Cutaneous Melanoma Patients Research Articles

Cutaneous melanoma in adolescents and young adults.

Cutaneous malignant melanoma (CMM) ranks among the five most common cancers in young people in high-income countries and it features peculiar clinicopathological traits. Very few studies have addressed the quality of care and the costs for adolescents and young adults (AYA) population. To provide a comprehensive epidemiological and clinicopathological profile of CMM in AYA. The study also addresses the cost-of-illness and the diagnostic-therapeutic performance indicators by patient age category. This population-based cohort study included 2435 incident CMM (age range 15-65 years; age 15-39 = 394; age 40-65 = 2041), as recorded in 2015, 2017 and 2019 by the Regional Veneto Cancer Registry (Italy). Cramer's-V tested the strength of association between pairs of variables. The Kaplan-Meier method was used to test the association between age and survival rate. The clinical performance indicators were computed using the Clopper-Pearson exact method. In AYA patients (16.2%), CMM incidence rates increased significantly from 1990 to 2019. Low-stage CMM (p = 0.007), radial growth pattern (p = 0.026) and lower Clark levels (p = 0.007) prevailed; males had less advanced malignancies (p = 0.003), with the trunk as the most common primary site (67.5%); the lower limbs (32.6%) were the most common primary site for females (p < 0.001). Overall survival was better in AYA than adults. No significant difference was detected in the clinical management of the two age groups, with the only exception of the margin in wide local excision. The care costs were lower in AYA (€195.99 vs. €258.94, p = 0.004). In AYA patients, the CMM clinicopathological presentation shows a distinctive profile. The present results provide critical information for optimizing primary and secondary prevention strategies and for tailoring diagnostic therapeutic procedures to the peculiar profile of AYA CMM patients.

Assessing melanoma prognosis: the interplay between patient profiles, survival, and BRAF, NRAS, KIT, and TWT mutations in a retrospective multi-study analysis.

The incidence and prevalence of melanoma are increasing globally, presenting a significant public health concern. The main genetic drivers of melanoma include BRAF, NRAS, KIT and triple wild-type (TWT) mutations. Little is known about the effects of these mutations on outcomes in terms of demographics and patient characteristics. We examined differences in melanoma mortality risk and mutation count across mutation type and patient disease profile. We extrapolated primary melanoma patient data from 14 studies via the cBioportal database. Patients were divided into demographic groups and classified according to BRAF, NRAS, KIT and TWT mutation status. Analyses included two-sample Student t -test and two-way analysis of variance tests analysis with Tukey's post hoc test. Survival outcomes were compared via Kaplan-Meier curve and Cox regression. NRAS-mutated patients exhibited decreased overall survival compared to BRAF-mutated patients. Male patients had higher mutation counts across all gene groups than females, with the fewest TWT mutations in comparison to BRAF, NRAS and KIT mutations. Males also exhibited increased mortality risk for NRAS, KIT and TWT mutations compared to BRAF mutations. An unknown primary melanoma was associated with increased mortality risk across all gene groups. NRAS-mutated acral melanoma patients had an increased mortality risk compared to NRAS-mutated cutaneous melanoma patients. Older patients had a higher mortality risk than younger patients. Patients with heavier versus lower weights had lower mortality risk, which was more pronounced for BRAF-mutated patients. These relationships highlight the importance of demographic and pathologic relationships to aid in risk assessment and personalize treatment plans.

Abstract 3780: From diagnostic labs to rapid near-patient testing: Bridging across RT-qPCR platforms of a clinicopathological and gene expression model for cutaneous melanoma patients

