-fold increase in expression of the cancer stem cell biomarkers, CD271 and ABCB5, which play a key role in melanoma survival and recurrence, compared to cells cultured on plastic or glass substrates. Further study identified BRAF mutant, drug resistant patient cells, regained resistance to standard of care targeted therapies, trametinib and dabrafenib. Through hydrogel microarrays featuring physiological similarities, the technology has enabled the exploration of heterogeneous cell populations with novel and combinatorial therapeutics. Citation Format: Yi L. Liu, Justyna Gleba, Chantal Kopecky, Matthew Pawlush, John A. Copland, Kristopher A. Kilian. Biomimetic hydrogels at physiological stiffness reprogram patient derived melanoma cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6896.

Outcome of adjuvant immunotherapy in a real-world nation-wide cohort of patients with melanoma

BackgroundClinical trials have demonstrated promising outcomes for adjuvant immunotherapy in patients with resected melanoma. Real-life data provide valuable insights to support patient guidance and treatment decisions. MethodsObservational population-based study examining a national cohort of patients with resected stage III-IV melanoma referred for adjuvant therapy. Data were extracted from the Danish Metastatic Melanoma Database (DAMMED). ResultsBetween November 2018 and January 2022, 785 patients received adjuvant anti-PD-1. The majority had stage III resected melanoma (87%), normal LDH levels (80%), and performance score 0 (87%). Patients were followed for a median of 25.6 months (95%CI 24−28). The median recurrence-free survival (RFS) and melanoma-specific survival (MSS) were not reached. The RFS was 78% (95%CI 75−81), 66% (63−70), and 59% (55−63); MSS was 97% (95−98), 93% (91−95), and 87% (84−90) at 1-, 2-, and 3-year; respectively. Less than half (42%) of the patients finalized planned therapy, 32% discontinued due to toxicity, and 19% due to melanoma recurrence. Patients discontinuing adjuvant treatment prematurely, without recurrence, had similar outcomes as patients finalizing therapy. In a multivariable analysis, ipilimumab plus nivolumab did not improve outcomes compared to ipilimumab monotherapy as a first-line metastatic treatment after adjuvant anti-PD-1. ConclusionSurvival outcomes in real-world patients with melanoma treated with adjuvant anti-PD-1 align with results from the randomized controlled trials. Patients discontinuing therapy prematurely, for other reasons than recurrence, had similar outcomes as patients finalizing planned treatment. First-line metastatic treatment with ipilimumab and nivolumab post-adjuvant anti-PD-1 did not show improved outcomes compared to ipilimumab/anti-PD-1 monotherapy.

Feasibility and efficacy of indocyanine green in monitoring systemic drug leakage during isolated limb perfusion for recurrent melanoma of extremity.

Melanoma is known for its high metastatic potential and aggressive growth. Recurrence is common post-surgery, sometimes leading to unresectable disease. Locally recurrent unresectable melanoma of extremity has been treated with high-dose anticancer chemotherapy via isolated limb perfusion (ILP) to improve local efficacy of drug and salvage limbs. Standard ILP monitoring uses radiolabeled dyes, requiring specialized personnel and involving radiation exposure. In this case, we used indocyanine green (ICG) to track systemic drug leakage during ILP. A 47-year-old gentleman with recurrent malignant melanoma of the left foot, operated twice earlier and treated with adjuvant pembrolizumab, presented with multiple in-transit metastases in the limb. ILP was planned, with 5 mg ICG administered in the perfusion solution along with high-dose melphalan. Stryker's SPI PHI handheld device was employed to visualize ICG during ILP. Absence of fluorescence beyond the involved extremity, such as fingers, ears, and the abdominal wall, indicated no systemic drug dispersion. For control, technetium radiocolloid dye was co-administered, monitored by a precordial gamma probe, confirming no systemic leakage, and validating effectiveness of ICG in leakage monitoring. ICG proves to be a safe, reliable, cost-effective, radiation-free approach for precise systemic drug leakage monitoring during ILP for recurrent melanoma of extremity.