Abstract Background: Gene expression signatures are becoming increasingly common in clinical settings, for diagnosis, risk stratification, and treatment response prediction. However, deployment in clinical practice often entails a molecular platform different from the one used for development. Transporting molecular signatures across platforms (“bridging”) cannot be achieved directly, due to differences in scales and distributions in gene expression and requires bespoke methods. Here, we focused on the bridging of a clinicopathological and gene expression model (CP-GEP) across two reverse transcription-quantitative polymerase chain reaction (RT-qPCR) platforms: a single-plex SYBR Green qPCR, and a multiplex TaqMan probe-based qPCR (Idylla TM platform). CP-GEP is a regression model, combining eight genes (plus two housekeeping genes) and two clinicopathologic variables (age and Breslow thickness), able to stratify patients with melanoma into two groups based on their risk of sentinel lymph node metastasis. Methods: For the bridging, we selected 150 samples of primary melanoma patients who underwent a sentinel lymph node biopsy from a cohort of stage I-III melanoma patients. We measured the expression of the eight genes on both qPCR platforms and quantified them as ∆Ct. Within a bootstrapping scheme (500 repeats), for each gene, we learned a mapping (“bridging function”) between ∆Ct spaces, using all eight genes as regressors. Exploiting the linearity of per-gene bridging functions, we reparametrized the CP-GEP model so that we could directly use it in the target platform. We assessed the performance of the bridging, in terms of Percent Agreement (PA), defined as the percentage of the concordant binary outputs between the original and the bridged models; both in the bootstrapped samples and in 15 samples from an independent cohort. Results: In the bootstrapped samples, we obtained a PA of 100%, in the intervals for which we had pre-defined acceptance criteria, based on the distance from the cut point; and we had a mean PA of 89.2% [95% CI, 85.23%, 94.6%] when we considered all samples. In the external validation, we achieved a PA of 100%; all performance metrics were identical. The continuous scores of the original and bridged models were in excellent agreement, with an R2 equal to 0.95 both in the bridging and external validation cohorts. Conclusions: We showed that a model, combining gene expression and clinicopathologic variables, originally developed on a single-plex SYBR Green RT-qPCR, often used in diagnostic labs, could be robustly reparametrized to be compatible with a multiplex TaqMan probe-based qPCR (Idylla TM platform), more suitable for point-of-care-diagnostics. The ability to transfer models across different molecular platforms can greatly accelerate the translation of fundamental research to clinical practice. Citation Format: Lara Pozza, Sena Zumrutcu, Lizanne Bosman, Ashley van der Spek, Melanie Moreau, Dennie Tempel, Jvalini Dwarkasing, Domenico Bellomo. From diagnostic labs to rapid near-patient testing: Bridging across RT-qPCR platforms of a clinicopathological and gene expression model for cutaneous melanoma patients [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 3780.

Antibody dependent cellular cytotoxicity-inducing anti-EGFR antibodies as effective therapeutic option for cutaneous melanoma resistant to BRAF inhibitors.

About 50% of cutaneous melanoma (CM) patients present activating BRAF mutations that can be effectively targeted by BRAF inhibitors (BRAFi). However, 20% of CM patients exhibit intrinsic drug resistance to BRAFi, while most of the others develop adaptive resistance over time. The mechanisms involved in BRAFi resistance are disparate and globally seem to rewire the cellular signaling profile by up-regulating different receptor tyrosine kinases (RTKs), such as the epidermal growth factor receptor (EGFR). RTKs inhibitors have not clearly demonstrated anti-tumor activity in BRAFi resistant models. To overcome this issue, we wondered whether the shared up-regulated RTK phenotype associated with BRAFi resistance could be exploited by using immune weapons as the antibody-dependent cell cytotoxicity (ADCC)-mediated effect of anti-RTKs antibodies, and kill tumor cells independently from the mechanistic roots. By using an in vitro model of BRAFi resistance, we detected increased membrane expression of EGFR, both at mRNA and protein level in 4 out of 9 BRAFi-resistant (VR) CM cultures as compared to their parental sensitive cells. Increased EGFR phosphorylation and AKT activation were observed in the VR CM cultures. EGFR signaling appeared dispensable for maintaining resistance, since small molecule-, antibody- and CRISPR-targeting of EGFR did not restore sensitivity of VR cells to BRAFi. Importantly, immune-targeting of EGFR by the anti-EGFR antibody cetuximab efficiently and specifically killed EGFR-expressing VR CM cells, both in vitro and in humanized mouse models in vivo, triggering ADCC by healthy donors' and patients' peripheral blood cells. Our data demonstrate the efficacy of immune targeting of RTKs expressed by CM relapsing on BRAFi, providing the proof-of-concept supporting the assessment of anti-RTK antibodies in combination therapies in this setting. This strategy might be expected to concomitantly trigger the crosstalk of adaptive immune response leading to a complementing T cell immune rejection of tumors.