The impact of prognostic factors and comorbidities on survival in older adults with stage I − III cutaneous melanoma in Southwest Finland: A register study

IntroductionDespite being diagnosed with thicker and more often ulcerated melanomas, cancer-specific survival (CSS) is not necessarily inferior in older adults with melanoma compared to younger patients. Materials and MethodsOur aim was to evaluate the impact of baseline melanoma-specific prognostic factors and comorbidities on recurrence-free survival (RFS), CSS, and overall survival (OS) in patients aged 70–79 (n = 474) and ≥ 80 years (n = 286) with resected stage I − III cutaneous melanoma in Southwest Finland between January 1, 2000 and December 31, 2020. Patients were restaged according to the 8th edition of TNM classification, and comorbidities were assessed using the Charlson Comorbidity Index (CCI). ResultsPatients aged ≥80 years had thicker and more commonly ulcerated melanomas: 43.0%, 40.9%, and 16.1% of patients aged ≥80 and 56.5%, 25.3%, and 18.1% of patients aged 70–79 years were diagnosed with stage I, II, and III melanoma, respectively. Multiple comorbidities (CCI ≥2) were more common and sentinel lymph node biopsy less frequently performed in patients aged ≥80 years. RFS and CSS were similar in patients aged 70–79 years and ≥ 80 years: median RFS 13.8 years vs not reached, with the hazard ratio of melanoma recurrence or death from melanoma 1.25 (95% confidence interval [CI]: 0.91–1.71); median CSS was not reached, with the hazard ratio of death from melanoma 1.12 (95%CI: 0.81–1.75). The proportion of patients who were alive with melanoma recurrence or had died from melanoma was similar in both age groups. In multivariable analysis, higher pathological stage was the only independent risk factor for short RFS regardless of age group, sex, CCI, and tumor ulceration. Higher stage and male sex were associated with short CSS. Age ≥ 80 years, stage III disease, and CCI ≥ 2 were associated with short OS and female sex with long OS in multivariable analysis. DiscussionPathological stage was the most influential factor determining RFS and CSS in older adults with resected stage I − III melanoma. Concerning OS, age ≥ 80 years, stage III disease, and multiple comorbidities had a significant negative impact.

Diffuse preretinal vitreous seeding as a recurrence of uveal melanoma

Diffuse preretinal vitreous seeding as a recurrence of uveal melanoma

Lymphatic expression of the proliferation marker Ki67 is linked to sentinel node positivity, recurrence and mortality in primary cutaneous melanoma.

Lymphangiogenesis is a precursor to lymphovascular invasion, and may therefore signal a higher risk of metastasis and mortality in primary cutaneous melanoma. This retrospective longitudinal study aimed to evaluate whether emergent lymphangiogenesis, as measured through co-expression of endothelial proteins with the proliferation marker Ki67, was associated with poorer prognosis in a cohort of patients with single primary cutaneous melanoma. We screened all patients with a single locally invasive primary cutaneous melanoma who received sentinel lymph node biopsy at a tertiary dermatology centre in Brisbane, Australia between 1994 and 2007. Primary melanoma sections were stained via Opal multiplex immunofluorescence, and categorized according to the presence of Ki67 within either CD31+ or D2-40+ endothelial cells. Multivariate Cox regression modelling was used to evaluate associations between endothelial Ki67 positivity and clinical outcomes, with adjustment for age, sex, Breslow depth, ulceration, and anatomical location. Overall, 264 patients were available for analysis, with a median follow-up duration of 7.1 years. The presence of D2-40+ /Ki67+ co-expression was associated with greater melanoma-specific mortality (adjusted hazard ratio [HR]: 2.03; 95% confidence interval [CI]: 1.33-3.10; p = 0.001) and recurrence (adjusted HR: 1.70; 95% CI: 1.33-3.10; p = 0.001) relative to absence. CD31+ /Ki67+ co-expression was not prognostic in this cohort. Lymphatic proliferation, as measured through D2-40+ /Ki67+ co-expression, predicted greater melanoma-specific mortality and recurrence in this cohort of primary cutaneous melanoma.

Treatment of Stage III Resectable Melanoma-Adjuvant and Neoadjuvant Approaches.

Patients with stage III resectable melanoma carry a high risk of melanoma recurrence that ranges from approximately 40% to 90% at 5 years following surgical management alone. Postoperative systemic adjuvant therapy targets residual micrometastatic disease that could be the source of future recurrence and death from melanoma. Randomized phase III adjuvant trials reported significant improvements in overall survival with high-dose interferon α in 2 of 3 studies (compared with observation and GMK ganglioside vaccine) and with anti-cytotoxic T-lymphocyte antigen 4 ipilimumab at 10 mg/kg compared with placebo and ipilimumab 3 mg/kg compared with high-dose interferon α. In the modern era, more recent phase III trials demonstrated significant recurrence-free survival improvements with anti-programmed cell death protein 1, pembrolizumab, and BRAF-MEK inhibitor combination dabrafenib-trametinib (for BRAF mutant melanoma) versus placebo. Furthermore, anti-programmed cell death protein 1, nivolumab and pembrolizumab have both been shown to significantly improve recurrence-free survival as compared with ipilimumab 10 mg/kg. For melanoma patients with clinically or radiologically detectable locoregionally advanced disease, emerging data support an important role for preoperative systemic neoadjuvant therapy. Importantly, a recent cooperative group trial (S1801) reported superior event-free survival rates with neoadjuvant versus adjuvant therapy. Collectively, current data from neoadjuvant immunotherapy and targeted therapy trials support a future change in clinical practice in favor of neoadjuvant therapy for eligible melanoma patients.