Cutaneous melanoma in older patients

BackgroundIn industrialized countries, the aging population is steadily rising. The incidence of cutaneous malignant melanoma (CMM) is highest in old people. This study focuses on the clinicopathological profile of CMM and indicators of diagnostic-therapeutic performance in older patients.MethodsThis retrospective population-based cohort study included 1,368 incident CMM, as recorded in 2017 by the Regional Veneto Cancer Registry (Northeast Italy). Older subjects were defined as ≥ 80, old as 65–79, and adults as < 65 years of age. The strength of association between pairs of variables was tested by Cramer’s-V. Using age groups as the dependent variable, ordered logistic regression was fitted using the clinicopathological CMM profiles as covariates. In each of the three age-groups, the indicators of clinical performance were computed using the Clopper-Pearson exact method.ResultsCompared to patients aged younger than 80 years (1,187), CMM in older patients (181; 13.2%) featured different CMM topography, a higher prevalence of ulcers (43.3% versus 12.7%; p < 0.001), a higher Breslow index (p < 0.001), a lower prevalence of tumor-infiltrating lymphocytes (64.4% versus 76.5%, p < 0.01), and a more advanced pTNM stage at clinical presentation (p < 0.001). Elderly patients with a positive sentinel-lymph node less frequently underwent sentinel- lymph node biopsy and lymphadenectomy (60.0% versus 94.2%, and 44.4% versus 85.5%, respectively; p < 0.001).ConclusionsIn older CMM patients, the clinicopathological presentation of CMM shows a distinctive profile. The present results provide critical information to optimize secondary prevention strategies and refine diagnostic-therapeutic procedures tailored to older patients.

Complete lymph node dissection in cutaneous melanoma patients with positive sentinel lymph node: Outcome and predictors in a retrospective cohort study over 16 years

BackgroundIn melanoma treatment, complete lymph node dissection (CLND) has been considered the therapeutic gold standard in patients with positive sentinel lymph node biopsy (SLNB). This long-held approach was revised in 2017, with recent evidence questioning the therapeutic benefit of CLND in malignant melanoma (MM) therapy. In this study, we aimed to fill this knowledge gap by retrospectively analyzing the impact of CLND on MM patients’ survival. Methods: We retrospectively analyzed the multi-center population-based Clinical Cancer Registry at the Tumor Center Regensburg (TUDOK) database (2004–2020) to identify patients who had been diagnosed with SLN-positive MM and underwent (non)invasive management thereof. Patient cohorts were subdivided according to the treatment received (CLND and waiving CLND). Primary outcomes included overall survival (OS), recurrence-free survival (RFS), and cumulative recurrence rate. Results: We identified 1143 MM patients, of whom 126 (11.0%) had positive SLN status. CLND was waived in the majority of SLN-positive MM cases (n = 71; 56.3%), with 55 (43.7%) patients undergoing CLND. Univariable and multivariable Cox regression revealed no significant advantage for CLND patients compared to non-CLND patients in OS (HR=0.970, p = 0.915 and HR=1.295, p = 0.479, respectively), RFS (HR=1.050, p = 0.849 and HR=1.220, p = 0.544, respectively), and cumulative recurrence rate (HR=1.234, p = 0.441 and HR=1.220, p = 0.544), respectively). Conclusion: We found that CLND had no significant impact on patient survival and MM recurrence rate, thus corroborating the validity of current clinical guidelines.

TNFRSF1B Gene Variants in Clinicopathological Aspects and Prognosis of Patients with Cutaneous Melanoma.

Regulatory T lymphocytes play a critical role in immune regulation and are involved in the aberrant cell elimination by facilitating tumor necrosis factor connection to the TNFR2 receptor, encoded by the TNFRSF1B polymorphic gene. We aimed to examine the effects of single nucleotide variants TNFRSF1B c.587T>G, c.*188A>G, c.*215C>T, and c.*922C>T on the clinicopathological characteristics and survival of cutaneous melanoma (CM) patients. Patients were genotyped using RT-PCR. TNFRSF1B levels were measured using qPCR. Luciferase reporter assay evaluated the interaction of miR-96 and miR-1271 with the 3'-UTR of TNFRSF1B. The c.587TT genotype was more common in patients younger than 54 years old than in older patients. Patients with c.*922CT or TT, c.587TG or GG + c.*922CT or TT genotypes, as well as those with the haplotype TATT, presented a higher risk of tumor progression and death due to the disease effects. Individuals with the c.*922TT genotype had a higher TNFRSF1B expression than those with the CC genotype. miR-1271 had less efficient binding with the 3'-UTR of the T allele when compared with the C allele of the SNV c.*922C>T. Our findings, for the first time, demonstrate that TNFRSF1B c.587T>G and c.*922C>T variants can serve as independent prognostic factors in CM patients.

Melanoma and sex hormones: Pathogenesis, progressive disease and response to treatments.

Cutaneous melanoma represents the fifth tumor in terms of incidence in young adults, with a major involvement of males than females. Despite the significant changes in available effective treatments for cutaneous melanoma, there is still a proportion of patients that do not benefit long-term disease control with immune checkpoint inhibitors and/or BRAF/MEK inhibitors, and eventually develop progressive disease. In addition to the emerging biomarkers under investigation to understand resistance to treatments, recent studies resumed the role of sex hormones (estrogens, progesterone and androgens) in melanoma patients. In the last decades, the impact of sex hormones has been considered controversial in melanoma patients, but actual growing preclinical and clinical evidence underline the potential influence on melanoma cells' growth, tumor microenvironment, the immune system and consequently on the course of disease.This review will provide available insights on the role of sex hormones in melanoma pathogenesis, disease progression and response/resistance to systemic treatments. We will also offer an overview on the recent studies on the theme, describing the hormonal contribution to disease response and the interaction with targeted therapies and immune-checkpoint inhibitors in cutaneous melanoma patients, illustrating an insight into future research in this field.

Machine learning developed an intratumor heterogeneity signature for predicting prognosis and immunotherapy benefits in skin cutaneous melanoma.

Intratumor heterogeneity (ITH) is defined as differences in molecular and phenotypic profiles between different tumor cells and immune cells within a tumor. ITH was involved in the cancer progression, aggressiveness, therapy resistance and cancer recurrence. Integrative machine learning procedure including 10 methods was conducted to develop an ITH-related signature (IRS) in The Cancer Genome Atlas (TCGA), GSE54467, GSE59455 and GSE65904 cohort. Several scores, including tumor immune dysfunction and exclusion (TIDE) score, tumor mutation burden (TMB) score and immunophenoscore (IPS), were used to evaluate the role of IRS in predicting immunotherapy benefits. Two immunotherapy datasets (GSE91061 and GSE78220) were utilized to the role of IRS in predicting immunotherapy benefits of skin cutaneous melanoma (SKCM) patients. The optimal prognostic IRS constructed by Lasso method acted as an independent risk factor and had a stable and powerful performance in predicting the overall survival rate in SKCM, with the area under the curve of 2-, 3- and 4-year receiver operating characteristic curve being 0.722, 0.722 and 0.737 in TCGA cohort. We also constructed a nomogram and the actual 1-, 3- and 5-year survival times were highly consistent with the predicted survival times. SKCM patients with low IRS scores had a lower TIDE score, lower immune escape score and higher TMB score, higher PD1&CTLA4 IPS. Moreover, SKCM patients with low IRS scores had a lower gene sets score involved in DNA repair, angiogenesis, glycolysis, hypoxia, IL2-STAT5 signaling, MTORC1 signaling, NOTCH signaling and P53 pathway. The current study constructed a novel IRS in SKCM using 10 machine learning methods. This IRS acted as an indicator for predicting the prognosis and immunotherapy benefits of SKCM patients.

Clinical and genetic determinants of vitamin D receptor expression in cutaneous melanoma patients.

Decrease of vitamin D receptor (VDR) expression is observed in melanocytic naevi and melanoma compared to normal skin. Little is known about factors influencing VDR expression in cutaneous melanoma (CM). We investigated the correlation of VDR expression in CM with 25-hydroxy vitamin D (25OHD) levels, demographic/clinical parameters, genetic variants of VDR and pathology of the primary tumor. Demographic/clinical parameters were recorded in 407 prospectively recruited CM patients of a multi-center controlled study (ViDMe trial). We determined VDR expression both in the nucleus and in the cytoplasm by semi-quantitative assessment in CM tissue using histochemistry in 279 patients, expressed in percentages and histoscore (H-score). Genomic DNA from 332 patients was extracted to genotype thirteen VDR single nucleotide polymorphisms (SNPs) using TaqMan. VDR expression in CM tissue from 279 patients was correlated with clinical/demographic parameters and 25OHD levels (univariable and multivariable analysis), VDR SNPs (univariable analysis) and pathology parameters of primary CM tissue (univariable analysis). Cytoplasmic VDR expression was increased in patients who stated to have a high sun exposure during their life compared to patients with low sun exposure (p H-score,univariable : 0.001, p H-score,multivariable : 0.004). The A allele of the genetic VDR polymorphism Fok1 was associated with a higher expression of the VDR in the cytoplasm (p cytoplasmic, univariable : 0.001 and p H-score, univariable : 0.02). In the primary tumor, presence of mitosis (p nucleus,%, univariable : 0.002) and perineural invasion (p nucleus,%,univariable : 0.03) were significantly associated with low nuclear VDR expression. ClinicalTrials.gov Identifier: NCT01748448.