High-risk histopathologic features in local advanced conjunctival melanoma.

To identify high-risk histopathologic and molecular features of local recurrence, nodal metastasis, distant metastasis (DM) and disease-specific death (DSD) in conjunctival melanoma (CoM). Ninety patients with pathologically diagnosed CoM between 2008 and 2023 were enrolled. Immunohistochemistry staining of BRAFV600E, NRASQ61R, CD117, PD-1 and PD-L1 was performed in 65 and 45 patients, respectively. Cox regression and Kaplan-Meier survival analysis were conducted to identify risk factors for local recurrence, nodal metastasis, DM and DSD. Pathologically, ulceration (hazard ratio [HR]: 3.170; 95% CI: 1.312-7.659; p = 0.01) and regression (HR: 3.196; 95% CI: 1.094-9.335; p = 0.034) were risk factors for DM. Tumour thickness ≥ 4 mm (HR: 4.889; 95% CI: 1.846-12.946; p = 0.001) and regression (HR: 4.011; 95% CI: 1.464-10.991; p = 0.007) were risk factors for DSD. For patients with tumour thickness < 4 mm, the presence of ulceration indicated a higher risk of nodal metastasis (log-rank p = 0.0011), DM (log-rank p = 0.00051) and DSD (log-rank p = 0.02). Patients with regression (+)/tumour-infiltrating lymphocytes (TILs) (+) had a higher risk for DM (log-rank p = 0.011) and DSD (log-rank p = 0.0032). Molecularly, the positive rate of BRAFV600E, NRASQ61R, CD117, PD-1 and PD-L1 was 40.00% (26/65), 43.08% (28/65), 70.77% (46/65), 46.67% (21/45) and 28.89% (13/45), respectively. Positive BRAFV600E was identified as an independent risk factor for DM (HR: 2.533; 95% CI: 1.046-6.136, p = 0.039). The expression level of BRAFV600E was positively correlated with vascular invasion (p = 0.01), as well as the expression levels of PD-1 (p = 0.038) and PD-L1 (p = 0.049). Tumour thickness ≥ 4 mm, ulceration, the coexistence of regression and TILs, and positive BRAFV600E were risk factors for poor prognosis of CoM patients. Besides, expression level of BRAFV600E was positively correlated with the expression levels of PD-1 and PD-L1.

A Digital Intervention to Improve Skin Self-Examination Among Survivors of Melanoma: Protocol for a Type-1 Hybrid Effectiveness-Implementation Randomized Trial.

Although melanoma survival rates have improved in recent years, survivors remain at risk of recurrence, second primary cancers, and keratinocyte carcinomas. The National Comprehensive Cancer Network recommends skin examinations by a physician every 3 to 12 months. Regular thorough skin self-examinations (SSEs) are recommended for survivors of melanoma to promote the detection of earlier-stage, thinner melanomas, which are associated with improved survival and lower treatment costs. Despite their importance, less than a quarter of survivors of melanoma engage in SSEs. Previously, our team developed and evaluated a web-based, fully automated intervention called mySmartSkin (MSS) that successfully improved SSE among survivors of melanoma. Enhancements were proposed to improve engagement with and outcomes of MSS. The purpose of this paper is to describe the rationale and methodology for a type-1 hybrid effectiveness-implementation randomized trial evaluating the enhanced MSS versus control and exploring implementation outcomes and contextual factors. This study will recruit from state cancer registries and social media 300 individuals diagnosed with cutaneous malignant melanoma between 3 months and 5 years after surgery who are currently cancer free. Participants will be randomly assigned to either enhanced MSS or a noninteractive educational web page. Surveys will be collected from both arms at baseline and at 3, 6, 12, and 18 months to assess measures of intervention engagement, barriers, self-efficacy, habit, and SSE. The primary outcome is thorough SSE. The secondary outcomes are the diagnosis of new or recurrent melanomas and sun protection practices. Multilevel modeling will be used to examine whether there are significant differences in survivor outcomes between MSS and the noninteractive web page over time. Mixed methods will evaluate reach, adoption, implementation (including costs), and potential for maintenance of MSS, as well as contextual factors relevant to those outcomes and future scale-up. This trial has the potential to improve outcomes in survivors of melanoma. If MSS is effective, the results could guide its implementation in oncology care and nonprofit organizations focused on skin cancers. RR1-10.2196/52689.