ARID2 mutations may relay a distinct subset of cutaneous melanoma patients with different outcomes

ARID genes encode subunits of SWI/SNF chromatin remodeling complexes and are frequently mutated in human cancers. We investigated the correlation between ARID mutations, molecular features, and clinical outcomes in melanoma patients. Cutaneous melanoma samples (n = 1577) were analyzed by next-generation sequencing. Samples were stratified by pathogenic/likely pathogenic mutation in ARID genes (ARID1A/2/1B/5B). PD-L1 expression was assessed using IHC (SP142; positive (+): ≥ 1%). Tumor mutation burden (TMB)-high was defined as ≥ 10 mutations/Mb. Transcriptomic signatures predictive of response to immune checkpoint inhibitors—interferon gamma and T-cell inflamed score were calculated. Real-world overall survival (OS) information was obtained from insurance claims data, with Kaplan–Meier estimates calculated from time of tissue collection until last date of contact. Mann–Whitney U, Chi-square, and Fisher exact tests were applied where appropriate, with p values adjusted for multiple comparisons. ARID2 mutations were more prevalent in cutaneous melanoma compared to ARID1A (11.0%: n = 451 vs 2.8%: n = 113), with concurrent ARID1A/ARID2 mutation in 1.1% (n = 46) of samples. ARID mutations were associated with a high prevalence of RAS pathway mutations—NF1 (ARID1A, 52.6%; ARID2, 48.5%; ARID1A/2, 63.6%; and ARID-WT, 13.3%; p < 0.0001) and KRAS (ARID1A, 3.5%; ARID2, 3.1%; ARID1A/2, 6.5%; and ARID-WT, 1.0%; p = 0.018)), although BRAF mutations were less common in ARID-mutated cohorts (ARID1A, 31.9%; ARID2, 35.6%; ARID1A/2, 26.1%; and ARID-WT, 50.4%; p < 0.0001). TMB-high was more common in ARID-mutated samples (ARID1A, 80.9%; ARID2, 89.9%; ARID1A/2, 100%; and ARID-WT, 49.4%; p < 0.0001), while PD-L1 positivity was similar across subgroups (ARID1A, 43.8%; ARID2, 51.1%; ARID1A/2, 52.5%; and ARID-WT, 44.9%; p = 0.109). Patients with ARID1A mutations had a higher prevalence of dMMR/MSI-H compared to those with ARID-WT (2.7% vs 0.2%, p = 0.030). Median IFN-γ and T-cell signatures were higher in ARID2-mutated samples compared to ARID-WT (IFN-γ: − 0.15 vs − 0.21, p = 0.0066; T-cell: 23.5 vs − 18.5, p = 0.041). ARID2-mutated patients had improved survival compared to ARID-WT; (HR: 1.22 (95% CI 1.0–1.5), p = 0.022). No additional OS benefit was observed with anti-PD-1 therapy for ARID2 mutation compared to ARID-WT. Melanoma patients with ARID mutations exhibited higher prevalence of markers associated with ICI response, including TMB-H, and immune-related signatures. Our data also suggests improved survival outcome in patients with ARID2 mutations, irrespective of anti-PD1 therapy.

Absence of Tils in Biopsy is Associated with Worse Progression Free Survival in Early Stage Melanoma

Background: Recent data suggest that a subset of early stage melanoma patients may benefit from adjuvant immunotherapy. Objective: To identify findings in biopsy or surgical pathology reports associated with poor prognosis in patients diagnosed with stage I and II cutaneous melanoma. Methods: This was a retrospective cohort study of 68 stage I and II cutaneous melanoma patients treated at our institution from 2010 to 2022. Inclusion criteria were patients with stage I or II melanoma with both a biopsy and surgical pathology report. The primary outcome of the study was the prognostic value of biopsy findings on progression free survival (PFS). KaplanMeier and Cox-proportional hazards models were used to evaluate risk factors for progression. Results: Patients with ulceration on biopsy had a 16.1x greater risk of progression than those without ulceration [HR 16.1, 95% CI: 2.60-99.5]. Patients with absent lymphocytes on biopsy had a 9.5x greater risk of progressing compared to those with lymphocytes present [HR 9.45, 95% CI: 1.99-44.8]. Ulceration or absent TILs were associated with significantly worse PFS. Conclusions: Ulceration and absence of TILs on biopsy are associated with increased risk of progression in stage I and II melanoma patients.

Diagnostic value of [ 68 Ga]Ga-Pentixafor PET/CT in malignant melanoma: a pilot study.

To evaluate the diagnostic value of [ 68 Ga] Ga-Pentixafor in malignant melanoma patients. In this prospective study, patients with histology-proven melanoma were included and underwent [ 18 F]fluoro-D-glucose ([ 18 F]FDG) and [ 68 Ga] Ga-Pentixafor PET/computed tomography (CT) within a week. Suspicious lesions were interpreted as benign vs. malignant, and the corresponding semi-quantitative PET/CT parameters were recorded and compared. Twelve consecutive melanoma patients (mean age: 60 ± 6) were included. Two patients were referred for initial staging, two for detecting recurrence and eight for evaluating the extent of metastases. Overall, [ 18 F]FDG PET/CT showed 236 tumoral lesions, including two primary tumors, two recurrent lesions, 29 locoregional metastases and 203 distant metastases. In [ 68 Ga]Ga-Pentixafor PET/CT, 101 tumoral lesions were detected, including two primary tumors, one recurrence, 16 locoregional metastases and 82 distant metastases. Notably, a documented brain metastasis was only visualized on [ 68 Ga]Ga-Pentixafor PET/CT images. Compared with [ 18 F]FDG, [ 68 Ga]Ga-Pentixafor PET/CT provided a 42% detection rate. Regarding semi-quantitative measures, the intensity of uptake and tumor-to-background ratios were significantly lower on [ 68 Ga]Ga-Pentixafor PET/CT [average maximum standard uptake value (SUV max ) of 2.72 ± 1.33 vs. 11.41 ± 14.79; P value <0.001 and 1.17 ± 0.53 vs. 5.32 ± 7.34; P value <0.001, respectively]. When comparing [ 68 Ga]Ga-Pentixafor PET/CT with [ 18 F]FDG PET/CT, not only did [ 68 Ga]Ga-Pentixafor PET/CT detect fewer lesions, but the intensity of uptake and the TBRs were also lower on [ 68 Ga]Ga-Pentixafor PET/CT. Thus, our results may indicate a limited potential of this novel tracer in cutaneous melanoma patients compared to [ 18 F]FDG PET/CT. Given the lower TBRs, applying this radiotracer in radioligand therapies is also questionable.

Validation of the Melanoma Institute of Australia's Sentinel Lymph Node Biopsy Risk Prediction Tool for Cutaneous Melanoma.

For patients with cutaneous melanoma, sentinel lymph node biopsy (SLNB) is used to stage regional lymph nodes pathologically and inform prognosis, treatment, and surveillance. To reduce unnecessary surgeries, predictive tools aim to identify those at lowest risk for node-positive disease. The Melanoma Institute of Australia (MIA)'s Prediction Tool for Sentinel Node Metastasis Risk estimates risk of a positive SLNB using patient age and primary melanoma Breslow depth, histologic subtype, ulceration, mitotic rate, and lymphovascular invasion. A single-institution validation was performedof the MIA Calculator with 982 cutaneous melanoma patients that included all relevant clinicopathologic factors and SLNB pathology outcomes. The study evaluated discrimination via receiver operating characteristic (ROC) curves, calibration via calibration plots, and clinical utility via decision curve analysis of the MIA model in various subgroups. The data were fit to MIA model parameters via a generalized linear model to assess the odds ratio of parameters in our dataset. The Calculator demonstrated limited discrimination based on ROC curves (C-statistic, 0.709) and consistently underestimated risk of SLN positivity. It did not provide a net benefit over SLNB performed on all patients or reduce unnecessary procedures in the risk domain of 0% to 16%. Compared with the original development and validation cohorts, the current study cohort had thinner tumors and a larger proportion of acral melanomas. The Calculator generally underestimated SLN positivity risk, including assessment in patients who would be counseled to forego SLNB based on a predicted risk lower than 5%. Recognition of the tool's current limitations emphasizes the need to refine it further for use in medical decision-making.

Assessment of Variables Related to the Risk of Severe Adverse Events in Cutaneous Melanoma Patients Treated with Immune Checkpoint Inhibitors.