Diffuse Melanosis Cutis as the First Sign of Recurrence of Low-Risk Melanoma: Case Report and Systematic Review.

Diffuse Melanosis Cutis (DMC) is a rare and late complication of metastatic malignant melanoma (MM) characterized by progressive pigmentation of skin and sometimes mucous membranes. The distinctive feature is the widespread and progressive deposition of melanin precursors in the dermis. The purpose of this review is to define the clinical and demographic features of DMC and to promote a deeper insight into the clinical manifestation, histological findings, and pathophysiology behind DMC. We have conducted a systematic review of the literature on published DMC in compliance with the Preferred Reporting Items for Systematic Reviews and Meta-Analysis. We also reported a case of DMC secondary to low-risk melanoma. Overall, including our case report, we reported 53 articles described 62 DMC patients. Breslow level of primary melanoma was reported having a mean value of 3.3 mm. The mean survival rate from onset of DMC resulted being 4.36 months. Among the most widely accepted etiopathogenetic hypotheses are deposition of melanic precursors in the dermis following tumor lysis, melanocyte proliferation induced by neoplastic growth factors, and the presence of diffuse dermal micro-metastases of MM. However, unanimous consensus on the proposed etiopathogenetic models of DMC is still lacking.

CD133-Dependent Activation of Phosphoinositide 3-Kinase /AKT/Mammalian Target of Rapamycin Signaling in Melanoma Progression and Drug Resistance.

Melanoma frequently harbors genetic alterations in key molecules leading to the aberrant activation of PI3K and its downstream pathways. Although the role of PI3K/AKT/mTOR in melanoma progression and drug resistance is well documented, targeting the PI3K/AKT/mTOR pathway showed less efficiency in clinical trials than might have been expected, since the suppression of the PI3K/mTOR signaling pathway-induced feedback loops is mostly associated with the activation of compensatory pathways such as MAPK/MEK/ERK. Consequently, the development of intrinsic and acquired resistance can occur. As a solid tumor, melanoma is notorious for its heterogeneity. This can be expressed in the form of genetically divergent subpopulations including a small fraction of cancer stem-like cells (CSCs) and non-cancer stem cells (non-CSCs) that make the most of the tumor mass. Like other CSCs, melanoma stem-like cells (MSCs) are characterized by their unique cell surface proteins/stemness markers and aberrant signaling pathways. In addition to its function as a robust marker for stemness properties, CD133 is crucial for the maintenance of stemness properties and drug resistance. Herein, the role of CD133-dependent activation of PI3K/mTOR in the regulation of melanoma progression, drug resistance, and recurrence is reviewed.

Chemoimmunotherapeutic Nanogel for Pre- and Postsurgical Treatment of Malignant Melanoma by Reprogramming Tumor-Associated Macrophages.

Surgery is the primary method to treat malignant melanoma; however, the residual microtumors that cannot be resected completely often trigger tumor recurrence, causing tumor-related mortality following melanoma resection. Herein, we developed a feasible strategy based on the combinational chemoimmunotherapy by cross-linking carboxymethyl chitosan (CMCS)-originated polymetformin (PolyMetCMCS) with cystamine to prepare stimuli-responsive nanogel (PMNG) owing to the disulfide bond in cystamine that can be cleaved by the massive glutathione (GSH) in tumor sites. Then, chemotherapeutic agent doxorubicin (DOX) was loaded in PMNG, which was followed by a hyaluronic acid coating to improve the overall biocompatibility and targeting ability of the prepared nanogel (D@HPMNG). Notably, PMNG effectively reshaped the tumor immune microenvironment by reprogramming tumor-associated macrophage phenotypes and recruiting intratumoral CD8+ T cells owing to the inherited immunomodulatory capability of metformin. Consequently, D@HPMNG treatment remarkably suppressed melanoma growth and inhibited its recurrence after surgical resection, proposing a promising solution for overcoming lethal melanoma recurrence.