Malignant melanoma is a prevalent and aggressive cancer, with globally increasing incidences. While immune checkpoint inhibitors (ICIs) have prolonged the survival of patients with advanced melanoma over the last decade, this improvement comes with the risk of severe immune-related adverse events (irAEs). This systematic review investigates patient baseline characteristics (BCs) as predictive factors for developing severe gastrointestinal, hepatic, and pulmonary irAEs in patients treated with ipilimumab (anti-CTLA-4) and/or nivolumab/pembrolizumab (anti-PD-1). A systematic literature search was conducted in the Ovid databases MEDLINE and EMBASE on 22 April 2022, following the PRISMA guidelines. Out of 1694 articles, 13 were included in the final analysis. We analyzed BCs and the occurrence of severe colitis, hepatitis, and pneumonitis in 22 treatment arms and 3 treatment groups: anti-CTLA-4 (n = 2904), anti-PD-1 (n = 1301), or combination therapy (n = 822). However, missing data preclude a direct comparison of individual BCs and the association to specific irAEs between studies. Descriptive analysis did not identify any significant association between median age, gender distribution, or performance status and severe colitis, hepatitis, or pneumonitis for any of the three treatment groups. We call for greater transparency and standardization in the reporting of patient-specific irAEs.

Sentinel lymph node biopsy is unreliable in predicting melanoma mortality for both younger and older patients.

Melanoma disease patterns vary with patient age. To evaluate sentinel lymph node biopsy (SLNB) in managing melanoma at differing patient ages. Online prediction tools were applied to compare SLNB positivity (SLNB+) and survival risk at patient ages 20-80. Tübingen melanoma data were used to determine variations in the hazard ratio of SLNB+ for mortality at different patient ages. Regardless of tumour thickness, predicted SLNB+ rates were markedly higher than mortality rates for 20-year-old patients. For 80-year-old patients, it is the opposite. If 1000 20-year-olds with a 0.4 mm thickness non-ulcerated melanoma underwent SLNB, 100 would likely be positive. If all 100 were to be offered adjuvant drug therapy (ADT), fewer than three more melanoma deaths in those 1000 patients would be avoided. In total, 97 patients would have received medication they may never have needed. If 1000 80-year-olds with a 3 mm thickness non-ulcerated melanoma underwent SLNB, only 40 would likely be positive. In total, 274 patients would be predicted to die of melanoma, 245 being SLNB negative and 29 SLNB+. ADT linked to SLNB+ could deny treatment to 89% of these high-risk patients. The authors relied on published risk data. SLNB has poor specificity at predicting mortality in young melanoma patients and poor sensitivity in older patients. SLNB is not indicated in managing cutaneous melanoma for patients under 40 or over 60 years of age. Many such patients could be managed with wide local excision alone in their clinician's office-based practice. For all cutaneous melanoma patients at all ages, linking ADT to BAUSSS biomarker, (an algorithm of Breslow thickness, age, ulceration, subtype, sex and Site) rather than SLNB+ is likely more appropriate. BAUSSS provides a more accurate melanoma-specific mortality risk assessment for patients without burdening them with added surgery, hospitalization, costs or morbidity risk.

Polo-Like Kinase 4 Correlates with Aggressive Tumor Characteristics, Shortened Disease-Free Survival and Overall Survival in Patients with Cutaneous Melanoma who Undergo Surgical Resection.

Polo-like kinase 4 (PLK4) involves in tumor progression via regulating centriole duplication. This study aimed to investigate correlations of PLK4 with tumor characteristics and survival in cutaneous melanoma patients undergoing surgical resection. Tumor specimens of 43 patients were retrieved for PLK4 determination by immunohistochemistry (IHC). The IHC score was a multiplication of staining intensity and percentage of staining-positive cells. This study found the median and mean tumor PLK4 IHC score was 0.0 (interquartile range: 0.0-6.0) and 3.5 ± 3.2 (mean ± SD), respectively. Elevated tumor PLK4 IHC score correlated with lymph node metastasis (P = 0.028), higher tumor node metastasis (TNM) stage (P = 0.004), and adjuvant therapy (P =0.029). Tumor PLK4 IHC score > 0 did not relate to disease-free survival (DFS) or overall survival (OS) (both P > 0.050). Tumor PLK4 IHC score > 3 associated with decreased DFS (P = 0.027), but not OS (P = 0.098). Five-year DFS rate of patients with tumor PLK4 IHC score = 0 and > 0 was 75.0% and 53.9%, correspondingly; while the rate of patients with the score ≤ 3 and > 3 was 81.0% and 37.5%, respectively. Five-year OS rate of patients with the score = 0 and > 0 was 100.0% and 66.3%, accordingly; whereas the rate of patients with the score ≤ 3 and > 3 was 85.7% and 61.5%, correspondingly. According to forward-step multivariate analysis, neither the score > 0 nor > 3 independently related to worse DFS and OS (all P > 0.050). Further validation via THE HUMAN PROTEIN ATLAS database showed high PLK4 RNA expression associated with shortened OS in melanoma patients (P = 0.001). PLK4 correlates with lymph node metastasis, increased TNM stage, and poor DFS in cutaneous melanoma patients undergoing surgical resection.