Mechanisms of Melanoma Progression and Treatment Resistance: Role of Cancer Stem-like Cells.

Melanoma is the third most common type of skin cancer, characterized by its heterogeneity and propensity to metastasize to distant organs. Melanoma is a heterogeneous tumor, composed of genetically divergent subpopulations, including a small fraction of melanoma-initiating cancer stem-like cells (CSCs) and many non-cancer stem cells (non-CSCs). CSCs are characterized by their unique surface proteins associated with aberrant signaling pathways with a causal or consequential relationship with tumor progression, drug resistance, and recurrence. Melanomas also harbor significant alterations in functional genes (BRAF, CDKN2A, NRAS, TP53, and NF1). Of these, the most common are the BRAF and NRAS oncogenes, with 50% of melanomas demonstrating the BRAF mutation (BRAFV600E). While the successful targeting of BRAFV600E does improve overall survival, the long-term efficacy of available therapeutic options is limited due to adverse side effects and reduced clinical efficacy. Additionally, drug resistance develops rapidly via mechanisms involving fast feedback re-activation of MAPK signaling pathways. This article updates information relevant to the mechanisms of melanoma progression and resistance and particularly the mechanistic role of CSCs in melanoma progression, drug resistance, and recurrence.

Efficacy and safety of ‘Second Adjuvant’ therapy with BRAF/MEK inhibitors after local therapy for recurrent melanoma following adjuvant PD-1 based immunotherapy

BackgroundAnti-PD-1 antibodies and BRAK/MEK inhibitors (BRAF/MEKi) reduce the risk of recurrence for patients with resected stage III melanoma. BRAFV600-mutated (BRAFmut) melanoma patients who recur with isolated disease following adjuvant therapy may be suitable for ‘second adjuvant' treatment after local therapy. We sought to examine the efficacy and safety of ‘second adjuvant’ BRAF/MEKi. Patients and methodsPatients with BRAFmut melanoma treated with adjuvant PD-1 based immunotherapy who recurred, underwent definitive local therapy and were then treated with adjuvant BRAF/MEKi were identified retrospectively from 13 centres (second adjuvant group). Demographics, disease and treatment characteristics and outcome data were examined. Outcomes were compared to BRAFmut patients who did not receive ‘second adjuvant’ therapy (no second adjuvant group). Results73 patients were included; 61 who received ‘second adjuvant’ therapy and 12 who did not. Most initially recurred on PD-1 therapy (66%). There were no differences in characteristics between groups. 92% of second adjuvant group received dabrafenib and trametinib and median duration of therapy was 11.8 months (0.4, 34.5). 72% required dose adjustments, 23% had grade 3 + toxicity and 38% permanently discontinued drug due to toxicity. After median 26.1 months (1.9, 56.3) follow-up, recurrence-free survival (RFS) was improved in second adjuvant group versus no second adjuvant group (median 30.8 vs 4 months, HR 0.35; p = 0.014), largely driven by a delay in early recurrence, with no difference in overall survival (p = 0.59). ConclusionThis is the first study examining outcomes of ‘second adjuvant’ targeted therapy for melanoma, after failure of adjuvant PD-1 based immunotherapy. Data suggest a short-term improvement in RFS, but at the cost of toxicity. Alternative strategies and more data on sequencing adjuvant therapies are required to improve outcomes.

Long-term preservation of the effect of immunotherapy with pembrolizumab as a second line treatment for recurrent skin melanoma

Over the past two decades, the medical community around the world has been not only a witness, but an active participant in the global transformation of healthcare taking place against the backdrop of the rapid development of modern biomedical technologies. Of course, within the framework of these transformations, several quite independent directions can be distinguished. However, most of them, one way or another, can be united by the concept of “personalized medicine”, which is the subject of discussion among doctors of all specialties, which emphasizes its undoubted relevance. One of the clearest confirmations of this is the rapid growth in the number of review publications devoted to the consideration of issues of a personalized approach in medicine. Using the example of one of the most unpredictable tumors – skin melanoma – in recent years, expressive data have been obtained indicating the effectiveness of individual approaches, personalization of treatment as a result of the use of timely, gene-molecular studies. Despite the fact that in most cases melanoma is localized on the skin and, with a certain degree of oncological alertness, can be detected in the early stages, statistics indicate disappointing facts about the advanced state of the disease. Over the past 40 years, the incidence has increased by 300%. The possibilities of targeted and immunotherapy in the treatment of melanoma in patients with an advanced and unresectable stage of the disease allow long-term effective control of the disease and its symptoms.