Prognostic value of the number of biopsied sentinel lymph nodes for Chinese patients with melanoma: A single-center retrospective study.

Sentinel lymph node biopsy (SLNB) helps to determine accurate pathological stages and facilitates strategies for regional disease control in melanoma. However, whether the number of biopsied sentinel lymph nodes (SLNs) influences the patients' survival is rarely investigated. Acral or cutaneous melanoma patients with no history of nodal disease who received SLNB in Fudan University Shanghai Cancer Center (FUSCC) from January 1, 2017, to December 31, 2021 were retrospectively enrolled. Clinicopathological variables including Breslow index, ulceration, number of positive SLNs, SLN/non-SLN status were analyzed. The pathologic nodal (pN) stage and pathological stage were defined. A total of 381 eligible patients were enrolled in this study, of whom 132 (34.7%) patients were diagnosed with SLN-positive. The median number of biopsied SLNs was 2 (range: 1 to 20). Different numbers of biopsied SLNs did not influence the release-free survival (RFS) of the general patients. However, patients with >2 SLNs had a longer RFS than those with 1-2 SLNs in T4, N1a group and those who rejected complete lymph node dissection (CLND). In patients with T4 melanomas, N1a melanomas and those that did not undergo a CLND, the prognosis of those with three or more SLNs retrieved seemed to be improved.

Prognostic and predictive biomarkers in melanoma

Biomarkers help to inform the clinical management of patients with melanoma. For patients with clinically localised primary melanoma, biomarkers can help to predict post-surgical outcome (including via the use of risk prediction tools), better select patients for sentinel lymph node biopsy, and tailor catch-all follow-up protocols to the individual. Systemic drug treatments, including immune checkpoint inhibitor (ICI) therapies and BRAF-targeted therapies, have radically improved the prognosis of metastatic (stage III and IV) cutaneous melanoma patients, and also shown benefit in the earlier setting of stage IIB/C primary melanoma. Unfortunately, a response is far from guaranteed. Here, we review clinically relevant, established, and emerging, prognostic, and predictive pathological biomarkers that refine clinical decision-making in primary and metastatic melanoma patients. Gene expression profile assays and nomograms are emerging tools for prognostication and sentinel lymph node risk prediction in primary melanoma patients. Biomarkers incorporated into clinical practice guidelines include BRAF V600 mutations for the use of targeted therapies in metastatic cutaneous melanoma, and the HLA-A∗02:01 allele for the use of a bispecific fusion protein in metastatic uveal melanoma. Several predictive biomarkers have been proposed for ICI therapies but have not been incorporated into Australian clinical practice guidelines. Further research, validation, and assessment of clinical utility is required before more prognostic and predictive biomarkers are fluidly integrated into routine care.

Histopathologic regression in patients with primary cutaneous melanoma undergoing sentinel lymph node biopsy is associated with favorable survival and, after metastasis, with improved progression-free survival on immune checkpoint inhibitor therapy: A single-institutional cohort study

Histopathologic regression of cutaneous melanoma is considered a favorable prognostic factor, but its significance in clinical practice remains controversial. To investigate the prognostic importance of regression in patients with primary cutaneous melanoma undergoing sentinel lymph node (SLN) biopsy and to assess its significance in patients progressing to an unresectable stage requiring systemic therapy. We retrospectively reviewed patients with newly diagnosed melanoma undergoing SLN biopsy between 2010 and 2015 and available information on histopathologic regression (n=1179). Survival data and associations of clinical variables with SLN status were assessed. Patients with regressive melanoma showed favorable relapse-free (hazard ratio [HR], 0.52; P=.00013), distant metastasis-free (HR, 0.56; P=.0020), and melanoma-specific survival (HR, 0.35; P=.00053). Regression was associated with negative SLN (odds ratio, 0.48; P=.0077). In patients who progressed to an unresectable stage, regression was associated with favorable progression-free survival under immune checkpoint inhibition (HR, 0.43; P=.031) but not under targeted therapy (HR, 1.14; P=.73) or chemotherapy (HR, 3.65; P=.0095). Retrospective, single-institutional design. Regression of cutaneous melanoma is associated with improved prognosis in patients eligible for SLN biopsy as well as in patients with unresectable disease receiving systemic therapy with immune checkpoint inhibitors.